Enzymatic single-chain antibody tagging: a universal approach to targeted molecular imaging and cell homing in cardiovascular disease.

PubMed

Ta, H T; Prabhu, S; Leitner, E; Jia, F; von Elverfeldt, D; Jackson, Katherine E; Heidt, T; Nair, A K N; Pearce, H; von Zur Muhlen, C; Wang, X; Peter, K; Hagemeyer, C E

2011-08-05

Antibody-targeted delivery of imaging agents can enhance the sensitivity and accuracy of current imaging techniques. Similarly, homing of effector cells to disease sites increases the efficacy of regenerative cell therapy while reducing the number of cells required. Currently, targeting can be achieved via chemical conjugation to specific antibodies, which typically results in the loss of antibody functionality and in severe cell damage. An ideal conjugation technique should ensure retention of antigen-binding activity and functionality of the targeted biological component. To develop a biochemically robust, highly reproducible, and site-specific coupling method using the Staphylococcus aureus sortase A enzyme for the conjugation of a single-chain antibody (scFv) to nanoparticles and cells for molecular imaging and cell homing in cardiovascular diseases. This scFv specifically binds to activated platelets, which play a pivotal role in thrombosis, atherosclerosis, and inflammation. The conjugation procedure involves chemical and enzyme-mediated coupling steps. The scFv was successfully conjugated to iron oxide particles (contrast agents for magnetic resonance imaging) and to model cells. Conjugation efficiency ranged between 50% and 70%, and bioactivity of the scFv after coupling was preserved. The targeting of scFv-coupled cells and nanoparticles to activated platelets was strong and specific as demonstrated in in vitro static adhesion assays, in a flow chamber system, in mouse intravital microscopy, and in in vivo magnetic resonance imaging of mouse carotid arteries. This unique biotechnological approach provides a versatile and broadly applicable tool for procuring targeted regenerative cell therapy and targeted molecular imaging in cardiovascular and inflammatory diseases and beyond.

Calibration and evaluation of a magnetically tracked ICE probe for guidance of left atrial ablation therapy

NASA Astrophysics Data System (ADS)

Linte, Cristian A.; Rettmann, Maryam E.; Dilger, Ben; Gunawan, Mia S.; Arunachalam, Shivaram P.; Holmes, David R., III; Packer, Douglas L.; Robb, Richard A.

2012-02-01

The novel prototype system for advanced visualization for image-guided left atrial ablation therapy developed in our laboratory permits ready integration of multiple imaging modalities, surgical instrument tracking, interventional devices and electro-physiologic data. This technology allows subject-specific procedure planning and guidance using 3D dynamic, patient-specific models of the patient's heart, augmented with real-time intracardiac echocardiography (ICE). In order for the 2D ICE images to provide intuitive visualization for accurate catheter to surgical target navigation, the transducer must be tracked, so that the acquired images can be appropriately presented with respect to the patient-specific anatomy. Here we present the implementation of a previously developed ultrasound calibration technique for a magnetically tracked ICE transducer, along with a series of evaluation methods to ensure accurate imaging and faithful representation of the imaged structures. Using an engineering-designed phantom, target localization accuracy is assessed by comparing known target locations with their transformed locations inferred from the tracked US images. In addition, the 3D volume reconstruction accuracy is also estimated by comparing a truth volume to that reconstructed from sequential 2D US images. Clinically emulating validation studies are conducted using a patient-specific left atrial phantom. Target localization error of clinically-relevant surgical targets represented by nylon fiducials implanted within the endocardial wall of the phantom was assessed. Our studies have demonstrated 2.4 +/- 0.8 mm target localization error in the engineering-designed evaluation phantoms, 94.8 +/- 4.6 % volume reconstruction accuracy, and 3.1 +/- 1.2 mm target localization error in the left atrial-mimicking phantom. These results are consistent with those disseminated in the literature and also with the accuracy constraints imposed by the employed technology and the clinical application.

Effect of Patient Set-up and Respiration motion on Defining Biological Targets for Image-Guided Targeted Radiotherapy

NASA Astrophysics Data System (ADS)

McCall, Keisha C.

Identification and monitoring of sub-tumor targets will be a critical step for optimal design and evaluation of cancer therapies in general and biologically targeted radiotherapy (dose-painting) in particular. Quantitative PET imaging may be an important tool for these applications. Currently radiotherapy planning accounts for tumor motion by applying geometric margins. These margins create a motion envelope to encompass the most probable positions of the tumor, while also maintaining the appropriate tumor control and normal tissue complication probabilities. This motion envelope is effective for uniform dose prescriptions where the therapeutic dose is conformed to the external margins of the tumor. However, much research is needed to establish the equivalent margins for non-uniform fields, where multiple biological targets are present and each target is prescribed its own dose level. Additionally, the size of the biological targets and close proximity make it impractical to apply planning margins on the sub-tumor level. Also, the extent of high dose regions must be limited to avoid excessive dose to the surrounding tissue. As such, this research project is an investigation of the uncertainty within quantitative PET images of moving and displaced dose-painting targets, and an investigation of the residual errors that remain after motion management. This included characterization of the changes in PET voxel-values as objects are moved relative to the discrete sampling interval of PET imaging systems (SPECIFIC AIM 1). Additionally, the repeatability of PET distributions and the delineating dose-painting targets were measured (SPECIFIC AIM 2). The effect of imaging uncertainty on the dose distributions designed using these images (SPECIFIC AIM 3) has also been investigated. This project also included analysis of methods to minimize motion during PET imaging and reduce the dosimetric impact of motion/position-induced imaging uncertainty (SPECIFIC AIM 4).

Ultrasonic Nanobubbles Carrying Anti-PSMA Nanobody: Construction and Application in Prostate Cancer-Targeted Imaging.

PubMed

Fan, Xiaozhou; Wang, Luofu; Guo, Yanli; Tu, Zhui; Li, Lang; Tong, Haipeng; Xu, Yang; Li, Rui; Fang, Kejing

2015-01-01

To facilitate prostate cancer imaging using targeted molecules, we constructed ultrasonic nanobubbles coupled with specific anti-PSMA (prostate specific membrane antigen) nanobodies, and evaluated their in vitro binding capacity and in vivo imaging efficacy. The "targeted" nanobubbles, which were constructed via a biotin-streptavidin system, had an average diameter of 487.60 ± 33.55 nm and carried the anti-PSMA nanobody as demonstrated by immunofluorescence. Microscopy revealed targeted binding of nanobubbles in vitro to PSMA-positive cells. Additionally, ultrasonography indicators of nanobubble imaging (including arrival time, peak time, peak intensity and enhanced duration) were evaluated for the ultrasound imaging in three kinds of animal xenografts (LNCaP, C4-2 and MKN45), and showed that these four indicators of targeted nanobubbles exhibited significant differences from blank nanobubbles. Therefore, this study not only presents a novel approach to target prostate cancer ultrasonography, but also provides the basis and methods for constructing small-sized and high-efficient targeted ultrasound nanobubbles.

Integrin Targeted MR Imaging

PubMed Central

Tan, Mingqian; Lu, Zheng-Rong

2011-01-01

Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution. Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize. There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T1, T2, chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents. Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions. The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging. Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent. Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging. An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging. An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging. By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models. PMID:21547154

Method calibration of the model 13145 infrared target projectors

NASA Astrophysics Data System (ADS)

Huang, Jianxia; Gao, Yuan; Han, Ying

2014-11-01

The SBIR Model 13145 Infrared Target Projectors ( The following abbreviation Evaluation Unit ) used for characterizing the performances of infrared imaging system. Test items: SiTF, MTF, NETD, MRTD, MDTD, NPS. Infrared target projectors includes two area blackbodies, a 12 position target wheel, all reflective collimator. It provide high spatial frequency differential targets, Precision differential targets imaged by infrared imaging system. And by photoelectricity convert on simulate signal or digital signal. Applications software (IR Windows TM 2001) evaluate characterizing the performances of infrared imaging system. With regards to as a whole calibration, first differently calibration for distributed component , According to calibration specification for area blackbody to calibration area blackbody, by means of to amend error factor to calibration of all reflective collimator, radiance calibration of an infrared target projectors using the SR5000 spectral radiometer, and to analyze systematic error. With regards to as parameter of infrared imaging system, need to integrate evaluation method. According to regulation with -GJB2340-1995 General specification for military thermal imaging sets -testing parameters of infrared imaging system, the results compare with results from Optical Calibration Testing Laboratory . As a goal to real calibration performances of the Evaluation Unit.

A Targeting Microbubble for Ultrasound Molecular Imaging

PubMed Central

Yeh, James Shue-Min; Sennoga, Charles A.; McConnell, Ellen; Eckersley, Robert; Tang, Meng-Xing; Nourshargh, Sussan; Seddon, John M.; Haskard, Dorian O.; Nihoyannopoulos, Petros

2015-01-01

Rationale Microbubbles conjugated with targeting ligands are used as contrast agents for ultrasound molecular imaging. However, they often contain immunogenic (strept)avidin, which impedes application in humans. Although targeting bubbles not employing the biotin-(strept)avidin conjugation chemistry have been explored, only a few reached the stage of ultrasound imaging in vivo, none were reported/evaluated to show all three of the following properties desired for clinical applications: (i) low degree of non-specific bubble retention in more than one non-reticuloendothelial tissue; (ii) effective for real-time imaging; and (iii) effective for acoustic quantification of molecular targets to a high degree of quantification. Furthermore, disclosures of the compositions and methodologies enabling reproduction of the bubbles are often withheld. Objective To develop and evaluate a targeting microbubble based on maleimide-thiol conjugation chemistry for ultrasound molecular imaging. Methods and Results Microbubbles with a previously unreported generic (non-targeting components) composition were grafted with anti-E-selectin F(ab’)2 using maleimide-thiol conjugation, to produce E-selectin targeting microbubbles. The resulting targeting bubbles showed high specificity to E-selectin in vitro and in vivo. Non-specific bubble retention was minimal in at least three non-reticuloendothelial tissues with inflammation (mouse heart, kidneys, cremaster). The bubbles were effective for real-time ultrasound imaging of E-selectin expression in the inflamed mouse heart and kidneys, using a clinical ultrasound scanner. The acoustic signal intensity of the targeted bubbles retained in the heart correlated strongly with the level of E-selectin expression (|r|≥0.8), demonstrating a high degree of non-invasive molecular quantification. Conclusions Targeting microbubbles for ultrasound molecular imaging, based on maleimide-thiol conjugation chemistry and the generic composition described, may possess properties (i)–(iii) desired for clinical applications. PMID:26161541

M13 phage-functionalized single-walled carbon nanotubes as nanoprobes for second near-infrared window fluorescence imaging of targeted tumors

PubMed Central

HAM, MOON-HO; QI, JIFA; BARONE, PAUL W.; STRANO, MICHAEL S.; BELCHER, ANGELA M.

2014-01-01

Second near-infrared (NIR) window light (950-1,400 nm) is attractive for in vivo fluorescence imaging due to its deep penetration depth in tissues and low tissue autofluorescence. Here we show genetically engineered multifunctional M13 phage can assemble fluorescent single-walled carbon nanotubes (SWNTs) and ligands for targeted fluorescence imaging of tumors. M13-SWNT probe is detectable in deep tissues even at a low dosage of 2 μg/mL and up to 2.5 cm in tissue-like phantoms. Moreover, targeted probes show specific and up to four-fold improved uptake in prostate specific membrane antigen positive prostate tumors compared to control non-targeted probes. This M13 phage-based second NIR window fluorescence imaging probe has great potential for specific detection and therapy monitoring of hard-to-detect areas. PMID:22268625

Ultrasonic Nanobubbles Carrying Anti-PSMA Nanobody: Construction and Application in Prostate Cancer-Targeted Imaging

PubMed Central

Guo, Yanli; Tu, Zhui; Li, Lang; Tong, Haipeng; Xu, Yang; Li, Rui; Fang, Kejing

2015-01-01

To facilitate prostate cancer imaging using targeted molecules, we constructed ultrasonic nanobubbles coupled with specific anti-PSMA (prostate specific membrane antigen) nanobodies, and evaluated their in vitro binding capacity and in vivo imaging efficacy. The “targeted” nanobubbles, which were constructed via a biotin-streptavidin system, had an average diameter of 487.60 ± 33.55 nm and carried the anti-PSMA nanobody as demonstrated by immunofluorescence. Microscopy revealed targeted binding of nanobubbles in vitro to PSMA-positive cells. Additionally, ultrasonography indicators of nanobubble imaging (including arrival time, peak time, peak intensity and enhanced duration) were evaluated for the ultrasound imaging in three kinds of animal xenografts (LNCaP, C4-2 and MKN45), and showed that these four indicators of targeted nanobubbles exhibited significant differences from blank nanobubbles. Therefore, this study not only presents a novel approach to target prostate cancer ultrasonography, but also provides the basis and methods for constructing small-sized and high-efficient targeted ultrasound nanobubbles. PMID:26111008

Targeting of Pancreatic Cancer with Magneto-Fluorescent Theranostic Gold Nanoshells

PubMed Central

Chen, Wenxue; Ayala-Orozco, Ciceron; Biswal, Nrusingh C.; Perez-Torres, Carlos; Bartels, Marc; Bardhan, Rizia; Stinnet, Gary; Liu, Xian-De; Ji, Baoan; Deorukhkar, Amit; Brown, Lisa V.; Guha, Sushovan; Pautler, Robia G.; Krishnan, Sunil; Halas, Naomi J; Joshi, Amit

2014-01-01

Aim We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. Materials and Methods Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the NIR dye ICG, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. Results AntiNGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2 weighted MR imaging with higher tumor contrast than can be obtained using long-circulating but non-targeted PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. Conclusions Theranostic gold nanoshells with embedded NIR and MR contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy. PMID:24063415

Receptor-Targeted Nanoparticles for In Vivo Imaging of Breast Cancer

PubMed Central

Yang, Lily; Peng, Xiang-Hong; Wang, Y. Andrew; Wang, Xiaoxia; Cao, Zehong; Ni, Chunchun; Karna, Prasanthi; Zhang, Xinjian; Wood, William C.; Gao, Xiaohu; Nie, Shuming; Mao, Hui

2009-01-01

Purpose Cell surface receptor-targeted magnetic iron oxide (IO) nanoparticles provide molecular magnetic resonance imaging (MRI) contrast agents for improving specificity of the detection of human cancer. Experimental design The present study reports the development of a novel targeted IO nanoparticle using a recombinant peptide containing the amino-terminal fragment (ATF) of urokinase plasminogen activator conjugated to IO nanoparticles (ATF-IO). This nanoparticle targets urokinase plasminogen activator receptor (uPAR), which is overexpressed in breast cancer tissues. Results ATF-IO nanoparticles are able to specifically bind to and be internalized by uPAR-expressing tumor cells. Systemic delivery of ATF-IO nanoparticles into mice bearing subcutaneous and intraperitoneal mammary tumors leads to the accumulation of the particles in tumors, generating a strong MRI contrast detectable by a clinical MRI scanner at a field strength of 3 Tesla. Target specificity of ATF-IO nanoparticles demonstrated by in vivo MRI is further confirmed by near infrared (NIR) fluorescence imaging of the mammary tumors using NIR dye-labeled ATF peptides conjugated to IO nanoparticles. Furthermore, mice administered ATF-IO nanoparticles exhibit lower uptake of the particles in the liver and spleen compared to those receiving non-targeted IO nanoparticles. Conclusions Our results suggest that uPAR-targeted ATF-IO nanoparticles have potential as molecularly-targeted, dual modality imaging agents for in vivo imaging of breast cancer. PMID:19584158

Prostate-specific membrane antigen for prostate cancer theranostics: from imaging to targeted therapy.

PubMed

Arsenault, Frédéric; Beauregard, Jean-Mathieu; Pouliot, Frédéric

2018-06-22

In recent years, major advances in molecular imaging of prostate cancers (PCa) were made with the development and clinical validation of highly accurate PET tracers to stage and restage the disease. Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in PCa, and its expression has led to the development of PSMA-binding radiopharmaceuticals for molecular imaging or radioligand therapy (RLT). We herein review the recent literature published on diagnostic and therapeutic (i.e. theranostic) PSMA tracers. Development in small PSMA-targeted molecules labeled with gallium-68 and fluorine-18 show promising results for primary staging and detection of disease at biochemical recurrence using PET/computed tomography (PET/CT). Studies show a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and bone scan) or choline PET tracers, especially for restaging after prostate-specific antigen failure following loco-regional therapy. In addition, some PSMA tracers can be labeled with beta-minus and alpha particle emitters, yielding encouraging response rates and low toxicity, and potentially offering a new line of targeted therapy for metastatic castration-resistant PCa. PSMA-targeted tracers have shown unprecedented accuracy to stage and restage PCa using PET/CT. Given their specific biodistribution toward PCa tissue, PSMA RLT now offers new therapeutic possibilities to target metastatic PCa. Prospective multicenter randomized studies investigating the clinical impact management impacts of PSMA-targeted molecules are urgently needed.

JPRS Report, Science & Technology, Japan, 27th Aircraft Symposium

DTIC Science & Technology

1990-10-29

screen; the relative attitude is then determined . 2) Video Sensor System Specific patterns (grapple target, etc.) drawn on the target spacecraft , or the...entire target spacecraft , is imaged by camera . Navigation information is obtained by on-board image processing, such as extraction of contours and...standard figure called "grapple target" located in the vicinity of the grapple fixture on the target spacecraft is imaged by camera . Contour lines and

Targeting Apoptosis for Optical Imaging of Infection

PubMed Central

Thakur, Mathew L.; Zhang, Kaijun; Paudyal, Bishnuhari; Devakumar, Devadhas; Covarrubias, Maria Y.; Cheng, Changpo; Gray, Brian D.; Wickstrom, Eric; Pak, Koon Y.

2018-01-01

Purpose Infection is ubiquitous and a major cause of morbidity and mortality. The most reliable method for localizing infection requires radiolabeling autologous white blood cells ex vivo. A compound that can be injected directly into a patient and can selectively image infectious foci will eliminate the drawbacks. The resolution of infection is associated with neutrophil apoptosis and necrosis presenting phosphatidylserine (PS) on the neutrophil outer leaflet. Targeting PS with intravenous administration of a PS-specific, near-infrared (NIR) fluorophore will permit localization of infectious foci by optical imaging. Methods Bacterial infection and sterile inflammation were induced in separate groups (n=5) of mice. PS was targeted with a NIR fluorophore, PSVue®794 (2.7 pmol). Imaging was performed (ex=730 nm, em=830 nm) using Kodak Multispectral FX-Pro system. The contralateral normal thigh served as an individualized control. Confocal microscopy of normal and apoptotic neutrophils and bacteria confirmed PS specificity. Results Lesions, with a 10-s image acquisition, were unequivocally visible at 5 min post-injection. At 3 h post-injection, the lesion to background intensity ratios in the foci of infection (6.6±0.2) were greater than those in inflammation (3.2±0.5). Image fusions confirmed anatomical locations of the lesions. Confocal microscopy determined the fluorophore specificity for PS. Conclusions Targeting PS presented on the outer leaflet of apoptotic or necrotic neutrophils as well as gram-positive microorganism with PS-specific NIR fluorophore provides a sensitive means of imaging infection. Literature indicates that NIR fluorophores can be detected 7-14 cm deep in tissue. This observation together with the excellent results and the continued development of versatile imaging devices could make optical imaging a simple, specific, and rapid modality for imaging infection. PMID:21538153

Molecular Imaging: Current Status and Emerging Strategies

PubMed Central

Pysz, Marybeth A.; Gambhir, Sanjiv S.; Willmann, Jürgen K.

2011-01-01

In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific therapeutic treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use PET- or SPECT-based techniques. In ongoing preclinical research novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multimodality molecular imaging. Contrast-enhanced molecular ultrasound with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and ultrasound imaging with molecularly-targeted microbubbles are attractive strategies since they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and ultrasound modalities involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with ultrasound. Current preclinical findings and advances in instrumentation such as endoscopes and microcatheters suggest that these molecular imaging modalities have numerous clinical applications and will be translated into clinical use in the near future. PMID:20541650

Multimodal molecular imaging reveals high target uptake and specificity of 111In and 68Ga labeled fibrin-binding probes for thrombus detection in rats

PubMed Central

Oliveira, Bruno L.; Blasi, Francesco; Rietz, Tyson A.; Rotile, Nicholas J.; Day, Helen; Caravan, Peter

2016-01-01

We recently showed the high target specificity and favorable imaging properties of 64Cu and Al18F positron emission tomography (PET) probes for non-invasive imaging of thrombosis. Here, our aim was to evaluate new derivatives labeled with either with 68Ga, 111In, or 99mTc as thrombus imaging agents for PET and single-photon emission computed tomography (SPECT). In this study, the feasibility and potential of these probes for thrombus imaging was assessed in detail in two animal models of arterial thrombosis. The specificity of the probes was further evaluated using a triple-isotope approach with multimodal SPECT/PET/CT imaging. Methods Radiotracers were synthesized using a known fibrin-binding peptide conjugated to NODAGA, DOTA-MA, or a diethylenetriamine ligand (DETA-PA), followed by labeling with 68Ga (FBP14, 68Ga-NODAGA), 111In (FBP15, 111In-DOTA-MA) or 99mTc (FBP16, 99mTc(CO)3-DETA-PA), respectively. PET or SPECT imaging, biodistribution, pharmacokinetics and metabolic stability were evaluated in rat models of mural and occlusive carotid artery thrombosis. In vivo target specificity was evaluated by comparing the distribution of the SPECT and PET probes with preformed 125I-labeled thrombi and with a non-binding control probe using SPECT/PET/CT imaging. Results All three radiotracers showed similar affinity to soluble fibrin fragment DD(E) (Ki = 0.53–0.83 μM). After the kidneys, the highest uptake of 68Ga-FBP14 and 111In-FBP15 was in the thrombus (1.0 ± 0.2% ID/g) with low off-target accumulation. Both radiotracers underwent fast systemic elimination (t1/2 = 8-15 min) through the kidneys, which led to highly conspicuous thrombi on PET and SPECT images. 99mTc-FBP16 displayed low target uptake and distribution consistent with aggregation and/or degradation. Triple isotope imaging experiments showed that both 68Ga-FBP14 and 111In-FBP15, but not the nonbinding derivative 64Cu-D-Cys-FBP8, detected the location of the 125I-labeled thrombus, confirming high target specificity. Conclusion 68Ga-FBP14 and 111In-FBP15 have high fibrin affinity and thrombus specificity, and represent useful PET and SPECT probes for thrombus detection. PMID:26251420

Evaluation of a PSMA-targeted BNF nanoparticle construct

NASA Astrophysics Data System (ADS)

Behnam Azad, Babak; Banerjee, Sangeeta R.; Pullambhatla, Mrudula; Lacerda, Silvia; Foss, Catherine A.; Wang, Yuchuan; Ivkov, Robert; Pomper, Martin G.

2015-02-01

Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo.Early detection enables improved prognosis for prostate cancer (PCa). A promising target for imaging and therapy of PCa is the prostate-specific membrane antigen (PSMA), which exhibits both expression within the epithelium of PCa cells, and becomes internalized upon ligand binding. Here we report the synthesis of a PSMA-targeted bionized nanoferrite (BNF) nanoparticle and its biological evaluation in an experimental model of PCa. The BNF nanoparticle formulation exhibits properties conducive to targeted imaging such as stealth, prolonged circulation time and enhanced clearance from non-target sites. Optical imaging of the targeted BNF in vivo indicates preferential accumulation in PSMA+ tumors 4 h post-injection, suggesting target specificity. On the other hand, non-targeted nanoparticles exhibit lower uptake with similar accumulation in both PSMA+ and PSMA- tumors indicating tumor access without preferential accumulation. Imaging with single photon emission computed tomography (SPECT) and biodistribution studies of a modified construct indicate highest tumor accumulation at 48 h post-injection [4.3 +/- 0.4 percentage injected dose per gram of tissue (%ID g-1)], with tumor/blood and tumor/muscle ratios of 7.5 +/- 2.4 and 11.6 +/- 1.2 %ID g-1, respectively. Ex vivo fluorescence microscopy, Prussian blue staining, immunohistochemistry and biodistribution studies confirm enhanced nanoparticle uptake in PSMA+ tumors compared to those not expressing PSMA. The BNF nano-formulation described is promising for PSMA-targeted imaging applications in vivo. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06069e

Identification of Carbonic Anhydrase IX as a Novel Target for Endoscopic Molecular Imaging of Human Bladder Cancer.

PubMed

Wang, Jiaqi; Fang, Ruizhe; Wang, Lu; Chen, Guang; Wang, Hongzhi; Wang, Zhichao; Zhao, Danfeng; Pavlov, Valentin N; Kabirov, Ildar; Wang, Ziqi; Guo, Pengyu; Peng, Li; Xu, Wanhai

2018-06-27

Emerging novel optical imaging techniques with cancer-specific molecular imaging agents offer a powerful and promising platform for cancer detection and resection. White-light cystoscopy and random bladder biopsies remain the most appropriate but nonetheless suboptimal diagnostic technique for bladder cancer, which is associated with high morbidity and recurrence. However, white-light cystoscopy has intrinsic shortcomings. Although current optical imaging technologies hold great potential for improved diagnostic accuracy, there are few imaging agents for specific molecular targeting. Carbonic anhydrase IX (CAIX) plays a pivotal role in tumorigenesis and tumor progression with potential value as an imaging target. Here, we investigated the feasibility of CAIX as a target and validated the diagnostic performance and significance of CAIX as an imaging agent. We first analyzed the data from The Cancer Genome Atlas (TCGA). Pairs of samples comprising bladder cancer and adjacent normal tissue were collected. All tissue samples were used for real-time PCR and immunohistochemistry to compare CAIX expression in normal and cancer tissue. Using blue-light cystoscopy, we observed the optical distribution of fluorescently labeled CAIX antibody in freshly excised human bladders and obtained random bladder biopsies to assess sensitivity and specificity. The TCGA data revealed that CAIX expression was significantly higher in bladder cancer specimens than in normal tissue. The outcome was similar in quantitative real-time PCR analysis. In immunohistochemical analysis, bladder cancer specimens classified in four pathological subtypes presented a variety of positive staining intensities, whereas no benign specimens showed CAIX staining. Using blue-light cystoscopy, we distinguished bladder cancers that were mainly papillary, some variants of urothelial carcinoma, and less carcinoma in situ, from benign tissue, despite the presence of suspicious-appearing mucosa. The sensitivity and specificity for CAIX-targeted imaging were 88.00% and 93.75%, respectively. CAIX-targeted molecular imaging could be a feasible and adaptive alternative approach for the accurate diagnosis and complete resection of bladder cancer. © 2018 The Author(s). Published by S. Karger AG, Basel.

Perspectives in molecular imaging through translational research, human medicine, and veterinary medicine.

PubMed

Berry, Clifford R; Garg, Predeep

2014-01-01

The concept of molecular imaging has taken off over the past 15 years to the point of the renaming of the Society of Nuclear Medicine (Society of Nuclear Medicine and Molecular Imaging) and Journals (European Journal of Nuclear Medicine and Molecular Imaging) and offering of medical fellowships specific to this area of study. Molecular imaging has always been at the core of functional imaging related to nuclear medicine. Even before the phrase molecular imaging came into vogue, radionuclides and radiopharmaceuticals were developed that targeted select physiological processes, proteins, receptor analogs, antibody-antigen interactions, metabolites and specific metabolic pathways. In addition, with the advent of genomic imaging, targeted genomic therapy, and theranostics, a number of novel radiopharmaceuticals for the detection and therapy of specific tumor types based on unique biological and cellular properties of the tumor itself have been realized. However, molecular imaging and therapeutics as well as the concept of theranostics are yet to be fully realized. The purpose of this review article is to present an overview of the translational approaches to targeted molecular imaging with application to some naturally occurring animal models of human disease. © 2013 Published by Elsevier Inc.

Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung.

PubMed

Oh, Phil; Borgström, Per; Witkiewicz, Halina; Li, Yan; Borgström, Bengt J; Chrastina, Adrian; Iwata, Koji; Zinn, Kurt R; Baldwin, Richard; Testa, Jacqueline E; Schnitzer, Jan E

2007-03-01

How effectively and quickly endothelial caveolae can transcytose in vivo is unknown, yet critical for understanding their function and potential clinical utility. Here we use quantitative proteomics to identify aminopeptidase P (APP) concentrated in caveolae of lung endothelium. Electron microscopy confirms this and shows that APP antibody targets nanoparticles to caveolae. Dynamic intravital fluorescence microscopy reveals that targeted caveolae operate effectively as pumps, moving antibody within seconds from blood across endothelium into lung tissue, even against a concentration gradient. This active transcytosis requires normal caveolin-1 expression. Whole body gamma-scintigraphic imaging shows rapid, specific delivery into lung well beyond that achieved by standard vascular targeting. This caveolar trafficking in vivo may underscore a key physiological mechanism for selective transvascular exchange and may provide an enhanced delivery system for imaging agents, drugs, gene-therapy vectors and nanomedicines. 'In vivo proteomic imaging' as described here integrates organellar proteomics with multiple imaging techniques to identify an accessible target space that includes the transvascular pumping space of the caveola.

Aptamer-Targeted Gold Nanoparticles As Molecular-Specific Contrast Agents for Reflectance Imaging

PubMed Central

2008-01-01

Targeted metallic nanoparticles have shown potential as a platform for development of molecular-specific contrast agents. Aptamers have recently been demonstrated as ideal candidates for molecular targeting applications. In this study, we investigated the development of aptamer-based gold nanoparticles as contrast agents, using aptamers as targeting agents and gold nanoparticles as imaging agents. We devised a novel conjugation approach using an extended aptamer design where the extension is complementary to an oligonucleotide sequence attached to the surface of the gold nanoparticles. The chemical and optical properties of the aptamer−gold conjugates were characterized using size measurements and oligonucleotide quantitation assays. We demonstrate this conjugation approach to create a contrast agent designed for detection of prostate-specific membrane antigen (PSMA), obtaining reflectance images of PSMA(+) and PSMA(−) cell lines treated with the anti-PSMA aptamer−gold conjugates. This design strategy can easily be modified to incorporate multifunctional agents as part of a multimodal platform for reflectance imaging applications. PMID:18512972

Bioresponsive probes for molecular imaging: concepts and in vivo applications.

PubMed

van Duijnhoven, Sander M J; Robillard, Marc S; Langereis, Sander; Grüll, Holger

2015-01-01

Molecular imaging is a powerful tool to visualize and characterize biological processes at the cellular and molecular level in vivo. In most molecular imaging approaches, probes are used to bind to disease-specific biomarkers highlighting disease target sites. In recent years, a new subset of molecular imaging probes, known as bioresponsive molecular probes, has been developed. These probes generally benefit from signal enhancement at the site of interaction with its target. There are mainly two classes of bioresponsive imaging probes. The first class consists of probes that show direct activation of the imaging label (from "off" to "on" state) and have been applied in optical imaging and magnetic resonance imaging (MRI). The other class consists of probes that show specific retention of the imaging label at the site of target interaction and these probes have found application in all different imaging modalities, including photoacoustic imaging and nuclear imaging. In this review, we present a comprehensive overview of bioresponsive imaging probes in order to discuss the various molecular imaging strategies. The focus of the present article is the rationale behind the design of bioresponsive molecular imaging probes and their potential in vivo application for the detection of endogenous molecular targets in pathologies such as cancer and cardiovascular disease. Copyright © 2015 John Wiley & Sons, Ltd.

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging

PubMed Central

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-01-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane–modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. PMID:26874280

A dual-targeting upconversion nanoplatform for two-color fluorescence imaging-guided photodynamic therapy.

PubMed

Wang, Xu; Yang, Cheng-Xiong; Chen, Jia-Tong; Yan, Xiu-Ping

2014-04-01

The targetability of a theranostic probe is one of the keys to assuring its theranostic efficiency. Here we show the design and fabrication of a dual-targeting upconversion nanoplatform for two-color fluorescence imaging-guided photodynamic therapy (PDT). The nanoplatform was prepared from 3-aminophenylboronic acid functionalized upconversion nanocrystals (APBA-UCNPs) and hyaluronated fullerene (HAC60) via a specific diol-borate condensation. The two specific ligands of aminophenylboronic acid and hyaluronic acid provide synergistic targeting effects, high targetability, and hence a dramatically elevated uptake of the nanoplatform by cancer cells. The high generation yield of (1)O2 due to multiplexed Förster resonance energy transfer between APBA-UCNPs (donor) and HAC60 (acceptor) allows effective therapy. The present nanoplatform shows great potential for highly selective tumor-targeted imaging-guided PDT.

Quantitative imaging as cancer biomarker

NASA Astrophysics Data System (ADS)

Mankoff, David A.

2015-03-01

The ability to assay tumor biologic features and the impact of drugs on tumor biology is fundamental to drug development. Advances in our ability to measure genomics, gene expression, protein expression, and cellular biology have led to a host of new targets for anticancer drug therapy. In translating new drugs into clinical trials and clinical practice, these same assays serve to identify patients most likely to benefit from specific anticancer treatments. As cancer therapy becomes more individualized and targeted, there is an increasing need to characterize tumors and identify therapeutic targets to select therapy most likely to be successful in treating the individual patient's cancer. Thus far assays to identify cancer therapeutic targets or anticancer drug pharmacodynamics have been based upon in vitro assay of tissue or blood samples. Advances in molecular imaging, particularly PET, have led to the ability to perform quantitative non-invasive molecular assays. Imaging has traditionally relied on structural and anatomic features to detect cancer and determine its extent. More recently, imaging has expanded to include the ability to image regional biochemistry and molecular biology, often termed molecular imaging. Molecular imaging can be considered an in vivo assay technique, capable of measuring regional tumor biology without perturbing it. This makes molecular imaging a unique tool for cancer drug development, complementary to traditional assay methods, and a potentially powerful method for guiding targeted therapy in clinical trials and clinical practice. The ability to quantify, in absolute measures, regional in vivo biologic parameters strongly supports the use of molecular imaging as a tool to guide therapy. This review summarizes current and future applications of quantitative molecular imaging as a biomarker for cancer therapy, including the use of imaging to (1) identify patients whose tumors express a specific therapeutic target; (2) determine whether the drug reaches the target; (3) identify an early response to treatment; and (4) predict the impact of therapy on long-term outcomes such as survival. The manuscript reviews basic concepts important in the application of molecular imaging to cancer drug therapy, in general, and will discuss specific examples of studies in humans, and highlight future directions, including ongoing multi-center clinical trials using molecular imaging as a cancer biomarker.

Multimodal Molecular Imaging Reveals High Target Uptake and Specificity of 111In- and 68Ga-Labeled Fibrin-Binding Probes for Thrombus Detection in Rats.

PubMed

Oliveira, Bruno L; Blasi, Francesco; Rietz, Tyson A; Rotile, Nicholas J; Day, Helen; Caravan, Peter

2015-10-01

We recently showed the high target specificity and favorable imaging properties of 64Cu and Al18F PET probes for noninvasive imaging of thrombosis. Here, our aim was to evaluate new derivatives labeled with either with 68Ga, 111In, or 99mTc as thrombus imaging agents for PET and SPECT. In this study, the feasibility and potential of these probes for thrombus imaging was assessed in detail in 2 animal models of arterial thrombosis. The specificity of the probes was further evaluated using a triple-isotope approach with multimodal SPECT/PET/CT imaging. Radiotracers were synthesized using a known fibrin-binding peptide conjugated to 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DOTA-MA), or a diethylenetriamine ligand (DETA-propanoic acid [PA]), followed by labeling with 68Ga (FBP14, 68Ga-NODAGA), 111In (FBP15, 111In-DOTA-MA), or 99mTc (FBP16, 99mTc(CO)3-DETA-PA), respectively. PET or SPECT imaging, biodistribution, pharmacokinetics, and metabolic stability were evaluated in rat models of mural and occlusive carotid artery thrombosis. In vivo target specificity was evaluated by comparing the distribution of the SPECT and PET probes with preformed 125I-labeled thrombi and with a nonbinding control probe using SPECT/PET/CT imaging. All 3 radiotracers showed affinity similar to soluble fibrin fragment DD(E) (inhibition constant=0.53-0.83 μM). After the kidneys, the highest uptake of 68Ga-FBP14 and 111In-FBP15 was in the thrombus (1.0±0.2 percentage injected dose per gram), with low off-target accumulation. Both radiotracers underwent fast systemic elimination (half-life, 8-15 min) through the kidneys, which led to highly conspicuous thrombi on PET and SPECT images. 99mTc-FBP16 displayed low target uptake and distribution consistent with aggregation or degradation. Triple-isotope imaging experiments showed that both 68Ga-FBP14 and 111In-FBP15, but not the nonbinding derivative 64Cu-D-Cys-FBP8, detected the location of the 125I-labeled thrombus, confirming high target specificity. 68Ga-FBP14 and 111In-FBP15 have high fibrin affinity and thrombus specificity and represent useful PET and SPECT probes for thrombus detection. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study

PubMed Central

2014-01-01

Background Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours. Methods The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup. Results Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys. Conclusions We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies. PMID:24598405

Fabrication and bioconjugation of BIII and CrIII co-doped ZnGa2O4 persistent luminescent nanoparticles for dual-targeted cancer bioimaging.

PubMed

Zhao, Huai-Xin; Yang, Cheng-Xiong; Yan, Xiu-Ping

2016-12-07

Persistent luminescent nanoparticles (PLNPs) show great potential in realizing precision imaging due to the absence of in situ excitation and no background interference. However, the current PLNP-based tumour imaging is usually achieved by single targeting or passive targeting strategies, and thus it lacks high specificity and affinity for efficient persistent luminescence imaging in vivo. Herein we report the bioconjugation of multiple targeting ligands on the surface of PLNPs for dual-targeted bioimaging to improve the specificity and affinity of the PLNP nanoprobe for in vitro and in vivo bioimaging. The PLNPs were prepared by co-doping Cr III and B III into ZnGa 2 O 4 via a hydrothermal-calcination method. While Cr III doped ZnGa 2 O 4 PLNPs possess excellent near-infrared luminescence along with long afterglow and red light renewable near-infrared luminescence, doping of B III into the PLNPs further improves the persistent luminescence. Conjugation of two targeting ligands, hyaluronic acid and folic acid, which have specificity toward the cluster determinant 44 receptor and folic acid receptor in tumour cells, respectively, provides synergistic targeting effects to enhance the specificity and affinity toward tumour cells. This work provides a dual-targeting strategy for fabricating PLNP-based nanoprobes to realize precision tumour-targeted bioimaging.

A review of NIR dyes in cancer targeting and imaging.

PubMed

Luo, Shenglin; Zhang, Erlong; Su, Yongping; Cheng, Tianmin; Shi, Chunmeng

2011-10-01

The development of multifunctional agents for simultaneous tumor targeting and near infrared (NIR) fluorescence imaging is expected to have significant impact on future personalized oncology owing to the very low tissue autofluorescence and high tissue penetration depth in the NIR spectrum window. Cancer NIR molecular imaging relies greatly on the development of stable, highly specific and sensitive molecular probes. Organic dyes have shown promising clinical implications as non-targeting agents for optical imaging in which indocyanine green has long been implemented in clinical use. Recently, significant progress has been made on the development of unique NIR dyes with tumor targeting properties. Current ongoing design strategies have overcome some of the limitations of conventional NIR organic dyes, such as poor hydrophilicity and photostability, low quantum yield, insufficient stability in biological system, low detection sensitivity, etc. This potential is further realized with the use of these NIR dyes or NIR dye-encapsulated nanoparticles by conjugation with tumor specific ligands (such as small molecules, peptides, proteins and antibodies) for tumor targeted imaging. Very recently, natively multifunctional NIR dyes that can preferentially accumulate in tumor cells without the need of chemical conjugation to tumor targeting ligands have been developed and these dyes have shown unique optical and pharmaceutical properties for biomedical imaging with superior signal-to-background contrast index. The main focus of this article is to provide a concise overview of newly developed NIR dyes and their potential applications in cancer targeting and imaging. The development of future multifunctional agents by combining targeting, imaging and even therapeutic routes will also be discussed. We believe these newly developed multifunctional NIR dyes will broaden current concept of tumor targeted imaging and hold promise to make an important contribution to the diagnosis and therapeutics for the treatment of cancer. Copyright © 2011 Elsevier Ltd. All rights reserved.

M13 phage-functionalized single-walled carbon nanotubes as nanoprobes for second near-infrared window fluorescence imaging of targeted tumors.

PubMed

Yi, Hyunjung; Ghosh, Debadyuti; Ham, Moon-Ho; Qi, Jifa; Barone, Paul W; Strano, Michael S; Belcher, Angela M

2012-03-14

Second near-infrared (NIR) window light (950-1400 nm) is attractive for in vivo fluorescence imaging due to its deep penetration depth in tissues and low tissue autofluorescence. Here we show genetically engineered multifunctional M13 phage can assemble fluorescent single-walled carbon nanotubes (SWNTs) and ligands for targeted fluorescence imaging of tumors. M13-SWNT probe is detectable in deep tissues even at a low dosage of 2 μg/mL and up to 2.5 cm in tissue-like phantoms. Moreover, targeted probes show specific and up to 4-fold improved uptake in prostate specific membrane antigen positive prostate tumors compared to control nontargeted probes. This M13 phage-based second NIR window fluorescence imaging probe has great potential for specific detection and therapy monitoring of hard-to-detect areas. © 2012 American Chemical Society

A targeted illumination optical fiber probe for high resolution fluorescence imaging and optical switching

NASA Astrophysics Data System (ADS)

Shinde, Anant; Perinchery, Sandeep Menon; Murukeshan, Vadakke Matham

2017-04-01

An optical imaging probe with targeted multispectral and spatiotemporal illumination features has applications in many diagnostic biomedical studies. However, these systems are mostly adapted in conventional microscopes, limiting their use for in vitro applications. We present a variable resolution imaging probe using a digital micromirror device (DMD) with an achievable maximum lateral resolution of 2.7 μm and an axial resolution of 5.5 μm, along with precise shape selective targeted illumination ability. We have demonstrated switching of different wavelengths to image multiple regions in the field of view. Moreover, the targeted illumination feature allows enhanced image contrast by time averaged imaging of selected regions with different optical exposure. The region specific multidirectional scanning feature of this probe has facilitated high speed targeted confocal imaging.

The Inextricable Axis Of Targeted Diagnostic Imaging And Therapy: An Immunological Natural History Approach

PubMed Central

Cope, FO; Abbruzzese, B; Sanders, J; Metz, W; Sturms, K; Ralph, D; Blue, M; Zhang, J; Bracci, P; Bshara, W; Behr, S; Maurer, T; Beverly, A; Blay, B; Damughatla, A; Larsen, M; Mountain, C; Neylon, E; Parcel, K; Raghuraman, K; Ricks, K; Rose, L; Sivakumar, A; Streck, N; Wang, B; Wasco, C; Williams, A; McGrath, M

2016-01-01

Summary In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. 99mTc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10−11 M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 minutes to bind more tilmanocept (acting as intracellular “drug compilers” of tilmanocept into non-degraded vesicles), give serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate 99mTc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy. PMID:26924502

The inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach.

PubMed

Cope, Frederick O; Abbruzzese, Bonnie; Sanders, James; Metz, Wendy; Sturms, Kristyn; Ralph, David; Blue, Michael; Zhang, Jane; Bracci, Paige; Bshara, Wiam; Behr, Spencer; Maurer, Toby; Williams, Kenneth; Walker, Joshua; Beverly, Allison; Blay, Brooke; Damughatla, Anirudh; Larsen, Mark; Mountain, Courtney; Neylon, Erin; Parcel, Kaeli; Raghuraman, Kapil; Ricks, Kevin; Rose, Lucas; Sivakumar, Akhilesh; Streck, Nicholas; Wang, Bryan; Wasco, Christopher; Williams, Amifred; McGrath, Michael

2016-03-01

In considering the challenges of approaches to clinical imaging, we are faced with choices that sometimes are impacted by rather dogmatic notions about what is a better or worse technology to achieve the most useful diagnostic image for the patient. For example, is PET or SPECT most useful in imaging any particular disease dissemination? The dictatorial approach would be to choose PET, all other matters being equal. But is such a totalitarian attitude toward imaging selection still valid? In the face of new receptor targeted SPECT agents one must consider the remarkable specificity and sensitivity of these agents. (99m)Tc-Tilmanocept is one of the newest of these agents, now approved for guiding sentinel node biopsy (SLNB) in several solid tumors. Tilmanocept has a Kd of 3×10(-11)M, and it specificity for the CD206 receptor is unlike any other agent to date. This coupled with a number of facts, that specific disease-associated macrophages express this receptor (100 to 150 thousand receptors), that the receptor has multiple binding sites for tilmanocept (>2 sites per receptor) and that these receptors are recycled every 15 min to bind more tilmanocept (acting as intracellular "drug compilers" of tilmanocept into non-degraded vesicles), gives serious pause as to how we select our approaches to diagnostic imaging. Clinically, the size of SLNs varies greatly, some, anatomically, below the machine resolution of SPECT. Yet, with tilmanocept targeting, the SLNs are highly visible with macrophages stably accruing adequate (99m)Tc-tilmanocept counting statistics, as high target-to-background ratios can compensate for spatial resolution blurring. Importantly, it may be targeted imaging agents per se, again such as tilmanocept, which may significantly shrink any perceived chasm between the imaging technologies and anchor the diagnostic considerations in the targeting and specificity of the agent rather than any lingering dogma about the hardware as the basis for imaging approaches. Beyond the elements of imaging applications of these agents is their evolution to therapeutic agents as well, and even in the neo-logical realm of theranostics. Characteristics of agents such as tilmanocept that exploit the natural history of diseases with remarkably high specificity are the expectations for the future of patient- and disease-centered diagnosis and therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of macrophages in large vessel vasculitis: Current status and future prospects.

PubMed

Jiemy, William Febry; Heeringa, Peter; Kamps, Jan A A M; van der Laken, Conny J; Slart, Riemer H J A; Brouwer, Elisabeth

2018-05-03

Macrophages are key players in the pathogenesis of large-vessel vasculitis (LVV) and may serve as a target for diagnostic imaging of LVV. The radiotracer, 18 F-FDG has proven to be useful in the diagnosis of giant cell arteritis (GCA), a form of LVV. Although uptake of 18 F-FDG is high in activated macrophages, it is not a specific radiotracer as its uptake is high in any proliferating cell and other activated immune cells resulting in high non-specific background radioactivity especially in aging and atherosclerotic vessels which dramatically lowers the diagnostic accuracy. Evidence also exists that the sensitivity of 18 F-FDG PET drops in patients upon glucocorticoid treatment. Therefore, there is a clinical need for more specific radiotracers in imaging GCA to improve diagnostic accuracy. Numerous clinically established and newly developed macrophage targeted radiotracers for oncological and inflammatory diseases can potentially be utilized for LVV imaging. These tracers are more target specific and therefore may provide lower background radioactivity, higher diagnostic accuracy and the ability to assess treatment effectiveness. However, current knowledge regarding macrophage subsets in LVV lesions is limited. Further understanding regarding macrophage subsets in vasculitis lesion is needed for better selection of tracers and new targets for tracer development. This review summarizes the development of macrophage targeted tracers in the last decade and the potential application of macrophage targeted tracers currently used in other inflammatory diseases in imaging LVV. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery.

PubMed

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y Andrew; Mao, Hui; Yang, Lily

2015-01-01

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.

Infrared moving small target detection based on saliency extraction and image sparse representation

NASA Astrophysics Data System (ADS)

Zhang, Xiaomin; Ren, Kan; Gao, Jin; Li, Chaowei; Gu, Guohua; Wan, Minjie

2016-10-01

Moving small target detection in infrared image is a crucial technique of infrared search and tracking system. This paper present a novel small target detection technique based on frequency-domain saliency extraction and image sparse representation. First, we exploit the features of Fourier spectrum image and magnitude spectrum of Fourier transform to make a rough extract of saliency regions and use a threshold segmentation system to classify the regions which look salient from the background, which gives us a binary image as result. Second, a new patch-image model and over-complete dictionary were introduced to the detection system, then the infrared small target detection was converted into a problem solving and optimization process of patch-image information reconstruction based on sparse representation. More specifically, the test image and binary image can be decomposed into some image patches follow certain rules. We select the target potential area according to the binary patch-image which contains salient region information, then exploit the over-complete infrared small target dictionary to reconstruct the test image blocks which may contain targets. The coefficients of target image patch satisfy sparse features. Finally, for image sequence, Euclidean distance was used to reduce false alarm ratio and increase the detection accuracy of moving small targets in infrared images due to the target position correlation between frames.

Beyond the margins: real-time detection of cancer using targeted fluorophores

PubMed Central

Zhang, Ray R.; Schroeder, Alexandra B.; Grudzinski, Joseph J.; Rosenthal, Eben L.; Warram, Jason M.; Pinchuk, Anatoly N.; Eliceiri, Kevin W.; Kuo, John S.; Weichert, Jamey P.

2017-01-01

Over the past two decades, synergistic innovations in imaging technology have resulted in a revolution in which a range of biomedical applications are now benefiting from fluorescence imaging. Specifically, advances in fluorophore chemistry and imaging hardware, and the identification of targetable biomarkers have now positioned intraoperative fluorescence as a highly specific real-time detection modality for surgeons in oncology. In particular, the deeper tissue penetration and limited autofluorescence of near-infrared (NIR) fluorescence imaging improves the translational potential of this modality over visible-light fluorescence imaging. Rapid developments in fluorophores with improved characteristics, detection instrumentation, and targeting strategies led to the clinical testing in the early 2010s of the first targeted NIR fluorophores for intraoperative cancer detection. The foundations for the advances that underline this technology continue to be nurtured by the multidisciplinary collaboration of chemists, biologists, engineers, and clinicians. In this Review, we highlight the latest developments in NIR fluorophores, cancer-targeting strategies, and detection instrumentation for intraoperative cancer detection, and consider the unique challenges associated with their effective application in clinical settings. PMID:28094261

Advances in targeting strategies for nanoparticles in cancer imaging and therapy.

PubMed

Yhee, Ji Young; Lee, Sangmin; Kim, Kwangmeyung

2014-11-21

In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine.

A targeted nanoglobular contrast agent from host-guest self-assembly for MR cancer molecular imaging.

PubMed

Zhou, Zhuxian; Han, Zhen; Lu, Zheng-Rong

2016-04-01

The clinical application of nanoparticular Gd(III) based contrast agents for tumor molecular MRI has been hindered by safety concerns associated with prolonged tissue retention, although they can produce strong tumor enhancement. In this study, a targeted well-defined cyclodextrin-based nanoglobular contrast agent was developed through self-assembly driven by host-guest interactions for safe and effective cancer molecular MRI. Multiple β-cyclodextrins attached POSS (polyhedral oligomeric silsesquioxane) nanoglobule was used as host molecule. Adamantane-modified macrocyclic Gd(III) contrast agent, cRGD (cyclic RGDfK peptide) targeting ligand and fluorescent probe was used as guest molecules. The targeted host-guest nanoglobular contrast agent cRGD-POSS-βCD-(DOTA-Gd) specifically bond to αvβ3 integrin in malignant 4T1 breast tumor and provided greater contrast enhancement than the corresponding non-targeted agent. The agent also provided significant fluorescence signal in tumor tissue. The histological analysis of the tumor tissue confirmed its specific and effective targeting to αvβ3 integrin. The targeted imaging agent has a potential for specific cancer molecular MR and fluorescent imaging. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hierarchical Multi-atlas Label Fusion with Multi-scale Feature Representation and Label-specific Patch Partition

PubMed Central

Wu, Guorong; Kim, Minjeong; Sanroma, Gerard; Wang, Qian; Munsell, Brent C.; Shen, Dinggang

2014-01-01

Multi-atlas patch-based label fusion methods have been successfully used to improve segmentation accuracy in many important medical image analysis applications. In general, to achieve label fusion a single target image is first registered to several atlas images, after registration a label is assigned to each target point in the target image by determining the similarity between the underlying target image patch (centered at the target point) and the aligned image patch in each atlas image. To achieve the highest level of accuracy during the label fusion process it’s critical the chosen patch similarity measurement accurately captures the tissue/shape appearance of the anatomical structure. One major limitation of existing state-of-the-art label fusion methods is that they often apply a fixed size image patch throughout the entire label fusion procedure. Doing so may severely affect the fidelity of the patch similarity measurement, which in turn may not adequately capture complex tissue appearance patterns expressed by the anatomical structure. To address this limitation, we advance state-of-the-art by adding three new label fusion contributions: First, each image patch now characterized by a multi-scale feature representation that encodes both local and semi-local image information. Doing so will increase the accuracy of the patch-based similarity measurement. Second, to limit the possibility of the patch-based similarity measurement being wrongly guided by the presence of multiple anatomical structures in the same image patch, each atlas image patch is further partitioned into a set of label-specific partial image patches according to the existing labels. Since image information has now been semantically divided into different patterns, these new label-specific atlas patches make the label fusion process more specific and flexible. Lastly, in order to correct target points that are mislabeled during label fusion, a hierarchically approach is used to improve the label fusion results. In particular, a coarse-to-fine iterative label fusion approach is used that gradually reduces the patch size. To evaluate the accuracy of our label fusion approach, the proposed method was used to segment the hippocampus in the ADNI dataset and 7.0 tesla MR images, sub-cortical regions in LONI LBPA40 dataset, mid-brain regions in SATA dataset from MICCAI 2013 segmentation challenge, and a set of key internal gray matter structures in IXI dataset. In all experiments, the segmentation results of the proposed hierarchical label fusion method with multi-scale feature representations and label-specific atlas patches are more accurate than several well-known state-of-the-art label fusion methods. PMID:25463474

Imaging and targeted therapy of pancreatic ductal adenocarcinoma using the theranostic sodium iodide symporter (NIS) gene

PubMed Central

Trajkovic-Arsic, Marija; Klutz, Kathrin; Braren, Rickmer; Schwaiger, Markus; Nelson, Peter J.; Ogris, Manfred; Wagner, Ernst; Siveke, Jens T.; Spitzweg, Christine

2017-01-01

The theranostic sodium iodide symporter (NIS) gene allows detailed molecular imaging of transgene expression and application of therapeutic radionuclides. As a crucial step towards clinical application, we investigated tumor specificity and transfection efficiency of epidermal growth factor receptor (EGFR)-targeted polyplexes as systemic NIS gene delivery vehicles in an advanced genetically engineered mouse model of pancreatic ductal adenocarcinoma (PDAC) that closely reflects human disease. PDAC was induced in mice by pancreas-specific activation of constitutively active KrasG12D and deletion of Trp53. We used tumor-targeted polyplexes (LPEI-PEG-GE11/NIS) based on linear polyethylenimine, shielded by polyethylene glycol and coupled with the EGFR-specific peptide ligand GE11, to target a NIS-expressing plasmid to high EGFR-expressing PDAC. In vitro iodide uptake studies in cell explants from murine EGFR-positive and EGFR-ablated PDAC lesions demonstrated high transfection efficiency and EGFR-specificity of LPEI-PEG-GE11/NIS. In vivo 123I gamma camera imaging and three-dimensional high-resolution 124I PET showed significant tumor-specific accumulation of radioiodide after systemic LPEI-PEG-GE11/NIS injection. Administration of 131I in LPEI-PEG-GE11/NIS-treated mice resulted in significantly reduced tumor growth compared to controls as determined by magnetic resonance imaging, though survival was not significantly prolonged. This study opens the exciting prospect of NIS-mediated radionuclide imaging and therapy of PDAC after systemic non-viral NIS gene delivery. PMID:28380420

Targeting pancreatic cancer with magneto-fluorescent theranostic gold nanoshells.

PubMed

Chen, Wenxue; Ayala-Orozco, Ciceron; Biswal, Nrusingh C; Perez-Torres, Carlos; Bartels, Marc; Bardhan, Rizia; Stinnet, Gary; Liu, Xian-De; Ji, Baoan; Deorukhkar, Amit; Brown, Lisa V; Guha, Sushovan; Pautler, Robia G; Krishnan, Sunil; Halas, Naomi J; Joshi, Amit

2014-01-01

We report a magneto-fluorescent theranostic nanocomplex targeted to neutrophil gelatinase-associated lipocalin (NGAL) for imaging and therapy of pancreatic cancer. Gold nanoshells resonant at 810 nm were encapsulated in silica epilayers doped with iron oxide and the near-infrared (NIR) dye indocyanine green, resulting in theranostic gold nanoshells (TGNS), which were subsequently conjugated with antibodies targeting NGAL in AsPC-1-derived xenografts in nude mice. Anti-NGAL-conjugated TGNS specifically targeted pancreatic cancer cells in vitro and in vivo providing contrast for both NIR fluorescence and T2-weighted MRI with higher tumor contrast than can be obtained using long-circulating, but nontargeted, PEGylated nanoparticles. The nanocomplexes also enabled highly specific cancer cell death via NIR photothermal therapy in vitro. TGNS with embedded NIR and magnetic resonance contrasts can be specifically targeted to pancreatic cancer cells with expression of early disease marker NGAL, and enable molecularly targeted imaging and photothermal therapy.

In vivo targeting and imaging of tumor vasculature with radiolabeled, antibody-conjugated nanographene.

PubMed

Hong, Hao; Yang, Kai; Zhang, Yin; Engle, Jonathan W; Feng, Liangzhu; Yang, Yunan; Nayak, Tapas R; Goel, Shreya; Bean, Jero; Theuer, Charles P; Barnhart, Todd E; Liu, Zhuang; Cai, Weibo

2012-03-27

Herein we demonstrate that nanographene can be specifically directed to the tumor neovasculature in vivo through targeting of CD105 (i.e., endoglin), a vascular marker for tumor angiogenesis. The covalently functionalized nanographene oxide (GO) exhibited excellent stability and target specificity. Pharmacokinetics and tumor targeting efficacy of the GO conjugates were investigated with serial noninvasive positron emission tomography imaging and biodistribution studies, which were validated by in vitro, in vivo, and ex vivo experiments. The incorporation of an active targeting ligand (TRC105, a monoclonal antibody that binds to CD105) led to significantly improved tumor uptake of functionalized GO, which was specific for the neovasculature with little extravasation, warranting future investigation of these GO conjugates for cancer-targeted drug delivery and/or photothermal therapy to enhance therapeutic efficacy. Since poor extravasation is a major hurdle for nanomaterial-based tumor targeting in vivo, this study also establishes CD105 as a promising vascular target for future cancer nanomedicine. © 2012 American Chemical Society

Hapten-derivatized nanoparticle targeting and imaging of gene expression by multimodality imaging systems.

PubMed

Cheng, C-M; Chu, P-Y; Chuang, K-H; Roffler, S R; Kao, C-H; Tseng, W-L; Shiea, J; Chang, W-D; Su, Y-C; Chen, B-M; Wang, Y-M; Cheng, T-L

2009-01-01

Non-invasive gene monitoring is important for most gene therapy applications to ensure selective gene transfer to specific cells or tissues. We developed a non-invasive imaging system to assess the location and persistence of gene expression by anchoring an anti-dansyl (DNS) single-chain antibody (DNS receptor) on the cell surface to trap DNS-derivatized imaging probes. DNS hapten was covalently attached to cross-linked iron oxide (CLIO) to form a 39+/-0.5 nm DNS-CLIO nanoparticle imaging probe. DNS-CLIO specifically bound to DNS receptors but not to a control single-chain antibody receptor. DNS-CLIO (100 microM Fe) was non-toxic to both B16/DNS (DNS receptor positive) and B16/phOx (control receptor positive) cells. Magnetic resonance (MR) imaging could detect as few as 10% B16/DNS cells in a mixture in vitro. Importantly, DNS-CLIO specifically bound to a B16/DNS tumor, which markedly reduced signal intensity. Similar results were also shown with DNS quantum dots, which specifically targeted CT26/DNS cells but not control CT26/phOx cells both in vitro and in vivo. These results demonstrate that DNS nanoparticles can systemically monitor the expression of DNS receptor in vivo by feasible imaging systems. This targeting strategy may provide a valuable tool to estimate the efficacy and specificity of different gene delivery systems and optimize gene therapy protocols in the clinic.

Novel dual-mode nanobubbles as potential targeted contrast agents for female tumors exploration.

PubMed

Yang, Hengli; Zhou, Tian; Cai, Wenbin; Yi, Xiaomin; Liu, Xi; Wang, Yixiao; Zhang, Li; Duan, Yunyou

2016-10-01

The purpose of this study was to prepare tumor-specific dual-mode nanobubbles as both ultrasound contrast agents (UCAs) and near-infrared fluorescence (NIRF) imaging agents for female tumors. Recent studies have demonstrated the conjugation of anti-tumor ligands on the surface of nanobubbles for use as molecule-targeting ultrasound contrast agents for tumor visualization. However, this complicated procedure has also posed a challenge to nanobubble stability. Thus, in the present study, we combined the fluorescent dye, NIRF IR-780 iodide, which has lipid solubility and tumor-targeting characteristics, with the phospholipid film of nanobubbles that we constructed. We then characterized the physical features of the IR-780-nanobubbles, observed their tumor-targeting capacity in multiple female tumor cell types in vitro, and verified their capability for use in tumor-specific ultrasound contrast imaging and NIRF imaging in vivo. The results showed that the new IR-780-nanobubbles had a uniform nano-size (442.5 ± 48.6 nm) and stability and that they were safe and effective at NIRF imaging and ultrasound imaging in vitro. The IR-780-nanobubbles were found to automatically accumulate on different female tumor cells in vitro with a considerable targeting rate (close to 40 %) but did not accumulate on cardiac muscle cells used as a negative control. Importantly, the IR-780-nanobubbles can detect female tumors precisely via dual-mode imaging in vivo. In conclusion, the new dual-mode IR-780-nanobubbles are stable and have potential advantages in non-invasive tumor-specific detection for female tumors via contrast-enhanced ultrasound and NIRF imaging.

Targeting of MPEG-protected polyamino acid carrier to human E-selectin in vitro.

PubMed

Kang, H W; Weissleder, R; Bogdanov, A

2002-01-01

Targeted diagnostic agents are expected to have a significant impact in molecular imaging of cell-surface associated markers of proliferation, inflammation and angiogenesis. In this communication, we describe a new class of targeted polyamino acid-based protected graft copolymers (PGC) of poly-(L-lysine) and methyl poly-(ethylene glycol) (PGC) covalently conjugated with a monoclonal antibody fragment, F(ab')(2). We utilized targeted PGC conjugates as carriers of near-infrared indocyanine fluorophores (Cy5.5) for optical imaging of endothelial cell populations expressing IL-1 beta inducible proinflammatory marker E-selectin. We compared two conjugation chemistries, involving either introduction of sulfhydryl group to F(ab')(2), or via direct attachment of the antibody fragment directly to the chemically activated PGC. Both PGC-based targeted agents demonstrated high binding specificity (20-30 fold over non-specific uptake) and were utilized for imaging E-selectin expression on human endothelial cells activated with IL-1 beta.

PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status

PubMed Central

Lütje, Susanne; Heskamp, Sandra; Cornelissen, Alexander S.; Poeppel, Thorsten D.; van den Broek, Sebastiaan A. M. W.; Rosenbaum-Krumme, Sandra; Bockisch, Andreas; Gotthardt, Martin; Rijpkema, Mark; Boerman, Otto C.

2015-01-01

Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided. PMID:26681984

Cancer Stratification by Molecular Imaging

PubMed Central

Weber, Justus; Haberkorn, Uwe; Mier, Walter

2015-01-01

The lack of specificity of traditional cytotoxic drugs has triggered the development of anticancer agents that selectively address specific molecular targets. An intrinsic property of these specialized drugs is their limited applicability for specific patient subgroups. Consequently, the generation of information about tumor characteristics is the key to exploit the potential of these drugs. Currently, cancer stratification relies on three approaches: Gene expression analysis and cancer proteomics, immunohistochemistry and molecular imaging. In order to enable the precise localization of functionally expressed targets, molecular imaging combines highly selective biomarkers and intense signal sources. Thus, cancer stratification and localization are performed simultaneously. Many cancer types are characterized by altered receptor expression, such as somatostatin receptors, folate receptors or Her2 (human epidermal growth factor receptor 2). Similar correlations are also known for a multitude of transporters, such as glucose transporters, amino acid transporters or hNIS (human sodium iodide symporter), as well as cell specific proteins, such as the prostate specific membrane antigen, integrins, and CD20. This review provides a comprehensive description of the methods, targets and agents used in molecular imaging, to outline their application for cancer stratification. Emphasis is placed on radiotracers which are used to identify altered expression patterns of cancer associated markers. PMID:25749472

Hyperspectral small animal fluorescence imaging: spectral selection imaging

NASA Astrophysics Data System (ADS)

Leavesley, Silas; Jiang, Yanan; Patsekin, Valery; Hall, Heidi; Vizard, Douglas; Robinson, J. Paul

2008-02-01

Molecular imaging is a rapidly growing area of research, fueled by needs in pharmaceutical drug-development for methods for high-throughput screening, pre-clinical and clinical screening for visualizing tumor growth and drug targeting, and a growing number of applications in the molecular biology fields. Small animal fluorescence imaging employs fluorescent probes to target molecular events in vivo, with a large number of molecular targeting probes readily available. The ease at which new targeting compounds can be developed, the short acquisition times, and the low cost (compared to microCT, MRI, or PET) makes fluorescence imaging attractive. However, small animal fluorescence imaging suffers from high optical scattering, absorption, and autofluorescence. Much of these problems can be overcome through multispectral imaging techniques, which collect images at different fluorescence emission wavelengths, followed by analysis, classification, and spectral deconvolution methods to isolate signals from fluorescence emission. We present an alternative to the current method, using hyperspectral excitation scanning (spectral selection imaging), a technique that allows excitation at any wavelength in the visible and near-infrared wavelength range. In many cases, excitation imaging may be more effective at identifying specific fluorescence signals because of the higher complexity of the fluorophore excitation spectrum. Because the excitation is filtered and not the emission, the resolution limit and image shift imposed by acousto-optic tunable filters have no effect on imager performance. We will discuss design of the imager, optimizing the imager for use in small animal fluorescence imaging, and application of spectral analysis and classification methods for identifying specific fluorescence signals.

New generation of magnetic and luminescent nanoparticles for in vivo real-time imaging

PubMed Central

Lacroix, Lise-Marie; Delpech, Fabien; Nayral, Céline; Lachaize, Sébastien; Chaudret, Bruno

2013-01-01

A new generation of optimized contrast agents is emerging, based on metallic nanoparticles (NPs) and semiconductor nanocrystals for, respectively, magnetic resonance imaging (MRI) and near-infrared (NIR) fluorescent imaging techniques. Compared with established contrast agents, such as iron oxide NPs or organic dyes, these NPs benefit from several advantages: their magnetic and optical properties can be tuned through size, shape and composition engineering, their efficiency can exceed by several orders of magnitude that of contrast agents clinically used, their surface can be modified to incorporate specific targeting agents and antifolding polymers to increase blood circulation time and tumour recognition, and they can possibly be integrated in complex architecture to yield multi-modal imaging agents. In this review, we will report the materials of choice based on the understanding of the basic physics of NIR and MRI techniques and their corresponding syntheses as NPs. Surface engineering, water transfer and specific targeting will be highlighted prior to their first use for in vivo real-time imaging. Highly efficient NPs that are safer and target specific are likely to enter clinical application in a near future. PMID:24427542

Molecular Targeted Viral Nanoparticles as Tools for Imaging Cancer

PubMed Central

Cho, C.F.; Sourabh, S.; Simpson, E.J.; Steinmetz, N.F.; Luyt, L.G.; Lewis, J.D.

2015-01-01

Viral nanoparticles (VNPs) are a novel class of bionanomaterials that harness the natural biocompatibility of viruses for the development of therapeutics, vaccines, and imaging tools. The plant virus, cowpea mosaic virus (CPMV), has been successfully engineered to create novel cancer-targeted imaging agents by incorporating fluorescent dyes, polyethylene glycol (PEG) polymers, and targeting moieties. Using straightforward conjugation strategies, VNPs with high selectivity for cancer-specific molecular targets can be synthesized for in vivo imaging of tumors. Here we describe the synthesis and purification of CPMV-based VNPs, the functionalization of these VNPs using click chemistry, and their use for imaging xenograft tumors in animal models. VNPs decorated with fluorescent dyes, PEG, and targeting ligands can be synthesized in one day, and imaging studies can be performed over hours, days, or weeks, depending on the application. PMID:24243252

Targeted Nanodiamonds as Phenotype Specific Photoacoustic Contrast Agents for Breast Cancer

PubMed Central

Zhang, Ti; Cui, Huizhong; Fang, Chia-Yi; Cheng, Kun; Yang, Xinmai; Chang, Huan-Cheng; Forrest, M. Laird

2015-01-01

Aim The aim is to develop irradiated nanodiamonds (INDs) as a molecularly-targeted contrast agent for high resolution and phenotype-specific detection of breast cancer with photoacoustic (PA) imaging. Materials & Methods The surface of acid treated radiation-damaged nanodiamonds was grafted with polyethylene glycol (PEG) to improve its stability and circulation time in blood, followed by conjugation to an anti-Human epidermal growth factor receptor-2 (HER2) peptide (KCCYSL) with a final nanoparticle size of ca. 92 nm. Immunocompetent mice bearing orthotopic HER2 positive or negative tumors were administered INDs and PA imaged using an 820-nm near infrared laser. Results PA images demonstrated that INDs accumulate in tumors and completely delineated the entire tumor within 10 hours. HER2 targeting significantly enhanced imaging of HER2-positive tumors. Pathological examination demonstrated INDs are non-toxic. Conclusions PA technology is adaptable to low-cost bedside medicine, and with new contrast agents described herein, PA can achieve high resolution (sub-mm) and phenotype specific monitoring of cancer growth. PMID:25723091

Bench to bedside molecular functional imaging in translational cancer medicine: to image or to imagine?

PubMed

Mahajan, A; Goh, V; Basu, S; Vaish, R; Weeks, A J; Thakur, M H; Cook, G J

2015-10-01

Ongoing research on malignant and normal cell biology has substantially enhanced the understanding of the biology of cancer and carcinogenesis. This has led to the development of methods to image the evolution of cancer, target specific biological molecules, and study the anti-tumour effects of novel therapeutic agents. At the same time, there has been a paradigm shift in the field of oncological imaging from purely structural or functional imaging to combined multimodal structure-function approaches that enable the assessment of malignancy from all aspects (including molecular and functional level) in a single examination. The evolving molecular functional imaging using specific molecular targets (especially with combined positron-emission tomography [PET] computed tomography [CT] using 2- [(18)F]-fluoro-2-deoxy-D-glucose [FDG] and other novel PET tracers) has great potential in translational research, giving specific quantitative information with regard to tumour activity, and has been of pivotal importance in diagnoses and therapy tailoring. Furthermore, molecular functional imaging has taken a key place in the present era of translational cancer research, producing an important tool to study and evolve newer receptor-targeted therapies, gene therapies, and in cancer stem cell research, which could form the basis to translate these agents into clinical practice, popularly termed "theranostics". Targeted molecular imaging needs to be developed in close association with biotechnology, information technology, and basic translational scientists for its best utility. This article reviews the current role of molecular functional imaging as one of the main pillars of translational research. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Instrumentation of Molecular Imaging on Site-Specific Targeting Fluorescent Peptide for Early Detection of Breast Cancer

NASA Astrophysics Data System (ADS)

Yu, Ping; Ma, Lixin

2012-02-01

In this work we developed two biomedical imaging techniques for early detection of breast cancer. Both image modalities provide molecular imaging capability to probe site-specific targeting dyes. The first technique, heterodyne CCD fluorescence mediated tomography, is a non-invasive biomedical imaging that uses fluorescent photons from the targeted dye on the tumor cells inside human breast tissue. The technique detects a large volume of tissue (20 cm) with a moderate resolution (1 mm) and provides the high sensitivity. The second technique, dual-band spectral-domain optical coherence tomography, is a high-resolution tissue imaging modality. It uses a low coherence interferometer to detect coherent photons hidden in the incoherent background. Due to the coherence detection, a high resolution (20 microns) is possible. We have finished prototype imaging systems for the development of both image modalities and performed imaging experiments on tumor tissues. The spectroscopic/tomographic images show contrasts of dense tumor tissues and tumor necrotic regions. In order to correlate the findings from our results, a diffusion-weighted magnetic resonance imaging (MRI) of the tumors was performed using a small animal 7-Telsa MRI and demonstrated excellent agreement.

64Cu-PSMA-617: A novel PSMA-targeted radio-tracer for PET imaging in gastric adenocarcinoma xenografted mice model.

PubMed

Han, Xue-Di; Liu, Chen; Liu, Fei; Xie, Qing-Hua; Liu, Te-Li; Guo, Xiao-Yi; Xu, Xiao-Xia; Yang, Xing; Zhu, Hua; Yang, Zhi

2017-09-26

Here, we report that it's feasible for imaging gastric adenocarcinoma mice model with prostate-specific membrane antigen (PSMA) targeting imaging agents, which could potentially provide an alternate and readily translational tool for managing gastric adenocarcinoma. DKFZ-PSMA-617, a PSMA targeting ligand reported recently, was chosen to be radio-labeled with nuclide 64 Cu. 64 Cu-PSMA-617 was radio-synthesized in high radio-chemical yield and specific activity up to 19.3 GBq/µmol. It showed good stability in vitro . The specificity of 64 Cu-PSMA-617 was confirmed by cell uptake experiments in PSMA (+) LNCaP cell and PSMA (-) PC-3 and gastric adenocarcinoma BGC-823 cells. Micro-PET imaging in BGC-823 and PC-3 xenografts nude mice was evaluated ( n = 4). And the tumors were visualized and better tumor-to-background achieved till 24 h. Co-administration of N- [[[(1S)-1-Carboxy-3-methylbutyl]amino]-carbonyl]-L-glutamic acid (ZJ-43) can substantially block the uptake in those tumors. Dissected tumor tissues were analyzed by auto-radiography and immunohistochemistry, and these results confirmed the PSMA expression in neo-vasculature which explained the target molecular imaging of 64 Cu-PSMA-617. All those results suggested 64 Cu-PSMA-617 may serve as a novel radio-tracer for tumor imaging more than prostate cancer.

64Cu-PSMA-617: A novel PSMA-targeted radio-tracer for PET imaging in gastric adenocarcinoma xenografted mice model

PubMed Central

Han, Xue-Di; Liu, Chen; Liu, Fei; Xie, Qing-Hua; Liu, Te-Li; Guo, Xiao-Yi; Xu, Xiao-Xia; Yang, Xing; Zhu, Hua; Yang, Zhi

2017-01-01

Here, we report that it’s feasible for imaging gastric adenocarcinoma mice model with prostate-specific membrane antigen (PSMA) targeting imaging agents, which could potentially provide an alternate and readily translational tool for managing gastric adenocarcinoma. DKFZ-PSMA-617, a PSMA targeting ligand reported recently, was chosen to be radio-labeled with nuclide 64Cu. 64Cu-PSMA-617 was radio-synthesized in high radio-chemical yield and specific activity up to 19.3 GBq/µmol. It showed good stability in vitro. The specificity of 64Cu-PSMA-617 was confirmed by cell uptake experiments in PSMA (+) LNCaP cell and PSMA (-) PC-3 and gastric adenocarcinoma BGC-823 cells. Micro-PET imaging in BGC-823 and PC-3 xenografts nude mice was evaluated (n = 4). And the tumors were visualized and better tumor-to-background achieved till 24 h. Co-administration of N- [[[(1S)-1-Carboxy-3-methylbutyl]amino]-carbonyl]-L-glutamic acid (ZJ-43) can substantially block the uptake in those tumors. Dissected tumor tissues were analyzed by auto-radiography and immunohistochemistry, and these results confirmed the PSMA expression in neo-vasculature which explained the target molecular imaging of 64Cu-PSMA-617. All those results suggested 64Cu-PSMA-617 may serve as a novel radio-tracer for tumor imaging more than prostate cancer. PMID:29088775

A novel solid lipid nanoparticle formulation for active targeting to tumor α(v) β(3) integrin receptors reveals cyclic RGD as a double-edged sword.

PubMed

Shuhendler, Adam J; Prasad, Preethy; Leung, Michael; Rauth, Andrew M; Dacosta, Ralph S; Wu, Xiao Yu

2012-09-01

The overexpression of α(v) β(3) integrin receptors on tumor cells and tumor vascular endothelium makes it a useful target for imaging, chemotherapy and anti-angiogenic therapy. However integrin-targeted delivery of therapeutics by nanoparticles have provided only marginal, if any, enhancement of therapeutic effect. This work was thus focused on the development of novel α(v) β(3) -targeted near infrared light-emitting solid lipid nanoparticles (SLN) through conjugation to the α(v) β(3) integrin-specific ligand cyclic Arg-Gly-Asp (cRGD), and the assessment of the effects of α(v) β(3) targeting on nanoparticle biodistribution. Since our previously developed non-targeted "stealth" SLN showed little hepatic accumulation, unlike most reported liposomes and micelles, they served as a reference for quantifying the effects of cRGD-conjugation on tumor uptake and whole animal biodistribution of SLN. Non-targeted SLN, actively targeted (RGD-SLN) and blocked RGD-SLN were prepared to contain near infrared quantum dots for live animal imaging. They were injected intravenously to nude mice bearing xenograft orthotopic human breast tumors or dorsal window chamber breast tumors. Tumor micropharmacokinetics of various SLN formulations were determined using intravital microscopy, and whole animal biodistribution was followed over time by optical imaging. The active tumor targeting with cRGD was found to be a "double-edged sword": while the specificity of RGD-SLN accumulation in tumor blood vessels and their tumor residence time increased, their distribution in the liver, spleen, and kidneys was significantly greater than the non-targeted SLN, leaving a smaller amount of nanoparticles in the tumor tissue. Nevertheless the enhanced specificity and retention of RGD-SLN in tumor neovasculature could make this novel formulation useful for tumor neovascular-specific therapies and imaging applications. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Emotion Modulation of Visual Attention: Categorical and Temporal Characteristics

PubMed Central

Ciesielski, Bethany G.; Armstrong, Thomas; Zald, David H.; Olatunji, Bunmi O.

2010-01-01

Background Experimental research has shown that emotional stimuli can either enhance or impair attentional performance. However, the relative effects of specific emotional stimuli and the specific time course of these differential effects are unclear. Methodology/Principal Findings In the present study, participants (n = 50) searched for a single target within a rapid serial visual presentation of images. Irrelevant fear, disgust, erotic or neutral images preceded the target by two, four, six, or eight items. At lag 2, erotic images induced the greatest deficits in subsequent target processing compared to other images, consistent with a large emotional attentional blink. Fear and disgust images also produced a larger attentional blinks at lag 2 than neutral images. Erotic, fear, and disgust images continued to induce greater deficits than neutral images at lag 4 and 6. However, target processing deficits induced by erotic, fear, and disgust images at intermediate lags (lag 4 and 6) did not consistently differ from each other. In contrast to performance at lag 2, 4, and 6, enhancement in target processing for emotional stimuli was observed in comparison to neutral stimuli at lag 8. Conclusions/Significance These findings suggest that task-irrelevant emotion information, particularly erotica, impairs intentional allocation of attention at early temporal stages, but at later temporal stages, emotional stimuli can have an enhancing effect on directed attention. These data suggest that the effects of emotional stimuli on attention can be both positive and negative depending upon temporal factors. PMID:21079773

Comparison of Kinetic Models for Dual-Tracer Receptor Concentration Imaging in Tumors

PubMed Central

Hamzei, Nazanin; Samkoe, Kimberley S; Elliott, Jonathan T; Holt, Robert W; Gunn, Jason R; Hasan, Tayyaba; Pogue, Brian W; Tichauer, Kenneth M

2014-01-01

Molecular differences between cancerous and healthy tissue have become key targets for novel therapeutics specific to tumor receptors. However, cancer cell receptor expression can vary within and amongst different tumors, making strategies that can quantify receptor concentration in vivo critical for the progression of targeted therapies. Recently a dual-tracer imaging approach capable of providing quantitative measures of receptor concentration in vivo was developed. It relies on the simultaneous injection and imaging of receptor-targeted tracer and an untargeted tracer (to account for non-specific uptake of the targeted tracer). Early implementations of this approach have been structured on existing “reference tissue” imaging methods that have not been optimized for or validated in dual-tracer imaging. Using simulations and mouse tumor model experimental data, the salient findings in this study were that all widely used reference tissue kinetic models can be used for dual-tracer imaging, with the linearized simplified reference tissue model offering a good balance of accuracy and computational efficiency. Moreover, an alternate version of the full two-compartment reference tissue model can be employed accurately by assuming that the K1s of the targeted and untargeted tracers are similar to avoid assuming an instantaneous equilibrium between bound and free states (made by all other models). PMID:25414912

Imaging specific cellular glycan structures using glycosyltransferases via click chemistry.

PubMed

Wu, Zhengliang L; Person, Anthony D; Anderson, Matthew; Burroughs, Barbara; Tatge, Timothy; Khatri, Kshitij; Zou, Yonglong; Wang, Lianchun; Geders, Todd; Zaia, Joseph; Sackstein, Robert

2018-02-01

Heparan sulfate (HS) is a polysaccharide fundamentally important for biologically activities. T/Tn antigens are universal carbohydrate cancer markers. Here, we report the specific imaging of these carbohydrates using a mesenchymal stem cell line and human umbilical vein endothelial cells (HUVEC). The staining specificities were demonstrated by comparing imaging of different glycans and validated by either removal of target glycans, which results in loss of signal, or installation of target glycans, which results in gain of signal. As controls, representative key glycans including O-GlcNAc, lactosaminyl glycans and hyaluronan were also imaged. HS staining revealed novel architectural features of the extracellular matrix (ECM) of HUVEC cells. Results from T/Tn antigen staining suggest that O-GalNAcylation is a rate-limiting step for O-glycan synthesis. Overall, these highly specific approaches for HS and T/Tn antigen imaging should greatly facilitate the detection and functional characterization of these biologically important glycans. © The Author(s) 2017. Published by Oxford University Press.

64Cu-Labeled multifunctional dendrimers for targeted tumor PET imaging.

PubMed

Ma, Wenhui; Fu, Fanfan; Zhu, Jingyi; Huang, Rui; Zhu, Yizhou; Liu, Zhenwei; Wang, Jing; Conti, Peter S; Shi, Xiangyang; Chen, Kai

2018-03-29

We report the use of multifunctional folic acid (FA)-modified dendrimers as a platform to radiolabel with 64Cu for PET imaging of folate receptor (FR)-expressing tumors. In this study, amine-terminated generation 5 (G5) poly(amidoamine) dendrimers were sequentially modified with fluorescein isothiocyanate (FI), FA, and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), followed by acetylation of the remaining dendrimer terminal amines. The as-formed multifunctional DOTA-FA-FI-G5·NHAc dendrimers were then radiolabeled with 64Cu via the DOTA chelation. We show that the FA modification renders the dendrimers with targeting specificity to cancer cells overexpressing FR in vitro. Importantly, the radiolabeled 64Cu-DOTA-FA-FI-G5·NHAc dendrimers can be used as a nanoprobe for specific targeting of FR-overexpressing cancer cells in vitro and targeted microPET imaging of the FR-expressing xenografted tumor model in vivo. The developed 64Cu-labeled multifunctional dendrimeric nanoprobe may hold great promise to be used for targeted PET imaging of different types of FR-expressing cancer.

Magnetic Gold Nanoparticle-Labeled Heparanase Monoclonal Antibody and its Subsequent Application for Tumor Magnetic Resonance Imaging

NASA Astrophysics Data System (ADS)

Li, Ning; Jie, Meng-Meng; Yang, Min; Tang, Li; Chen, Si-Yuan; Sun, Xue-Mei; Tang, Bo; Yang, Shi-Ming

2018-04-01

Heparanase (HPA) is ubiquitously expressed in various metastatic malignant tumors; previous studies have demonstrated that HPA was a potential tumor-associated antigen (TAA) for tumor immunotherapy. We sought to evaluate the feasibility of HPA as a common TAA for magnetic resonance imaging (MRI) of tumor metastasis and its potential application in tumor molecular imaging. We prepared a targeted probe based on magnetic gold nanoparticles coupled with an anti-HPA antibody for the specific detection of HPA by MRI. The specificity of the targeted probe was validated in vitro by incubation of the probe with various tumor cells, and the probe was able to selectively detect HPA (+) cells. We found the probes displayed significantly reduced signal intensity in several tumor cells, and the signal intensity decreased significantly after the targeted probe was injected in tumor-bearing nude mice. In the study, we demonstrated that the HPA&GoldMag probe had excellent physical and chemical properties and immune activities and could specifically target many tumor cell tissues both in vitro and in vivo. This may provide an experimental base for molecular imaging of tumor highly expressing heparanase using HPA mAbs.

Phosphatidylserine-targeted liposome for enhanced glioma-selective imaging.

PubMed

Zhang, Liang; Habib, Amyn A; Zhao, Dawen

2016-06-21

Phosphatidylserine (PS), which is normally intracellular, becomes exposed on the outer surface of viable endothelial cells (ECs) of tumor vasculature. Utilizing a PS-targeting antibody, we have recently established a PS-targeted liposomal (PS-L) nanoplatform that has demonstrated to be highly tumor-selective. Because of the vascular lumen-exposed PS that is immediately accessible without a need to penetrate the intact blood brain barrier (BBB), we hypothesize that the systemically administered PS-L binds specifically to tumor vascular ECs, becomes subsequently internalized into the cells and then enables its cargos to be efficiently delivered to glioma parenchyma. To test this, we exploited the dual MRI/optical imaging contrast agents-loaded PS-L and injected it intravenously into mice bearing intracranial U87 glioma. At 24 h, both in vivo optical imaging and MRI depicted enhanced tumor contrast, distinct from the surrounding normal brain. Intriguingly, longitudinal MRI revealed temporal and spatial intratumoral distribution of the PS-L by following MRI contrast changes, which appeared punctate in tumor periphery at an earlier time point (4 h), but became clustering and disseminated throughout the tumor at 24 h post injection. Importantly, glioma-targeting specificity of the PS-L was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the glioma. Together, these results indicate that the PS-L nanoplatform enables the enhanced, glioma-targeted delivery of imaging contrast agents by crossing the tumor BBB efficiently, which may also serve as a useful nanoplatform for anti-glioma drugs.

Fluorescence in vivo imaging of live tumor cells with pH-activatable targeted probes via receptor-mediated endocytosis

NASA Astrophysics Data System (ADS)

Asanuma, Daisuke; Urano, Yasuteru; Nagano, Tetsuo; Hama, Yukihiro; Koyama, Yoshinori; Kobayashi, Hisataka

2009-02-01

One goal of molecular imaging is to establish a widely applicable technique for specific detection of tumors with minimal background. Here, we achieve specific in vivo tumor visualization with a newly-designed "activatable" targeted fluorescence probe. This agent is activated after cellular internalization by sensing the pH change in the lysosome. Novel acidic pH-activatable probes based on the BODIPY fluorophore were synthesized, and then conjugated to a cancer-targeting monoclonal antibody, Trastuzumab, or galactosyl serum albumin (GSA). As proof of concept, ex and in vivo imaging of two different tumor mouse models was performed: HER2-overexpressed lung metastasis tumor with Trastuzumab-pH probe conjugates and lectin-overexpressed i.p. disseminated tumor with GSA-pH probe conjugates. These pH-activatable targeted probes were highly specific for tumors with minimal background signal. Because the acidic pH in lysosomes is maintained by the energy-consuming proton pump, only viable cancer cells were successfully visualized. Furthermore, this strategy was also applied to fluorescence endoscopy in tumor mouse models, resulting in specific visualization of tumors as small as submillimeter in size that could hardly detected by naked eyes because of their poor contrast against normal tissues. The design concept can be widely adapted to cancer-specific cell-surface-targeting molecules that result in cellular internalization.

Nanoparticle imaging probes for molecular imaging with computed tomography and application to cancer imaging

NASA Astrophysics Data System (ADS)

Roeder, Ryan K.; Curtis, Tyler E.; Nallathamby, Prakash D.; Irimata, Lisa E.; McGinnity, Tracie L.; Cole, Lisa E.; Vargo-Gogola, Tracy; Cowden Dahl, Karen D.

2017-03-01

Precision imaging is needed to realize precision medicine in cancer detection and treatment. Molecular imaging offers the ability to target and identify tumors, associated abnormalities, and specific cell populations with overexpressed receptors. Nuclear imaging and radionuclide probes provide high sensitivity but subject the patient to a high radiation dose and provide limited spatiotemporal information, requiring combined computed tomography (CT) for anatomic imaging. Therefore, nanoparticle contrast agents have been designed to enable molecular imaging and improve detection in CT alone. Core-shell nanoparticles provide a powerful platform for designing tailored imaging probes. The composition of the core is chosen for enabling strong X-ray contrast, multi-agent imaging with photon-counting spectral CT, and multimodal imaging. A silica shell is used for protective, biocompatible encapsulation of the core composition, volume-loading fluorophores or radionuclides for multimodal imaging, and facile surface functionalization with antibodies or small molecules for targeted delivery. Multi-agent (k-edge) imaging and quantitative molecular imaging with spectral CT was demonstrated using current clinical agents (iodine and BaSO4) and a proposed spectral library of contrast agents (Gd2O3, HfO2, and Au). Bisphosphonate-functionalized Au nanoparticles were demonstrated to enhance sensitivity and specificity for the detection of breast microcalcifications by conventional radiography and CT in both normal and dense mammary tissue using murine models. Moreover, photon-counting spectral CT enabled quantitative material decomposition of the Au and calcium signals. Immunoconjugated Au@SiO2 nanoparticles enabled highly-specific targeting of CD133+ ovarian cancer stem cells for contrast-enhanced detection in model tumors.

Fluorescent probes for nucleic Acid visualization in fixed and live cells.

PubMed

Boutorine, Alexandre S; Novopashina, Darya S; Krasheninina, Olga A; Nozeret, Karine; Venyaminova, Alya G

2013-12-11

This review analyses the literature concerning non-fluorescent and fluorescent probes for nucleic acid imaging in fixed and living cells from the point of view of their suitability for imaging intracellular native RNA and DNA. Attention is mainly paid to fluorescent probes for fluorescence microscopy imaging. Requirements for the target-binding part and the fluorophore making up the probe are formulated. In the case of native double-stranded DNA, structure-specific and sequence-specific probes are discussed. Among the latest, three classes of dsDNA-targeting molecules are described: (i) sequence-specific peptides and proteins; (ii) triplex-forming oligonucleotides and (iii) polyamide oligo(N-methylpyrrole/N-methylimidazole) minor groove binders. Polyamides seem to be the most promising targeting agents for fluorescent probe design, however, some technical problems remain to be solved, such as the relatively low sequence specificity and the high background fluorescence inside the cells. Several examples of fluorescent probe applications for DNA imaging in fixed and living cells are cited. In the case of intracellular RNA, only modified oligonucleotides can provide such sequence-specific imaging. Several approaches for designing fluorescent probes are considered: linear fluorescent probes based on modified oligonucleotide analogs, molecular beacons, binary fluorescent probes and template-directed reactions with fluorescence probe formation, FRET donor-acceptor pairs, pyrene excimers, aptamers and others. The suitability of all these methods for living cell applications is discussed.

A Novel ¹¹¹In-Labeled Anti-Prostate-Specific Membrane Antigen Nanobody for Targeted SPECT/CT Imaging of Prostate Cancer.

PubMed

Chatalic, Kristell L S; Veldhoven-Zweistra, Joke; Bolkestein, Michiel; Hoeben, Sander; Koning, Gerben A; Boerman, Otto C; de Jong, Marion; van Weerden, Wytske M

2015-07-01

Prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer (PCa) and a promising target for molecular imaging and therapy. Nanobodies (single-domain antibodies, VHH) are the smallest antibody-based fragments possessing ideal molecular imaging properties, such as high target specificity and rapid background clearance. We developed a novel anti-PSMA Nanobody (JVZ-007) for targeted imaging and therapy of PCa. Here, we report on the application of the (111)In-radiolabeled Nanobody for SPECT/CT imaging of PCa. A Nanobody library was generated by immunization of a llama with 4 human PCa cell lines. Anti-PSMA Nanobodies were captured by biopanning on PSMA-overexpressing cells. JVZ-007 was selected for evaluation as an imaging probe. JVZ-007 was initially produced with a c-myc-hexahistidine (his) tag allowing purification and detection. The c-myc-his tag was subsequently replaced by a single cysteine at the C terminus, allowing site-specific conjugation of chelates for radiolabeling. JVZ-007-c-myc-his was conjugated to 2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid (p-SCN-DTPA) via the lysines, whereas JVZ-007-cys was conjugated to maleimide-DTPA via the C-terminal cysteine. PSMA targeting was analyzed in vitro by cell-binding experiments using flow cytometry, autoradiography, and internalization assays with various PCa cell lines and patient-derived xenografts (PDXs). The targeting properties of radiolabeled Nanobodies were evaluated in vivo in biodistribution and SPECT/CT imaging experiments, using nude mice bearing PSMA-positive PC-310 and PSMA-negative PC-3 tumors. JVZ-007 was successfully conjugated to DTPA for radiolabeling with (111)In at room temperature. (111)In-JVZ007-c-myc-his and (111)In-JVZ007-cys internalized in LNCaP cells and bound to PSMA-expressing PDXs and, importantly, not to PSMA-negative PDXs and human kidneys. Good tumor targeting and fast blood clearance were observed for (111)In-JVZ-007-c-myc-his and (111)In-JVZ-007-cys. Renal uptake of (111)In-JVZ-007-c-myc-his was initially high but was efficiently reduced by coinjection of gelofusine and lysine. The replacement of the c-myc-his tag by the cysteine contributed to a further reduction of renal uptake without loss of targeting. PC-310 tumors were clearly visualized by SPECT/CT with both tracers, with low renal uptake (<4 percentage injected dose per gram) for (111)In-JVZ-007-cys already at 3 h after injection. We developed an (111)In-radiolabeled anti-PSMA Nanobody, showing good tumor targeting, low uptake in nontarget tissues, and low renal retention, allowing excellent SPECT/CT imaging of PCa within a few hours after injection. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Targeted Nuclear Imaging Probes for Cardiac Amyloidosis.

PubMed

Bravo, Paco E; Dorbala, Sharmila

2017-07-01

The aim of the present manuscript is to review the latest advancements of radionuclide molecular imaging in the diagnosis and prognosis of individuals with cardiac amyloidosis. 99m Technetium labeled bone tracer scintigraphy had been known to image cardiac amyloidosis, since the 1980s; over the past decade, bone scintigraphy has been revived specifically to diagnose transthyretin cardiac amyloidosis. 18 F labeled and 11 C labeled amyloid binding radiotracers developed for imaging Alzheimer's disease, have been repurposed since 2013, to image light chain and transthyretin cardiac amyloidosis. 99m Technetium bone scintigraphy for transthyretin cardiac amyloidosis, and amyloid binding targeted PET imaging for light chain and transthyretin cardiac amyloidosis, are emerging as highly accurate methods. Targeted radionuclide imaging may soon replace endomyocardial biopsy in the evaluation of patients with suspected cardiac amyloidosis. Further research is warranted on the role of targeted imaging to quantify cardiac amyloidosis and to guide therapy.

Incorporate Imaging Characteristics Into an Arteriovenous Malformation Radiosurgery Plan Evaluation Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Pengpeng; Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY; Wu, Leester

Purpose: To integrate imaging performance characteristics, specifically sensitivity and specificity, of magnetic resonance angiography (MRA) and digital subtraction angiography (DSA) into arteriovenous malformation (AVM) radiosurgery planning and evaluation. Methods and Materials: Images of 10 patients with AVMs located in critical brain areas were analyzed in this retrospective planning study. The image findings were first used to estimate the sensitivity and specificity of MRA and DSA. Instead of accepting the imaging observation as a binary (yes or no) mapping of AVM location, our alternative is to translate the image into an AVM probability distribution map by incorporating imagers' sensitivity and specificity,more » and to use this map as a basis for planning and evaluation. Three sets of radiosurgery plans, targeting the MRA and DSA positive overlap, MRA positive, and DSA positive were optimized for best conformality. The AVM obliteration rate (ORAVM) and brain complication rate served as endpoints for plan comparison. Results: In our 10-patient study, the specificities and sensitivities of MRA and DSA were estimated to be (0.95, 0.74) and (0.71, 0.95), respectively. The positive overlap of MRA and DSA accounted for 67.8% {+-} 4.9% of the estimated true AVM volume. Compared with plans targeting MRA and DSA-positive overlap, plans targeting MRA-positive or DSA-positive improved ORAVM by 4.1% {+-} 1.9% and 15.7% {+-} 8.3%, while also increasing the complication rate by 1.0% {+-} 0.8% and 4.4% {+-} 2.3%, respectively. Conclusions: The impact of imagers' quality should be quantified and incorporated in AVM radiosurgery planning and evaluation to facilitate clinical decision making.« less

Future and Advances in Endoscopy

PubMed Central

Elahi, Sakib F.; Wang, Thomas D.

2012-01-01

The future of endoscopy will be dictated by rapid technological advances in the development of light sources, optical fibers, and miniature scanners that will allow for images to be collected in multiple spectral regimes, with greater tissue penetration, and in three dimensions. These engineering breakthroughs will be integrated with novel molecular probes that are highly specific for unique proteins to target diseased tissues. Applications include early cancer detection by imaging molecular changes that occur before gross morphological abnormalities, personalized medicine by visualizing molecular targets specific to individual patients, and image guided therapy by localizing tumor margins and monitoring for recurrence. PMID:21751414

Cranial nerve contrast using nerve-specific fluorophores improved by paired-agent imaging with indocyanine green as a control agent

NASA Astrophysics Data System (ADS)

Torres, Veronica C.; Vuong, Victoria D.; Wilson, Todd; Wewel, Joshua; Byrne, Richard W.; Tichauer, Kenneth M.

2017-09-01

Nerve preservation during surgery is critical because damage can result in significant morbidity. This remains a challenge especially for skull base surgeries where cranial nerves (CNs) are involved because visualization and access are particularly poor in that location. We present a paired-agent imaging method to enhance identification of CNs using nerve-specific fluorophores. Two myelin-targeting imaging agents were evaluated, Oxazine 4 and Rhodamine 800, and coadministered with a control agent, indocyanine green, either intravenously or topically in rats. Fluorescence imaging was performed on excised brains ex vivo, and nerve contrast was evaluated via paired-agent ratiometric data analysis. Although contrast was improved among all experimental groups using paired-agent imaging compared to conventional, solely targeted imaging, Oxazine 4 applied directly exhibited the greatest enhancement, with a minimum 3 times improvement in CNs delineation. This work highlights the importance of accounting for nonspecific signal of targeted agents, and demonstrates that paired-agent imaging is one method capable of doing so. Although staining, rinsing, and imaging protocols need to be optimized, these findings serve as a demonstration for the potential use of paired-agent imaging to improve contrast of CNs, and consequently, surgical outcome.

Imaging of Tumor Characteristics and Molecular Pathways With PET: Developments Over the Last Decade Toward Personalized Cancer Therapy.

PubMed

Marcu, Loredana Gabriela; Moghaddasi, Leyla; Bezak, Eva

2018-05-04

Improvements in personalized therapy are made possible by the advances in molecular biology that led to developments in molecular imaging, allowing highly specific in vivo imaging of biological processes. Positron emission tomography (PET) is the most specific and sensitive imaging technique for in vivo molecular targets and pathways, offering quantification and evaluation of functional properties of the targeted anatomy. This work is an integrative research review that summarizes and evaluates the accumulated current status of knowledge of recent advances in PET imaging for cancer diagnosis and treatment, concentrating on novel radiotracers and evaluating their advantages and disadvantages in cancer characterization. Medline search was conducted, limited to English publications from 2007 onward. Identified manuscripts were evaluated for most recent developments in PET imaging of cancer hypoxia, angiogenesis, proliferation, and clonogenic cancer stem cells (CSC). There is an expansion observed from purely metabolic-based PET imaging toward antibody-based PET to achieve more information on cancer characteristics to identify hypoxia, proangiogenic factors, CSC, and others. 64 Cu-ATSM, for example, can be used both as a hypoxia and a CSC marker. Progress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life. Copyright © 2018 Elsevier Inc. All rights reserved.

Screening phage display libraries for organ-specific vascular immunotargeting in vivo

PubMed Central

Valadon, Philippe; Garnett, Jeff D.; Testa, Jacqueline E.; Bauerle, Marc; Oh, Phil; Schnitzer, Jan E.

2006-01-01

The molecular diversity of the luminal endothelial cell surface arising in vivo from local variations in genetic expression and tissue microenvironment may create opportunities for achieving targeted molecular imaging and therapies. Here, we describe a strategy to identify probes and their cognate antigens for targeting vascular endothelia of specific organs in vivo. We differentially screen phage libraries to select organ-targeting antibodies by using luminal endothelial cell plasma membranes isolated directly from tissue and highly enriched in natively expressed proteins exposed to the bloodstream. To obviate liver uptake of intravenously injected phage, we convert the phage-displayed antibodies into scFv-Fc fusion proteins, which then are able to rapidly target select organ(s) in vivo as visualized directly by γ-scintigraphic whole-body imaging. Mass spectrometry helps identify the antigen targets. This comprehensive strategy provides new promise for harnessing the power of phage display for mapping vascular endothelia natively in tissue and for achieving vascular targeting of specific tissues in vivo. PMID:16384919

Folic acid-functionalized up-conversion nanoparticles: toxicity studies in vivo and in vitro and targeted imaging applications

NASA Astrophysics Data System (ADS)

Sun, Lining; Wei, Zuwu; Chen, Haige; Liu, Jinliang; Guo, Jianjian; Cao, Ming; Wen, Tieqiao; Shi, Liyi

2014-07-01

Folate receptors (FRs) are overexpressed on a variety of human cancer cells and tissues, including cancers of the breast, ovaries, endometrium, and brain. This over-expression of FRs can be used to target folate-linked imaging specifically to FR-expressing tumors. Fluorescence is emerging as a powerful new modality for molecular imaging in both the diagnosis and treatment of disease. Combining innovative molecular biology and chemistry, we prepared three kinds of folate-targeted up-conversion nanoparticles as imaging agents (UCNC-FA: UCNC-Er-FA, UCNC-Tm-FA, and UCNC-Er,Tm-FA). In vivo and in vitro toxicity studies showed that these nanoparticles have both good biocompatibility and low toxicity. Moreover, the up-conversion luminescence imaging indicated that they have good targeting to HeLa cells and can therefore serve as potential fluorescent contrast agents.Folate receptors (FRs) are overexpressed on a variety of human cancer cells and tissues, including cancers of the breast, ovaries, endometrium, and brain. This over-expression of FRs can be used to target folate-linked imaging specifically to FR-expressing tumors. Fluorescence is emerging as a powerful new modality for molecular imaging in both the diagnosis and treatment of disease. Combining innovative molecular biology and chemistry, we prepared three kinds of folate-targeted up-conversion nanoparticles as imaging agents (UCNC-FA: UCNC-Er-FA, UCNC-Tm-FA, and UCNC-Er,Tm-FA). In vivo and in vitro toxicity studies showed that these nanoparticles have both good biocompatibility and low toxicity. Moreover, the up-conversion luminescence imaging indicated that they have good targeting to HeLa cells and can therefore serve as potential fluorescent contrast agents. Electronic supplementary information (ESI) available: Up-conversion luminescence spectra of UCNC-Er and UCNC-Er-FA, UCNC-Tm and UCNC-Tm-FA. Confocal luminescence imaging data collected as a series along the Z optical axis. See DOI: 10.1039/c4nr02312a

Discriminating crop and other canopies by overlapping binary image layers

NASA Astrophysics Data System (ADS)

Doi, Ryoichi

2013-02-01

For optimal management of agricultural fields by remote sensing, discrimination of the crop canopy from weeds and other objects is essential. In a digital photograph, a rice canopy was discriminated from a variety of weed and tree canopies and other objects by overlapping binary image layers of red-green-blue and other color components indicating the pixels with target canopy-specific (intensity) values based on the ranges of means ±(3×) standard deviations. By overlapping and merging the binary image layers, the target canopy specificity improved to 0.0015 from 0.027 for the yellow 1× standard deviation binary image layer, which was the best among all combinations of color components and means ±(3×) standard deviations. The most target rice canopy-likely pixels were further identified by limiting the pixels at different luminosity values. The discriminatory power was also visually demonstrated in this manner.

Galactosylated magnetic nanovectors for regulation of lipid metabolism based on biomarker-specific RNAi and MR imaging.

PubMed

Heo, Dan; Lee, Chanjoo; Ku, Minhee; Haam, Seungjoo; Suh, Jin-Suck; Huh, Yong-Min; Park, Sahng Wook; Yang, Jaemoon

2015-08-21

The specific delivery of ribonucleic acid (RNA) interfering molecules to disease-related cells is still a critical blockade for in vivo systemic treatment. Here, this study suggests a robust delivery carrier for targeted delivery of RNA-interfering molecules using galactosylated magnetic nanovectors (gMNVs). gMNVs are an organic-inorganic polymeric nanomaterial composed of polycationics and magnetic nanocrystal for delivery of RNA-interfering molecules and tracking via magnetic resonance (MR) imaging. In particular, the surface of gMNVs was modified by galactosylgluconic groups for targeted delivering to asialoglycoprotein receptor (ASGPR) of hepatocytes. Moreover, the small interfering RNAs were used to regulate target proteins related with low-density lipoprotein level and in vivo MR imaging was conducted for tracking of nanovectors. The obtained results show that the prepared gMNVs demonstrate potential as a systemic theragnostic nanoplatform for RNA interference and MR imaging.

Cetuximab-conjugated nanodiamonds drug delivery system for enhanced targeting therapy and 3D Raman imaging.

PubMed

Li, Dandan; Chen, Xin; Wang, Hong; Liu, Jie; Zheng, Meiling; Fu, Yang; Yu, Yuan; Zhi, Jinfang

2017-12-01

In this study, a multicomponent nanodiamonds (NDs)-based targeting drug delivery system, cetuximab-NDs-cisplatin bioconjugate, combining both specific targeting and enhanced therapeutic efficacy capabilities, is developed and characterized. The specific targeting ability of cetuximab-NDs-cisplatin system on human liver hepatocellular carcinoma (HepG2) cells is evaluated through epidermal growth factor receptor (EGFR) blocking experiments, since EGFR is over-expressed on HepG2 cell membrane. Besides, cytotoxic evaluation confirms that cetuximab-NDs-cisplatin system could significantly inhibit the growth of HepG2 cells, and the therapeutic activity of this system is proven to be better than that of both nonspecific NDs-cisplatin conjugate and specific EGF-NDs-cisplatin conjugate. Furthermore, a 3-dimensional (3D) Raman imaging technique is utilized to visualize the targeting efficacy and enhanced internalization of cetuximab-NDs-cisplatin system in HepG2 cells, using the NDs existing in the bioconjugate as Raman probes, based on the characteristic Raman signal of NDs at 1332 cm -1 . These advantageous properties of cetuximab-NDs-cisplatin system propose a prospective imaging and treatment tool for further diagnostic and therapeutic purposes. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Aptamer-conjugated Magnetic Nanoparticles as Targeted Magnetic Resonance Imaging Contrast Agent for Breast Cancer.

PubMed

Keshtkar, Mohammad; Shahbazi-Gahrouei, Daryoush; Khoshfetrat, Seyyed Mehdi; Mehrgardi, Masoud A; Aghaei, Mahmoud

2016-01-01

Early detection of breast cancer is the most effective way to improve the survival rate in women. Magnetic resonance imaging (MRI) offers high spatial resolution and good anatomic details, and its lower sensitivity can be improved by using targeted molecular imaging. In this study, AS1411 aptamer was conjugated to Fe 3 O 4 @Au nanoparticles for specific targeting of mouse mammary carcinoma (4T1) cells that overexpress nucleolin. In vitro cytotoxicity of aptamer-conjugated nanoparticles was assessed on 4T1 and HFFF-PI6 (control) cells. The ability of the synthesized nanoprobe to target specifically the nucleolin overexpressed cells was assessed with the MRI technique. Results show that the synthesized nanoprobe produced strongly darkened T 2 -weighted magnetic resonance (MR) images with 4T1 cells, whereas the MR images of HFFF-PI6 cells incubated with the nanoprobe are brighter, showing small changes compared to water. The results demonstrate that in a Fe concentration of 45 μg/mL, the nanoprobe reduced by 90% MR image intensity in 4T1 cells compared with the 27% reduction in HFFF-PI6 cells. Analysis of MR signal intensity showed statistically significant signal intensity difference between 4T1 and HFFF-PI6 cells treated with the nanoprobe. MRI experiments demonstrate the high potential of the synthesized nanoprobe as a specific MRI contrast agent for detection of nucleolin-expressing breast cancer cells.

Early detection of ovarian cancer by serum marker and targeted ultrasound imaging | Division of Cancer Prevention

Cancer.gov

We propose to test the validity and specificity of our targeted ultrasound imaging probes in detecting early stage ovarian cancer (OVCA) by transvaginal ultrasound imaging (TVUS). We then test the predictive validity of these probes in a longitudinal study using the laying hen – the only widely available animal model of spontaneous OVCA. OVCA is a fatal gynecological

Activateable Imaging Probes Light Up Inside Cancer Cells | Center for Cancer Research

Cancer.gov

Imaging can be used to help diagnose cancer as well as monitor tumor progression and response to treatment. The field of molecular imaging focuses on techniques capable of detecting specific molecular targets associated with cancer; the agents used for molecular imaging—often called probes—are multifunctional, with components that allow them to both interact with their molecular target and emit a detectable signal.

Assessment of α-fetoprotein targeted HSV1-tk expression in hepatocellular carcinoma with in vivo imaging.

PubMed

Park, Ju Hui; Kim, Kwang Il; Lee, Kyo Chul; Lee, Yong Jin; Lee, Tae Sup; Chung, Wee Sup; Lim, Sang Moo; Kang, Joo Hyun

2015-02-01

Tumor-specific enhancer/promoter is applicable for targeting gene expression in tumors and helpful for tumor-targeting imaging and therapy. We aimed to acquire α-fetoprotein (AFP)-producing hepatocellular carcinoma (HCC) specific images using adenovirus containing HSV1-tk gene controlled by AFP enhancer/promoter and evaluate in vivo ganciclovir (GCV)-medicated therapeutic effects on AFP-targeted HSV1-tk expression with (18)F-FDG positron emission tomography (PET). Recombinant adenovirus expressing HSV1-tk under AFP enhancer/promoter was produced (AdAFP-TK) and the expression levels were evaluated by RT-PCR and (125)I-IVDU uptake. GCV-mediated HSV1-tk cytotoxicity was determined by MTT assay. After the mixture of AdAFP-fLuc and AdAFP-TK was administrated, bioluminescent images (BLIs) and (18)F-FHBG PET images were obtained in tumor-bearing mice. In vivo therapeutic effects of AdAFP-TK and GCV in the HuH-7 xenograft model were monitored by (18)F-FDG PET. When infected with AdAFP-TK, cell viability in HuH-7 was reduced, but those in HT-29 and SK-Hep-1 were not significantly decreased at any GCV concentration less than 100 μM. AFP-targeted fLuc and HSV1-tk expression were clearly visualized by BLI and (18)F-FHBG PET images in AFP-producing HCC, respectively. In vivo GCV-mediated tumor growth inhibition by AFP-targeted HSV1-tk expression was monitored by (18)F-FDG PET. Recombinant AdAFP-TK could be applied for AFP-targeted HCC gene therapy and imaging in AFP-producing HCC.

Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis

PubMed Central

Kluza, Ewelina; Van Tilborg, Geralda A. F.; van der Schaft, Daisy W. J.; Griffioen, Arjan W.; Mulder, Willem J. M.; Nicolay, Klaas

2010-01-01

Angiogenesis is essential for tumor growth and metastatic potential and for that reason considered an important target for tumor treatment. Noninvasive imaging technologies, capable of visualizing tumor angiogenesis and evaluating the efficacy of angiostatic therapies, are therefore becoming increasingly important. Among the various imaging modalities, magnetic resonance imaging (MRI) is characterized by a superb spatial resolution and anatomical soft-tissue contrast. Revolutionary advances in contrast agent chemistry have delivered versatile angiogenesis-specific molecular MRI contrast agents. In this paper, we review recent advances in the preclinical application of paramagnetic and fluorescent liposomes for noninvasive visualization of the molecular processes involved in tumor angiogenesis. This liposomal contrast agent platform can be prepared with a high payload of contrast generating material, thereby facilitating its detection, and is equipped with one or more types of targeting ligands for binding to specific molecules expressed at the angiogenic site. Multimodal liposomes endowed with contrast material for complementary imaging technologies, e.g., MRI and optical, can be exploited to gain important preclinical insights into the mechanisms of binding and accumulation at angiogenic vascular endothelium and to corroborate the in vivo findings. Interestingly, liposomes can be designed to contain angiostatic therapeutics, allowing for image-supervised drug delivery and subsequent monitoring of therapeutic efficacy. PMID:20390447

Investigation of SP94 Peptide as a Specific Probe for Hepatocellular Carcinoma Imaging and Therapy

PubMed Central

Li, Yanli; Hu, Yan; Xiao, Jie; Liu, Guobing; Li, Xiao; Zhao, Yanzhao; Tan, Hui; Shi, Hongcheng; Cheng, Dengfeng

2016-01-01

SP94 (SFSIIHTPILPL), a novel peptide, has shown specific binding to hepatocellular carcinoma (HCC) cells. We aimed to investigate the capability of SP94 as a targeting probe for HCC imaging and therapy following labeling with technetium-99m (99mTc) and rhenium-188 (188Re). HYNIC-SP94 was prepared by solid phase synthesis and then labeled with 99mTc. Cell competitive binding, internalization assay, in vitro and in vivo stability, biodistribution and micro-single photon emission computed tomography /computed tomography (SPECT/CT) imaging studies were performed to investigate the capability of 99mTc tricine-EDDA/HYNIC-SP94 as a specific HCC imaging probe. Initial promising targeting results inspired evaluation of its therapeutic effect when labeled by 188Re. HYNIC-SP94 was then labeled again with 188Re to perform cell apoptosis, microSPECT/CT imaging evaluation and immunohistochemistry. Huh-7 cells exhibited typical apoptotic changes after 188Re irradiation. According to 99mTc tricine-EDDA/HYNIC-SP94 microSPECT/CT imaging, tumor uptake was significantly decreased compared with that of pre-treatment with 188Re-HYNIC-SP94. The immunohistochemistry also displayed obvious necrosis and apoptosis as well as inhibition of proliferation in the 188Re-HYNIC-SP94 treatment group. The results supported that 99mTc tricine-EDDA/HYNIC-SP94 is able to target HCC cells and 188Re-HYNIC- SP94 holds potential as a therapeutic agent for HCC, making 99mTc/188Re-HYNIC-SP94 a promising targeting probe for HCC imaging and therapy. PMID:27649935

On-orbit point spread function estimation for THEOS imaging system

NASA Astrophysics Data System (ADS)

Khetkeeree, Suphongsa; Liangrocapart, Sompong

2018-03-01

In this paper, we present two approaches for net Point Spread Function (net-PSF) estimation of Thailand Earth Observation System (THEOS) imaging system. In the first approach, we estimate the net- PSF by employing the specification information of the satellite. The analytic model of the net- PSF based on the simple model of push-broom imaging system. This model consists of a scanner, optical system, detector and electronics system. The mathematical PSF model of each component is demonstrated in spatial domain. In the second approach, the specific target images from THEOS imaging system are analyzed to determine the net-PSF. For panchromatic imaging system, the images of the checkerboard target at Salon de Provence airport are used to analysis the net-PSF by slant-edge method. For multispectral imaging system, the new man-made targets are proposed. It is a pier bridge in Lamchabang, Chonburi, Thailand. This place has had a lot of bridges which have several width sizes and orientation. The pulse method is used to analysis the images of this bridge for estimating the net-PSF. Finally, the Full Width at Half Maximums (FWHMs) of the net-PSF of both approaches is compared. The results show that both approaches coincide and all Modulation Transfer Functions (MTFs) at Nyquist of both approaches are better than the requirement. However, the FWHM of multispectral system more deviate than panchromatic system, because the targets are not specially constructed for estimating the characteristics of the satellite imaging system.

Ratiometric spectral imaging for fast tumor detection and chemotherapy monitoring in vivo

PubMed Central

Hwang, Jae Youn; Gross, Zeev; Gray, Harry B.; Medina-Kauwe, Lali K.; Farkas, Daniel L.

2011-01-01

We report a novel in vivo spectral imaging approach to cancer detection and chemotherapy assessment. We describe and characterize a ratiometric spectral imaging and analysis method and evaluate its performance for tumor detection and delineation by quantitatively monitoring the specific accumulation of targeted gallium corrole (HerGa) into HER2-positive (HER2 +) breast tumors. HerGa temporal accumulation in nude mice bearing HER2 + breast tumors was monitored comparatively by a. this new ratiometric imaging and analysis method; b. established (reflectance and fluorescence) spectral imaging; c. more commonly used fluorescence intensity imaging. We also tested the feasibility of HerGa imaging in vivo using the ratiometric spectral imaging method for tumor detection and delineation. Our results show that the new method not only provides better quantitative information than typical spectral imaging, but also better specificity than standard fluorescence intensity imaging, thus allowing enhanced in vivo outlining of tumors and dynamic, quantitative monitoring of targeted chemotherapy agent accumulation into them. PMID:21721808

Recent advances in targeted endoscopic imaging: Early detection of gastrointestinal neoplasms

PubMed Central

Kwon, Yong-Soo; Cho, Young-Seok; Yoon, Tae-Jong; Kim, Ho-Shik; Choi, Myung-Gyu

2012-01-01

Molecular imaging has emerged as a new discipline in gastrointestinal endoscopy. This technology encompasses modalities that can visualize disease-specific morphological or functional tissue changes based on the molecular signature of individual cells. Molecular imaging has several advantages including minimal damage to tissues, repetitive visualization, and utility for conducting quantitative analyses. Advancements in basic science coupled with endoscopy have made early detection of gastrointestinal cancer possible. Molecular imaging during gastrointestinal endoscopy requires the development of safe biomarkers and exogenous probes to detect molecular changes in cells with high specificity anda high signal-to-background ratio. Additionally, a high-resolution endoscope with an accurate wide-field viewing capability must be developed. Targeted endoscopic imaging is expected to improve early diagnosis and individual therapy of gastrointestinal cancer. PMID:22442742

Imaging Metastasis Using an Integrin-Targeting Chain-Shaped Nanoparticle

PubMed Central

Peiris, Pubudu M.; Toy, Randall; Doolittle, Elizabeth; Pansky, Jenna; Abramowski, Aaron; Tam, Morgan; Vicente, Peter; Tran, Emily; Hayden, Elliott; Camann, Andrew; Mayer, Aaron; Erokwu, Bernadette O.; Berman, Zachary; Wilson, David; Baskaran, Harihara; Flask, Chris A.; Keri, Ruth A.; Karathanasis, Efstathios

2012-01-01

While the enhanced permeability and retention effect may promote the preferential accumulation of nanoparticles into well-vascularized primary tumors, it is ineffective in the case of metastases hidden within a large population of normal cells. Due to their small size, high dispersion to organs, and low vascularization, metastatic tumors are less accessible to targeted nanoparticles. To tackle these challenges, we designed a nanoparticle for vascular targeting based on an αvβ3 integrin-targeted nanochain particle composed of four iron oxide nanospheres chemically linked in a linear assembly. The chain-shaped nanoparticles enabled enhanced ‘sensing’ of the tumor-associated remodeling of the vascular bed offering increased likelihood of specific recognition of metastatic tumors. Compared to spherical nanoparticles, the chain-shaped nanoparticles resulted in superior targeting of αvβ3 integrin due to geometrically enhanced multivalent docking. We performed multimodal in vivo imaging (Fluorescence Molecular Tomography and Magnetic Resonance Imaging) in a non-invasive and quantitative manner, which showed that the nanoparticles targeted metastases in the liver and lungs with high specificity in a highly aggressive breast tumor model in mice. PMID:23005348

Image-guided positioning and tracking.

PubMed

Ruan, Dan; Kupelian, Patrick; Low, Daniel A

2011-01-01

Radiation therapy aims at maximizing tumor control while minimizing normal tissue complication. The introduction of stereotactic treatment explores the volume effect and achieves dose escalation to tumor target with small margins. The use of ablative irradiation dose and sharp dose gradients requires accurate tumor definition and alignment between patient and treatment geometry. Patient geometry variation during treatment may significantly compromise the conformality of delivered dose and must be managed properly. Setup error and interfraction/intrafraction motion are incorporated in the target definition process by expanding the clinical target volume to planning target volume, whereas the alignment between patient and treatment geometry is obtained with an adaptive control process, by taking immediate actions in response to closely monitored patient geometry. This article focuses on the monitoring and adaptive response aspect of the problem. The term "image" in "image guidance" will be used in a most general sense, to be inclusive of some important point-based monitoring systems that can be considered as degenerate cases of imaging. Image-guided motion adaptive control, as a comprehensive system, involves a hierarchy of decisions, each of which balances simplicity versus flexibility and accuracy versus robustness. Patient specifics and machine specifics at the treatment facility also need to be incorporated into the decision-making process. Identifying operation bottlenecks from a system perspective and making informed compromises are crucial in the proper selection of image-guidance modality, the motion management mechanism, and the respective operation modes. Not intended as an exhaustive exposition, this article focuses on discussing the major issues and development principles for image-guided motion management systems. We hope these information and methodologies will facilitate conscientious practitioners to adopt image-guided motion management systems accounting for patient and institute specifics and to embrace advances in knowledge and new technologies subsequent to the publication of this article.

Prostate-specific membrane antigen targeted imaging and therapy of prostate cancer using a PSMA inhibitor as a homing ligand.

PubMed

Kularatne, Sumith A; Wang, Kevin; Santhapuram, Hari-Krishna R; Low, Philip S

2009-01-01

Prostate cancer (PCa) is a major cause of mortality and morbidity in Western society today. Current methods for detecting PCa are limited, leaving most early malignancies undiagnosed and sites of metastasis in advanced disease undetected. Major deficiencies also exist in the treatment of PCa, especially metastatic disease. In an effort to improve both detection and therapy of PCa, we have developed a PSMA-targeted ligand that delivers attached imaging and therapeutic agents selectively to PCa cells without targeting normal cells. The PSMA-targeted radioimaging agent (DUPA-(99m)Tc) was found to bind PSMA-positive human PCa cells (LNCaP cell line) with nanomolar affinity (K(D) = 14 nM). Imaging and biodistribution studies revealed that DUPA-(99m)Tc localizes primarily to LNCaP cell tumor xenografts in nu/nu mice (% injected dose/gram = 11.3 at 4 h postinjection; tumor-to-muscle ratio = 75:1). Two PSMA-targeted optical imaging agents (DUPA-FITC and DUPA-rhodamine B) were also shown to efficiently label PCa cells and to internalize and traffic to intracellular endosomes. A PSMA-targeted chemotherapeutic agent (DUPA-TubH) was demonstrated to kill PSMA-positive LNCaP cells in culture (IC(50) = 3 nM) and to eliminate established tumor xenografts in nu/nu mice with no detectable weight loss. Blockade of tumor targeting upon administration of excess PSMA inhibitor (PMPA) and the absence of targeting to PSMA-negative tumors confirmed the specificity of each of the above targeted reagents for PSMA. Tandem use of the imaging and therapeutic agents targeted to the same receptor could allow detection, staging, monitoring, and treatment of PCa with improved accuracy and efficacy.

Antibody-Unfolding and Metastable-State Binding in Force Spectroscopy and Recognition Imaging

PubMed Central

Kaur, Parminder; Qiang-Fu; Fuhrmann, Alexander; Ros, Robert; Kutner, Linda Obenauer; Schneeweis, Lumelle A.; Navoa, Ryman; Steger, Kirby; Xie, Lei; Yonan, Christopher; Abraham, Ralph; Grace, Michael J.; Lindsay, Stuart

2011-01-01

Force spectroscopy and recognition imaging are important techniques for characterizing and mapping molecular interactions. In both cases, an antibody is pulled away from its target in times that are much less than the normal residence time of the antibody on its target. The distribution of pulling lengths in force spectroscopy shows the development of additional peaks at high loading rates, indicating that part of the antibody frequently unfolds. This propensity to unfold is reversible, indicating that exposure to high loading rates induces a structural transition to a metastable state. Weakened interactions of the antibody in this metastable state could account for reduced specificity in recognition imaging where the loading rates are always high. The much weaker interaction between the partially unfolded antibody and target, while still specific (as shown by control experiments), results in unbinding on millisecond timescales, giving rise to rapid switching noise in the recognition images. At the lower loading rates used in force spectroscopy, we still find discrepancies between the binding kinetics determined by force spectroscopy and those determined by surface plasmon resonance—possibly a consequence of the short tethers used in recognition imaging. Recognition imaging is nonetheless a powerful tool for interpreting complex atomic force microscopy images, so long as specificity is calibrated in situ, and not inferred from equilibrium binding kinetics. PMID:21190677

Before In Vivo Imaging: Evaluation of Fluorescent Probes Using Fluorescence Microscopy, Multiplate Reader, and Cytotoxicity Assays.

PubMed

Zhang, Shaojuan

2016-01-01

Fluorescent probes are widely utilized for noninvasive fluorescence imaging. Continuing efforts have been made in developing novel fluorescent probes with improved fluorescence quantum yield, enhanced target-specificity, and lower cytotoxicity. Before such probes are administrated into a living system, it is essential to evaluate the subcellular uptake, targeting specificity, and cytotoxicity in vitro. In this chapter, we briefly outline common methods used to evaluate fluorescent probes using fluorescence microscopy, multiplate reader, and cytotoxicity assay.

Aptamer-conjugated and drug-loaded acoustic droplets for ultrasound theranosis.

PubMed

Wang, Chung-Hsin; Kang, Shih-Tsung; Lee, Ya-Hsuan; Luo, Yun-Ling; Huang, Yu-Fen; Yeh, Chih-Kuang

2012-02-01

Tumor therapy requires multi-functional treatment strategies with specific targeting of therapeutics to reduce general toxicity and increase efficacy. In this study we fabricated and functionally tested aptamer-conjugated and doxorubicin (DOX)-loaded acoustic droplets comprising cores of liquid perfluoropentane compound and lipid-based shell materials. Conjugation of sgc8c aptamers provided the ability to specifically target CCRF-CEM cells for both imaging and therapy. High-intensity focused ultrasound (HIFU) was introduced to trigger targeted acoustic droplet vaporization (ADV) which resulted in both mechanical cancer cell destruction by inertial cavitation and chemical treatment through localized drug release. HIFU insonation showed a 56.8% decrease in cell viability with aptamer-conjugated droplets, representing a 4.5-fold increase in comparison to non-conjugated droplets. In addition, the fully-vaporized droplets resulted in the highest DOX uptake by cancer cells, compared to non-vaporized or partially vaporized droplets. Optical studies clearly illustrated the transient changes that occurred upon ADV of droplet-targeted CEM cells, and B-mode ultrasound imaging revealed contrast enhancement by ADV in ultrasound images. In conclusion, our fabricated droplets functioned as a hybrid chemical and mechanical strategy for the specific destruction of cancer cells upon ultrasound-mediated ADV, while simultaneously providing ultrasound imaging capability. Copyright © 2011 Elsevier Ltd. All rights reserved.

Research on vehicle detection based on background feature analysis in SAR images

NASA Astrophysics Data System (ADS)

Zhang, Bochuan; Tang, Bo; Zhang, Cong; Hu, Ruiguang; Yun, Hongquan; Xiao, Liping

2017-10-01

Aiming at vehicle detection on the ground through low resolution SAR images, a method is proposed for determining the region of the vehicles first and then detecting the target in the specific region. The experimental results show that this method not only reduces the target detection area, but also reduces the influence of terrain clutter on the detection, which greatly improves the reliability of the target detection.

Recognition Imaging of Acetylated Chromatin Using a DNA Aptamer

PubMed Central

Lin, Liyun; Fu, Qiang; Williams, Berea A.R.; Azzaz, Abdelhamid M.; Shogren-Knaak, Michael A.; Chaput, John C.; Lindsay, Stuart

2009-01-01

Histone acetylation plays an important role in the regulation of gene expression. A DNA aptamer generated by in vitro selection to be highly specific for histone H4 protein acetylated at lysine 16 was used as a recognition element for atomic force microscopy-based recognition imaging of synthetic nucleosomal arrays with precisely controlled acetylation. The aptamer proved to be reasonably specific at recognizing acetylated histones, with recognition efficiencies of 60% on-target and 12% off-target. Though this selectivity is much poorer than the >2000:1 equilibrium specificity of the aptamer, it is a large improvement on the performance of a ChIP-quality antibody, which is not selective at all in this application, and it should permit high-fidelity recognition with repeated imaging. The ability to image the precise location of posttranslational modifications may permit nanometer-scale investigation of their effect on chromatin structure. PMID:19751687

Molecular Imaging and Precision Medicine in Breast Cancer.

PubMed

Chudgar, Amy V; Mankoff, David A

2017-01-01

Precision medicine, basing treatment approaches on patient traits and specific molecular features of disease processes, has an important role in the management of patients with breast cancer as targeted therapies continue to improve. PET imaging offers noninvasive information that is complementary to traditional tissue biomarkers, including information about tumor burden, tumor metabolism, receptor status, and proliferation. Several PET agents that image breast cancer receptors can visually demonstrate the extent and heterogeneity of receptor-positive disease and help predict which tumors are likely to respond to targeted treatments. This review presents applications of PET imaging in the targeted treatment of breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Nanoparticle-facilitated functional and molecular imaging for the early detection of cancer

PubMed Central

Sivasubramanian, Maharajan; Hsia, Yu; Lo, Leu-Wei

2014-01-01

Cancer detection in its early stages is imperative for effective cancer treatment and patient survival. In recent years, biomedical imaging techniques, such as magnetic resonance imaging, computed tomography and ultrasound have been greatly developed and have served pivotal roles in clinical cancer management. Molecular imaging (MI) is a non-invasive imaging technique that monitors biological processes at the cellular and sub-cellular levels. To achieve these goals, MI uses targeted imaging agents that can bind targets of interest with high specificity and report on associated abnormalities, a task that cannot be performed by conventional imaging techniques. In this respect, MI holds great promise as a potential therapeutic tool for the early diagnosis of cancer. Nevertheless, the clinical applications of targeted imaging agents are limited due to their inability to overcome biological barriers inside the body. The use of nanoparticles has made it possible to overcome these limitations. Hence, nanoparticles have been the subject of a great deal of recent studies. Therefore, developing nanoparticle-based imaging agents that can target tumors via active or passive targeting mechanisms is desirable. This review focuses on the applications of various functionalized nanoparticle-based imaging agents used in MI for the early detection of cancer. PMID:25988156

Real Time Intelligent Target Detection and Analysis with Machine Vision

NASA Technical Reports Server (NTRS)

Howard, Ayanna; Padgett, Curtis; Brown, Kenneth

2000-01-01

We present an algorithm for detecting a specified set of targets for an Automatic Target Recognition (ATR) application. ATR involves processing images for detecting, classifying, and tracking targets embedded in a background scene. We address the problem of discriminating between targets and nontarget objects in a scene by evaluating 40x40 image blocks belonging to an image. Each image block is first projected onto a set of templates specifically designed to separate images of targets embedded in a typical background scene from those background images without targets. These filters are found using directed principal component analysis which maximally separates the two groups. The projected images are then clustered into one of n classes based on a minimum distance to a set of n cluster prototypes. These cluster prototypes have previously been identified using a modified clustering algorithm based on prior sensed data. Each projected image pattern is then fed into the associated cluster's trained neural network for classification. A detailed description of our algorithm will be given in this paper. We outline our methodology for designing the templates, describe our modified clustering algorithm, and provide details on the neural network classifiers. Evaluation of the overall algorithm demonstrates that our detection rates approach 96% with a false positive rate of less than 0.03%.

Near Infrared Fluorescence Imaging in Nano-Therapeutics and Photo-Thermal Evaluation

PubMed Central

Vats, Mukti; Mishra, Sumit Kumar; Baghini, Mahdieh Shojaei; Chauhan, Deepak S.; Srivastava, Rohit; De, Abhijit

2017-01-01

The unresolved and paramount challenge in bio-imaging and targeted therapy is to clearly define and demarcate the physical margins of tumor tissue. The ability to outline the healthy vital tissues to be carefully navigated with transection while an intraoperative surgery procedure is performed sets up a necessary and under-researched goal. To achieve the aforementioned objectives, there is a need to optimize design considerations in order to not only obtain an effective imaging agent but to also achieve attributes like favorable water solubility, biocompatibility, high molecular brightness, and a tissue specific targeting approach. The emergence of near infra-red fluorescence (NIRF) light for tissue scale imaging owes to the provision of highly specific images of the target organ. The special characteristics of near infra-red window such as minimal auto-fluorescence, low light scattering, and absorption of biomolecules in tissue converge to form an attractive modality for cancer imaging. Imparting molecular fluorescence as an exogenous contrast agent is the most beneficial attribute of NIRF light as a clinical imaging technology. Additionally, many such agents also display therapeutic potentials as photo-thermal agents, thus meeting the dual purpose of imaging and therapy. Here, we primarily discuss molecular imaging and therapeutic potentials of two such classes of materials, i.e., inorganic NIR dyes and metallic gold nanoparticle based materials. PMID:28452928

Nanoparticles for multimodal in vivo imaging in nanomedicine

PubMed Central

Key, Jaehong; Leary, James F

2014-01-01

While nanoparticles are usually designed for targeted drug delivery, they can also simultaneously provide diagnostic information by a variety of in vivo imaging methods. These diagnostic capabilities make use of specific properties of nanoparticle core materials. Near-infrared fluorescent probes provide optical detection of cells targeted by real-time nanoparticle-distribution studies within the organ compartments of live, anesthetized animals. By combining different imaging modalities, we can start with deep-body imaging by magnetic resonance imaging or computed tomography, and by using optical imaging, get down to the resolution required for real-time fluorescence-guided surgery. PMID:24511229

Single-domain antibody bioconjugated near-IR quantum dots for targeted cellular imaging of pancreatic cancer.

PubMed

Zaman, Md Badruz; Baral, Toya Nath; Jakubek, Zygmunt J; Zhang, Jianbing; Wu, Xiaohua; Lai, Edward; Whitfield, Dennis; Yu, Kui

2011-05-01

Successful targeted imaging of BxPC3 human pancreatic cancer cells is feasible with near-IR CdTeSe/CdS quantum dots (QDs) functionalized with single-domain antibody (sdAb) 2A3. For specific targeting, sdAbs are superior to conventional antibodies, especially in terms of stability, aggregation, and production cost. The bright CdTeSe/CdS QDs were synthesized to emit in the diagnostic window of 650-900 nm with a narrow emission band. 2A3 was derived from llama and is small in size of 13 kDa, but with fully-functional recognition to the target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a possible biomarker as a therapeutic target of pancreatic cancer. For compelling imaging, optical may be the most sensible among the various imaging modalities, regarding the sensitivity and cost. This first report on sdAb-conjugated near-IR QDs with high signal to background sensitivity for targeted cellular imaging brings insights into the development of optical molecular imaging for early stage cancer diagnosis.

Targeted delivery of cancer-specific multimodal contrast agents for intraoperative detection of tumor boundaries and therapeutic margins

NASA Astrophysics Data System (ADS)

Xu, Ronald X.; Xu, Jeff S.; Huang, Jiwei; Tweedle, Michael F.; Schmidt, Carl; Povoski, Stephen P.; Martin, Edward W.

2010-02-01

Background: Accurate assessment of tumor boundaries and intraoperative detection of therapeutic margins are important oncologic principles for minimal recurrence rates and improved long-term outcomes. However, many existing cancer imaging tools are based on preoperative image acquisition and do not provide real-time intraoperative information that supports critical decision-making in the operating room. Method: Poly lactic-co-glycolic acid (PLGA) microbubbles (MBs) and nanobubbles (NBs) were synthesized by a modified double emulsion method. The MB and NB surfaces were conjugated with CC49 antibody to target TAG-72 antigen, a human glycoprotein complex expressed in many epithelial-derived cancers. Multiple imaging agents were encapsulated in MBs and NBs for multimodal imaging. Both one-step and multi-step cancer targeting strategies were explored. Active MBs/NBs were also fabricated for therapeutic margin assessment in cancer ablation therapies. Results: The multimodal contrast agents and the cancer-targeting strategies were tested on tissue simulating phantoms, LS174 colon cancer cell cultures, and cancer xenograft nude mice. Concurrent multimodal imaging was demonstrated using fluorescence and ultrasound imaging modalities. Technical feasibility of using active MBs and portable imaging tools such as ultrasound for intraoperative therapeutic margin assessment was demonstrated in a biological tissue model. Conclusion: The cancer-specific multimodal contrast agents described in this paper have the potential for intraoperative detection of tumor boundaries and therapeutic margins.

Progress in molecular imaging in endoscopy and endomicroscopy for cancer imaging

PubMed Central

Khondee, Supang; Wang, Thomas D.

2014-01-01

Imaging is an essential tool for effective cancer management. Endoscopes are important medical instruments for performing in vivo imaging in hollow organs. Early detection of cancer can be achieved with surveillance using endoscopy, and has been shown to reduce mortality and to improve outcomes. Recently, great advancements have been made in endoscopic instruments, including new developments in optical designs, light sources, optical fibers, miniature scanners, and multimodal systems, allowing for improved resolution, greater tissue penetration, and multispectral imaging. In addition, progress has been made in the development of highly-specific optical probes, allowing for improved specificity for molecular targets. Integration of these new endoscopic instruments with molecular probes provides a unique opportunity for significantly improving patient outcomes and has potential to further improve early detection, image guided therapy, targeted therapy, and personalized medicine. This work summarizes current and evolving endoscopic technologies, and provides an overview of various promising optical molecular probes. PMID:23502247

In vivo NIRF imaging-guided delivery of a novel NGR-VEGI fusion protein for targeting tumor vasculature.

PubMed

Ma, Wenhui; Li, Guoquan; Wang, Jing; Yang, Weidong; Zhang, Yingqi; Conti, Peter S; Chen, Kai

2014-12-01

Pathological angiogenesis is crucial in tumor growth, invasion and metastasis. Previous studies demonstrated that the vascular endothelial growth inhibitor (VEGI), a member of the tumor necrosis factor superfamily, can be used as a potent endogenous inhibitor of tumor angiogenesis. Molecular probes containing the asparagine-glycine-arginine (NGR) sequence can specifically bind to CD13 receptor which is overexpressed on neovasculature and several tumor cells. Near-infrared fluorescence (NIRF) optical imaging for targeting tumor vasculature offers a noninvasive method for early detection of tumor angiogenesis and efficient monitoring of response to anti-tumor vasculature therapy. The aim of this study was to develop a new NIRF imaging probe on the basis of an NGR-VEGI protein for the visualization of tumor vasculature. The NGR-VEGI fusion protein was prepared from prokaryotic expression, and its function was characterized in vitro. The NGR-VEGI protein was then labeled with a Cy5.5 fluorophore to afford Cy5.5-NGR-VEGI probe. Using the NIRF imaging technique, we visualized and quantified the specific delivery of Cy5.5-NGR-VEGI protein to subcutaneous HT-1080 fibrosarcoma tumors in mouse xenografts. The Cy5.5-NGR-VEGI probe exhibited rapid HT-1080 tumor targeting, and highest tumor-to-background contrast at 8 h post-injection (pi). Tumor specificity of Cy5.5-NGR-VEGI was confirmed by effective blocking of tumor uptake in the presence of unlabeled NGR-VEGI (20 mg/kg). Ex vivo NIRF imaging further confirmed in vivo imaging findings, demonstrating that Cy5.5-NGR-VEGI displayed an excellent tumor-to-muscle ratio (18.93 ± 2.88) at 8 h pi for the non-blocking group and significantly reduced ratio (4.92 ± 0.75) for the blocking group. In conclusion, Cy5.5-NGR-VEGI provided highly sensitive, target-specific, and longitudinal imaging of HT-1080 tumors. As a novel theranostic protein, Cy5.5-NGR-VEGI has the potential to improve cancer treatment by targeting tumor vasculature.

Targeted Multiplex Imaging Mass Spectrometry with Single Chain Fragment Variable (scfv) Recombinant Antibodies

NASA Astrophysics Data System (ADS)

Thiery, Gwendoline; Mernaugh, Ray L.; Yan, Heping; Spraggins, Jeffrey M.; Yang, Junhai; Parl, Fritz F.; Caprioli, Richard M.

2012-10-01

Recombinant scfv antibodies specific for CYP1A1 and CYP1B1 P450 enzymes were combined with targeted imaging mass spectrometry to simultaneously detect the P450 enzymes present in archived, paraffin-embedded, human breast cancer tissue sections. By using CYP1A1 and CYP1B1 specific scfv, each coupled to a unique reporter molecule (i.e., a mass tag) it was possible to simultaneously detect multiple antigens within a single tissue sample with high sensitivity and specificity using mass spectrometry. The capability of imaging multiple antigens at the same time is a significant advance that overcomes technical barriers encountered when using present day approaches to develop assays that can simultaneously detect more than a single antigen in the same tissue sample.

Synthesis and radiolabeling of chelator-RNA aptamer bioconjugates with copper-64 for targeted molecular imaging

PubMed Central

Rockey, William M.; Huang, Ling; Kloepping, Kyle C.; Baumhover, Nicholas J.; Giangrande, Paloma H.; Schultz, Michael K.

2014-01-01

Ribonucleic acid (RNA) aptamers with high affinity and specificity for cancer-specific cell-surface antigens are promising reagents for targeted molecular imaging of cancer using positron emission tomography (PET). For this application, aptamers must be conjugated to chelators capable of coordinating PET-radionuclides (e.g. copper-64, 64Cu) to enable radiolabeling for in vivo imaging of tumors. This study investigates the choice of chelator and radiolabeling parameters such as pH and temperature for the development of 64Cu-labeled RNA-based targeted agents for PET imaging. The characterization and optimization of labeling conditions are described for four chelator-aptamer complexes. Three commercially available bifunctional macrocyclic chelators (1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid mono N-hydroxysuccinimide [DOTA-NHS]; S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid [p-SCN-Bn-NOTA]; and p-SCN-Bn-3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid [p-SCN-Bn-PCTA]), as well as the polyamino-macrocyclic diAmSar (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane-1,8-diamine) were conjugated to A10–3.2, a RNA aptamer which has been shown to bind specifically to a prostate cancer-specific cell-surface antigen (PSMA). Although a commercial bifunctional version of diAmSar was not available, RNA conjugation with this chelator was achieved in a two-step reaction by the addition of a disuccinimidyl suberate linker. Radiolabeling parameters (e.g. pH, temperature, and time) for each chelator-RNA conjugate were assessed in order to optimize specific activity and RNA stability. Furthermore, the radiolabeled chelator-coupled RNA aptamers were evaluated for binding specificity to their target antigen. In summary, key parameters were established for optimal radiolabeling of RNA aptamers for eventual PET imaging with 64Cu. PMID:21658962

Use of a leukocyte-targeted peptide probe as a potential tracer for imaging the tuberculosis granuloma.

PubMed

Locke, Landon W; Kothandaraman, Shankaran; Tweedle, Michael; Chaney, Sarah; Wozniak, Daniel J; Schlesinger, Larry S

2018-01-01

Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma. We report the binding specificity of Cyanine 3 (Cy3)-labeled cFLFLFK-PEG 12 to human leukocytes and cellular constituents within a human in vitro granuloma model. We also report use of the probe in in vivo studies using a mouse model of lung granulomatous inflammation. We found that the probe preferentially binds human neutrophils and macrophages in human granuloma structures. Inhibition studies showed that peptide binding to human neutrophils is mediated by the receptor formyl peptide receptor 1 (FPR1). Imaging the distribution of intravenously administered cFLFLFK-PEG 12 -Cy3 in the mouse model revealed probe accumulation within granulomatous inflammatory responses in the lung. Further characterization revealed that the probe preferentially associated with neutrophils and cells of the monocyte/macrophage lineage. As there is no current clinical diagnostic imaging tool that specifically targets granulomas, the use of this probe in the context of latent and active TB may provide a unique advantage over current clinical imaging probes. We anticipate that utilizing a FPR1-targeted radiopharmaceutical analog of cFLFLFK in preclinical imaging studies may greatly contribute to our understanding of granuloma influx patterns and the biological roles and consequences of FPR1-expressing cells in contributing to disease pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Developing Targeted Hybrid Imaging Probes by Chelator Scaffolding

PubMed Central

2017-01-01

Positron emission tomography (PET) as well as optical imaging (OI) with peptide receptor targeting probes have proven their value for oncological applications but also show restrictions depending on the clinical field of interest. Therefore, the combination of both methods, particularly in a single molecule, could improve versatility in clinical routine. This proof of principle study aims to show that a chelator, Fusarinine C (FSC), can be utilized as scaffold for novel dimeric dual-modality imaging agents. Two targeting vectors (a minigastrin analogue (MG11) targeting cholecystokinin-2 receptor overexpression (CCK2R) or integrin αVβ3 targeting cyclic pentapeptides (RGD)) and a near-infrared fluorophore (Sulfo-Cyanine7) were conjugated to FSC. The probes were efficiently labeled with gallium-68 and in vitro experiments including determination of logD, stability, protein binding, cell binding, internalization, and biodistribution studies as well as in vivo micro-PET/CT and optical imaging in U-87MG αVβ3- and A431-CCK2R expressing tumor xenografted mice were carried out. Novel bioconjugates showed high receptor affinity and highly specific targeting properties at both receptors. Ex vivo biodistribution and micro-PET/CT imaging studies revealed specific tumor uptake accompanied by slow blood clearance and retention in nontargeted tissues (spleen, liver, and kidneys) leading to visualization of tumors at early (30 to 120 min p.i.). Excellent contrast in corresponding optical imaging studies was achieved especially at delayed time points (24 to 72 h p.i.). Our findings show the proof of principle of chelator scaffolding for hybrid imaging agents and demonstrate FSC being a suitable bifunctional chelator for this approach. Improvements to fine-tune pharmacokinetics are needed to translate this into a clinical setting. PMID:28462989

Highly Sensitive Detection of Target Biomolecules on Cell Surface Using Gold Nanoparticle Conjugated with Aptamer Probe

NASA Astrophysics Data System (ADS)

Kim, Hyonchol; Terazono, Hideyuki; Hayashi, Masahito; Takei, Hiroyuki; Yasuda, Kenji

2012-06-01

A method of gold nanoparticle (Au NP) labeling with backscattered electron (BE) imaging of field emission scanning electron microscopy (FE-SEM) was applied for specific detection of target biomolecules on a cell surface. A single-stranded DNA aptamer, which specifically binds to the target molecule on a human acute lymphoblastic leukemia cell, was conjugated with a 20 nm Au NP and used as a probe to label its target molecule on the cell. The Au NP probe was incubated with the cell, and the interaction was confirmed using BE imaging of FE-SEM through direct counting of the number of Au NPs attached on the target cell surface. Specific Au NP-aptamer probes were observed on a single cell surface and their spatial distributions including submicron-order localizations were also clearly visualized, whereas the nonspecific aptamer probes were not observed on it. The aptamer probe can be potentially dislodged from the cell surface with treatment of nucleases, indicating that Au NP-conjugated aptamer probes can be used as sensitive and reversible probes to label target biomolecules on cells.

A new target ligand Ser-Glu for PEPT1-overexpressing cancer imaging.

PubMed

Dai, Tongcheng; Li, Na; Zhang, Lingzhi; Zhang, Yuanxing; Liu, Qin

2016-01-01

Nanoparticles functionalized with active target ligands have been widely used for tumor-specific diagnosis and therapy. The target ligands include antibodies, peptides, proteins, small molecules, and nucleic acid aptamers. Here, we utilize dipeptide Ser-Glu (DIP) as a new ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for pancreatic cancer target imaging. We demonstrate that in the first step, Ser-Glu-conjugated NPs (NPs-DIP) efficiently bind to AsPC-1 and in the following NPs-DIP are internalized into AsPC-1 in vitro. The peptide transporter 1 inhibition experiment reveals that the targeting effects mainly depend on the specific binding of DIP to peptide transporter 1, which is remarkably upregulated in pancreatic cancer cells compared with varied normal cells. Furthermore, NPs-DIP specifically accumulate in the site of pancreatic tumor xenograft and are further internalized into the tumor cells in vivo after intravenous administration, indicating that DIP successfully enhanced nanoparticles internalization efficacy into tumor cells in vivo. This work establishes Ser-Glu to be a new tumor-targeting ligand and provides a promising tool for future tumor diagnostic or therapeutic applications.

Molecular Imaging and Therapy of Prostate Cancer

DTIC Science & Technology

2015-10-01

arsenic-based, IGF1R-targeted radiopharmaceuticals can allow for PET imaging, IRT, and monitoring the therapeutic response of PCa. Specific Aims: Aim 1: To...models with PET imaging. Aim 3: To monitor the efficacy of 76As-based IRT of PCa with multimodality imaging.

Image-guided urologic surgery: intraoperative optical imaging and tissue interrogation (Conference Presentation)

NASA Astrophysics Data System (ADS)

Liao, Joseph C.

2017-02-01

Emerging optical imaging technologies can be integrated in the operating room environment during minimally invasive and open urologic surgery, including oncologic surgery of the bladder, prostate, and kidney. These technologies include macroscopic fluorescence imaging that provides contrast enhancement between normal and diseased tissue and microscopic imaging that provides tissue characterization. Optical imaging technologies that have reached the clinical arena in urologic surgery are reviewed, including photodynamic diagnosis, near infrared fluorescence imaging, optical coherence tomography, and confocal laser endomicroscopy. Molecular imaging represents an exciting future arena in conjugating cancer-specific contrast agents to fluorophores to improve the specificity of disease detection. Ongoing efforts are underway to translate optimal targeting agents and imaging modalities, with the goal to improve cancer-specific and functional outcomes.

[Clinical applications of molecular imaging methods for patients with ischemic stroke].

PubMed

Yamauchi, Hiroshi; Fukuyama, Hidenao

2007-02-01

Several molecular imaging methods have been developed to visualize pathophysiology of cerebral ischemia in humans in vivo. PET and SPECT with specific ligands have been mainly used as diagnostic tools for the clinical usage of molecular imaging in patients with ischemic stroke. Recently, cellular MR imaging with specific contrast agents has been developed to visualize targeted cells in human stroke patients. This article reviews the current status in the clinical applications of those molecular imaging methods for patients with ischemic stroke.

Beyond the Sparsity-Based Target Detector: A Hybrid Sparsity and Statistics Based Detector for Hyperspectral Images.

PubMed

Du, Bo; Zhang, Yuxiang; Zhang, Liangpei; Tao, Dacheng

2016-08-18

Hyperspectral images provide great potential for target detection, however, new challenges are also introduced for hyperspectral target detection, resulting that hyperspectral target detection should be treated as a new problem and modeled differently. Many classical detectors are proposed based on the linear mixing model and the sparsity model. However, the former type of model cannot deal well with spectral variability in limited endmembers, and the latter type of model usually treats the target detection as a simple classification problem and pays less attention to the low target probability. In this case, can we find an efficient way to utilize both the high-dimension features behind hyperspectral images and the limited target information to extract small targets? This paper proposes a novel sparsitybased detector named the hybrid sparsity and statistics detector (HSSD) for target detection in hyperspectral imagery, which can effectively deal with the above two problems. The proposed algorithm designs a hypothesis-specific dictionary based on the prior hypotheses for the test pixel, which can avoid the imbalanced number of training samples for a class-specific dictionary. Then, a purification process is employed for the background training samples in order to construct an effective competition between the two hypotheses. Next, a sparse representation based binary hypothesis model merged with additive Gaussian noise is proposed to represent the image. Finally, a generalized likelihood ratio test is performed to obtain a more robust detection decision than the reconstruction residual based detection methods. Extensive experimental results with three hyperspectral datasets confirm that the proposed HSSD algorithm clearly outperforms the stateof- the-art target detectors.

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential

PubMed Central

Wang, Lulu; Habib, Amyn A.; Mintz, Akiva; Li, King C.; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood–brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors. PMID:28654387

Phosphatidylserine-Targeted Nanotheranostics for Brain Tumor Imaging and Therapeutic Potential.

PubMed

Wang, Lulu; Habib, Amyn A; Mintz, Akiva; Li, King C; Zhao, Dawen

2017-01-01

Phosphatidylserine (PS), the most abundant anionic phospholipid in cell membrane, is strictly confined to the inner leaflet in normal cells. However, this PS asymmetry is found disruptive in many tumor vascular endothelial cells. We discuss the underlying mechanisms for PS asymmetry maintenance in normal cells and its loss in tumor cells. The specificity of PS exposure in tumor vasculature but not normal blood vessels may establish it a useful biomarker for cancer molecular imaging. Indeed, utilizing PS-targeting antibodies, multiple imaging probes have been developed and multimodal imaging data have shown their high tumor-selective targeting in various cancers. There is a critical need for improved diagnosis and therapy for brain tumors. We have recently established PS-targeted nanoplatforms, aiming to enhance delivery of imaging contrast agents across the blood-brain barrier to facilitate imaging of brain tumors. Advantages of using the nanodelivery system, in particular, lipid-based nanocarriers, are discussed here. We also describe our recent research interest in developing PS-targeted nanotheranostics for potential image-guided drug delivery to treat brain tumors.

A smart telerobotic system driven by monocular vision

NASA Technical Reports Server (NTRS)

Defigueiredo, R. J. P.; Maccato, A.; Wlczek, P.; Denney, B.; Scheerer, J.

1994-01-01

A robotic system that accepts autonomously generated motion and control commands is described. The system provides images from the monocular vision of a camera mounted on a robot's end effector, eliminating the need for traditional guidance targets that must be predetermined and specifically identified. The telerobotic vision system presents different views of the targeted object relative to the camera, based on a single camera image and knowledge of the target's solid geometry.

a Coarse-To Model for Airplane Detection from Large Remote Sensing Images Using Saliency Modle and Deep Learning

NASA Astrophysics Data System (ADS)

Song, Z. N.; Sui, H. G.

2018-04-01

High resolution remote sensing images are bearing the important strategic information, especially finding some time-sensitive-targets quickly, like airplanes, ships, and cars. Most of time the problem firstly we face is how to rapidly judge whether a particular target is included in a large random remote sensing image, instead of detecting them on a given image. The problem of time-sensitive-targets target finding in a huge image is a great challenge: 1) Complex background leads to high loss and false alarms in tiny object detection in a large-scale images. 2) Unlike traditional image retrieval, what we need to do is not just compare the similarity of image blocks, but quickly find specific targets in a huge image. In this paper, taking the target of airplane as an example, presents an effective method for searching aircraft targets in large scale optical remote sensing images. Firstly, we used an improved visual attention model utilizes salience detection and line segment detector to quickly locate suspected regions in a large and complicated remote sensing image. Then for each region, without region proposal method, a single neural network predicts bounding boxes and class probabilities directly from full images in one evaluation is adopted to search small airplane objects. Unlike sliding window and region proposal-based techniques, we can do entire image (region) during training and test time so it implicitly encodes contextual information about classes as well as their appearance. Experimental results show the proposed method is quickly identify airplanes in large-scale images.

Riboswitch-Mediated Aptamer Binding for Imaging and Therapy (RABIT): A Novel Technique to Selectively Target an Intracellular Ligand Specific for Ovarian Cancer

DTIC Science & Technology

2014-10-01

AD_________________ Award Number: W81XWH-12-1-0554 TITLE: Riboswitch-Mediated Aptamer Binding for...TITLE AND SUBTITLE Riboswitch-Mediated Aptamer Binding for Imaging and Therapy (RABIT): A Novel Technique to Selectively Target an Intracellular...for imaging and low toxicity for therapy. We will make a riboswitch consisting of two aptamers and a sensor region that can hybridize with the

Multishot Targeted PROPELLER Magnetic Resonance Imaging: Description of the Technique and Initial Applications

PubMed Central

Deng, Jie; Larson, Andrew C.

2010-01-01

Objectives To test the feasibility of combining inner-volume imaging (IVI) techniques with conventional multishot periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) techniques for targeted-PROPELLER magnetic resonance imaging. Materials and Methods Perpendicular section-selective gradients for spatially selective excitation and refocusing RF pulses were applied to limit the refocused field-of-view (FOV) along the phase-encoding direction for each rectangular blade image. We performed comparison studies in phantoms and normal volunteers by using targeted-PROPELLER methods for a wide range of imaging applications that commonly use turbo-spin-echo (TSE) approaches (brain, abdominal, vessel wall, cardiac). Results In these initial studies, we demonstrated the feasibility of using targeted-PROPELLER approaches to limit the imaging FOV thereby reducing the number of blades or permitting increased spatial resolution without commensurate increases in scan time. Both phantom and in vivo motion studies demonstrated the potential for more robust regional self-navigated motion correction compared with conventional full FOV PROPELLER methods. Conclusion We demonstrated that the reduced FOV targeted-PROPELLER technique offers the potential for reducing imaging time, increasing spatial resolution, and targeting specific areas for robust regional motion correction. PMID:19465860

A CRISPR/molecular beacon hybrid system for live-cell genomic imaging.

PubMed

Wu, Xiaotian; Mao, Shiqi; Yang, Yantao; Rushdi, Muaz N; Krueger, Christopher J; Chen, Antony K

2018-04-30

The clustered regularly interspersed short palindromic repeat (CRISPR) gene-editing system has been repurposed for live-cell genomic imaging, but existing approaches rely on fluorescent protein reporters, making sensitive and continuous imaging difficult. Here, we present a fluorophore-based live-cell genomic imaging system that consists of a nuclease-deactivated mutant of the Cas9 protein (dCas9), a molecular beacon (MB), and an engineered single-guide RNA (sgRNA) harboring a unique MB target sequence (sgRNA-MTS), termed CRISPR/MB. Specifically, dCas9 and sgRNA-MTS are first co-expressed to target a specific locus in cells, followed by delivery of MBs that can then hybridize to MTS to illuminate the target locus. We demonstrated the feasibility of this approach for quantifying genomic loci, for monitoring chromatin dynamics, and for dual-color imaging when using two orthogonal MB/MTS pairs. With flexibility in selecting different combinations of fluorophore/quencher pairs and MB/MTS sequences, our CRISPR/MB hybrid system could be a promising platform for investigating chromatin activities.

Magnetic Resonance Imaging Targeted Biopsy Improves Selection of Patients Considered for Active Surveillance for Clinically Low Risk Prostate Cancer Based on Systematic Biopsies.

PubMed

Ouzzane, Adil; Renard-Penna, Raphaele; Marliere, François; Mozer, Pierre; Olivier, Jonathan; Barkatz, Johann; Puech, Philippe; Villers, Arnauld

2015-08-01

Current selection criteria for active surveillance based on systematic biopsy underestimate prostate cancer volume and grade. We investigated the role of additional magnetic resonance imaging targeted biopsy in reclassifying patients eligible for active surveillance based on systematic biopsy. We performed a study at 2 institutions in a total of 281 men with increased prostate specific antigen. All men met certain criteria, including 1) prebiopsy magnetic resonance imaging, 12-core transrectal systematic biopsy and 2 additional magnetic resonance imaging targeted biopsies of lesions suspicious for cancer during the same sequence as systematic biopsy, and 2) eligibility for active surveillance based on systematic biopsy results. Criteria for active surveillance were prostate specific antigen less than 10 ng/ml, no Gleason grade 4/5, 5 mm or less involvement of any biopsy core and 2 or fewer positive systematic biopsy cores. Patient characteristics were compared between reclassified and nonreclassified groups based on magnetic resonance imaging targeted biopsy results. On magnetic resonance imaging 58% of the 281 patients had suspicious lesions. Magnetic resonance imaging targeted biopsy was positive for cancer in 81 of 163 patients (50%). Of 281 patients 28 (10%) were reclassified by magnetic resonance imaging targeted biopsy as ineligible for active surveillance based on Gleason score in 8, cancer length in 20 and Gleason score plus cancer length in 9. Suspicious areas on magnetic resonance imaging were in the anterior part of the prostate in 15 of the 28 men (54%). Reclassified patients had a smaller prostate volume (37 vs 52 cc) and were older (66.5 vs 63 years) than those who were not reclassified (p < 0.05). Magnetic resonance imaging targeted biopsy reclassified 10% of patients who were eligible for active surveillance based on systematic biopsy. Its incorporation into the active surveillance eligibility criteria may decrease the risk of reclassification to higher stages during followup. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Matched pairs dosimetry: 124I/131I metaiodobenzylguanidine and 124I/131I and 86Y/90Y antibodies.

PubMed

Lopci, Egesta; Chiti, Arturo; Castellani, Maria Rita; Pepe, Giovanna; Antunovic, Lidija; Fanti, Stefano; Bombardieri, Emilio

2011-05-01

The technological advances in imaging and production of radiopharmaceuticals are driving an innovative way of evaluating the targets for antineoplastic therapies. Besides the use of imaging to better delineate the volume of external beam radiation therapy in oncology, modern imaging techniques are able to identify targets for highly specific medical therapies, using chemotherapeutic drugs and antiangiogenesis molecules. Moreover, radionuclide imaging is able to select targets for radionuclide therapy and to give the way to in vivo dose calculation to target tissues and to critical organs. This contribution reports the main studies published on matched pairs dosimetry with (124)I/(131)I- and (86)Y/(90)Y-labelled radiopharmaceuticals, with an emphasis on metaiodobenzylguanidine (MIBG) and monoclonal antibodies.

Molecular imaging of rheumatoid arthritis: emerging markers, tools, and techniques

PubMed Central

2014-01-01

Early diagnosis and effective monitoring of rheumatoid arthritis (RA) are important for a positive outcome. Instant treatment often results in faster reduction of inflammation and, as a consequence, less structural damage. Anatomical imaging techniques have been in use for a long time, facilitating diagnosis and monitoring of RA. However, mere imaging of anatomical structures provides little information on the processes preceding changes in synovial tissue, cartilage, and bone. Molecular imaging might facilitate more effective diagnosis and monitoring in addition to providing new information on the disease pathogenesis. A limiting factor in the development of new molecular imaging techniques is the availability of suitable probes. Here, we review which cells and molecules can be targeted in the RA joint and discuss the advances that have been made in imaging of arthritis with a focus on such molecular targets as folate receptor, F4/80, macrophage mannose receptor, E-selectin, intercellular adhesion molecule-1, phosphatidylserine, and matrix metalloproteinases. In addition, we discuss a new tool that is being introduced in the field, namely the use of nanobodies as tracers. Finally, we describe additional molecules displaying specific features in joint inflammation and propose these as potential new molecular imaging targets, more specifically receptor activator of nuclear factor κB and its ligand, chemokine receptors, vascular cell adhesion molecule-1, αVβ3 integrin, P2X7 receptor, suppression of tumorigenicity 2, dendritic cell-specific transmembrane protein, and osteoclast-stimulatory transmembrane protein. PMID:25099015

Thermoacoustic molecular tomography with magnetic nanoparticle contrast agents for targeted tumor detection.

PubMed

Nie, Liming; Ou, Zhongmin; Yang, Sihua; Xing, Da

2010-08-01

The primary feasibility steps of demonstrating the ability of microwave-induced thermoacoustic (TA) in phantoms have been previously reported. However, none were shown to target a diseased site in living subjects in thermoacoustic tomography (TAT) field so far. To determine the expressions of oncogenic surface molecules, it is quite necessary to image tumor lesions and acquire pathogenic status on them via TAT. Compared to biological tissues, iron oxide nanoparticles have a much higher microwave absorbance. Fe3O4/polyaniline (PANI) nanoparticles were prepared via polymerization of aniline in the Fe304 superparamagnetic fluids. Then Fe3O4/PANI was conjugated to folic acid (FA), which can bind specifically to the surface of the folate receptor used as a tumor marker. FA-Fe3O4/PANI targeted tumor was irradiated by pulsed microwave at 6 GHz for thermoacoustic detection and imaging. The effect of the Fe3O4/PANI superparamagnetic nanoparticles for enhancing TAT images was successfully investigated in ex vivo human blood and in vivo mouse tail. Intravenous administration of the targeted nanoparticles to mice bearing tumors showed fivefold greater thermoacoustic signal and much longer elimination time than that of mice injected with nontargeted nanoparticles in the tumor. The specific targeting ability of FA-Fe3O4/PANI to tumor was also verified on fluorescence microscopy. Fabricated iron oxide nanoparticles conjugated with tumor ligands for targeted TAT tumor detection at the molecular level was reported for the first time. The results indicate that thermoacoustic molecular imaging with functionalized iron oxide nanoparticles may contribute to targeted and functional early cancer imaging. Also, the modified iron oxide nanoparticles combined with suitable tumor markers may also be used as novel nanomaterials for targeted and guided cancer thermal therapy.

Robust multi-atlas label propagation by deep sparse representation

PubMed Central

Zu, Chen; Wang, Zhengxia; Zhang, Daoqiang; Liang, Peipeng; Shi, Yonghong; Shen, Dinggang; Wu, Guorong

2016-01-01

Recently, multi-atlas patch-based label fusion has achieved many successes in medical imaging area. The basic assumption in the current state-of-the-art approaches is that the image patch at the target image point can be represented by a patch dictionary consisting of atlas patches from registered atlas images. Therefore, the label at the target image point can be determined by fusing labels of atlas image patches with similar anatomical structures. However, such assumption on image patch representation does not always hold in label fusion since (1) the image content within the patch may be corrupted due to noise and artifact; and (2) the distribution of morphometric patterns among atlas patches might be unbalanced such that the majority patterns can dominate label fusion result over other minority patterns. The violation of the above basic assumptions could significantly undermine the label fusion accuracy. To overcome these issues, we first consider forming label-specific group for the atlas patches with the same label. Then, we alter the conventional flat and shallow dictionary to a deep multi-layer structure, where the top layer (label-specific dictionaries) consists of groups of representative atlas patches and the subsequent layers (residual dictionaries) hierarchically encode the patchwise residual information in different scales. Thus, the label fusion follows the representation consensus across representative dictionaries. However, the representation of target patch in each group is iteratively optimized by using the representative atlas patches in each label-specific dictionary exclusively to match the principal patterns and also using all residual patterns across groups collaboratively to overcome the issue that some groups might be absent of certain variation patterns presented in the target image patch. Promising segmentation results have been achieved in labeling hippocampus on ADNI dataset, as well as basal ganglia and brainstem structures, compared to other counterpart label fusion methods. PMID:27942077

Robust multi-atlas label propagation by deep sparse representation.

PubMed

Zu, Chen; Wang, Zhengxia; Zhang, Daoqiang; Liang, Peipeng; Shi, Yonghong; Shen, Dinggang; Wu, Guorong

2017-03-01

Recently, multi-atlas patch-based label fusion has achieved many successes in medical imaging area. The basic assumption in the current state-of-the-art approaches is that the image patch at the target image point can be represented by a patch dictionary consisting of atlas patches from registered atlas images. Therefore, the label at the target image point can be determined by fusing labels of atlas image patches with similar anatomical structures. However, such assumption on image patch representation does not always hold in label fusion since (1) the image content within the patch may be corrupted due to noise and artifact; and (2) the distribution of morphometric patterns among atlas patches might be unbalanced such that the majority patterns can dominate label fusion result over other minority patterns. The violation of the above basic assumptions could significantly undermine the label fusion accuracy. To overcome these issues, we first consider forming label-specific group for the atlas patches with the same label. Then, we alter the conventional flat and shallow dictionary to a deep multi-layer structure, where the top layer ( label-specific dictionaries ) consists of groups of representative atlas patches and the subsequent layers ( residual dictionaries ) hierarchically encode the patchwise residual information in different scales. Thus, the label fusion follows the representation consensus across representative dictionaries. However, the representation of target patch in each group is iteratively optimized by using the representative atlas patches in each label-specific dictionary exclusively to match the principal patterns and also using all residual patterns across groups collaboratively to overcome the issue that some groups might be absent of certain variation patterns presented in the target image patch. Promising segmentation results have been achieved in labeling hippocampus on ADNI dataset, as well as basal ganglia and brainstem structures, compared to other counterpart label fusion methods.

Adaptive tight frame based medical image reconstruction: a proof-of-concept study for computed tomography

NASA Astrophysics Data System (ADS)

Zhou, Weifeng; Cai, Jian-Feng; Gao, Hao

2013-12-01

A popular approach for medical image reconstruction has been through the sparsity regularization, assuming the targeted image can be well approximated by sparse coefficients under some properly designed system. The wavelet tight frame is such a widely used system due to its capability for sparsely approximating piecewise-smooth functions, such as medical images. However, using a fixed system may not always be optimal for reconstructing a variety of diversified images. Recently, the method based on the adaptive over-complete dictionary that is specific to structures of the targeted images has demonstrated its superiority for image processing. This work is to develop the adaptive wavelet tight frame method image reconstruction. The proposed scheme first constructs the adaptive wavelet tight frame that is task specific, and then reconstructs the image of interest by solving an l1-regularized minimization problem using the constructed adaptive tight frame system. The proof-of-concept study is performed for computed tomography (CT), and the simulation results suggest that the adaptive tight frame method improves the reconstructed CT image quality from the traditional tight frame method.

Molecular Imaging Probes for Positron Emission Tomography and Optical Imaging of Sentinel Lymph Node and Tumor

NASA Astrophysics Data System (ADS)

Qin, Zhengtao

Molecular imaging is visualizations and measurements of in vivo biological processes at the molecular or cellular level using specific imaging probes. As an emerging technology, biocompatible macromolecular or nanoparticle based targeted imaging probes have gained increasing popularities. Those complexes consist of a carrier, an imaging reporter, and a targeting ligand. The active targeting ability dramatically increases the specificity. And the multivalency effect may further reduce the dose while providing a decent signal. In this thesis, sentinel lymph node (SLN) mapping and cancer imaging are two research topics. The focus is to develop molecular imaging probes with high specificity and sensitivity, for Positron Emission Tomography (PET) and optical imaging. The objective of this thesis is to explore dextran radiopharmaceuticals and porous silicon nanoparticles based molecular imaging agents. Dextran polymers are excellent carriers to deliver imaging reporters or therapeutic agents due to its well established safety profile and oligosaccharide conjugation chemistry. There is also a wide selection of dextran polymers with different lengths. On the other hand, Silicon nanoparticles represent another class of biodegradable materials for imaging and drug delivery. The success in fluorescence lifetime imaging and enhancements of the immune activation potency was briefly discussed. Chapter 1 begins with an overview on current molecular imaging techniques and imaging probes. Chapter 2 presents a near-IR dye conjugated probe, IRDye 800CW-tilmanocept. Fluorophore density was optimized to generate the maximum brightness. It was labeled with 68Ga and 99mTc and in vivo SLN mapping was successfully performed in different animals, such as mice, rabbits, dogs and pigs. With 99mTc labeled IRDye 800CW-tilmanocept, chapter 3 introduces a two-day imaging protocol with a hand-held imager. Chapter 4 proposed a method to dual radiolabel the IRDye 800CW-tilmanocept with both 68Ga and 99mTc. Chapter 5 introduces a 68Ga metal chelating bioorthogonal tetrazine dextran probe for multistep imaging of a colon cancer. Chapter 6 presents the synthesis and in vivo evaluation of a Hepatocellular Carcinoma targeting PET probe 68Ga-Insulin-Dextran. Chapter 7 discusses a novel method to prepare silicon nanoparticles with great yield and size control. The last chapter 8 concludes all probes developed in this thesis and their clinical relevance.

Target-specific contrast agents for magnetic resonance microscopy

PubMed Central

Blackwell, Megan L.; Farrar, Christian T.; Fischl, Bruce; Rosen, Bruce R.

2009-01-01

High-resolution ex vivo magnetic resonance (MR) imaging can be used to delineate prominent architectonic features in the human brain, but increased contrast is required to visualize more subtle distinctions. To aid MR sensitivity to cell density and myelination, we have begun the development of target-specific paramagnetic contrast agents. This work details the first application of luxol fast blue (LFB), an optical stain for myelin, as a white matter-selective MR contrast agent for human ex vivo brain tissue. Formalin-fixed human visual cortex was imaged with an isotropic resolution between 80 and 150 μm at 4.7 and 14 T before and after en bloc staining with LFB. Longitudinal (R1) and transverse (R2) relaxation rates in LFB-stained tissue increased proportionally with myelination at both field strengths. Changes in R1 resulted in larger contrast-to-noise ratios (CNR), per unit time, on T1-weighted images between more myelinated cortical layers (IV–VI) and adjacent, superficial layers (I–III) at both field strengths. Specifically, CNR for LFB-treated samples increased by 229±13% at 4.7 T and 269±25% at 14 T when compared to controls. Also, additional cortical layers (IVca, IVd, and Va) were resolvable in 14T-MR images of LFB-treated samples but not in control samples. After imaging, samples were sliced in 40-micron sections, mounted, and photographed. Both the macroscopic and microscopic distributions of LFB were found to mimic those of traditional histological preparations. Our results suggest target-specific contrast agents will enable more detailed MR images with applications in imaging pathological ex vivo samples and constructing better MR atlases from ex vivo brains. PMID:19385012

Chemically-defined camelid antibody bioconjugate for the magnetic resonance imaging of Alzheimer's disease.

PubMed

Vandesquille, Matthias; Li, Tengfei; Po, Chrystelle; Ganneau, Christelle; Lenormand, Pascal; Dudeffant, Clémence; Czech, Christian; Grueninger, Fiona; Duyckaerts, Charles; Delatour, Benoît; Dhenain, Marc; Lafaye, Pierre; Bay, Sylvie

Today, molecular imaging of neurodegenerative diseases is mainly based on small molecule probes. Alternatively, antibodies are versatile tools that may be developed as new imaging agents. Indeed, they can be readily obtained to specifically target any antigen of interest and their scaffold can be functionalized. One of the critical issues involved in translating antibody-based probes to the clinic is the design and synthesis of perfectly-defined conjugates. Camelid single-domain antibody-fragments (VHHs) are very small and stable antibodies that are able to diffuse in tissues and potentially cross the blood brain barrier (BBB). Here, we selected a VHH (R3VQ) specifically targeting one of the main lesions of Alzheimer's disease (AD), namely the amyloid-beta (Aß) deposits. It was used as a scaffold for the design of imaging probes for magnetic resonance imaging (MRI) and labeled with the contrastophore gadolinium using either a random or site-specific approach. In contrast to the random strategy, the site-specific conjugation to a single reduced cysteine in the C-terminal part of the R3VQ generates a well-defined bioconjugate in a high yield process. This new imaging probe is able to cross the BBB and label Aß deposits after intravenous injection. Also, it displays improved r1 and r2 relaxivities, up to 30 times higher than a widely used clinical contrast agent, and it allows MRI detection of amyloid deposits in post mortem brain tissue of a mouse model of AD. The ability to produce chemically-defined VHH conjugates that cross the BBB opens the way for future development of tailored imaging probes targeting intracerebral antigens.

Molecular Platform for Design and Synthesis of Targeted Dual-Modality Imaging Probes

PubMed Central

2015-01-01

We report a versatile dendritic structure based platform for construction of targeted dual-modality imaging probes. The platform contains multiple copies of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) branching out from a 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA) core. The specific coordination chemistries of the NOTA and DOTA moieties offer specific loading of 68/67Ga3+ and Gd3+, respectively, into a common molecular scaffold. The platform also contains three amino groups which can potentiate targeted dual-modality imaging of PET/MRI or SPECT/MRI (PET: positron emission tomography; SPECT: single photon emission computed tomography; MRI: magnetic resonance imaging) when further functionalized by targeting vectors of interest. To validate this design concept, a bimetallic complex was synthesized with six peripheral Gd-DOTA units and one Ga-NOTA core at the center, whose ion T1 relaxivity per gadolinium atom was measured to be 15.99 mM–1 s–1 at 20 MHz. Further, the bimetallic agent demonstrated its anticipated in vivo stability, tissue distribution, and pharmacokinetic profile when labeled with 67Ga. When conjugated with a model targeting peptide sequence, the trivalent construct was able to visualize tumors in a mouse xenograft model by both PET and MRI via a single dose injection. PMID:25615011

Tc-99m Labeled and VIP Receptor Targeted Liposomes for Effective Imaging of Breast Cancer

DTIC Science & Technology

2004-09-01

conjugated VIP to an activated DSPE-PEG-NHS and the DSPE-PEG-VIP was inserted into preformed radionuclide (Technetium)-loaded SSL by incubation at 37TC...Chemotherapy with Actively Targeted Phospholipid Nanocarriers". CONCLUSIONS We have successfully conjugated VIP to DSPE-PEG34oo and incorporated this conjugate ...loaded with imaging or therapeutic agents, and with surface ligands specific to VIP-R could potentially be actively targeted to breast cancer. This

Targeted Molecular Imaging of Cancer Cells Using MS2-Based 129 Xe NMR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeong, Keunhong; Netirojjanakul, Chawita; Munch, Henrik K.

Targeted, selective, and highly sensitive 129Xe NMR nanoscale biosensors have been synthesized using a spherical MS2 viral capsid, Cryptophane A molecules, and DNA aptamers. The biosensors showed strong binding specificity toward targeted lymphoma cells (Ramos line). Hyperpolarized 129Xe NMR signal contrast and hyper-CEST 129Xe MRI image contrast indicated its promise as highly sensitive hyperpolarized 129Xe NMR nanoscale biosensor for future applications in cancer detection in vivo.

Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe

NASA Astrophysics Data System (ADS)

Wu, Zhiyuan; Shao, Pin; Zhang, Shaojuan; Ling, Xiaoxi; Bai, Mingfeng

2014-07-01

Cannabinoid CB2 receptors (CB2R) hold promise as therapeutic targets for treating diverse diseases, such as cancers, neurodegenerative diseases, pain, inflammation, osteoporosis, psychiatric disorders, addiction, and immune disorders. However, the fundamental role of CBR in the regulation of diseases remains unclear, largely due to a lack of reliable imaging tools for the receptors. The goal of this study was to develop a CBR-targeted molecular imaging probe and evaluate the specificity of the probe using human tumor cells that naturally overexpress CBR. To synthesize the CBR-targeted probe (NIR760-Q), a conjugable CBR ligand based on the quinolone structure was first prepared, followed by bioconjugation with a near-infrared (NIR) fluorescent dye, NIR760. In vitro fluorescence imaging and competitive binding studies showed higher uptake of NIR760-Q than free NIR760 dye in Jurkat human acute T-lymphoblastic leukemia cells. In addition, the high uptake of NIR760-Q was significantly inhibited by the blocking agent, 4-quinolone-3-carboxamide, indicating specific binding of NIR760-Q to the target receptors. These results indicate that the NIR760-Q has potential in diagnostic imaging of CBR positive cancers and elucidating the role of CBR in the regulation of disease progression.

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

PubMed Central

Jacobson, Orit

2013-01-01

Positron emission tomography (PET) is a noninvasive molecular imaging technology that is becoming increasingly important for the measurement of physiologic, biochemical, and pharmacological functions at cellular and molecular levels in patients with cancer. Formation, development, and aggressiveness of tumor involve a number of molecular pathways, including intrinsic tumor cell mutations and extrinsic interaction between tumor cells and the microenvironment. Currently, evaluation of these processes is mainly through biopsy, which is invasive and limited to the site of biopsy. Ongoing research on specific target molecules of the tumor and its microenvironment for PET imaging is showing great potential. To date, the use of PET for diagnosing local recurrence and metastatic sites of various cancers and evaluation of treatment response is mainly based on [18F]fluorodeoxyglucose ([18F]FDG), which measures glucose metabolism. However, [18F]FDG is not a target-specific PET tracer and does not give enough insight into tumor biology and/or its vulnerability to potential treatments. Hence, there is an increasing need for the development of selective biologic radiotracers that will yield specific biochemical information and allow for noninvasive molecular imaging. The possibility of cancer-associated targets for imaging will provide the opportunity to use PET for diagnosis and therapy response monitoring (theranostics) and thus personalized medicine. This article will focus on the review of non-[18F]FDG PET tracers for specific tumor biology processes and their preclinical and clinical applications. PMID:24064460

Biomarker-specific conjugated nanopolyplexes for the active coloring of stem-like cancer cells

NASA Astrophysics Data System (ADS)

Hong, Yoochan; Lee, Eugene; Choi, Jihye; Haam, Seungjoo; Suh, Jin-Suck; Yang, Jaemoon

2016-06-01

Stem-like cancer cells possess intrinsic features and their CD44 regulate redox balance in cancer cells to survive under stress conditions. Thus, we have fabricated biomarker-specific conjugated polyplexes using CD44-targetable hyaluronic acid and redox-sensible polyaniline based on a nanoemulsion method. For the most sensitive recognition of the cellular redox at a single nanoparticle scale, a nano-scattering spectrum imaging analyzer system was introduced. The conjugated polyplexes showed a specific targeting ability toward CD44-expressing cancer cells as well as a dramatic change in its color, which depended on the redox potential in the light-scattered images. Therefore, these polyaniline-based conjugated polyplexes as well as analytical processes that include light-scattering imaging and measurements of scattering spectra, clearly establish a systematic method for the detection and monitoring of cancer microenvironments.

Multifunctional iron platinum stealth immunomicelles: targeted detection of human prostate cancer cells using both fluorescence and magnetic resonance imaging

NASA Astrophysics Data System (ADS)

Taylor, Robert M.; Huber, Dale L.; Monson, Todd C.; Ali, Abdul-Mehdi S.; Bisoffi, Marco; Sillerud, Laurel O.

2011-10-01

Superparamagnetic iron oxide nanoparticles (SPIONs) are the most common type of contrast agents used in contrast agent-enhanced magnetic resonance imaging (MRI). Still, there is a great deal of room for improvement, and nanoparticles with increased MRI relaxivities are needed to increase the contrast enhancement in MRI applied to various medical conditions including cancer. We report the synthesis of superparamagnetic iron platinum nanoparticles (SIPPs) and subsequent encapsulation using PEGylated phospholipids to create stealth immunomicelles (DSPE-SIPPs) that can be specifically targeted to human prostate cancer cell lines and detected using both MRI and fluorescence imaging. SIPP cores and DSPE-SIPPs were 8.5 ± 1.6 nm and 42.9 ± 8.2 nm in diameter, respectively, and the SIPPs had a magnetic moment of 120 A m2/kg iron. J591, a monoclonal antibody against prostate specific membrane antigen (PSMA), was conjugated to the DSPE-SIPPs (J591-DSPE-SIPPs), and specific targeting of J591-DSPE-SIPPs to PSMA-expressing human prostate cancer cell lines was demonstrated using fluorescence confocal microscopy. The transverse relaxivity of the DSPE-SIPPs, measured at 4.7 Tesla, was 300.6 ± 8.5 s-1 mM-1, which is 13-fold better than commercially available SPIONs (23.8 ± 6.9 s-1 mM-1) and 3-fold better than reported relaxivities for Feridex® and Resovist®. Our data suggest that J591-DSPE-SIPPs specifically target human prostate cancer cells in vitro, are superior contrast agents in T 2-weighted MRI, and can be detected using fluorescence imaging. To our knowledge, this is the first report on the synthesis of multifunctional SIPP micelles and using SIPPs for the specific detection of prostate cancer.

Reliability of image-free navigation to monitor lower-limb alignment.

PubMed

Pearle, Andrew D; Goleski, Patrick; Musahl, Volker; Kendoff, Daniel

2009-02-01

Proper alignment of the mechanical axis of the lower limb is the principal goal of a high tibial osteotomy. A well-accepted and relevant technical specification is the coronal plane lower-limb alignment. Target values for coronal plane alignment after high tibial osteotomy include 2 degrees of overcorrection, while tolerances for this specification have been established as 2 degrees to 4 degrees. However, the role of axial plane and sagittal plane realignment after high tibial osteotomy is poorly understood; consequently, targets and tolerance for this technical specification remain undefined. This article reviews the literature concerning the reliability and precision of navigation in monitoring the clinically relevant specification of lower-limb alignment in high tibial osteotomy. We conclude that image-free navigation registration may be clinically useful for intraoperative monitoring of the coronal plane only. Only fair and poor results for the axial and sagittal planes can be obtained by image-free navigation systems. In the future, combined image-based data, such as those from radiographs, magnetic resonance imaging, and gait analysis, may be used to help to improve the accuracy and reproducibility of quantitative intraoperative monitoring of lower-limb alignment.

Heterobivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen (PSMA) and Hepsin

DTIC Science & Technology

2014-11-01

Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin PRINCIPAL INVESTIGATOR: Youngjoo Byun, Ph. D. CONTRACTING ORGANIZATION: Korea...Simultaneous Targeting Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin 5b. GRANT NUMBER W81XWH-10-1-0189 5c. PROGRAM ELEMENT NUMBER 6...heterobivalent conjugates of PSMA /hepsin-binding ligands labeled with optical dyes or radionuclides. The sensitivity and accuracy of prostate cancer

Effective evaluation of privacy protection techniques in visible and thermal imagery

NASA Astrophysics Data System (ADS)

Nawaz, Tahir; Berg, Amanda; Ferryman, James; Ahlberg, Jörgen; Felsberg, Michael

2017-09-01

Privacy protection may be defined as replacing the original content in an image region with a (less intrusive) content having modified target appearance information to make it less recognizable by applying a privacy protection technique. Indeed, the development of privacy protection techniques also needs to be complemented with an established objective evaluation method to facilitate their assessment and comparison. Generally, existing evaluation methods rely on the use of subjective judgments or assume a specific target type in image data and use target detection and recognition accuracies to assess privacy protection. An annotation-free evaluation method that is neither subjective nor assumes a specific target type is proposed. It assesses two key aspects of privacy protection: "protection" and "utility." Protection is quantified as an appearance similarity, and utility is measured as a structural similarity between original and privacy-protected image regions. We performed an extensive experimentation using six challenging datasets (having 12 video sequences), including a new dataset (having six sequences) that contains visible and thermal imagery. The new dataset is made available online for the community. We demonstrate effectiveness of the proposed method by evaluating six image-based privacy protection techniques and also show comparisons of the proposed method over existing methods.

Prostate-specific membrane antigen as a target for cancer imaging and therapy

PubMed Central

KIESS, A. P.; BANERJEE, S. R.; MEASE, R. C.; ROWE, S. P.; RAO, A.; FOSS, C. A.; CHEN, Y.; YANG, X.; CHO, S. Y.; NIMMAGADDA, S.; POMPER, M. G.

2016-01-01

The prostate-specific membrane antigen (PSMA) is a molecular target whose use has resulted in some of the most productive work toward imaging and treating prostate cancer over the past two decades. A wide variety of imaging agents extending from intact antibodies to low-molecular-weight compounds permeate the literature. In parallel there is a rapidly expanding pool of antibody-drug conjugates, radiopharmaceutical therapeutics, small-molecule drug conjugates, theranostics and nanomedicines targeting PSMA. Such productivity is motivated by the abundant expression of PSMA on the surface of prostate cancer cells and within the neovasculature of other solid tumors, with limited expression in most normal tissues. Animating the field is a variety of small-molecule scaffolds upon which the radionuclides, drugs, MR-detectable species and nanoparticles can be placed with relative ease. Among those, the urea-based agents have been most extensively leveraged, with expanding clinical use for detection and more recently for radiopharmaceutical therapy of prostate cancer, with surprisingly little toxicity. PSMA imaging of other cancers is also appearing in the clinical literature, and may overtake FDG for certain indications. Targeting PSMA may provide a viable alternative or first-line approach to managing prostate and other cancers. PMID:26213140

Near-infrared optical imaging in glioblastoma xenograft with ligand targeting α3 integrin

PubMed Central

Xiao, Wenwu; Yao, Nianhuan; Peng, Li; Liu, Ruiwu; Lam, Kit S

2010-01-01

Purpose Patients with glioblastoma usually have a very poor prognosis. Even with a combination of radiotherapy plus temozolomide, the median survival of these patients is only 14.6 months. New treatment approaches to this cancer are needed. Our purpose is to develop new cell-surface binding ligands for glioblastoma cells, and use them as targeted imaging and therapeutic agents for this deadly disease. Methods One-bead one-compound combinatorial cyclic peptide libraries were screened with live human glioblastoma U-87MG cells. The binding affinity and targeting specificity of peptides identified were tested with in vitro experiments on cells and in vivo, and ex vivo experiments on U-87MG xegnograft mouse model. Results A cyclic peptide, LXY1, was identified and shown to be binding to the α3 integrin of U-87MG cells with moderately high affinity (Kd = 0.5+/−0.1 μM) and high specificity. Biotinylated LXY1, when complexed with streptavidin-Cy5.5 (SA-Cy5.5) conjugate, targeted both subcutaneous and orthotopic U-87MG xenograft implants in nude mice. The in vivo targeting specificity was further verified by strong inhibition of tumor uptake of LXY1-biotin-SA-Cy5.5 complex when intravenously injecting the animals with anti-α3 integrin antibody or excess unlabeled LXY1 prior to administrating the imaging probe. The smaller univalent LXY1-Cy5.5 conjugate (2279 Da) was found to have a faster accumulation in the U-87MG tumor and shorter retention time compared with the larger tetravalent LXY1-biotin-SA-Cy5.5 complex (~ 64 KDa). Conclusions Collectively, the data reveals that LXY1 has the potential to be developed into an effective imaging and therapeutic targeting agent for human glioblastoma. PMID:18712382

RGD peptide-targeted polyethylenimine-entrapped gold nanoparticles for targeted CT imaging of an orthotopic model of human hepatocellular carcinoma

NASA Astrophysics Data System (ADS)

Zhou, Benqing; Wang, Meng; Zhou, Feifan; Song, Jun; Qu, Junle; Chen, Wei R.

2018-02-01

We report the synthesis and characterization of arginine-glycine-aspartic acid (RGD) peptide-targeted polyethylenimine (PEI)-entrapped gold nanoparticles (RGD-Au PENPs) for targeted CT imaging of hepatic carcinomas in situ. In this work, PEI sequentially modified with polyethylene glycol (PEG), and RGD linked-PEG was used as a nanoplatform to prepare AuNPs, followed by complete acetylation of PEI surface amines. We showed that the designed RGD-Au PENPs were colloidally stable and biocompatible in the given concentration range, and could be specifically taken up by αvβ3 integrin-overexpressing liver cancer cells in vitro. Furthermore, in vivo CT imaging results revealed that the particles displayed a great contrast enhancement of hepatic carcinomas region, and could target to hepatic carcinomas region in situ. With the proven biodistribution and histological examinations in vivo, the synthesized RGD-Au PENPs show a great formulation to be used as a contrast agent for targeted CT imaging of different αvβ3 integrin receptoroverexpressing tumors.

Quantifying cancer cell receptors with paired-agent fluorescent imaging: a novel method to account for tissue optical property effects

NASA Astrophysics Data System (ADS)

Sadeghipour, Negar; Davis, Scott C.; Tichauer, Kenneth M.

2018-02-01

Dynamic fluorescence imaging approaches can be used to estimate the concentration of cell surface receptors in vivo. Kinetic models are used to generate the final estimation by taking the targeted imaging agent concentration as a function of time. However, tissue absorption and scattering properties cause the final readout signal to be on a different scale than the real fluorescent agent concentration. In paired-agent imaging approaches, simultaneous injection of a suitable control imaging agent with a targeted one can account for non-specific uptake and retention of the targeted agent. Additionally, the signal from the control agent can be a normalizing factor to correct for tissue optical property differences. In this study, the kinetic model used for paired-agent imaging analysis (i.e., simplified reference tissue model) is modified and tested in simulation and experimental data in a way that accounts for the scaling correction within the kinetic model fit to the data to ultimately extract an estimate of the targeted biomarker concentration.

Aptamers: Active Targeting Ligands for Cancer Diagnosis and Therapy

PubMed Central

Wu, Xu; Chen, Jiao; Wu, Min; Zhao, Julia Xiaojun

2015-01-01

Aptamers, including DNA, RNA and peptide aptamers, are a group of promising recognition units that can specifically bind to target molecules and cells. Due to their excellent specificity and high affinity to targets, aptamers have attracted great attention in various fields in which selective recognition units are required. They have been used in biosensing, drug delivery, disease diagnosis and therapy (especially for cancer treatment). In this review, we summarized recent applications of DNA and RNA aptamers in cancer theranostics. The specific binding ability of aptamers to cancer-related markers and cancer cells ensured their high performance for early diagnosis of cancer. Meanwhile, the efficient targeting ability of aptamers to cancer cells and tissues provided a promising way to deliver imaging agents and drugs for cancer imaging and therapy. Furthermore, with the development of nanoscience and nanotechnology, the conjugation of aptamers with functional nanomaterials paved an exciting way for the fabrication of theranostic agents for different types of cancers, which might be a powerful tool for cancer treatment. PMID:25699094

Tumor homing indocyanine green encapsulated micelles for near infrared and photoacoustic imaging of tumors.

PubMed

Uthaman, Saji; Bom, Joon-suk; Kim, Hyeon Sik; John, Johnson V; Bom, Hee-Seung; Kim, Seon-Jong; Min, Jung-Joon; Kim, Il; Park, In-Kyu

2016-05-01

Photoacoustic imaging (PAI) is an emerging analytical modality that is under intense preclinical development for the early diagnosis of various medical conditions, including cancer. However, the lack of specific tumor targeting by various contrast agents used in PAI obstructs its clinical applications. In this study, we developed indocyanine green (ICG)-encapsulated micelles specific for the CD 44 receptor and used in near infrared and photoacoustic imaging of tumors. ICG was hydrophobically modified prior to loading into hyaluronic acid (HA)-based micelles utilized for CD 44 based-targeting. We investigated the physicochemical characteristics of prepared HA only and ICG-encapsulated HA micelles (HA-ICG micelles). After intravenous injection of tumor-bearing mice, the bio-distribution and in vivo photoacoustic images of ICG-encapsulated HA micelles accumulating in tumors were also investigated. Our study further encourages the application of this HA-ICG-based nano-platform as a tumor-specific contrast agent for PAI. © 2016 Wiley Periodicals, Inc.

Imaging of oxidation-specific epitopes with targeted nanoparticles to detect high-risk atherosclerotic lesions: Progress and future directions

PubMed Central

Briley-Saebo, Karen; Yeang, Calvin; Witztum, Joseph L.; Tsimikas, Sotirios

2014-01-01

Oxidation-specific epitopes (OSE) within developing atherosclerotic lesions are key antigens that drive innate and adaptive immune responses in atherosclerosis, leading to chronic inflammation. Oxidized phospholipids and malondialdehyde-lysine epitopes are well-characterized OSE present in human atherosclerotic lesions, particularly in pathologically defined vulnerable plaques. Using murine and human OSE-specific antibodies as targeting agents, we have developed radionuclide and magnetic resonance based nanoparticles, containing gadolinium, manganese or lipid-coated ultrasmall superparamagnetic iron oxide, to noninvasively image OSE within experimental atherosclerotic lesions. These methods quantitate plaque burden, allow detection of lesion progression and regression, plaque stabilization, and accumulation of OSE within macrophage-rich areas of the artery wall, suggesting they detect the most active lesions. Future studies will focus on using “natural” antibodies, lipopeptides and mimotopes for imaging applications. These approaches should enhance the clinical translation of this technique to image, monitor, evaluate efficacy of novel therapeutic agents and guide optimal therapy of high-risk atherosclerotic lesions. PMID:25297940

Optical imaging of gastric cancer with near-infrared heptamethine carbocyanine fluorescence dyes.

PubMed

Zhao, Ningning; Zhang, Caiqin; Zhao, Yong; Bai, Bing; An, Jiaze; Zhang, Hai; Wu, Jason Boyang; Shi, Changhong

2016-08-30

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the tumor-specific targeting ability of NIRF heptamethine carbocyanine MHI-148 dye in cultured gastric cancer cells, gastric cancer cell-derived and patient-derived tumor xenograft (PDX) models. We show that the NIRF dye specifically accumulated in tumor regions of both xenograft models, suggesting the potential utility of the dye for tumor-specific imaging and targeting in gastric cancer. We also demonstrated significant correlations between NIRF signal intensity and tumor volume in PDX models. Mechanistically, the higher cellular uptake of MHI-148 in gastric cancer cells than in normal cells was stimulated by hypoxia and activation of a group of organic anion-transporting polypeptide (OATP) genes. Importantly, this NIRF dye was not retained in inflammatory stomach tissues induced by gastric ulcer in mice. In addition, fresh clinical gastric tumor specimens, when perfused with NIR dye, exhibited increased uptake of NIR dye in situ. Together, these results show the possibility of using NIRF dyes as novel candidate agents for clinical imaging and detection of gastric cancer.

In vivo type 2 cannabinoid receptor-targeted tumor optical imaging using a near infrared fluorescent probe.

PubMed

Zhang, Shaojuan; Shao, Pin; Bai, Mingfeng

2013-11-20

The type 2 cannabinoid receptor (CB2R) plays a vital role in carcinogenesis and progression and is emerging as a therapeutic target for cancers. However, the exact role of CB2R in cancer progression and therapy remains unclear. This has driven the increasing efforts to study CB2R and cancers using molecular imaging tools. In addition, many types of cancers overexpress CB2R, and the expression levels of CB2R appear to be associated with tumor aggressiveness. Such upregulation of the receptor in cancer cells provides opportunities for CB2R-targeted imaging with high contrast and for therapy with low side effects. In the present study, we report the first in vivo tumor-targeted optical imaging using a novel CB2R-targeted near-infrared probe. In vitro cell fluorescent imaging and a competitive binding assay indicated specific binding of NIR760-mbc94 to CB2R in CB2-mid delayed brain tumor (DBT) cells. NIR760-mbc94 also preferentially labeled CB2-mid DBT tumors in vivo, with a 3.7-fold tumor-to-normal contrast enhancement at 72 h postinjection, whereas the fluorescence signal from the tumors of the mice treated with NIR760 free dye was nearly at the background level at the same time point. SR144528, a CB2R competitor, significantly inhibited tumor uptake of NIR760-mbc94, indicating that NIR760-mbc94 binds to CB2R specifically. In summary, NIR760-mbc94 specifically binds to CB2R in vitro and in vivo and appears to be a promising molecular tool that may have great potential for use in diagnostic imaging of CB2R-positive cancers and therapeutic monitoring as well as in elucidating the role of CB2R in cancer progression and therapy.

Molecular Imaging of Tumors Using a Quantitative T1 Mapping Technique via Magnetic Resonance Imaging

PubMed Central

Herrmann, Kelsey; Johansen, Mette L.; Craig, Sonya E.; Vincent, Jason; Howell, Michael; Gao, Ying; Lu, Lan; Erokwu, Bernadette; Agnes, Richard S.; Lu, Zheng-Rong; Pokorski, Jonathan K.; Basilion, James; Gulani, Vikas; Griswold, Mark; Flask, Chris; Brady-Kalnay, Susann M.

2015-01-01

Magnetic resonance imaging (MRI) of glioblastoma multiforme (GBM) with molecular imaging agents would allow for the specific localization of brain tumors. Prior studies using T1-weighted MR imaging demonstrated that the SBK2-Tris-(Gd-DOTA)3 molecular imaging agent labeled heterotopic xenograft models of brain tumors more intensely than non-specific contrast agents using conventional T1-weighted imaging techniques. In this study, we used a dynamic quantitative T1 mapping strategy to more objectively compare intra-tumoral retention of the SBK2-Tris-(Gd-DOTA)3 agent over time in comparison to non-targeted control agents. Our results demonstrate that the targeted SBK2-Tris-(Gd-DOTA)3 agent, a scrambled-Tris-(Gd-DOTA)3 control agent, and the non-specific clinical contrast agent Optimark™ all enhanced flank tumors of human glioma cells with similar maximal changes on T1 mapping. However, the retention of the agents differs. The non-specific agents show significant recovery within 20 min by an increase in T1 while the specific agent SBK2-Tris-(Gd-DOTA)3 is retained in the tumors and shows little recovery over 60 min. The retention effect is demonstrated by percent change in T1 values and slope calculations as well as by calculations of gadolinium concentration in tumor compared to muscle. Quantitative T1 mapping demonstrates the superior binding and retention in tumors of the SBK2-Tris-(Gd-DOTA)3 agent over time compared to the non-specific contrast agent currently in clinical use. PMID:26435847

In Vivo Demonstration of Cancer Molecular Imaging with Ultrasound Radiation Force and Buried-Ligand Microbubbles

PubMed Central

Borden, Mark A.; Streeter, Jason E.; Sirsi, Shashank R.; Dayton, Paul A.

2015-01-01

In designing targeted contrast agent materials for imaging, the need to present a targeting ligand for recognition and binding by the target is counterbalanced by the need to minimize interactions with plasma components and to avoid recognition by the immune system. We have previously reported on a microbubble imaging probe for ultrasound molecular imaging that uses a buried-ligand surface architecture to minimize unwanted interactions and immunogenicity. Here we examine for the first time the utility of this approach for in vivo molecular imaging. In accordance with previous results, we showed a threefold increase in circulation persistence through the tumor of a fibrosarcoma model in comparison with controls. The buried-ligand microbubbles were then activated for targeted adhesion through the application of noninvasive ultrasound radiation forces applied specifically to the tumor region. Using a clinical ultrasound scanner, microbubbles were activated, imaged, and silenced. The results showed visually conspicuous images of tumor neovasculature and a twofold increase in ultrasound radiation force enhancement of acoustic contrast intensity for buried-ligand microbubbles, whereas no such increase was found for exposed-ligand microbubbles. We therefore conclude that the use of acoustically active buried-ligand microbubbles for ultrasound molecular imaging bridges the demand for low immunogenicity with the necessity of maintaining targeting efficacy and imaging conspicuity in vivo. PMID:23981781

Molecular imaging with targeted contrast ultrasound.

PubMed

Piedra, Mark; Allroggen, Achim; Lindner, Jonathan R

2009-01-01

Molecular imaging with contrast-enhanced ultrasound uses targeted microbubbles that are retained in diseased tissue. The resonant properties of these microbubbles produce acoustic signals in an ultrasound field. The microbubbles are targeted to diseased tissue by using certain chemical constituents in the microbubble shell or by attaching disease-specific ligands such as antibodies to the microbubble. In this review, we discuss the applications of this technique to pathological states in the cerebrovascular system including atherosclerosis, tumor angiogenesis, ischemia, intravascular thrombus, and inflammation. Copyright 2009 S. Karger AG, Basel.

Integrated framework for developing search and discrimination metrics

NASA Astrophysics Data System (ADS)

Copeland, Anthony C.; Trivedi, Mohan M.

1997-06-01

This paper presents an experimental framework for evaluating target signature metrics as models of human visual search and discrimination. This framework is based on a prototype eye tracking testbed, the Integrated Testbed for Eye Movement Studies (ITEMS). ITEMS determines an observer's visual fixation point while he studies a displayed image scene, by processing video of the observer's eye. The utility of this framework is illustrated with an experiment using gray-scale images of outdoor scenes that contain randomly placed targets. Each target is a square region of a specific size containing pixel values from another image of an outdoor scene. The real-world analogy of this experiment is that of a military observer looking upon the sensed image of a static scene to find camouflaged enemy targets that are reported to be in the area. ITEMS provides the data necessary to compute various statistics for each target to describe how easily the observers located it, including the likelihood the target was fixated or identified and the time required to do so. The computed values of several target signature metrics are compared to these statistics, and a second-order metric based on a model of image texture was found to be the most highly correlated.

Component-based target recognition inspired by human vision

NASA Astrophysics Data System (ADS)

Zheng, Yufeng; Agyepong, Kwabena

2009-05-01

In contrast with machine vision, human can recognize an object from complex background with great flexibility. For example, given the task of finding and circling all cars (no further information) in a picture, you may build a virtual image in mind from the task (or target) description before looking at the picture. Specifically, the virtual car image may be composed of the key components such as driver cabin and wheels. In this paper, we propose a component-based target recognition method by simulating the human recognition process. The component templates (equivalent to the virtual image in mind) of the target (car) are manually decomposed from the target feature image. Meanwhile, the edges of the testing image can be extracted by using a difference of Gaussian (DOG) model that simulates the spatiotemporal response in visual process. A phase correlation matching algorithm is then applied to match the templates with the testing edge image. If all key component templates are matched with the examining object, then this object is recognized as the target. Besides the recognition accuracy, we will also investigate if this method works with part targets (half cars). In our experiments, several natural pictures taken on streets were used to test the proposed method. The preliminary results show that the component-based recognition method is very promising.

LyP-1 ultrasonic microbubbles targeting to cancer cell as tumor bio-acoustics markers or drug carriers: targeting efficiency evaluation in, microfluidic channels.

PubMed

Li, Xiang; Jin, Qiaofeng; Chen, Tan; Zhang, Baoyue; Zheng, Rongqin; Wang, Zhanhui; Zheng, Hairong

2009-01-01

Using ultrasonic contrast microbubbles as acoustic biomarkers and drug carrier vehicles by conjugating tumor specific antibody to microbubbles has shown great potential in ultrasonic tumor molecular imaging or drug-delivery and therapy. Microbubble probe targeting efficiency is one of the major challenges. In this study, we developed a novel method to evaluate the targeting capability and efficiency of microbubbles to cells, and more specifically, microbubbles binding LyP-1 (a cyclic nonapeptide acid peptide) target to cancer cell within a microfluidic system. The micro cell sieves within the microfludic channels could trap the tumor cells and enhance the microbubble's interaction with the cell. Assisted with the controllable fluid shear stress, the microbubble's targeting to the cell and the corresponding affinity efficiency could be quantitatively evaluated under a florescent microscope. The system provides a useful low-cost high efficient in vitro platform for studying microbubble-cell interaction for ultrasonic tumor molecular imaging or drug-delivery and therapy.

AirMSPI PODEX Big Sur Ellipsoid Images

Atmospheric Science Data Center

2013-12-11

... Browse Images from the PODEX 2013 Campaign   Big Sur target 02/03/2013 Ellipsoid-projected   Select link to ...   Version number   For more information, see the  Data Product Specifications (DPS) ...

Image-based in vivo assessment of targeting accuracy of stereotactic brain surgery in experimental rodent models

NASA Astrophysics Data System (ADS)

Rangarajan, Janaki Raman; Vande Velde, Greetje; van Gent, Friso; de Vloo, Philippe; Dresselaers, Tom; Depypere, Maarten; van Kuyck, Kris; Nuttin, Bart; Himmelreich, Uwe; Maes, Frederik

2016-11-01

Stereotactic neurosurgery is used in pre-clinical research of neurological and psychiatric disorders in experimental rat and mouse models to engraft a needle or electrode at a pre-defined location in the brain. However, inaccurate targeting may confound the results of such experiments. In contrast to the clinical practice, inaccurate targeting in rodents remains usually unnoticed until assessed by ex vivo end-point histology. We here propose a workflow for in vivo assessment of stereotactic targeting accuracy in small animal studies based on multi-modal post-operative imaging. The surgical trajectory in each individual animal is reconstructed in 3D from the physical implant imaged in post-operative CT and/or its trace as visible in post-operative MRI. By co-registering post-operative images of individual animals to a common stereotaxic template, targeting accuracy is quantified. Two commonly used neuromodulation regions were used as targets. Target localization errors showed not only variability, but also inaccuracy in targeting. Only about 30% of electrodes were within the subnucleus structure that was targeted and a-specific adverse effects were also noted. Shifting from invasive/subjective 2D histology towards objective in vivo 3D imaging-based assessment of targeting accuracy may benefit a more effective use of the experimental data by excluding off-target cases early in the study.

Theranostics and metabolotheranostics for precision medicine in oncology

NASA Astrophysics Data System (ADS)

Bhujwalla, Zaver M.; Kakkad, Samata; Chen, Zhihang; Jin, Jiefu; Hapuarachchige, Sudath; Artemov, Dmitri; Penet, Marie-France

2018-06-01

Most diseases, especially cancer, would significantly benefit from precision medicine where treatment is shaped for the individual. The concept of theragnostics or theranostics emerged around 2002 to describe the incorporation of diagnostic assays into the selection of therapy for this purpose. Increasingly, theranostics has been used for strategies that combine noninvasive imaging-based diagnostics with therapy. Within the past decade theranostic imaging has transformed into a rapidly expanding field that is located at the interface of diagnosis and therapy. A critical need in cancer treatment is to minimize damage to normal tissue. Molecular imaging can be applied to identify targets specific to cancer with imaging, design agents against these targets to visualize their delivery, and monitor response to treatment, with the overall purpose of minimizing collateral damage. Genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. With this cancer fingerprint, theranostic agents can be designed to personalize treatment for precision medicine of cancer, and minimize damage to normal tissue. Here, for the first time, we have introduced the term 'metabolotheranostics' to describe strategies where disease-based alterations in metabolic pathways detected by MRS are specifically targeted with image-guided delivery platforms to achieve disease-specific therapy. The versatility of MRI and MRS in molecular and functional imaging makes these technologies especially important in theranostic MRI and 'metabolotheranostics'. Our purpose here is to provide insights into the capabilities and applications of this exciting new field in cancer treatment with a focus on MRI and MRS.

Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions

PubMed Central

Laeseke, Paul F.; Chen, Ru; Jeffrey, R. Brooke; Brentnall, Teresa A.

2015-01-01

Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. © RSNA, 2015 PMID:26599925

Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen.

PubMed

Kulkarni, Harshad R; Singh, Aviral; Langbein, Thomas; Schuchardt, Christiane; Mueller, Dirk; Zhang, Jingjing; Lehmann, Coline; Baum, Richard P

2018-06-01

Alterations at the molecular level are a hallmark of cancer. Prostate cancer is associated with the overexpression of prostate-specific membrane antigen (PSMA) in a majority of cases, predominantly in advanced tumors, increasing with the grade or Gleason's score. PSMA can be selectively targeted using radiolabeled PSMA ligands. These small molecules binding the PSMA can be radiolabeled with γ-emitters like 99m Tc and 111 In or positron emitters like 68 Ga and 18 F for diagnosis as well as with their theranostic pairs such as 177 Lu (β-emitter) or 225 Ac (α-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology.

In Vitro Targeted Photodynamic Therapy with a Pyropheophorbide-a Conjugated Inhibitor of Prostate Specific Membrane Antigen

PubMed Central

Liu, Tiancheng; Wu, Lisa Y.; Choi, Joseph K.; Berkman, Clifford E.

2009-01-01

BACKROUND The lack of specific delivery of photosensitizers (PSs), represents a significant limitation of photodynamic therapy (PDT) of cancer. The biomarker prostate-specific membrane antigen (PSMA) has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. Although recent efforts have been made to conjugate inhibitors of PSMA with imaging agents, there have been no reports on photosensitizer-conjugated PSMA inhibitors for targeted PDT of prostate cancer. The present study focuses on the use of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2) for targeted PDT to achieve apoptosis in PSMA+ LNCaP cells. METHODS Confocal laser scanning microscopy with a combination of nuclear staining and immunofluorescence methods were employed to monitor the specific imaging and PDT-mediated apoptotic effects on PSMA-positive LNCaP and PSMA-negative (PC-3) cells. RESULTS Our results demonstrated that PDT-mediated effects by Ppa-conjugate 2 were specific to LNCaP cells, but not PC-3 cells. Cell permeability was detected as early as 2 h by HOE33342/PI double-staining, becoming more intense by 4 h. Evidence for the apoptotic caspase cascade being activated was based on the appearance of PARP p85 fragment. TUNEL assay detected DNA fragmentation 16 h post-PDT, confirming apoptotic events. CONCLUSIONS Cell permeability by HOE33342/PI double-staining as well as PARP p85 fragment and TUNEL assays confirm cellular apoptosis in PSMA+ cells when treated with PS-inhibitor conjugate 2 and subsequently irradiated. It is expected that the PSMA targeting small-molecule of this conjugate can serve as a delivery vehicle for PDT and other therapeutic applications for prostate cancer. PMID:19142895

In vitro targeted photodynamic therapy with a pyropheophorbide--a conjugated inhibitor of prostate-specific membrane antigen.

PubMed

Liu, Tiancheng; Wu, Lisa Y; Choi, Joseph K; Berkman, Clifford E

2009-05-01

The lack of specific delivery of photosensitizers (PSs), represents a significant limitation of photodynamic therapy (PDT) of cancer. The biomarker prostate-specific membrane antigen (PSMA) has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. Although recent efforts have been made to conjugate inhibitors of PSMA with imaging agents, there have been no reports on PS-conjugated PSMA inhibitors for targeted PDT of prostate cancer. The present study focuses on the use of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2) for targeted PDT to achieve apoptosis in PSMA+ LNCaP cells. Confocal laser scanning microscopy with a combination of nuclear staining and immunofluorescence methods were employed to monitor the specific imaging and PDT-mediated apoptotic effects on PSMA-positive LNCaP and PSMA-negative (PC-3) cells. Our results demonstrated that PDT-mediated effects by Ppa-conjugate 2 were specific to LNCaP cells, but not PC-3 cells. Cell permeability was detected as early as 2 hr by HOE33342/PI double staining, becoming more intense by 4 hr. Evidence for the apoptotic caspase cascade being activated was based on the appearance of poly-ADP-ribose polymerase (PARP) p85 fragment. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay detected DNA fragmentation 16 hr post-PDT, confirming apoptotic events. Cell permeability by HOE33342/PI double staining as well as PARP p85 fragment and TUNEL assays confirm cellular apoptosis in PSMA+ cells when treated with PS-inhibitor conjugate 2 and subsequently irradiated. It is expected that the PSMA targeting small-molecule of this conjugate can serve as a delivery vehicle for PDT and other therapeutic applications for prostate cancer. (c) 2009 Wiley-Liss, Inc.

Target-Oriented High-Resolution SAR Image Formation via Semantic Information Guided Regularizations

NASA Astrophysics Data System (ADS)

Hou, Biao; Wen, Zaidao; Jiao, Licheng; Wu, Qian

2018-04-01

Sparsity-regularized synthetic aperture radar (SAR) imaging framework has shown its remarkable performance to generate a feature enhanced high resolution image, in which a sparsity-inducing regularizer is involved by exploiting the sparsity priors of some visual features in the underlying image. However, since the simple prior of low level features are insufficient to describe different semantic contents in the image, this type of regularizer will be incapable of distinguishing between the target of interest and unconcerned background clutters. As a consequence, the features belonging to the target and clutters are simultaneously affected in the generated image without concerning their underlying semantic labels. To address this problem, we propose a novel semantic information guided framework for target oriented SAR image formation, which aims at enhancing the interested target scatters while suppressing the background clutters. Firstly, we develop a new semantics-specific regularizer for image formation by exploiting the statistical properties of different semantic categories in a target scene SAR image. In order to infer the semantic label for each pixel in an unsupervised way, we moreover induce a novel high-level prior-driven regularizer and some semantic causal rules from the prior knowledge. Finally, our regularized framework for image formation is further derived as a simple iteratively reweighted $\\ell_1$ minimization problem which can be conveniently solved by many off-the-shelf solvers. Experimental results demonstrate the effectiveness and superiority of our framework for SAR image formation in terms of target enhancement and clutters suppression, compared with the state of the arts. Additionally, the proposed framework opens a new direction of devoting some machine learning strategies to image formation, which can benefit the subsequent decision making tasks.

Detection of magnetically enhanced cancer tumors using SQUID magnetometry: A feasibility study

NASA Astrophysics Data System (ADS)

Kenning, G. G.; Rodriguez, R.; Zotev, V. S.; Moslemi, A.; Wilson, S.; Hawel, L.; Byus, C.; Kovach, J. S.

2005-01-01

Nanoparticles bound to various biological molecules and pharmacological agents can be administered systemically, to humans without apparent toxicity. This opens an era in the targeting of specific tissues and disease processes for noninvasive imaging and treatment. An important class of particles used predominantly for magnetic resonance imaging is based on iron-oxide ferrites. We performed computer simulations using experimentally determined values for concentrations of superparamagnetic particles achievable in specific tissues of the mouse in vivo and concentrations of particles linked to monoclonal antibodies specific to antigens of two human cancer cell lines in vitro. An instrument to target distance of 12cm, into the body, was selected as relevant to our goal of developing a rapid inexpensive method of scanning the body for occult disease. The simulations demonstrate the potential feasibility of superconducting quantum interference device magnetometry to detect induced magnetic fields in focal concentrations of superparamagnetic particles targeted, in vivo, to sites of disease.

Multimodal targeted high relaxivity thermosensitive liposome for in vivo imaging

NASA Astrophysics Data System (ADS)

Kuijten, Maayke M. P.; Hannah Degeling, M.; Chen, John W.; Wojtkiewicz, Gregory; Waterman, Peter; Weissleder, Ralph; Azzi, Jamil; Nicolay, Klaas; Tannous, Bakhos A.

2015-11-01

Liposomes are spherical, self-closed structures formed by lipid bilayers that can encapsulate drugs and/or imaging agents in their hydrophilic core or within their membrane moiety, making them suitable delivery vehicles. We have synthesized a new liposome containing gadolinium-DOTA lipid bilayer, as a targeting multimodal molecular imaging agent for magnetic resonance and optical imaging. We showed that this liposome has a much higher molar relaxivities r1 and r2 compared to a more conventional liposome containing gadolinium-DTPA-BSA lipid. By incorporating both gadolinium and rhodamine in the lipid bilayer as well as biotin on its surface, we used this agent for multimodal imaging and targeting of tumors through the strong biotin-streptavidin interaction. Since this new liposome is thermosensitive, it can be used for ultrasound-mediated drug delivery at specific sites, such as tumors, and can be guided by magnetic resonance imaging.

Local structure preserving sparse coding for infrared target recognition

PubMed Central

Han, Jing; Yue, Jiang; Zhang, Yi; Bai, Lianfa

2017-01-01

Sparse coding performs well in image classification. However, robust target recognition requires a lot of comprehensive template images and the sparse learning process is complex. We incorporate sparsity into a template matching concept to construct a local sparse structure matching (LSSM) model for general infrared target recognition. A local structure preserving sparse coding (LSPSc) formulation is proposed to simultaneously preserve the local sparse and structural information of objects. By adding a spatial local structure constraint into the classical sparse coding algorithm, LSPSc can improve the stability of sparse representation for targets and inhibit background interference in infrared images. Furthermore, a kernel LSPSc (K-LSPSc) formulation is proposed, which extends LSPSc to the kernel space to weaken the influence of the linear structure constraint in nonlinear natural data. Because of the anti-interference and fault-tolerant capabilities, both LSPSc- and K-LSPSc-based LSSM can implement target identification based on a simple template set, which just needs several images containing enough local sparse structures to learn a sufficient sparse structure dictionary of a target class. Specifically, this LSSM approach has stable performance in the target detection with scene, shape and occlusions variations. High performance is demonstrated on several datasets, indicating robust infrared target recognition in diverse environments and imaging conditions. PMID:28323824

Multi-atlas segmentation for abdominal organs with Gaussian mixture models

NASA Astrophysics Data System (ADS)

Burke, Ryan P.; Xu, Zhoubing; Lee, Christopher P.; Baucom, Rebeccah B.; Poulose, Benjamin K.; Abramson, Richard G.; Landman, Bennett A.

2015-03-01

Abdominal organ segmentation with clinically acquired computed tomography (CT) is drawing increasing interest in the medical imaging community. Gaussian mixture models (GMM) have been extensively used through medical segmentation, most notably in the brain for cerebrospinal fluid / gray matter / white matter differentiation. Because abdominal CT exhibit strong localized intensity characteristics, GMM have recently been incorporated in multi-stage abdominal segmentation algorithms. In the context of variable abdominal anatomy and rich algorithms, it is difficult to assess the marginal contribution of GMM. Herein, we characterize the efficacy of an a posteriori framework that integrates GMM of organ-wise intensity likelihood with spatial priors from multiple target-specific registered labels. In our study, we first manually labeled 100 CT images. Then, we assigned 40 images to use as training data for constructing target-specific spatial priors and intensity likelihoods. The remaining 60 images were evaluated as test targets for segmenting 12 abdominal organs. The overlap between the true and the automatic segmentations was measured by Dice similarity coefficient (DSC). A median improvement of 145% was achieved by integrating the GMM intensity likelihood against the specific spatial prior. The proposed framework opens the opportunities for abdominal organ segmentation by efficiently using both the spatial and appearance information from the atlases, and creates a benchmark for large-scale automatic abdominal segmentation.

AirMSPI PODEX BigSur Terrain Images

Atmospheric Science Data Center

2013-12-13

... Browse Images from the PODEX 2013 Campaign   Big Sur target (Big Sur, California) 02/03/2013 Terrain-projected   Select ...   Version number   For more information, see the Data Product Specifications (DPS)   ...

Novel gadopentetic acid-doped silica nanoparticles conjugated with YPSMA-1 targeting prostate cancer for MR imaging: an in vitro study.

PubMed

Jiang, Wei; He, Xiaojing; Fang, Huiying; Zhou, Xue; Ran, Haitao; Guo, Dajing

2018-05-05

The early diagnosis of prostate cancer (PCa) is particularly important for reducing its high mortality rate. With the development of molecular magnetic resonance imaging (MRI), early diagnosis via non-invasive imaging has become possible. In this study, gadopentetic acid (GA)-doped silica (Gd@SiO 2 ) was first synthesized by a reverse microemulsion method, and amino and carboxyl groups were then successively introduced onto the surface of this Gd@SiO 2 . After these steps, a monoclonal antibody (YPSMA-1) to prostate-specific membrane antigen (PSMA) was conjugated with carboxyl-modified Gd@SiO 2 (Gd@SiO 2 -COOH) nanoparticles (NPs) by the carbodiimide method. Gd@SiO 2 -Ab NPs were thus obtained as specific MR contrast agents for PCa-targeted imaging. Transmission electron microscopy showed that the Gd@SiO 2 -Ab NPs exhibited a dispersed spherical morphology with a relatively uniform size distribution. The Gd@SiO 2 -Ab NPs showed high stability and high the longitudinal relaxation rate (r 1 ). Cell-targeting experiments in vitro demonstrated the high potential of the synthesized NPs to target PSMA receptor-positive PCa cells. In vitro cytotoxicity assays showed that the Gd@SiO 2 -Ab NPs exhibited good biological safety. These results suggest that the synthesized Gd@SiO 2 -Ab NPs have great potential as specific MR contrast agents for PSMA receptor-positive PCa cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Polymeric nanocomposites loaded with fluoridated hydroxyapatite Ln3+ (Ln = Eu or Tb)/iron oxide for magnetic targeted cellular imaging

PubMed Central

Pan, Jie; Liu, Wei-Jiao; Hua, Chao; Wang, Li-Li; Wan, Dong; Gong, Jun-Bo

2015-01-01

Objective To fabricate polymeric nanocomposites with excellent photoluminescence, magnetic properties, and stability in aqueous solutions, in order to improve specificity and sensitivity of cellular imaging under a magnetic field. Methods Fluoridated Ln3+-doped HAP (Ln3+-HAP) NPs and iron oxides (IOs) can be encapsulated with biocompatible polymers via a modified solvent exaction/evaporation technique to prepare polymeric nanocomposites with fluoridated Ln3+-HAP/iron oxide. The nanocomposites were characterized for surface morphology, fluorescence spectra, magnetic properties and in vitro cytotoxicity. Magnetic targeted cellular imaging of such nanocomposites was also evaluated with confocal laser scanning microscope using A549 cells with or without magnetic field. Results The fabricated nanocomposites showed good stability and excellent luminescent properties, as well as low in vitro cytotoxicity, indicating that the nanocomposites are suitable for biological applications. Nanocomposites under magnetic field achieved much higher cellular uptake via an energy-dependent pathway than those without magnetic field. Conclusion The nanocomposites fabricated in this study will be a promising tool for magnetic targeted cellular imaging with improved specificity and enhanced selection. PMID:26487962

The Potential of Metabolic Imaging

PubMed Central

Di Gialleonardo, Valentina; Wilson, David M.; Keshari, Kayvan R.

2015-01-01

Metabolic imaging is a field of molecular imaging that focuses and targets changes in metabolic pathways for the evaluation of different clinical conditions. Targeting and quantifying metabolic changes non-invasively is a powerful approach to facilitate diagnosis and evaluate therapeutic response. This review addresses only techniques targeting metabolic pathways. Other molecular imaging strategies, such as affinity/receptor imaging or microenvironment-dependent methods are beyond the scope of this review. Here we describe the current state of the art in clinically translatable metabolic imaging modalities. Specifically, we will focus on positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), including conventional 1H and 13C MRS at thermal equilibrium and hyperpolarized magnetic resonance imaging (HP MRI). In this paper, we first provide an overview of metabolic pathways that are altered in many pathological conditions and the corresponding probes and techniques used to study those alterations. We will then describe the application of metabolic imaging to several common diseases including cancer, neurodegeneration, cardiac ischemia, and infection/inflammation. PMID:26687855

Optical cell monitoring system for underwater targets

NASA Astrophysics Data System (ADS)

Moon, SangJun; Manzur, Fahim; Manzur, Tariq; Demirci, Utkan

2008-10-01

We demonstrate a cell based detection system that could be used for monitoring an underwater target volume and environment using a microfluidic chip and charge-coupled-device (CCD). This technique allows us to capture specific cells and enumerate these cells on a large area on a microchip. The microfluidic chip and a lens-less imaging platform were then merged to monitor cell populations and morphologies as a system that may find use in distributed sensor networks. The chip, featuring surface chemistry and automatic cell imaging, was fabricated from a cover glass slide, double sided adhesive film and a transparent Polymethlymetacrylate (PMMA) slab. The optically clear chip allows detecting cells with a CCD sensor. These chips were fabricated with a laser cutter without the use of photolithography. We utilized CD4+ cells that are captured on the floor of a microfluidic chip due to the ability to address specific target cells using antibody-antigen binding. Captured CD4+ cells were imaged with a fluorescence microscope to verify the chip specificity and efficiency. We achieved 70.2 +/- 6.5% capturing efficiency and 88.8 +/- 5.4% specificity for CD4+ T lymphocytes (n = 9 devices). Bright field images of the captured cells in the 24 mm × 4 mm × 50 μm microfluidic chip were obtained with the CCD sensor in one second. We achieved an inexpensive system that rapidly captures cells and images them using a lens-less CCD system. This microfluidic device can be modified for use in single cell detection utilizing a cheap light-emitting diode (LED) chip instead of a wide range CCD system.

Tumor-Targeting Multifunctional Rattle-Type Theranostic Nanoparticles for MRI/NIRF Bimodal Imaging and Delivery of Hydrophobic Drugs.

PubMed

Jiao, Yunfeng; Sun, Yangfei; Tang, Xiaoling; Ren, Qingguang; Yang, Wuli

2015-04-24

The development of theranostic systems capable of diagnosis, therapy, and target specificity is considerably significant for accomplishing personalized medicine. Here, a multifunctional rattle-type nanoparticle (MRTN) as an effective biological bimodal imaging and tumor-targeting delivery system is fabricated, and an enhanced loading ability of hydrophobic anticancer drug (paclitaxel) is also realized. The rattle structure with hydrophobic Fe3 O4 as the inner core and mesoporous silica as the shell is obtained by one-step templates removal process, and the size of interstitial hollow space can be easily adjusted. The Fe3 O4 core with hydrophobic poly(tert-butyl acrylate) (PTBA) chains on the surface is not only used as a magnetic resonance imaging (MRI) agent, but contributes to improving hydrophobic drug loading amount. Transferrin (Tf) and a near-infrared fluorescent dye (Cy 7) are successfully modified on the surface of the nanorattle to increase the ability of near-infrared fluorescence (NIRF) imaging and tumor-targeting specificity. In vivo studies show the selective accumulation of MRTN in tumor tissues by Tf-receptor-mediated endocytosis. More importantly, paclitaxel-loaded MRTN shows sustained release character and higher cytotoxicity than the free paclitaxel. This theranostic nanoparticle as an effective MRI/NIRF bimodal imaging probe and drug delivery system shows great potential in cancer diagnosis and therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular Imaging of Vasa Vasorum Neovascularization via DEspR-targeted Contrast-enhanced Ultrasound Micro-imaging in Transgenic Atherosclerosis Rat Model

PubMed Central

Decano, Julius L.; Moran, Anne Marie; Ruiz-Opazo, Nelson; Herrera, Victoria L. M.

2011-01-01

Purpose Given that carotid vasa vasorum neovascularization is associated with increased risk for stroke and cardiac events, the present in vivo study was designed to investigate molecular imaging of carotid artery vasa vasorum neovascularization via target-specific contrast-enhanced ultrasound (CEU) micro-imaging. Procedures Molecular imaging was performed in male transgenic rats with carotid artery disease and non-transgenic controls using dual endothelin1/VEGFsp receptor (DEspR)-targeted microbubbles (MBD) and the Vevo770 micro-imaging system and CEU imaging software. Results DEspR-targeted CEU-positive imaging exhibited significantly higher contrast intensity signal (CIS)-levels and pre-/post-destruction CIS-differences in seven of 13 transgenic rats, in contrast to significantly lower CIS-levels and differences in control isotype-targeted microbubble (MBC)-CEU imaging (n =8) and in MBD CEU-imaging of five non-transgenic control rats (P<0.0001). Ex vivo immunofluorescence analysis demonstrated binding of MBD to DEspR-positive endothelial cells; and association of DEspR-targeted increased contrast intensity signals with DEspR expression in vasa vasorum neovessel and intimal lesions. In vitro analysis demonstrated dose-dependent binding of MBD to DEspR-positive human endothelial cells with increasing %cells bound and number of MBD per cell, in contrast to MBC or non-labeled microbubbles (P<0.0001). Conclusion In vivo DEspR-targeted molecular imaging detected increased DEspR-expression in carotid artery lesions and in expanded vasa vasorum neovessels in transgenic rats with carotid artery disease. Future studies are needed to determine predictive value for stroke or heart disease in this transgenic atherosclerosis rat model and translational applications. PMID:20972637

Magnetic nanobubbles with potential for targeted drug delivery and trimodal imaging in breast cancer: an in vitro study.

PubMed

Song, Weixiang; Luo, Yindeng; Zhao, Yajing; Liu, Xinjie; Zhao, Jiannong; Luo, Jie; Zhang, Qunxia; Ran, Haitao; Wang, Zhigang; Guo, Dajing

2017-05-01

The aim of this study was to improve tumor-targeted therapy for breast cancer by designing magnetic nanobubbles with the potential for targeted drug delivery and multimodal imaging. Herceptin-decorated and ultrasmall superparamagnetic iron oxide (USPIO)/paclitaxel (PTX)-embedded nanobubbles (PTX-USPIO-HER-NBs) were manufactured by combining a modified double-emulsion evaporation process with carbodiimide technique. PTX-USPIO-HER-NBs were examined for characterization, specific cell-targeting ability and multimodal imaging. PTX-USPIO-HER-NBs exhibited excellent entrapment efficiency of Herceptin/PTX/USPIO and showed greater cytotoxic effects than other delivery platforms. Low-frequency ultrasound triggered accelerated PTX release. Moreover, the magnetic nanobubbles were able to enhance ultrasound, magnetic resonance and photoacoustics trimodal imaging. These results suggest that PTX-USPIO-HER-NBs have potential as a multimodal contrast agent and as a system for ultrasound-triggered drug release in breast cancer.

A Sensitive TLRH Targeted Imaging Technique for Ultrasonic Molecular Imaging

PubMed Central

Hu, Xiaowen; Zheng, Hairong; Kruse, Dustin E.; Sutcliffe, Patrick; Stephens, Douglas N.; Ferrara, Katherine W.

2010-01-01

The primary goals of ultrasound molecular imaging are the detection and imaging of ultrasound contrast agents (microbubbles), which are bound to specific vascular surface receptors. Imaging methods that can sensitively and selectively detect and distinguish bound microbubbles from freely circulating microbubbles (free microbubbles) and surrounding tissue are critically important for the practical application of ultrasound contrast molecular imaging. Microbubbles excited by low frequency acoustic pulses emit wide-band echoes with a bandwidth extending beyond 20 MHz; we refer to this technique as TLRH (transmission at a low frequency and reception at a high frequency). Using this wideband, transient echo, we have developed and implemented a targeted imaging technique incorporating a multi-frequency co-linear array and the Siemens Antares® imaging system. The multi-frequency co-linear array integrates a center 5.4 MHz array, used to receive echoes and produce radiation force, and two outer 1.5 MHz arrays used to transmit low frequency incident pulses. The targeted imaging technique makes use of an acoustic radiation force sub-sequence to enhance accumulation and a TLRH imaging sub-sequence to detect bound microbubbles. The radiofrequency (RF) data obtained from the TLRH imaging sub-sequence are processsed to separate echo signatures between tissue, free microbubbles, and bound microbubbles. By imaging biotin-coated microbubbles targeted to avidin-coated cellulose tubes, we demonstrate that the proposed method has a high contrast-to-tissue ratio (up to 34 dB) and a high sensitivity to bound microbubbles (with the ratio of echoes from bound microbubbles versus free microbubbles extending up to 23 dB). The effects of the imaging pulse acoustic pressure, the radiation force sub-sequence and the use of various slow-time filters on the targeted imaging quality are studied. The TLRH targeted imaging method is demonstrated in this study to provide sensitive and selective detection of bound microbubbles for ultrasound molecularly-targeted imaging. PMID:20178897

Construction of ultrasonic nanobubbles carrying CAIX polypeptides to target carcinoma cells derived from various organs.

PubMed

Zhu, Lianhua; Guo, Yanli; Wang, Luofu; Fan, Xiaozhou; Xiong, Xingyu; Fang, Kejing; Xu, Dan

2017-09-29

Ultrasound molecular imaging is a novel diagnostic approach for tumors, whose key link is the construction of targeted ultrasound contrast agents. However, available targeted ultrasound contrast agents for molecular imaging of tumors are only achieving imaging in blood pool or one type tumor. No targeted ultrasound contrast agents have realized targeted ultrasound molecular imaging of tumor parenchymal cells in a variety of solid tumors so far. Carbonic anhydrase IX (CAIX) is highly expressed on cell membranes of various malignant solid tumors, so it's a good target for ultrasound molecular imaging. Here, targeted nanobubbles carrying CAIX polypeptides for targeted binding to a variety of malignant tumors were constructed, and targeted binding ability and ultrasound imaging effect in different types of tumors were evaluated. The mean diameter of lipid targeted nanobubbles was (503.7 ± 78.47) nm, and the polypeptides evenly distributed on the surfaces of targeted nanobubbles, which possessed the advantages of homogenous particle size, high stability, and good safety. Targeted nanobubbles could gather around CAIX-positive cells (786-O and Hela cells), while they cannot gather around CAIX-negative cells (BxPC-3 cells) in vitro, and the affinity of targeted nanobubbles to CAIX-positive cells were significantly higher than that to CAIX-negative cells (P < 0.05). Peak intensity and duration time of targeted nanobubbles and blank nanobubbles were different in CAIX-positive transplanted tumor tissues in vivo (P < 0.05). Moreover, targeted nanobubbles in CAIX-positive transplanted tumor tissues produced higher peak intensity and longer duration time than those in CAIX-negative transplanted tumor tissues (P < 0.05). Finally, immunofluorescence not only confirmed targeted nanobubbles could pass through blood vessels to enter in tumor tissue spaces, but also clarified imaging differences of targeted nanobubbles in different types of transplanted tumor tissues. Targeted nanobubbles carrying CAIX polypeptides can specifically enhance ultrasound imaging in CAIX-positive transplanted tumor tissues and could potentially be used in early diagnosis of a variety of solid tumors derived from various organs.

Configurations of a two-tiered amplified gene expression system in adenoviral vectors designed to improve the specificity of in vivo prostate cancer imaging

PubMed Central

Sato, M; Figueiredo, ML; Burton, JB; Johnson, M; Chen, M; Powell, R; Gambhir, SS; Carey, M; Wu, L

2009-01-01

Effective treatment for recurrent, disseminated prostate cancer is notably limited. We have developed adenoviral vectors with a prostate-specific two-step transcriptional amplification (TSTA) system that would express therapeutic genes at a robust level to target metastatic disease. The TSTA system employs the prostate-specific antigen (PSA) promoter/enhancer to drive a potent synthetic activator, which in turn activates the expression of the therapeutic gene. In this study, we explored different configurations of this bipartite system and discovered that physical separation of the two TSTA components into E1 and E3 regions of adenovirus was able to enhance androgen regulation and cell-discriminatory expression. The TSTA vectors that express imaging reporter genes were assessed by noninvasive imaging technologies in animal models. The improved selectivity of the E1E3 configured vector was reflected in silenced ectopic expression in the lung. Significantly, the enhanced specificity of the E1E3 vector enabled the detection of lung metastasis of prostate cancer. An E1E3 TSTA vector that expresses the herpes simplex virus thymidine kinase gene can effectively direct positron emission tomography (PET) imaging of the tumor. The prostate-targeted gene delivery vectors with robust and cell-specific expression capability will advance the development of safe and effective imaging guided therapy for recurrent metastatic stages of prostate cancer. PMID:18305574

Determining biosonar images using sparse representations.

PubMed

Fontaine, Bertrand; Peremans, Herbert

2009-05-01

Echolocating bats are thought to be able to create an image of their environment by emitting pulses and analyzing the reflected echoes. In this paper, the theory of sparse representations and its more recent further development into compressed sensing are applied to this biosonar image formation task. Considering the target image representation as sparse allows formulation of this inverse problem as a convex optimization problem for which well defined and efficient solution methods have been established. The resulting technique, referred to as L1-minimization, is applied to simulated data to analyze its performance relative to delay accuracy and delay resolution experiments. This method performs comparably to the coherent receiver for the delay accuracy experiments, is quite robust to noise, and can reconstruct complex target impulse responses as generated by many closely spaced reflectors with different reflection strengths. This same technique, in addition to reconstructing biosonar target images, can be used to simultaneously localize these complex targets by interpreting location cues induced by the bat's head related transfer function. Finally, a tentative explanation is proposed for specific bat behavioral experiments in terms of the properties of target images as reconstructed by the L1-minimization method.

Will nanotechnology influence targeted cancer therapy?

PubMed Central

Grimm, Jan; Scheinberg, David A.

2011-01-01

The rapid development of techniques that enable synthesis (and manipulation) of matter on the nanometer scale, as well as the development of new nano-materials, will play a large role in disease diagnosis and treatment, specifically in targeted cancer therapy. Targeted nanocarriers are an intriguing means to selectively deliver high concentrations of cytotoxic agents or imaging labels directly to the cancer site. Often solubility issues and an unfavorable biodistribution can result in a suboptimal response of novel agents even though they are very potent. New nanoparticulate formulations allow simultaneous imaging and therapy (“theranostics”), which can provide a realistic means for the clinical implementation of such otherwise suboptimal formulations. In this review we will not attempt to provide a complete overview of the rapidly enlarging field of nanotechnology in cancer; rather, we will present properties specific to nanoparticles, and examples of their uses, which demonstrate their importance for targeted cancer therapy. PMID:21356476

Magnetomotive Molecular Nanoprobes

PubMed Central

John, Renu; Boppart, Stephen A.

2012-01-01

Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogen-induced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications. PMID:21517766

Development of Prostate Specific Membrane Antigen (PSMA) Inhibitors Coupled to 99mTc(CO)3+ with Enhanced Specific Activity for SPECT Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Paul; D.; Benny,

2011-12-20

The overall objectives of the project were two fold: 1) the development of new facile reactions for coupling radioactive complexes with biomolecules and 2) the development of a novel molecular imaging targeting vector for Prostate Specific Membrane Antigen (PSMA) for prostate cancer. The didactic approach allowed the synergistic exploration of new technologies for coupling reactions of radioactive complexes that can be applied to a novel targeting moiety. As part of the project, a number of students (undergraduate, graduate and post-doctoral) were trained in radiochemical techniques for preparing and characterizing radiometal complexes. Results from the experiments within the project have generatedmore » several presentations and publications.« less

Radiolabeled, Antibody-Conjugated Manganese Oxide Nanoparticles for Tumor Vasculature Targeted Positron Emission Tomography and Magnetic Resonance Imaging.

PubMed

Zhan, Yonghua; Shi, Sixiang; Ehlerding, Emily B; Graves, Stephen A; Goel, Shreya; Engle, Jonathan W; Liang, Jimin; Tian, Jie; Cai, Weibo

2017-11-08

Manganese oxide nanoparticles (Mn 3 O 4 NPs) have attracted a great deal of attention in the field of biomedical imaging because of their ability to create an enhanced imaging signal in MRI as novel potent T 1 contrast agents. In this study, we present tumor vasculature-targeted imaging in mice using Mn 3 O 4 NPs through conjugation to the anti-CD105 antibody TRC105 and radionuclide copper-64 ( 64 Cu, t 1/2 : 12.7 h). The Mn 3 O 4 conjugated NPs, 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105, exhibited sufficient stability in vitro and in vivo. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies evaluated the pharmacokinetics and demonstrated targeting of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 to 4T1 murine breast tumors in vivo, compared to 64 Cu-NOTA-Mn 3 O 4 @PEG. The specificity of 64 Cu-NOTA-Mn 3 O 4 @PEG-TRC105 for the vascular marker CD105 was confirmed through in vivo, in vitro, and ex vivo experiments. Since Mn 3 O 4 conjugated NPs exhibited desirable properties for T 1 enhanced imaging and low toxicity, the tumor-specific Mn 3 O 4 conjugated NPs reported in this study may serve as promising multifunctional nanoplatforms for precise cancer imaging and diagnosis.

Imaging Prostate Cancer Microenvironment by Collagen Hybridization

DTIC Science & Technology

2016-10-01

affinity to denatured collagens and collagens undergoing remodeling which simulate the microenvironment of metastatic tumors. We will focus on previously...specifically target digested collagens with unfolded and partially denatured collagen triple helices. 2. Demonstration of ex vivo and in vivo targeting...invasive prostate cancer due to the absence of non-specific affinity and high propensity to hybridize with denatured collagen strand (Aim 1). We

Novel fluorescent contrast agents for optical imaging of in vivo tumors based on a receptor-targeted dye-peptide conjugate platform

NASA Astrophysics Data System (ADS)

Bugaj, Joseph E.; Achilefu, Samuel I.; Dorshow, Richard B.; Rajagopalan, Raghavan

2001-04-01

We have designed, synthesized, and evaluated the efficacy of novel dye-peptide conjugates that are receptor specific. Contrary to the traditional approach of conjugating dyes to large proteins and antibodies, we used small peptide-dye conjugates that target over-expressed receptors on tumors. Despite the fact that the peptide and the dye probe have similar molecular mass, our results demonstrate that the affinity of the peptide for its receptor and the dye fluorescence properties are both retained. The use of small peptides has several advantages over large biomolecules, including ease of synthesis of a variety of compounds for potential combinatorial screening of new targets, reproducibility of high purity compounds, diffusiveness to solid tumors, and the ability to incorporate a variety of functional groups that modify the pharmacokinetics of the peptide-dye conjugates. The efficacy of these new fluorescent optical contrast agents was evaluated in vivo in well-characterized rat tumor lines expressing somatostatin (sst2) and bombesin receptors. A simple continuous wave optical imaging system was employed. The resulting optical images clearly show that successful specific tumor targeting was achieved. Thus, we have demonstrated that small peptide- dye conjugates are effective as contrast agents for optical imaging of tumors.

Nanobubble-Affibody: Novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor.

PubMed

Yang, Hengli; Cai, Wenbin; Xu, Lei; Lv, Xiuhua; Qiao, Youbei; Li, Pan; Wu, Hong; Yang, Yilin; Zhang, Li; Duan, Yunyou

2015-01-01

Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 ± 29.7 nm with polydispersity index of 0.164 ± 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 ± 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative assessment of a 99mTc labeled H1299.2-HYNIC peptide bearing two different co-ligands for tumor-targeted imaging.

PubMed

Torabizadeh, Seyedeh Atekeh; Abedi, Seyed Mohammad; Noaparast, Zohreh; Hosseinimehr, Seyed Jalal

2017-05-01

Peptides are a class of targeting agents that bind to cancer-specific cell surfaces. Since they specifically target cancer cells, they could be used as molecular imaging tools. In this study, the 15-mer peptide Ac-H1299.2 (YAAWPASGAWTGTAP) was conjugated with HYNIC via lysine amino acid on C-terminus and labeled with 99m Tc using tricine and EDDA/tricine as the co-ligands. These radiotracers were evaluated for potential utilization in diagnostic imaging of ovarian cancer cells (SKOV-3). The cell-specificity of these radiolabeled peptides was determined based on their binding on an ovarian cancer cell line (SKOV-3), and displaying a low affinity for lung adenocarcinoma cell line (A549) and breast cancer cell line (MCF7). Biodistribution studies were conducted in normal mice as well as in nude mice bearing SKOV-3 ovarian cancer xenografts. HYNIC-peptide was labeled with 99m Tc with more than 99% efficiency and showed high stability in buffer and serum. We observed nanomolar binding affinities for both radiolabeled peptides. The tumor uptakes were 3.27%±0.46% and 1.55%±0.20% for tricine and 2.34±1.1% and 1.09%±0.18% for EDDA/tricine at 1 and 4h after injection, respectively. A higher tumor to background ratio and lower radioactivity in the blood were observed for EDDA/tricine co-ligands, leading to clear tumor visualization in imaging with injection of this peptide. This new 99m Tc-labeled peptide selectively targeted ovarian cancer and introduction of a (EDDA/tricine) as a co-ligand improved the pharmacokinetics of 99m Tc-labeled H1299.2 for tumor imaging in animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genomic biomarkers for molecular imaging: predicting the future.

PubMed

Thakur, Mathew L

2009-07-01

Over the past few decades, great strides have been made in anatomical imaging of disease that has led to their diagnosis with minimal invasion. Despite these advances, diseases such as cancer continue to take one human life every minute in the United States. Complimentary approaches that pertain directly to the genesis of the disease might contribute to its early diagnosis and subsequent management. In cancer, an array of molecular abnormalities leading to the modulations in expression of key proteins important in the cellular signaling pathways and cell proliferation has been identified. These specific disease fingerprints, biomarkers, are overexpressed on malignant cell surfaces or within the cytoplasm, and they provide unique targets that are promising for improving cancer diagnosis and therapy. We and others have designed, synthesized, and evaluated some novel probes specific for those oncogenes and oncogene product biomarkers for PET and SPECT molecular imaging of certain types of cancers. This article briefly describes this approach and gives specific examples that depict the ability of molecular imaging to detect occult lesions not detectable by current scintigraphic approaches. The article also outlines a few examples predicting other possible applications of targeting such specific probes not yet used.

Multifunctional magnetic nanoparticles for targeted imaging and therapy

PubMed Central

McCarthy, Jason R.; Weissleder, Ralph

2008-01-01

Magnetic nanoparticles have become important tools for the imaging of prevalent diseases, such as cancer, atherosclerosis, diabetes, and others. While first generation nanoparticles were fairly nonspecific, newer generations have been targeted to specific cell types and molecular targets via affinity ligands. Commonly, these ligands emerge from phage or small molecule screens, or are based on antibodies or aptamers. Secondary reporters and combined therapeutic molecules have further opened potential clinical applications of these materials. This review summarizes some of the recent biomedical applications of these newer magnetic nanomaterials. PMID:18508157

Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles

NASA Astrophysics Data System (ADS)

Sawant, Rishikesh M.; Sawant, Rupa R.; Gultepe, Evin; Nagesha, Dattatri; Papahadjopoulos-Sternberg, Brigitte; Sridhar, Srinivas; Torchilin, Vladimir P.

2009-10-01

Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to `plain' SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma.

PubMed

Kim, Kwang Il; Chung, Hye Kyung; Park, Ju Hui; Lee, Yong Jin; Kang, Joo Hyun

2016-07-21

Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.

Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma

PubMed Central

Kim, Kwang Il; Chung, Hye Kyung; Park, Ju Hui; Lee, Yong Jin; Kang, Joo Hyun

2016-01-01

Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene’s expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment. PMID:27468205

Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease

NASA Astrophysics Data System (ADS)

Viola, Kirsten L.; Sbarboro, James; Sureka, Ruchi; de, Mrinmoy; Bicca, Maíra A.; Wang, Jane; Vasavada, Shaleen; Satpathy, Sreyesh; Wu, Summer; Joshi, Hrushikesh; Velasco, Pauline T.; Macrenaris, Keith; Waters, E. Alex; Lu, Chang; Phan, Joseph; Lacor, Pascale; Prasad, Pottumarthi; Dravid, Vinayak P.; Klein, William L.

2015-01-01

One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

16th iWoRiD scientific summary and personal impressions

NASA Astrophysics Data System (ADS)

Vacchi, Andrea

2015-08-01

The development of Radiation Imaging Detectors dedicated to specific front edge use is a rapidly expanding galaxy taking force from a healthy mixture of growing ambitions within basic science targets and applicative use in many contiguous fields. The growth of the high technology imaging tools market is a relevant motivating element. On the scene of this conference a flow of very accurate and informative presentations has allowed to gather a vivid image on the almost frantic target oriented work, the results shown have often surpassed the most visionary expectations.

Inorganic chemistry in nuclear imaging and radiotherapy: current and future directions

PubMed Central

Carroll, Valerie; Demoin, Dustin W.; Hoffman, Timothy J; Jurisson, Silvia S

2013-01-01

Summary Radiometals play an important role in diagnostic and therapeutic radiopharmaceuticals. This field of radiochemistry is multidisciplinary, involving radiometal production, separation of the radiometal from its target, chelate design for complexing the radiometal in a biologically stable environment, specific targeting of the radiometal to its in vivo site, and nuclear imaging and/or radiotherapy applications of the resultant radiopharmaceutical. The critical importance of inorganic chemistry in the design and application of radiometal-containing imaging and therapy agents is described from a historical perspective to future directions. PMID:25382874

Targeted Multiplex Imaging Mass Spectrometry in Transmission Geometry for Subcellular Spatial Resolution

PubMed Central

Lavenant, Gwendoline Thiery; Zavalin, Andrey I.; Caprioli, Richard M.

2013-01-01

Targeted multiplex Imaging Mass Spectrometry utilizes several different antigen-specific primary antibodies, each directly labeled with a unique photocleavable mass tag, to detect multiple antigens in a single tissue section. Each photocleavable mass tag bound to an antibody has a unique molecular weight and can be readily ionized by laser desorption ionization mass spectrometry. This manuscript describes a mass spectrometry method that allows imaging of targeted single cells within tissue using transmission geometry laser desorption ionization mass spectrometry. Transmission geometry focuses the laser beam on the back side of the tissue placed on a glass slide, providing a 2 μm diameter laser spot irradiating the biological specimen. This matrix-free method enables simultaneous localization at the sub-cellular level of multiple antigens using specific tagged antibodies. We have used this technology to visualize the co-expression of synaptophysin and two major hormones peptides, insulin and somatostatin, in duplex assays in beta and delta cells contained in a human pancreatic islet. PMID:23397138

Intravital imaging of mouse colonic adenoma using MMP-based molecular probes with multi-channel fluorescence endoscopy.

PubMed

Oh, Gyungseok; Yoo, Su Woong; Jung, Yebin; Ryu, Yeon-Mi; Park, Youngrong; Kim, Sang-Yeob; Kim, Ki Hean; Kim, Sungjee; Myung, Seung-Jae; Chung, Euiheon

2014-05-01

Intravital imaging has provided molecular, cellular and anatomical insight into the study of tumor. Early detection and treatment of gastrointestinal (GI) diseases can be enhanced with specific molecular markers and endoscopic imaging modalities. We present a wide-field multi-channel fluorescence endoscope to screen GI tract for colon cancer using multiple molecular probes targeting matrix metalloproteinases (MMP) conjugated with quantum dots (QD) in AOM/DSS mouse model. MMP9 and MMP14 antibody (Ab)-QD conjugates demonstrate specific binding to colonic adenoma. The average target-to-background (T/B) ratios are 2.10 ± 0.28 and 1.78 ± 0.18 for MMP14 Ab-QD and MMP9 Ab-QD, respectively. The overlap between the two molecular probes is 67.7 ± 8.4%. The presence of false negative indicates that even more number of targeting could increase the sensitivity of overall detection given heterogeneous molecular expression in tumors. Our approach indicates potential for the screening of small or flat lesions that are precancerous.

Convection-enhanced delivery of targeted quantum dot-immunoliposome hybrid nanoparticles to intracranial brain tumor models.

PubMed

Weng, Kevin C; Hashizume, Rintaro; Noble, Charles O; Serwer, Laura P; Drummond, Daryl C; Kirpotin, Dmitri B; Kuwabara, Anne M; Chao, Lucy X; Chen, Fanqing F; James, Charles D; Park, John W

2013-12-01

The aim of this work is to evaluate combining targeting strategy and convection-enhanced delivery in brain tumor models by imaging quantum dot-immunoliposome hybrid nanoparticles. An EGF receptor-targeted, quantum dot-immunoliposome hybrid nanoparticle (QD-IL) was synthesized. In vitro uptake was measured by flow cytometry and intracellular localization was imaged by confocal microscopy. In the in vivo study, QD-ILs were delivered to intracranial xenografts via convection-enhanced delivery and fluorescence was monitored noninvasively in real-time. QD-ILs exhibited specific and efficient uptake in vitro and exhibited approximately 1.3- to 5.0-fold higher total fluorescence compared with nontargeted counterpart in intracranial brain tumor xenografts in vivo. QD-ILs serve as an effective imaging agent in vitro and in vivo, and the data suggest that ligand-directed liposomal nanoparticles in conjunction with convection-enhanced delivery may offer therapeutic benefits for glioblastoma treatment as a result of specific and efficient uptake by malignant cells.

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging.

PubMed

Zhang, Liang; Thurber, Greg M

2016-02-01

Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type 1 diabetes. The glucagon-like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower-clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, down-regulation of the GLP-1 receptor and non-specific background uptake result in a higher target-to-background ratio for fast-clearing agents.

Targeted Multiplex Imaging Mass Spectrometry in Transmission Geometry for Subcellular Spatial Resolution

NASA Astrophysics Data System (ADS)

Thiery-Lavenant, Gwendoline; Zavalin, Andre I.; Caprioli, Richard M.

2013-04-01

Targeted multiplex imaging mass spectrometry utilizes several different antigen-specific primary antibodies, each directly labeled with a unique photocleavable mass tag, to detect multiple antigens in a single tissue section. Each photocleavable mass tag bound to an antibody has a unique molecular weight and can be readily ionized by laser desorption ionization mass spectrometry. This article describes a mass spectrometry method that allows imaging of targeted single cells within tissue using transmission geometry laser desorption ionization mass spectrometry. Transmission geometry focuses the laser beam on the back side of the tissue placed on a glass slide, providing a 2 μm diameter laser spot irradiating the biological specimen. This matrix-free method enables simultaneous localization at the sub-cellular level of multiple antigens using specific tagged antibodies. We have used this technology to visualize the co-expression of synaptophysin and two major hormones peptides, insulin and somatostatin, in duplex assays in beta and delta cells contained in a human pancreatic islet.

Targeting of peptide conjugated magnetic nanoparticles to urokinase plasminogen activator receptor (uPAR) expressing cells

NASA Astrophysics Data System (ADS)

Hansen, Line; Unmack Larsen, Esben Kjær; Nielsen, Erik Holm; Iversen, Frank; Liu, Zhuo; Thomsen, Karen; Pedersen, Michael; Skrydstrup, Troels; Nielsen, Niels Chr.; Ploug, Michael; Kjems, Jørgen

2013-08-01

Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific targeting peptide onto polyethylene glycol (PEG) coated USPIO nanoparticles by click chemistry resulted in a five times higher uptake in vitro in a uPAR positive cell line compared to nanoparticles carrying a non-binding control peptide. In accordance with specific receptor-mediated recognition, a low uptake was observed in the presence of an excess of ATF, a natural ligand for uPAR. The uPAR specific magnetic nanoparticles can potentially provide a useful supplement for tumor patient management when combined with MRI and drug delivery.Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles are currently being used as a magnetic resonance imaging (MRI) contrast agent in vivo, mainly by their passive accumulation in tissues of interest. However, a higher specificity can ideally be achieved when the nanoparticles are targeted towards cell specific receptors and this may also facilitate specific drug delivery by an enhanced target-mediated endocytosis. We report efficient peptide-mediated targeting of magnetic nanoparticles to cells expressing the urokinase plasminogen activator receptor (uPAR), a surface biomarker for poor patient prognosis shared by several cancers including breast, colorectal, and gastric cancers. Conjugation of a uPAR specific targeting peptide onto polyethylene glycol (PEG) coated USPIO nanoparticles by click chemistry resulted in a five times higher uptake in vitro in a uPAR positive cell line compared to nanoparticles carrying a non-binding control peptide. In accordance with specific receptor-mediated recognition, a low uptake was observed in the presence of an excess of ATF, a natural ligand for uPAR. The uPAR specific magnetic nanoparticles can potentially provide a useful supplement for tumor patient management when combined with MRI and drug delivery. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr32922d

Development of Y-shaped peptide for constructing nanoparticle systems targeting tumor-associated macrophages in vitro and in vivo

NASA Astrophysics Data System (ADS)

Yan, Lu; Gao, Yunxiang; Pierce, Ryan; Dai, Liming; Kim, Julian; Zhang, Mei

2014-04-01

Tumor-associated macrophage (TAM) is increasingly being viewed as a target of great interest in tumor microenvironment due to its important role in the progression and metastasis of cancers. It has been shown that TAM indeed overexpresses unique surface marker legumain. In this study, we designed and synthesized a Y-shaped legumain-targeting peptide (Y-Leg) with functional groups allowing for further conjugation with imaging and therapeutic moieties (vide infra). The in vitro cell experiments using FITC-conjugated Y-Leg revealed its specific and selective interaction with M2-polarized macrophages (i.e., TAMs) with preference to M1 macrophages, and that the interaction was not interfered with by conjugating FITC to its functional group. Further, we constructed a nanotube system by grafting Y-Leg onto oxidized carbon nanotubes (OCNTs) loaded with paramagnetic Fe3O4 nanoparticles. The intravenous injection of the resultant Y-Leg-OCNT/Fe3O4 nanotubes to 4T1 mammary tumor-bearing mouse led to the magnetic resonance imaging (MRI) of TAM-infiltrated tumor microenvironment, revealing the targeting specificity of Y-Leg-conjugated nanotubes in vivo. The Y shape of peptide and its functional groups containing amines and imidazole can protonate at different pHs, contributing to the in vitro and in vivo targeting specificity. This study represents the first development of novel peptide and peptide-grafted nanotube system targeting M2-polarized TAMs in vivo. The methodology developed in this study is applicable to the construction of various multifunctional nanoparticle systems for selectively targeting, imaging and manipulating of TAMs for the diagnosis and treatment of cancers and inflammatory diseases identified with macrophage-infiltrated disease tissue.

Anti-EpCAM scFv gadolinium chelate: a novel targeted MRI contrast agent for imaging of colorectal cancer.

PubMed

Khantasup, Kannika; Saiviroonporn, Pairash; Jarussophon, Suwatchai; Chantima, Warangkana; Dharakul, Tararaj

2018-05-08

The development of targeted contrast agents for magnetic resonance imaging (MRI) facilitates enhanced cancer imaging and more accurate diagnosis. In the present study, a novel contrast agent was developed by conjugating anti-EpCAM humanized scFv with gadolinium chelate to achieve target specificity. The material design strategy involved site-specific conjugation of the chelating agent to scFv. The scFv monomer was linked to maleimide-DTPA via unpaired cysteine at the scFv C-terminus, followed by chelation with gadolinium (Gd). Successful scFv-DTPA conjugation was achieved at 1:10 molar ratio of scFv to maleimide-DTPA at pH 6.5. The developed anti-EpCAM-Gd-DTPA MRI contrast agent was evaluated for cell targeting ability, in vitro serum stability, cell cytotoxicity, relaxivity, and MR contrast enhancement. A high level of targeting efficacy of anti-EpCAM-Gd-DTPA to an EpCAM-overexpressing HT29 colorectal cell was demonstrated by confocal microscopy. Good stability of the contrast agent was obtained and no cytotoxicity was observed in HT29 cells after 48 h incubation with 25-100 µM of Gd. Favorable imaging was obtained using anti-EpCAM-Gd-DTPA, including 1.8-fold enhanced relaxivity compared with Gd-DTPA, and MR contrast enhancement observed after binding to HT29. The potential benefit of this contrast agent for in vivo MR imaging of colorectal cancer, as well as other EpCAM positive cancers, is suggested and warrants further investigation.

Assessment of sequence dependent geometric distortion in contrast-enhanced MR images employed in stereotactic radiosurgery treatment planning.

PubMed

Pappas, Eleftherios P; Seimenis, Ioannis; Dellios, Dimitrios; Kollias, Georgios; Lampropoulos, Kostas I; Karaiskos, Pantelis

2018-06-25

This work focuses on MR-related sequence dependent geometric distortions, which are associated with B 0 inhomogeneity and patient-induced distortion (susceptibility differences and chemical shift effects), in MR images used in stereotactic radiosurgery (SRS) applications. Emphasis is put on characterizing distortion at target brain areas identified by gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) paramagnetic contrast agent uptake. A custom-made phantom for distortion detection was modified to accommodate two small cylindrical inserts, simulating small brain targets. The inserts were filled with Gd-DTPA solutions of various concentrations (0-20 mM). The phantom was scanned at 1.5 T unit using both the reversed read gradient polarity (to determine the overall distortion as reflected by the inserts centroid offset) and the field mapping (to determine B 0 inhomogeneity related distortion in the vicinity of the inserts) techniques. Post-Gd patient images involving a total of 10 brain metastases/targets were also studied using a similar methodology. For the specific imaging conditions, contrast agent presence was found to evidently affect phantom insert position, with centroid offset extending up to 0.068 mm mM -1 (0.208 ppm mM -1 ). The Gd-DTPA induced distortion in patient images was of the order of 0.5 mm for the MRI protocol used, in agreement with the phantom results. Total localization uncertainty of metastases-targets in patient images ranged from 0.35 mm to 0.87 mm, depending on target location, with an average value of 0.54 mm (2.24 ppm). This relative wide range of target localization uncertainty results from the fact that the B 0 inhomogeneity distortion vector in a specific location may add to or partly counterbalance Gd-DTPA induced distortion, thus increasing or decreasing, respectively, the total sequence dependent distortion. Although relatively small, the sequence dependent distortion in Gd-DTPA enhanced brain images can be easily taken into account for SRS treatment planning and target definition purposes by carefully inspecting both the forward and reversed polarity series.

Cy5.5-labeled Affibody molecule for near-infrared fluorescent optical imaging of epidermal growth factor receptor positive tumors

NASA Astrophysics Data System (ADS)

Miao, Zheng; Ren, Gang; Liu, Hongguang; Jiang, Lei; Cheng, Zhen

2010-05-01

Affibody protein is an engineered protein scaffold with a three-helical bundle structure. Affibody molecules of small size (7 kD) have great potential for targeting overexpressed cancer biomarkers in vivo. To develop an Affibody-based molecular probe for in vivo optical imaging of epidermal growth factor receptor (EGFR) positive tumors, an anti-EGFR Affibody molecule, Ac-Cys-ZEGFR:1907 (7 kD), is site-specifically conjugated with a near-IR fluorescence dye, Cy5.5-mono-maleimide. Using fluorescent microscopy, the binding specificity of the probe Cy5.5-ZEGFR:1907 is checked by a high-EGFR-expressing A431 cell and low-EGFR-expressing MCF7 cells. The binding affinity of Cy5.5-ZEGFR:1907 (KD) to EGFR is 43.6+/-8.4 nM, as determined by flow cytometry. For an in vivo imaging study, the probe shows fast tumor targeting and good tumor contrast as early as 0.5 h postinjection (p.i.) for A431 tumors, while MCF7 tumors are barely visible. An ex vivo imaging study also demonstrates that Cy5.5-ZEGFR:1907 has high tumor, liver, and kidney uptakes at 24 h p.i.. In conclusion, Cy5.5-ZEGFR:1907 shows good affinity and high specificity to the EGFR. There is rapid achievement of good tumor-to-normal-tissue contrasts of Cy5.5-ZEGFR:1907, thus demonstrating its potential for EGFR-targeted molecular imaging of cancers.

Performance of target detection algorithm in compressive sensing miniature ultraspectral imaging compressed sensing system

NASA Astrophysics Data System (ADS)

Gedalin, Daniel; Oiknine, Yaniv; August, Isaac; Blumberg, Dan G.; Rotman, Stanley R.; Stern, Adrian

2017-04-01

Compressive sensing theory was proposed to deal with the high quantity of measurements demanded by traditional hyperspectral systems. Recently, a compressive spectral imaging technique dubbed compressive sensing miniature ultraspectral imaging (CS-MUSI) was presented. This system uses a voltage controlled liquid crystal device to create multiplexed hyperspectral cubes. We evaluate the utility of the data captured using the CS-MUSI system for the task of target detection. Specifically, we compare the performance of the matched filter target detection algorithm in traditional hyperspectral systems and in CS-MUSI multiplexed hyperspectral cubes. We found that the target detection algorithm performs similarly in both cases, despite the fact that the CS-MUSI data is up to an order of magnitude less than that in conventional hyperspectral cubes. Moreover, the target detection is approximately an order of magnitude faster in CS-MUSI data.

Focusing of light energy inside a scattering medium by controlling the time-gated multiple light scattering

NASA Astrophysics Data System (ADS)

Jeong, Seungwon; Lee, Ye-Ryoung; Choi, Wonjun; Kang, Sungsam; Hong, Jin Hee; Park, Jin-Sung; Lim, Yong-Sik; Park, Hong-Gyu; Choi, Wonshik

2018-05-01

The efficient delivery of light energy is a prerequisite for the non-invasive imaging and stimulating of target objects embedded deep within a scattering medium. However, the injected waves experience random diffusion by multiple light scattering, and only a small fraction reaches the target object. Here, we present a method to counteract wave diffusion and to focus multiple-scattered waves at the deeply embedded target. To realize this, we experimentally inject light into the reflection eigenchannels of a specific flight time to preferably enhance the intensity of those multiple-scattered waves that have interacted with the target object. For targets that are too deep to be visible by optical imaging, we demonstrate a more than tenfold enhancement in light energy delivery in comparison with ordinary wave diffusion cases. This work will lay a foundation to enhance the working depth of imaging, sensing and light stimulation.

Breast cancer cell targeted MR molecular imaging probe: Anti-MUC1 antibody-based magnetic nanoparticles

NASA Astrophysics Data System (ADS)

Moradi Khaniabadi, P.; S. A Majid, A. M.; Asif, M.; Moradi Khaniabadi, B.; Shahbazi-Gahrouei, D.; Jaafar, M. S.

2017-05-01

Effective and specific diagnostic imaging techniques are important in early-stage breast cancer treatment. The objective of this study was to develop a specific breast cancer contrast agent for magnetic resonance imaging (MRI). In so doing, superparamagnetic iron oxide nanoparticles (SPIONs) were conjugated to C595 monoclonal antibody using EDC chemistry to produce nanoprobe with high relaxivity and narrow size (87.4±0.7 nm). To test the developed nanoprobe in vitro, assessments including Cell toxicity, targeting efficacy, cellular binding, and MR imaging were carried out. The results indicated that after 6 hrs incubation with MCF-7 cells at 200 to 25 µg Fe/ml doses, 76% to 16% T2 reduction was obtained. The presence of iron localised in MCF-7 cells measured by atomic absorption spectroscopy (AAS) was about 9.95±0.09 ppm iron/cell at higher doses of nanoprobe. Moreover, a linear relationship between iron concentration of nontoxic SPION-C595 and T2 relaxation times was observed. This study also revealed that developed nanoprobe might be used as a specific negative contrast agent for detecting breast cancer.

S- Cis Diene Conformation: A New Bathochromic Shift Strategy for Near-Infrared Fluorescence Switchable Dye and the Imaging Applications.

PubMed

Chen, Hsiang-Jung; Chew, Chee Ying; Chang, En-Hao; Tu, Yu-Wei; Wei, Li-Yu; Wu, Bo-Han; Chen, Chien-Hung; Yang, Ya-Ting; Huang, Su-Chin; Chen, Jen-Kun; Chen, I-Chia; Tan, Kui-Thong

2018-04-18

In this paper, we present a novel charge-free fluorescence-switchable near-infrared (IR) dye based on merocyanine for target specific imaging. In contrast to the typical bathochromic shift approach by extending π-conjugation, the bathochromic shift of our merocyanine dye to the near-IR region is due to an unusual S- cis diene conformer. This is the first example where a fluorescent dye adopts the stable S- cis conformation. In addition to the novel bathochromic shift mechanism, the dye exhibits fluorescence-switchable properties in response to polarity and viscosity. By incorporating a protein-specific ligand to the dye, the probes (for SNAP-tag and hCAII proteins) exhibited dramatic fluorescence increase (up to 300-fold) upon binding with its target protein. The large fluorescence enhancement, near-IR absorption/emission, and charge-free scaffold enabled no-wash and site-specific imaging of target proteins in living cells and in vivo with minimum background fluorescence. We believe that our unconventional approach for a near-IR dye with the S- cis diene conformation can lead to new strategies for the design of near-IR dyes.

Image-algebraic design of multispectral target recognition algorithms

NASA Astrophysics Data System (ADS)

Schmalz, Mark S.; Ritter, Gerhard X.

1994-06-01

In this paper, we discuss methods for multispectral ATR (Automated Target Recognition) of small targets that are sensed under suboptimal conditions, such as haze, smoke, and low light levels. In particular, we discuss our ongoing development of algorithms and software that effect intelligent object recognition by selecting ATR filter parameters according to ambient conditions. Our algorithms are expressed in terms of IA (image algebra), a concise, rigorous notation that unifies linear and nonlinear mathematics in the image processing domain. IA has been implemented on a variety of parallel computers, with preprocessors available for the Ada and FORTRAN languages. An image algebra C++ class library has recently been made available. Thus, our algorithms are both feasible implementationally and portable to numerous machines. Analyses emphasize the aspects of image algebra that aid the design of multispectral vision algorithms, such as parameterized templates that facilitate the flexible specification of ATR filters.

3D space positioning and image feature extraction for workpiece

NASA Astrophysics Data System (ADS)

Ye, Bing; Hu, Yi

2008-03-01

An optical system of 3D parameters measurement for specific area of a workpiece has been presented and discussed in this paper. A number of the CCD image sensors are employed to construct the 3D coordinate system for the measured area. The CCD image sensor of the monitoring target is used to lock the measured workpiece when it enters the field of view. The other sensors, which are placed symmetrically beam scanners, measure the appearance of the workpiece and the characteristic parameters. The paper established target image segmentation and the image feature extraction algorithm to lock the target, based on the geometric similarity of objective characteristics, rapid locking the goal can be realized. When line laser beam scan the tested workpiece, a number of images are extracted equal time interval and the overlapping images are processed to complete image reconstruction, and achieve the 3D image information. From the 3D coordinate reconstruction model, the 3D characteristic parameters of the tested workpiece are gained. The experimental results are provided in the paper.

Riboswitch-Mediated Aptamer Binding for Imaging and Therapy (RABIT): A Novel Technique to Selectively Target an Intracelluar Ligand Specific for Ovarian Cancer

DTIC Science & Technology

2015-12-01

Award Number: W81XWH-12-1-0554 TITLE: Riboswitch-Mediated Aptamer Binding for Imaging and Therapy (RABIT): A Novel Technique to Selectively...ADDRESS. 1. REPORT DATE December 2015 2. REPORT TYPE Final 3. DATES COVERED 15Sep2012 - 14Sep2015 4. TITLE AND SUBTITLE Riboswitch-Mediated Aptamer ...with very high specificity, low background for imaging and low toxicity for therapy. We will make a riboswitch consisting of two aptamers and a

A philosophy for CNS radiotracer design.

PubMed

Van de Bittner, Genevieve C; Ricq, Emily L; Hooker, Jacob M

2014-10-21

Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test-retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood-brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.

Task demands determine the specificity of the search template.

PubMed

Bravo, Mary J; Farid, Hany

2012-01-01

When searching for an object, an observer holds a representation of the target in mind while scanning the scene. If the observer repeats the search, performance may become more efficient as the observer hones this target representation, or "search template," to match the specific demands of the search task. An effective search template must have two characteristics: It must reliably discriminate the target from the distractors, and it must tolerate variability in the appearance of the target. The present experiment examined how the tolerance of the search template is affected by the search task. Two groups of 18 observers trained on the same set of stimuli blocked either by target image (block-by-image group) or by target category (block-by-category group). One or two days after training, both groups were tested on a related search task. The pattern of test results revealed that the two groups of observers had developed different search templates, and that the templates of the block-by-category observers better captured the general characteristics of the category. These results demonstrate that observers match their search templates to the demands of the search task.

Image Guided Cervical Brachytherapy: 2014 Survey of the American Brachytherapy Society

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grover, Surbhi, E-mail: Surbhi.grover@uphs.upenn.edu; Harkenrider, Matthew M.; Cho, Linda P.

Purpose: To provide an update of the 2007 American brachytherapy survey on image-based brachytherapy, which showed that in the setting of treatment planning for gynecologic brachytherapy, although computed tomography (CT) was often used for treatment planning, most brachytherapists used point A for dose specification. Methods and Materials: A 45-question electronic survey on cervical cancer brachytherapy practice patterns was sent to all American Brachytherapy Society members and additional radiation oncologists and physicists based in the United States between January and September 2014. Responses from the 2007 survey and the present survey were compared using the χ{sup 2} test. Results: There weremore » 370 respondents. Of those, only respondents, not in training, who treat more than 1 cervical cancer patient per year and practice in the United States, were included in the analysis (219). For dose specification to the target (cervix and tumor), 95% always use CT, and 34% always use MRI. However, 46% use point A only for dose specification to the target. There was a lot of variation in parameters used for dose evaluation of target volume and normal tissues. Compared with the 2007 survey, use of MRI has increased from 2% to 34% (P<.0001) for dose specification to the target. Use of volume-based dose delineation to the target has increased from 14% to 52% (P<.0001). Conclusion: Although use of image-based brachytherapy has increased in the United States since the 2007 survey, there is room for further growth, particularly with the use of MRI. This increase may be in part due to educational initiatives. However, there is still significant heterogeneity in brachytherapy practice in the United States, and future efforts should be geared toward standardizing treatment.« less

Development of a Novel SPECT Tracer to Image c-Met Expression in Non-Small Cell Lung Cancer in a Human Tumor Xenograft.

PubMed

Han, Zhaoguo; Xiao, Yadi; Wang, Kai; Yan, Ji; Xiao, Zunyu; Fang, Fang; Jin, Zhongnan; Liu, Yang; Sun, Xilin; Shen, Baozhong

2018-05-18

Rationale: Elevated expression of the c-Met receptor plays a crucial role in cancers. In non-small cell lung cancer (NSCLC), aberrant activation of c-Met signaling pathway contributes to tumorigenesis and cancer progression, and may mediate acquired resistance to epidermal growth factor receptor-targeted therapy. c-Met is therefore emerging as a promising therapeutic target for treating NSCLC, and the methods for noninvasive in vivo assessment of c-Met expression will improve NSCLC treatment and diagnosis. Methods: A new peptide-based (cMBP) radiotracer targeting c-Met, 99m Tc-hydrazine nicotinamide (HYNIC)-cMBP, was developed for single photon emission computed tomography (SPECT) imaging. Cell uptake assays were performed on two NSCLC cell lines with different c-Met expression: H1993 (high expression) and H1299 (no expression). In vivo tumor specificity was assessed by SPECT imaging in tumor-bearing mice at 0.5, 1, 2 and 4 h after injection of the probe. Blocking assays, biodistribution and autoradiography were also conducted to determine probe specificity. Results: 99m Tc-HYNIC-cMBP was prepared with high efficiency and showed higher uptake in H1993 cells than H1299 cells. Biodistribution and autoradiography also showed significantly higher accumulation of 99m Tc-HYNIC-cMBP in H1993 tumors than H1299 (H1993: 4.74±1.43 %ID/g and H1299: 1.00±0.37 %ID/g at 0.5h, p<0.05). H1993 tumors were clearly visualized at 0.5h in SPECT images, whereas H1299 tumors were not observed at any time. Specificity of 99m Tc-HYNIC-cMBP to c-Met was demonstrated by competitive block with excess un-radiolabeled peptide. Conclusion: We developed a novel SPECT tracer, 99m Tc-HYNIC-cMBP, for c-Met-targeted imaging in NSCLC that specifically bound to c-Met with favorable pharmacokinetics in vitro and in vivo. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Performance considerations for high-definition head-mounted displays

NASA Technical Reports Server (NTRS)

Edwards, Oliver J.; Larimer, James; Gille, Jennifer

1992-01-01

Design image-optimization for helmet-mounted displays (HMDs) for military systems is presently discussed within the framework of a systems-engineering approach that encompasses (1) a description of natural targets in the field; (2) the characteristics of human visual perception; and (3) device specifications that directly relate to these ecological and human-factors parameters. Attention is given to target size and contrast and the relationship of the modulation transfer function to image resolution.

Development of targeted STORM for super resolution imaging of biological samples using digital micro-mirror device

NASA Astrophysics Data System (ADS)

Valiya Peedikakkal, Liyana; Steventon, Victoria; Furley, Andrew; Cadby, Ashley J.

2017-12-01

We demonstrate a simple illumination system based on a digital mirror device which allows for fine control over the power and pattern of illumination. We apply this to localization microscopy (LM), specifically stochastic optical reconstruction microscopy (STORM). Using this targeted STORM, we were able to image a selected area of a labelled cell without causing photo-damage to the surrounding areas of the cell.

The gastrin/cholecystokinin-B receptor on prostate cells--a novel target for bifunctional prostate cancer imaging.

PubMed

Sturzu, Alexander; Klose, Uwe; Sheikh, Sumbla; Echner, Hartmut; Kalbacher, Hubert; Deeg, Martin; Nägele, Thomas; Schwentner, Christian; Ernemann, Ulrike; Heckl, Stefan

2014-02-14

The means of identifying prostate carcinoma and its metastases are limited. The contrast agents used in magnetic resonance imaging clinical diagnostics are not taken up into the tumor cells, but only accumulate in the interstitial space of the highly vasculated tumor. We examined the gastrin/cholecystokinin-B receptor as a possible target for prostate-specific detection using the C-terminal seven amino acid sequence of the gastrin peptide hormone. The correct sequence and a scrambled control sequence were coupled to the fluorescent dye rhodamine and the magnetic resonance imaging contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). Expression analysis of the gastrin receptor mRNA was performed by reverse transcriptase polymerase chain reaction on PC3 prostate carcinoma cells, U373 glioma, U2OS osteosarcoma and Colo205 colon carcinoma cells. After having confirmed elevated expression of gastrin receptor in PC3 cells and very low expression of the receptor in Colo205 cells, these two cell lines were used to create tumor xenografts on nude mice for in vivo experiments. Confocal lasers scanning microscopy and magnetic resonance imaging showed a high specificity of the correct conjugate for the PC3 xenografts. Staining of the PC3 xenografts was much weaker with the scrambled conjugate while the Colo205 xenografts showed no marked staining with any of the conjugates. In vitro experiments comparing the correct and scrambled conjugates on PC3 cells by magnetic resonance relaxometry and fluorescence-activated cell sorting confirmed markedly higher specificity of the correct conjugate. The investigations show that the gastrin receptor is a promising tumor cell surface target for future prostate-cancer-specific imaging applications. Copyright © 2013 Elsevier B.V. All rights reserved.

Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE-/- atherosclerosis mouse model.

PubMed

Wei, Lihui; Petryk, Julia; Gaudet, Chantal; Kamkar, Maryam; Gan, Wei; Duan, Yin; Ruddy, Terrence D

2018-02-07

Chemokine receptor 5 (CCR5) plays an important role in atherosclerosis. Our objective was to develop a SPECT tracer targeting CCR5 for imaging plaque inflammation by radiolabeling D-Ala-peptide T-amide (DAPTA), a CCR5 antagonist, with 111 In. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated DAPTA (DOTA-DAPTA) was labeled with 111 In. Cell uptake studies were conducted in U87-CD4-CCR5 and U87-MG cells. Biodistribution was determined in C57BL/6 mice. Autoradiography, en face and Oil Red O (ORO) imaging studies were performed in ApoE -/- mice. DOTA-DAPTA was radiolabeled with 111 In with high radiochemical purity (> 98%) and specific activity (70 MBq·nmol). 111 In-DOTA-DAPTA exhibited fast blood and renal clearance and high spleen uptake. The U87-CD4-CCR5 cells had significantly higher uptake in comparison to the U87-MG cells. The cell uptake was reduced by three times with DAPTA, indicating the receptor specificity of the uptake. Autoradiographic images showed significantly higher lesion uptake of 111 In-DOTA-DAPTA in ApoE -/- mice than that in C57BL/6 mice. The tracer uptake in 4 month old ApoE -/- high fat diet (HFD) mice with blocking agent was twofold lower than the same mice without the blocking agent, demonstrating the specificity of the tracer for the CCR5 receptor. 111 In-DOTA-DAPTA, specifically targeting chemokine receptor CCR5, is a potential SPECT agent for imaging inflammation in atherosclerosis.

Identifying Novel Regulators of Vacuolar Trafficking by Combining Fluorescence Imaging-Based Forward Genetic Screening and In Vitro Pollen Germination.

PubMed

Feng, Qiang-Nan; Zhang, Yan

2017-01-01

Subcellular targeting of vacuolar proteins depends on cellular machinery regulating vesicular trafficking. Plant-specific vacuolar trafficking routes have been reported. However, regulators mediating these processes are obscure. By combining a fluorescence imaging-based forward genetic approach and in vitro pollen germination system, we show an efficient protocol of identifying regulators of plant-specific vacuolar trafficking routes.

Multifunctional SPIO/DOX-loaded A54 Homing Peptide Functionalized Dextran-g-PLGA Micelles for Tumor Therapy and MR Imaging

NASA Astrophysics Data System (ADS)

Situ, Jun-Qing; Wang, Xiao-Juan; Zhu, Xiu-Liang; Xu, Xiao-Ling; Kang, Xu-Qi; Hu, Jing-Bo; Lu, Chen-Ying; Ying, Xiao-Ying; Yu, Ri-Sheng; You, Jian; Du, Yong-Zhong

2016-10-01

Specific delivery of chemotherapy drugs and magnetic resonance imaging (MRI) contrast agent into tumor cells is one of the issues to highly efficient tumor targeting therapy and magnetic resonance imaging. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA could self-assemble to form micelles with a low critical micelle concentration of 22.51 μg. mL-1 and diameter of about 50 nm. The synthetic A54-Dex-PLGA micelles can encapsulate doxorubicin (DOX) as a model anti-tumor drug and superparamagnetic iron oxide (SPIO) as a contrast agent for MRI. The drug-encapsulation efficiency was about 80% and the in vitro DOX release was prolonged to 72 hours. The DOX/SPIO-loaded micelles could specifically target BEL-7402 cell line. In vitro MRI results also proved the specific binding ability of A54-Dex-PLGA/DOX/SPIO micelles to hepatoma cell BEL-7402. The in vivo MR imaging experiments using a BEL-7402 orthotopic implantation model further validated the targeting effect of DOX/SPIO-loaded micelles. In vitro and in vivo anti-tumor activities results showed that A54-Dex-PLGA/DOX/SPIO micelles revealed better therapeutic effects compared with Dex-PLGA/DOX/SPIO micelles and reduced toxicity compared with commercial adriamycin injection.

Radiolabeled Peptide Scaffolds for PET/SPECT - Optical in Vivo Imaging of Carbohydrate-Lectin Interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deutscher, Susan

2014-09-30

The objective of this research is to develop phage display-selected peptides into radio- and fluoresecently- labeled scaffolds for the multimodal imaging of carbohydrate-lectin interactions. While numerous protein and receptor systems are being explored for the development of targeted imaging agents, the targeting and analysis of carbohydrate-lectin complexes in vivo remains relatively unexplored. Antibodies, nanoparticles, and peptides are being developed that target carbohydrate-lectin complexes in living systems. However, antibodies and nanoparticles often suffer from slow clearance and toxicity problems. Peptides are attractive alternative vehicles for the specific delivery of radionuclides or fluorophores to sites of interest in vivo, although, because ofmore » their size, uptake and retention may be less than antibodies. We have selected high affinity peptides that bind a specific carbohydrate-lectin complex involved in cell-cell adhesion and cross-linking using bacteriophage (phage) display technologies (1,2). These peptides have allowed us to probe the role of these antigens in cell adhesion. Fluorescent versions of the peptides have been developed for optical imaging and radiolabeled versions have been used in single photon emission computed tomography (SPECT) and positron emission tomography (PET) in vivo imaging (3-6). A benefit in employing the radiolabeled peptides in SPECT and PET is that these imaging modalities are widely used in living systems and offer deep tissue sensitivity. Radiolabeled peptides, however, often exhibit poor stability and high kidney uptake in vivo. Conversely, optical imaging is sensitive and offers good spatial resolution, but is not useful for deep tissue penetration and is semi-quantitative. Thus, multimodality imaging that relies on the strengths of both radio- and optical- imaging is a current focus for development of new in vivo imaging agents. We propose a novel means to improve the efficacy of radiolabeled and fluorescently labeled peptides, including our lectin/carbohydrate- targeting peptides, by displaying the targeting epitopes on small ~29 amino acid cyclic plant protein scaffolds known as cyclotides. Cyclotides are extremely stable molecules with long serum half-lives and low kidney uptake (7). More than one copy of the peptide can be engineered into the cyclotide loops, thus increasing the avidity of the peptide construct for its target.« less

Clinically translatable nanotheranostic platforms for peripheral nerve regeneration: design with outcome in mind

NASA Astrophysics Data System (ADS)

Janjic, Jelena M.; Gorantla, Vijay S.

2018-02-01

Neuroinflammation is a dynamic immune phenomenon that changes in severity with time after neurotrauma and has a profound impact on neuroregeneration, tissue healing and neuropathic pain, which is a common consequence of peripheral nerve injury (PNI). Macrophages are key cellular mediators of neuroinflammation. Macrophage-targeted nanotherapies, such as complex (perfluorocarbon/hydrocarbon) multimodal nanoemulsions (NEs) provide highly specific imaging signatures of neuroinflammation and hence indirect surrogate metrics of regeneration. We present a novel strategy where these NEs incorporating multiple imaging modalities and biosensors are delivered locally to directly target key cellular players of neuroregeneration. Two representative formulations of a nanotheranostic platform for local delivery of cell targeted NEs are presented: 1) A dual (macrophage and neuronal) targeted nanoparticle laden hydrogel for synergistic modulation of neuroinflammation and analgesia following PNI; and 2) neurotherapeutic loaded nanoparticles with extended release profile for sustained support of neuroregeneration. Each platform is capable of dual imaging payloads (NIRF, MRI and/or PET) and/or cell specific targeting moieties for controlled drug release. In vitro and pilot in vivo results will be presented. Theranostic nanosystem based platforms offer a unique opportunity to sequentially monitor cellular and molecular events at the site of neuronal injury, enabling dynamic, in-vivo mechanistic insights rather than static, ex-vivo histopathologic evaluation. Given their targeted capabilities, these platforms can help achieve personalized treatments that are customized and optimized for patients with PNI.

Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm.

PubMed

Zheng, Fang; Devoogdt, Nick; Sparkes, Amanda; Morias, Yannick; Abels, Chloé; Stijlemans, Benoit; Lahoutte, Tony; Muyldermans, Serge; De Baetselier, Patrick; Schoonooghe, Steve; Beschin, Alain; Raes, Geert

2015-02-01

Kupffer cells (KCs) are liver resident macrophages which are important for tissue homeostasis and have been implicated in immunogenic, tolerogenic and pathogenic immune reactions depending on the insult. These cells and the biomarkers they express thus represent interesting in vivo sensors for monitoring liver inflammation. In the current study, we explored whether KCs can be monitored non-invasively using single-photon-emission computed tomography (SPECT) with (99m)Tc labeled nanobodies (Nbs) targeting selected biomarkers. Nbs targeting V-set and immunoglobulin domain-containing 4 (Vsig4) or macrophage mannose receptor (MMR) accumulated in the liver of untreated mice. The liver targeting of anti-Vsig4 Nbs, but not anti-MMR Nbs, was blunted upon depletion of macrophages, highlighting specificity of anti-Vsig4 Nbs for liver macrophage imaging. Ex vivo flow cytometry and immunohistochemistry analysis confirmed that anti-Vsig4 Nbs specifically targeted KCs but no other cell types in the liver. Upon induction of acute hepatitis using concanavalin A (ConA), down-regulation of the in vivo imaging signal obtained using anti-Vsig4 Nbs reflected reduction in KC numbers and transient modulation of Vsig4 expression on KCs. Overall, these results indicate that Nbs targeting Vsig4 as molecular imaging biomarker enable non-invasive monitoring of KCs during hepatic inflammation. Copyright © 2014 Elsevier GmbH. All rights reserved.

Tumor Targeting and Pharmacokinetics of a Near-Infrared Fluorescent-Labeled δ-Opioid Receptor Antagonist Agent, Dmt-Tic-Cy5.

PubMed

Huynh, Amanda Shanks; Estrella, Veronica; Stark, Valerie E; Cohen, Allison S; Chen, Tingan; Casagni, Todd J; Josan, Jatinder S; Lloyd, Mark C; Johnson, Joseph; Kim, Jongphil; Hruby, Victor J; Vagner, Josef; Morse, David L

2016-02-01

Fluorescence molecular imaging can be employed for the development of novel cancer targeting agents. Herein, we investigated the pharmacokinetics (PK) and cellular uptake of Dmt-Tic-Cy5, a delta-opioid receptor (δOR) antagonist-fluorescent dye conjugate, as a tumor-targeting molecular imaging agent. δOR expression is observed normally in the CNS, and pathologically in some tumors, including lung liver and breast cancers. In vitro, in vivo, and ex vivo experiments were conducted to image and quantify the fluorescence signal associated with Dmt-Tic-Cy5 over time using in vitro and intravital fluorescence microscopy and small animal fluorescence imaging of tumor-bearing mice. We observed specific retention of Dmt-Tic-Cy5 in tumors with maximum uptake in δOR-expressing positive tumors at 3 h and observable persistence for >96 h; clearance from δOR nonexpressing negative tumors by 6 h; and systemic clearance from normal organs by 24 h. Live-cell and intravital fluorescence microscopy demonstrated that Dmt-Tic-Cy5 had sustained cell-surface binding lasting at least 24 h with gradual internalization over the initial 6 h following administration. Dmt-Tic-Cy5 is a δOR-targeted agent that exhibits long-lasting and specific signal in δOR-expressing tumors, is rapidly cleared from systemic circulation, and is not retained in non-δOR-expressing tissues. Hence, Dmt-Tic-Cy5 has potential as a fluorescent tumor imaging agent.

Generating patient specific pseudo-CT of the head from MR using atlas-based regression

NASA Astrophysics Data System (ADS)

Sjölund, J.; Forsberg, D.; Andersson, M.; Knutsson, H.

2015-01-01

Radiotherapy planning and attenuation correction of PET images require simulation of radiation transport. The necessary physical properties are typically derived from computed tomography (CT) images, but in some cases, including stereotactic neurosurgery and combined PET/MR imaging, only magnetic resonance (MR) images are available. With these applications in mind, we describe how a realistic, patient-specific, pseudo-CT of the head can be derived from anatomical MR images. We refer to the method as atlas-based regression, because of its similarity to atlas-based segmentation. Given a target MR and an atlas database comprising MR and CT pairs, atlas-based regression works by registering each atlas MR to the target MR, applying the resulting displacement fields to the corresponding atlas CTs and, finally, fusing the deformed atlas CTs into a single pseudo-CT. We use a deformable registration algorithm known as the Morphon and augment it with a certainty mask that allows a tailoring of the influence certain regions are allowed to have on the registration. Moreover, we propose a novel method of fusion, wherein the collection of deformed CTs is iteratively registered to their joint mean and find that the resulting mean CT becomes more similar to the target CT. However, the voxelwise median provided even better results; at least as good as earlier work that required special MR imaging techniques. This makes atlas-based regression a good candidate for clinical use.

A new multi-spectral feature level image fusion method for human interpretation

NASA Astrophysics Data System (ADS)

Leviner, Marom; Maltz, Masha

2009-03-01

Various different methods to perform multi-spectral image fusion have been suggested, mostly on the pixel level. However, the jury is still out on the benefits of a fused image compared to its source images. We present here a new multi-spectral image fusion method, multi-spectral segmentation fusion (MSSF), which uses a feature level processing paradigm. To test our method, we compared human observer performance in a three-task experiment using MSSF against two established methods: averaging and principle components analysis (PCA), and against its two source bands, visible and infrared. The three tasks that we studied were: (1) simple target detection, (2) spatial orientation, and (3) camouflaged target detection. MSSF proved superior to the other fusion methods in all three tests; MSSF also outperformed the source images in the spatial orientation and camouflaged target detection tasks. Based on these findings, current speculation about the circumstances in which multi-spectral image fusion in general and specific fusion methods in particular would be superior to using the original image sources can be further addressed.

Performance evaluation of the multiple-image optical compression and encryption method by increasing the number of target images

NASA Astrophysics Data System (ADS)

Aldossari, M.; Alfalou, A.; Brosseau, C.

2017-08-01

In an earlier study [Opt. Express 22, 22349-22368 (2014)], a compression and encryption method that simultaneous compress and encrypt closely resembling images was proposed and validated. This multiple-image optical compression and encryption (MIOCE) method is based on a special fusion of the different target images spectra in the spectral domain. Now for the purpose of assessing the capacity of the MIOCE method, we would like to evaluate and determine the influence of the number of target images. This analysis allows us to evaluate the performance limitation of this method. To achieve this goal, we use a criterion based on the root-mean-square (RMS) [Opt. Lett. 35, 1914-1916 (2010)] and compression ratio to determine the spectral plane area. Then, the different spectral areas are merged in a single spectrum plane. By choosing specific areas, we can compress together 38 images instead of 26 using the classical MIOCE method. The quality of the reconstructed image is evaluated by making use of the mean-square-error criterion (MSE).

A semi-automated image analysis procedure for in situ plankton imaging systems.

PubMed

Bi, Hongsheng; Guo, Zhenhua; Benfield, Mark C; Fan, Chunlei; Ford, Michael; Shahrestani, Suzan; Sieracki, Jeffery M

2015-01-01

Plankton imaging systems are capable of providing fine-scale observations that enhance our understanding of key physical and biological processes. However, processing the large volumes of data collected by imaging systems remains a major obstacle for their employment, and existing approaches are designed either for images acquired under laboratory controlled conditions or within clear waters. In the present study, we developed a semi-automated approach to analyze plankton taxa from images acquired by the ZOOplankton VISualization (ZOOVIS) system within turbid estuarine waters, in Chesapeake Bay. When compared to images under laboratory controlled conditions or clear waters, images from highly turbid waters are often of relatively low quality and more variable, due to the large amount of objects and nonlinear illumination within each image. We first customized a segmentation procedure to locate objects within each image and extracted them for classification. A maximally stable extremal regions algorithm was applied to segment large gelatinous zooplankton and an adaptive threshold approach was developed to segment small organisms, such as copepods. Unlike the existing approaches for images acquired from laboratory, controlled conditions or clear waters, the target objects are often the majority class, and the classification can be treated as a multi-class classification problem. We customized a two-level hierarchical classification procedure using support vector machines to classify the target objects (< 5%), and remove the non-target objects (> 95%). First, histograms of oriented gradients feature descriptors were constructed for the segmented objects. In the first step all non-target and target objects were classified into different groups: arrow-like, copepod-like, and gelatinous zooplankton. Each object was passed to a group-specific classifier to remove most non-target objects. After the object was classified, an expert or non-expert then manually removed the non-target objects that could not be removed by the procedure. The procedure was tested on 89,419 images collected in Chesapeake Bay, and results were consistent with visual counts with >80% accuracy for all three groups.

A Semi-Automated Image Analysis Procedure for In Situ Plankton Imaging Systems

PubMed Central

Bi, Hongsheng; Guo, Zhenhua; Benfield, Mark C.; Fan, Chunlei; Ford, Michael; Shahrestani, Suzan; Sieracki, Jeffery M.

2015-01-01

Plankton imaging systems are capable of providing fine-scale observations that enhance our understanding of key physical and biological processes. However, processing the large volumes of data collected by imaging systems remains a major obstacle for their employment, and existing approaches are designed either for images acquired under laboratory controlled conditions or within clear waters. In the present study, we developed a semi-automated approach to analyze plankton taxa from images acquired by the ZOOplankton VISualization (ZOOVIS) system within turbid estuarine waters, in Chesapeake Bay. When compared to images under laboratory controlled conditions or clear waters, images from highly turbid waters are often of relatively low quality and more variable, due to the large amount of objects and nonlinear illumination within each image. We first customized a segmentation procedure to locate objects within each image and extracted them for classification. A maximally stable extremal regions algorithm was applied to segment large gelatinous zooplankton and an adaptive threshold approach was developed to segment small organisms, such as copepods. Unlike the existing approaches for images acquired from laboratory, controlled conditions or clear waters, the target objects are often the majority class, and the classification can be treated as a multi-class classification problem. We customized a two-level hierarchical classification procedure using support vector machines to classify the target objects (< 5%), and remove the non-target objects (> 95%). First, histograms of oriented gradients feature descriptors were constructed for the segmented objects. In the first step all non-target and target objects were classified into different groups: arrow-like, copepod-like, and gelatinous zooplankton. Each object was passed to a group-specific classifier to remove most non-target objects. After the object was classified, an expert or non-expert then manually removed the non-target objects that could not be removed by the procedure. The procedure was tested on 89,419 images collected in Chesapeake Bay, and results were consistent with visual counts with >80% accuracy for all three groups. PMID:26010260

Stroma Targeting Nuclear Imaging and Radiopharmaceuticals

PubMed Central

Shetty, Dinesh; Jeong, Jae-Min; Shim, Hyunsuk

2012-01-01

Malignant transformation of tumor accompanies profound changes in the normal neighboring tissue, called tumor stroma. The tumor stroma provides an environment favoring local tumor growth, invasion, and metastatic spreading. Nuclear imaging (PET/SPECT) measures biochemical and physiologic functions in the human body. In oncology, PET/SPECT is particularly useful for differentiating tumors from postsurgical changes or radiation necrosis, distinguishing benign from malignant lesions, identifying the optimal site for biopsy, staging cancers, and monitoring the response to therapy. Indeed, PET/SPECT is a powerful, proven diagnostic imaging modality that displays information unobtainable through other anatomical imaging, such as CT or MRI. When combined with coregistered CT data, [18F]fluorodeoxyglucose ([18F]FDG)-PET is particularly useful. However, [18F]FDG is not a target-specific PET tracer. This paper will review the tumor microenvironment targeting oncologic imaging such as angiogenesis, invasion, hypoxia, growth, and homing, and also therapeutic radiopharmaceuticals to provide a roadmap for additional applications of tumor imaging and therapy. PMID:22685650

Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors

NASA Astrophysics Data System (ADS)

Kim, Ji Bak; Park, Kyeongsoon; Ryu, Jiheun; Lee, Jae Joong; Lee, Min Woo; Cho, Han Saem; Nam, Hyeong Soo; Park, Ok Kyu; Song, Joon Woo; Kim, Tae Shik; Oh, Dong Joo; Gweon, Daegab; Oh, Wang-Yuhl; Yoo, Hongki; Kim, Jin Won

2016-03-01

Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high-risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications.

Development and Testing of a 212Pb/212Bi Peptide for Targeting Metastatic Melanoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fisher, Darrell R.

2012-10-25

The purpose of this project is to develop a new radiolabeled peptide for imaging and treating metastatic melanoma. The immunoconjugate consists of a receptor-specific peptide that targets melanoma cells. The beta-emitter lead-212 (half-life = 10.4 hours) is linked by coordination chemistry to the peptide. After injection, the peptide targets melanoma receptors on the surfaces of melanoma cells. Lead-212 decays to the alpha-emitter bismuth-212 (half-life = 60 minutes). Alpha-particles that hit melanoma cell nuclei are likely to kill the melanoma cell. For cancer cell imaging, the lead-212 is replaced by lead-203 (half-life = 52 hours). Lead-203 emits 279 keV photons (80.1%more » abundance) that can be imaged and measured for biodistribution analysis, cancer imaging, and quantitative dosimetry.« less

New Radiotracers for Imaging of Vascular Targets in Angiogenesis-related Diseases

PubMed Central

Hong, Hao; Chen, Feng; Zhang, Yin; Cai, Weibo

2014-01-01

Tremendous advances over the last several decades in positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for targeted imaging of molecular and cellular events in the living systems. Angiogenesis, a multistep process regulated by the network of different angiogenic factors, has attracted world-wide interests, due to its pivotal role in the formation and progression of different diseases including cancer, cardiovascular diseases (CVD), and inflammation. In this review article, we will summarize the recent progress in PET or SPECT imaging of a wide variety of vascular targets in three major angiogenesis-related diseases: cancer, cardiovascular diseases, and inflammation. Faster drug development and patient stratification for a specific therapy will become possible with the facilitation of PET or SPECT imaging and it will be critical for the maximum benefit of patients. PMID:25086372

Photoacoustic imaging of hepatocellular carcinoma targeting gold nanoshells (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Quan; Chen, Yan; Li, Zhao; Zhou, Juan; Duan, Xiyu; Wang, Thomas D.

2017-02-01

Plasmonic gold nanoshell (GNS) probe penetrates into tumors for deep imaging, enables superior photoacoustic contrast. Glypican-3 (GPC3) specific peptide (Kd = 71 nM) conjugated gold nanoshell (λabs=770nm) was used to detect HCC xenograft tumors in mice with photoacoustic imaging. This targeting probe demonstrated tumor uptake after 1 hr and cleared in 12 hrs. Images at a mean (±SD) depth of 9.7±1.4 mm from 0 to 2.1 cm beneath the skin revealed increased PA signal from tumors. Highest tumor uptake and tumor to normal tissue ratio occurred at 2 hrs post injection (T/B = 4.45±0.22, n = 8). Molecular targeting GNS showed potential as a simple, effective and rapid technique for noninvasive in vivo monitoring HCC tumor growth and GPC3 expression.

Precision Medicine in Multiple Sclerosis: Future of PET Imaging of Inflammation and Reactive Astrocytes

PubMed Central

Poutiainen, Pekka; Jaronen, Merja; Quintana, Francisco J.; Brownell, Anna-Liisa

2016-01-01

Non-invasive molecular imaging techniques can enhance diagnosis to achieve successful treatment, as well as reveal underlying pathogenic mechanisms in disorders such as multiple sclerosis (MS). The cooperation of advanced multimodal imaging techniques and increased knowledge of the MS disease mechanism allows both monitoring of neuronal network and therapeutic outcome as well as the tools to discover novel therapeutic targets. Diverse imaging modalities provide reliable diagnostic and prognostic platforms to better achieve precision medicine. Traditionally, magnetic resonance imaging (MRI) has been considered the golden standard in MS research and diagnosis. However, positron emission tomography (PET) imaging can provide functional information of molecular biology in detail even prior to anatomic changes, allowing close follow up of disease progression and treatment response. The recent findings support three major neuroinflammation components in MS: astrogliosis, cytokine elevation, and significant changes in specific proteins, which offer a great variety of specific targets for imaging purposes. Regardless of the fact that imaging of astrocyte function is still a young field and in need for development of suitable imaging ligands, recent studies have shown that inflammation and astrocyte activation are related to progression of MS. MS is a complex disease, which requires understanding of disease mechanisms for successful treatment. PET is a precise non-invasive imaging method for biochemical functions and has potential to enhance early and accurate diagnosis for precision therapy of MS. In this review we focus on modulation of different receptor systems and inflammatory aspect of MS, especially on activation of glial cells, and summarize the recent findings of PET imaging in MS and present the most potent targets for new biomarkers with the main focus on experimental MS research. PMID:27695400

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer

NASA Astrophysics Data System (ADS)

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.

2012-10-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer.

PubMed

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G; Yun, Dong Soo; Belcher, Angela M; Kelly, Kimberly A

2012-10-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and would improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection.

M13-templated magnetic nanoparticles for targeted in vivo imaging of prostate cancer

PubMed Central

Ghosh, Debadyuti; Lee, Youjin; Thomas, Stephanie; Kohli, Aditya G.; Yun, Dong Soo; Belcher, Angela M.; Kelly, Kimberly A.

2014-01-01

Molecular imaging allows clinicians to visualize the progression of tumours and obtain relevant information for patient diagnosis and treatment1. Owing to their intrinsic optical, electrical and magnetic properties, nanoparticles are promising contrast agents for imaging dynamic molecular and cellular processes such as protein-protein interactions, enzyme activity or gene expression2. Until now, nanoparticles have been engineered with targeting ligands such as antibodies and peptides to improve tumour specificity and uptake. However, excessive loading of ligands can reduce the targeting capabilities of the ligand3,4,5 and reduce the ability of the nanoparticle to bind to a finite number of receptors on cells6. Increasing the number of nanoparticles delivered to cells by each targeting molecule would lead to higher signal-to-noise ratios and improve image contrast. Here, we show that M13 filamentous bacteriophage can be used as a scaffold to display targeting ligands and multiple nanoparticles for magnetic resonance imaging of cancer cells and tumours in mice. Monodisperse iron oxide magnetic nanoparticles assemble along the M13 coat, and its distal end is engineered to display a peptide that targets SPARC glycoprotein, which is overexpressed in various cancers. Compared with nanoparticles that are directly functionalized with targeting peptides, our approach improves contrast because each SPARC-targeting molecule delivers a large number of nanoparticles into the cells. Moreover, the targeting ligand and nanoparticles could be easily exchanged for others, making this platform attractive for in vivo high-throughput screening and molecular detection. PMID:22983492

THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience

PubMed Central

Baum, Richard P.; Kulkarni, Harshad R.

2012-01-01

The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction. PMID:22768024

THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience.

PubMed

Baum, Richard P; Kulkarni, Harshad R

2012-01-01

The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction.

Synthesis of fluorescent dye-doped silica nanoparticles for target-cell-specific delivery and intracellular microRNA imaging.

PubMed

Li, Henan; Mu, Yawen; Qian, Shanshan; Lu, Jusheng; Wan, Yakun; Fu, Guodong; Liu, Songqin

2015-01-21

MicroRNA (miRNA) is found to be up-regulated in many kinds of cancer and therefore is classified as an oncomiR. Herein, we design a multifunctional fluorescent nanoprobe (FSiNP-AS/MB) with the AS1411 aptamer and a molecular beacon (MB) co-immobilized on the surface of the fluorescent dye-doped silica nanoparticles (FSiNPs) for target-cell-specific delivery and intracellular miRNA imaging. The FSiNPs were prepared by a facile reverse microemulsion method from tetraethoxysilane and silane derivatized coumarin that was previously synthesized by click chemistry. The as-prepared FSiNPs possess uniform size distribution, good optical stability and biocompatibility. In addition, there is a remarkable affinity interaction between the AS1411 aptamer and the nucleolin protein on the cancer cell surface. Thus, a target-cell-specific delivery system by the FSiNP-AS/MB is proposed for effectively transferring a MB into the cancer cells to recognize the target miRNA. Using miRNA-21 in MCF-7 cells (a human breast cancer cell line) as a model, the proposed multifunctional nanosystems not only allow target-cell-specific delivery with the binding affinity of AS1411, but also can track simultaneously the transfected cells and detect intracellular miRNA in situ. The proposed multifunctional nanosystems are a promising platform for a highly sensitive luminescent nonviral vector in biomedical and clinical research.

Limitations of contrast enhancement for infrared target identification

NASA Astrophysics Data System (ADS)

Du Bosq, Todd W.; Fanning, Jonathan D.

2009-05-01

Contrast enhancement and dynamic range compression are currently being used to improve the performance of infrared imagers by increasing the contrast between the target and the scene content. Automatic contrast enhancement techniques do not always achieve this improvement. In some cases, the contrast can increase to a level of target saturation. This paper assesses the range-performance effects of contrast enhancement for target identification as a function of image saturation. Human perception experiments were performed to determine field performance using contrast enhancement on the U.S. Army RDECOM CERDEC NVESD standard military eight target set using an un-cooled LWIR camera. The experiments compare the identification performance of observers viewing contrast enhancement processed images at various levels of saturation. Contrast enhancement is modeled in the U.S. Army thermal target acquisition model (NVThermIP) by changing the scene contrast temperature. The model predicts improved performance based on any improved target contrast, regardless of specific feature saturation or enhancement. The measured results follow the predicted performance based on the target task difficulty metric used in NVThermIP for the non-saturated cases. The saturated images reduce the information contained in the target and performance suffers. The model treats the contrast of the target as uniform over spatial frequency. As the contrast is enhanced, the model assumes that the contrast is enhanced uniformly over the spatial frequencies. After saturation, the spatial cues that differentiate one tank from another are located in a limited band of spatial frequencies. A frequency dependent treatment of target contrast is needed to predict performance of over-processed images.

Camelid single-domain antibodies: A versatile tool for in vivo imaging of extracellular and intracellular brain targets.

PubMed

Li, Tengfei; Vandesquille, Matthias; Koukouli, Fani; Dudeffant, Clémence; Youssef, Ihsen; Lenormand, Pascal; Ganneau, Christelle; Maskos, Uwe; Czech, Christian; Grueninger, Fiona; Duyckaerts, Charles; Dhenain, Marc; Bay, Sylvie; Delatour, Benoît; Lafaye, Pierre

2016-12-10

Detection of intracerebral targets with imaging probes is challenging due to the non-permissive nature of blood-brain barrier (BBB). The present work describes two novel single-domain antibodies (VHHs or nanobodies) that specifically recognize extracellular amyloid deposits and intracellular tau neurofibrillary tangles, the two core lesions of Alzheimer's disease (AD). Following intravenous administration in transgenic mouse models of AD, in vivo real-time two-photon microscopy showed gradual extravasation of the VHHs across the BBB, diffusion in the parenchyma and labeling of amyloid deposits and neurofibrillary tangles. Our results demonstrate that VHHs can be used as specific BBB-permeable probes for both extracellular and intracellular brain targets and suggest new avenues for therapeutic and diagnostic applications in neurology. Copyright © 2016 Elsevier B.V. All rights reserved.

Gold Nanoconstructs for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy

NASA Astrophysics Data System (ADS)

Coughlin, Andrew James

Cancer accounts for nearly 1 out of every 4 deaths in the United States, and because conventional treatments are limited by morbidity and off-target toxicities, improvements in cancer management are needed. This thesis further develops nanoparticle-assisted photothermal therapy (NAPT) as a viable treatment option for cancer patients. NAPT enables localized ablation of disease because heat generation only occurs where tissue permissive near-infrared (NIR) light and absorbing nanoparticles are combined, leaving surrounding normal tissue unharmed. Two principle approaches were investigated to improve the specificity of this technique: multimodal imaging and molecular targeting. Multimodal imaging affords the ability to guide NIR laser application for site-specific NAPT and more holistic characterization of disease by combining the advantages of several diagnostic technologies. Towards the goal of image-guided NAPT, gadolinium-conjugated gold-silica nanoshells were engineered and demonstrated to enhance imaging contrast across a range of diagnostic modes, including T1-weighted magnetic resonance imaging, X-Ray, optical coherence tomography, reflective confocal microscopy, and two-photon luminescence in vitro as well as within an animal tumor model. Additionally, the nanoparticle conjugates were shown to effectively convert NIR light to heat for applications in photothermal therapy. Therefore, the broad utility of gadolinium-nanoshells for anatomic localization of tissue lesions, molecular characterization of malignancy, and mediators of ablation was established. Molecular targeting strategies may also improve NAPT by promoting nanoparticle uptake and retention within tumors and enhancing specificity when malignant and normal tissue interdigitate. Here, ephrinA1 protein ligands were conjugated to nanoshell surfaces for particle homing to overexpressed EphA2 receptors on prostate cancer cells. In vitro, successful targeting and subsequent photothermal ablation of prostate cancer cells was achieved with negligible nanoshell binding to normal cells. In vivo however, ephrinA1-nanoshells did not promote enhanced therapeutic outcomes in mice bearing subcutaneous prostate cancer tumors treated with NAPT compared to nontargeted particles. Nonetheless, both treatment groups demonstrated effective ablation of prostate tumors, as evidenced by tumor tissue regression. Further investigation is warranted to overcome probable protein immunogenicity that offsets ephrinA1 targeting in vivo. With future study, photothermal therapy with multimodal gadolinium-conjugated and molecularly targeted nanoshells may offer a viable treatment option for cancer patients in the clinic.

Synthesis and characterization of a glycine-modified heptamethine indocyanine dye for in vivo cancer-targeted near-infrared imaging

PubMed Central

Liu, Tao; Luo, Shenglin; Wang, Yang; Tan, Xu; Qi, Qingrong; Shi, Chunmeng

2014-01-01

Near-infrared (NIR) fluorescent sensors have emerged as promising molecular tools for cancer imaging and detection in living systems. However, cancer NIR fluorescent sensors are very challenging to develop because they are required to exhibit good specificity and low toxicity as an eligible contrast agent. Here, we describe the synthesis of a new heptamethine indocyanine dye (NIR-27) modified with a glycine at the end of each N-alkyl side chain, and its biological characterization for in vivo cancer-targeted NIR imaging. In addition to its high specificity, NIR-27 also shows lower cytotoxicity than indocyanine green, a nonspecific NIR probe widely used in clinic. These characteristics suggest that NIR-27 is a promising prospect as a new NIR fluorescent sensor for sensitive cancer detection. PMID:25246770

Photoacoustic tomography of foreign bodies in soft biological tissue.

PubMed

Cai, Xin; Kim, Chulhong; Pramanik, Manojit; Wang, Lihong V

2011-04-01

In detecting small foreign bodies in soft biological tissue, ultrasound imaging suffers from poor sensitivity (52.6%) and specificity (47.2%). Hence, alternative imaging methods are needed. Photoacoustic (PA) imaging takes advantage of strong optical absorption contrast and high ultrasonic resolution. A PA imaging system is employed to detect foreign bodies in biological tissues. To achieve deep penetration, we use near-infrared light ranging from 750 to 800 nm and a 5-MHz spherically focused ultrasonic transducer. PA images were obtained from various targets including glass, wood, cloth, plastic, and metal embedded more than 1 cm deep in chicken tissue. The locations and sizes of the targets from the PA images agreed well with those of the actual samples. Spectroscopic PA imaging was also performed on the objects. These results suggest that PA imaging can potentially be a useful intraoperative imaging tool to identify foreign bodies.

Integrating Molecular Imaging Approaches to Monitor Prostate Targeted Suicide and Anti-angiogenic Gene Therapy

DTIC Science & Technology

2005-02-01

tissue-specific expression of prostate-specific antigen. Cancer Res. 57: 495–499. 11. Schuur, E. R ., Henderson, G . A., Kmetec, L. A., Miller, J. D...Lamparski, H. G ., and Henderson, D. R . (1996). Prostate-specific antigen expression is regulated by an up- stream enhancer. J. Biol. Chem. 271: 7043...5: 223–232. 29. Blasberg, R . G ., and Tjuvajev, J. G . (1999). Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene

Improved tumor identification using dual tracer molecular imaging in fluorescence guided brain surgery

NASA Astrophysics Data System (ADS)

Xu, Xiaochun; Torres, Veronica; Straus, David; Brey, Eric M.; Byrne, Richard W.; Tichauer, Kenneth M.

2015-03-01

Brain tumors represent a leading cause of cancer death for people under the age of 40 and the probability complete surgical resection of brain tumors remains low owing to the invasive nature of these tumors and the consequences of damaging healthy brain tissue. Molecular imaging is an emerging approach that has the potential to improve the ability for surgeons to correctly discriminate between healthy and cancerous tissue; however, conventional molecular imaging approaches in brain suffer from significant background signal in healthy tissue or an inability target more invasive sections of the tumor. This work presents initial studies investigating the ability of novel dual-tracer molecular imaging strategies to be used to overcome the major limitations of conventional "single-tracer" molecular imaging. The approach is evaluated in simulations and in an in vivo mice study with animals inoculated orthotopically using fluorescent human glioma cells. An epidermal growth factor receptor (EGFR) targeted Affibody-fluorescent marker was employed as a targeted imaging agent, and the suitability of various FDA approved untargeted fluorescent tracers (e.g. fluorescein & indocyanine green) were evaluated in terms of their ability to account for nonspecific uptake and retention of the targeted imaging agent. Signal-to-background ratio was used to measure and compare the amount of reporter in the tissue between targeted and untargeted tracer. The initial findings suggest that FDA-approved fluorescent imaging agents are ill-suited to act as untargeted imaging agents for dual-tracer fluorescent guided brain surgery as they suffer from poor delivery to the healthy brain tissue and therefore cannot be used to identify nonspecific vs. specific uptake of the targeted imaging agent where current surgery is most limited.

AEGIS Automated Targeting for the MSL ChemCam Instrument

NASA Astrophysics Data System (ADS)

Estlin, T.; Anderson, R. C.; Blaney, D. L.; Bornstein, B.; Burl, M. C.; Castano, R.; Gaines, D.; Judd, M.; Thompson, D. R.; Wiens, R. C.

2013-12-01

The Autonomous Exploration for Gathering Increased Science (AEGIS) system enables automated science data collection by a planetary rover. AEGIS has been in use on the Mars Exploration Rover (MER) mission Opportunity rover since 2010 to provide onboard targeting of the MER Panoramic Camera based on scientist-specified objectives. AEGIS is now being applied for use with the Mars Science Laboratory (MSL) mission ChemCam spectrometer. ChemCam uses a Laser Induced Breakdown Spectrometer (LIBS) to analyze the elemental composition of rocks and soil from up to seven meters away. ChemCam's tightly-focused laser beam (350-550 um) enables targeting of very fine-scale terrain features. AEGIS is being applied in two ways to help ChemCam collect valuable science data. The first application is to enable automated targeting of ChemCam during or after or in the middle of long drives. The majority of ChemCam measurements are collected by allowing the science team to select specific targets in rover images. However this requires the rover to stay in the same area while images are downlinked, analyzed for targets, and new commands uplinked. The only data that can be acquired without this communication cycle is via blind targeting, where measurements are often of soil patches vs. instead of more valuable targets such as rocks with specific properties. AEGIS is being applied to automatically analyze images onboard and select targets for ChemCam analysis. This approach allows the rover to autonomously select and sequence targeted measurements in an opportunistic fashion at different points along the rover's drive path. Rock targets can be prioritized for measurement based on various geologically relevant features, including size, shape and albedo. A second application is to enable intelligent pointing refinement of ChemCam when acquiring data of small targets, such as veins or concretions that are only a few millimeters wide. Due to backlash and other pointing challenges, it can often require several downlink cycles for LIBS measurements to be acquired on small targets. Often targets must first be imaged using the high resolution ChemCam Remote Micro Imager (RMI) and then ground analysis performed to enable a fine-tuned pointing correction on the next commanding cycle. AEGIS is being applied to analyze RMI images onboard and automatically determine the pointing refinement necessary to acquire LIBS data on small targets. This significantly decreases the amount of time and resources required to acquire ChemCam data on such targets. Work is currently in progress to adapt AEGIS algorithm for these applications and integrate the system with MSL flight software. Once integration and testing is complete, AEGIS will be uploaded to the spacecraft for operational use.

Retargeted human avidin-CAR T cells for adoptive immunotherapy of EGFRvIII expressing gliomas and their evaluation via optical imaging.

PubMed

Liu, Kaiyu; Liu, Xujie; Peng, Zhiping; Sun, Haojie; Zhang, Mingzhi; Zhang, Jianning; Liu, Shuang; Hao, Limin; Lu, Guoqiu; Zheng, Kangcheng; Gong, Xikui; Wu, Di; Wang, Fan; Shen, Li

2015-09-15

There has been significant progress in the design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. However, the challenge of monitoring the therapy in real time has been continually ignored. To address this issue, we developed optical molecular imaging approaches to evaluate a recently reported novel CAR strategy for adoptive immunotherapy against glioma xenografts expressing EGFRvIII. We initially biotinylated a novel anti-EGFRvIII monoclonal antibody (biotin-4G1) to pre-target EGFRvIII+ gliomas and then redirect activated avidin-CAR expressing T cells against the pre-targeted biotin-4G1. By optical imaging study and bio-distribution analysis, we confirmed the specificity of pre-target and target and determined the optimal time for T cells adoptive transfer in vivo. The results showed this therapeutic strategy offered efficient therapy effect to EGFRvIII+ glioma-bearing mice and implied that optical imaging is a highly useful tool in aiding in the instruction of clinical CAR-T cells adoptive transfer in future.

Liposomal nanocarriers for tumor imaging.

PubMed

Erdogan, Suna

2009-04-01

Currently used imaging modalities such as scintigraphy, computed tomography, magnetic resonance imaging and ultrasonography require the sufficient intensity of a corresponding signal from an area of interest to differentiate this area from the surrounding tissues. Targeting of various reporter moieties directly to the specific organs, tissues or tumors provide the highest dose of drug directly where it is needed. Many different types of nanoparticles are currently being studied for applications in nanomedicine. Among particulate drug carriers, liposomes are one of the most extensively studied and possess the most suitable characteristics for encapsulation of many drugs, genes, and diagnostic (imaging) agents. Among the many potential targets for such nanocarriers, tumors have been most often investigated. This review attempts to summarize the currently available information regarding liposomal nanocarriers for cancer imaging.

Tumor-targeting peptides from combinatorial libraries*

PubMed Central

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S.

2018-01-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges infighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. PMID:27210583

Eye-Target Synchrony and Attention

NASA Astrophysics Data System (ADS)

Contreras, R.; Kolster, R.; Basu, S.; Voss, H. U.; Ghajar, J.; Suh, M.; Bahar, S.

2007-03-01

Eye-target synchrony is critical during smooth pursuit. We apply stochastic phase synchronization to human pursuit of a moving target, in both normal and mild traumatic brain injured (TBI) subjects. Smooth pursuit utilizes the same neural networks used by attention. To test whether smooth pursuit is modulated by attention, subjects tracked a target while loaded with tasks involving working memory. Preliminary results suggest that additional cognitive load increases normal subjects' performance, while the effect is reversed in TBI patients. We correlate these results with eye-target synchrony. Additionally, we correlate eye-target synchrony with frequency of target motion, and discuss how the range of frequencies for optimal synchrony depends on the shift from attentional to automatic-response time scales. Synchrony deficits in TBI patients can be correlated with specific regions of brain damage imaged with diffusion tensor imaging (DTI).

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles

PubMed Central

Fan, Xiaozhou; Guo, Yanli; Wang, Luofu; Xiong, Xingyu; Zhu, Lianhua; Fang, Kejing

2016-01-01

In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times (P>0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different (P<0.05). In PC-3 xenografts, there were no differences in these four indicators. Fluorescent imaging indicated that targeted nanobubbles had an aggregation ability in C4-2 xenograft tumors. In conclusion, targeted nanobubbles carrying the anti-PSMA A10-3.2 aptamer have a targeted imaging effect in prostate cancer. PMID:27574424

Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles.

PubMed

Fan, Xiaozhou; Guo, Yanli; Wang, Luofu; Xiong, Xingyu; Zhu, Lianhua; Fang, Kejing

2016-01-01

In this study, the lipid targeted nanobubble carrying the A10-3.2 aptamer against prostate specific membrane antigen was fabricated, and its effect in the ultrasound imaging of prostate cancer was investigated. Materials including 2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphatidic acid, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol, carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, and polyethyleneglycol-2000 were for mechanical oscillation, and nanobubbles were obtained through the centrifugal flotation method. After mice were injected with nanobubbles, abdominal color Doppler blood flow imaging significantly improved. Through left ventricular perfusion with normal saline to empty the circulating nanobubbles, nanobubbles still existed in tumor tissue sections, which demonstrated that nanobubbles could enter tissue spaces via the permeability and retention effect. Fluorinated A10-3.2 aptamers obtained by chemical synthesis had good specificity for PSMA-positive cells, and were linked with carboxyl-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine lipid molecules from the outer shell of nanobubbles via amide reaction to construct targeted nanobubbles. Gel electrophoresis and immunofluorescence confirmed that targeted nanobubbles were fabricated successfully. Next, targeted nanobubbles could bind with PSMA-positive cells (C4-2 cells), while not with PSMA-negative cells (PC-3 cells), using in vitro binding experiments and flow cytometry at the cellular level. Finally, C4-2 and PC-3 xenografts in mice were used to observe changes in parameters of targeted and non-targeted nanobubbles in the contrast-enhanced ultrasound mode, and the distribution of Cy5.5-labeled targeted nanobubbles in fluorescent imaging of live small animals. Comparison of ultrasound indicators between targeted and non-targeted nanobubbles in C4-2 xenografts showed that they had similar peak times (P>0.05), while the peak intensity, half time of peak intensity, and area under the curve of ½ peak intensity were significantly different (P<0.05). In PC-3 xenografts, there were no differences in these four indicators. Fluorescent imaging indicated that targeted nanobubbles had an aggregation ability in C4-2 xenograft tumors. In conclusion, targeted nanobubbles carrying the anti-PSMA A10-3.2 aptamer have a targeted imaging effect in prostate cancer.

Multifunctional nanoparticle-EpCAM aptamer bioconjugates: a paradigm for targeted drug delivery and imaging in cancer therapy.

PubMed

Das, Manasi; Duan, Wei; Sahoo, Sanjeeb K

2015-02-01

The promising proposition of multifunctional nanoparticles for cancer diagnostics and therapeutics has inspired the development of theranostic approach for improved cancer therapy. Moreover, active targeting of drug carrier to specific target site is crucial for providing efficient delivery of therapeutics and imaging agents. In this regard, the present study investigates the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles, functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. A wide spectrum of in vitro analysis (cellular uptake study, cytotoxicity assay, cell cycle and apoptosis analysis, apoptosis associated proteins study) revealed superior therapeutic potentiality of targeted NPs over other formulations in EpCAM expressing cells. Moreover, our nanotheranostic system served as a superlative bio-imaging modality both in 2D monolayer culture and tumor spheroid model. Our result suggests that, these aptamer-guided multifunctional NPs may act as indispensable nanotheranostic approach toward cancer therapy. This study investigated the theranostic capabilities of nutlin-3a loaded poly (lactide-co-glycolide) nanoparticles functionalized with a targeting ligand (EpCAM aptamer) and an imaging agent (quantum dots) for cancer therapy and bioimaging. It was concluded that the studied multifunctional targeted nanoparticle may become a viable and efficient approach in cancer therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

Time-Resolved Spectroscopy and Near Infrared Imaging for Prostate Cancer Detection: Receptor-targeted and Native Biomarker

NASA Astrophysics Data System (ADS)

Pu, Yang

Optical spectroscopy and imaging using near-infrared (NIR) light provides powerful tools for non-invasive detection of cancer in tissue. Optical techniques are capable of quantitative reconstructions maps of tissue absorption and scattering properties, thus can map in vivo the differences in the content of certain marker chromophores and/or fluorophores in normal and cancerous tissues (for example: water, tryptophan, collagen and NADH contents). Potential clinical applications of optical spectroscopy and imaging include functional tumor detection and photothermal therapeutics. Optical spectroscopy and imaging apply contrasts from intrinsic tissue chromophores such as water, collagen and NADH, and extrinsic optical contrast agents such as Indocyanine Green (ICG) to distinguish disease tissue from the normal one. Fluorescence spectroscopy and imaging also gives high sensitivity and specificity for biomedical diagnosis. Recent developments on specific-targeting fluorophores such as small receptor-targeted dye-peptide conjugate contrast agent offer high contrast between normal and cancerous tissues hence provide promising future for early tumour detection. This thesis focus on a study to distinguish the cancerous prostate tissue from the normal prostate tissues with enhancement of specific receptor-targeted prostate cancer contrast agents using optical spectroscopy and imaging techniques. The scattering and absorption coefficients, and anisotropy factor of cancerous and normal prostate tissues were investigated first as the basis for the biomedical diagnostic and optical imaging. Understanding the receptors over-expressed prostate cancer cells and molecular target mechanism of ligand, two small ICG-derivative dye-peptides, namely Cypate-Bombesin Peptide Analogue Conjugate (Cybesin) and Cypate-Octreotate Peptide Conjugate (Cytate), were applied to study their clinical potential for human prostate cancer detection. In this work, the steady-state and time-resolved fluorescence spectroscopy of Cybesin (Cytate) in solution, and in cancerous and normal prostate tissues were studied. It was found that more Cybesin (Cytate) was uptaken in the cancerous prostate tissue than those in the normal tissue. The preferential uptake of Cybesin (Cytate) in cancerous tissue was used to image and distinguish cancerous areas from the normal tissue. To investigate rotational dynamics and fluorescence polarization anisotropy of the contrast agents in prostate tissues, an analytical model was used to extract the rotational times and polarization anisotropies, which were observed for higher values of Cybesin (Cytate)-stained cancerous prostate tissue in comparison with the normal tissue. These reflect changes of microstructures of cancerous and normal tissues and their different binding affinity with contrast agents. The results indicate that the use of optical spectroscopy and imaging combined with receptor-targeted contrast agents is a valuable tool to study microenvironmental changes of tissue, and detect prostate cancer in early stage.

Manually controlled targeted prostate biopsy with real-time fusion imaging of multiparametric magnetic resonance imaging and transrectal ultrasound: an early experience.

PubMed

Shoji, Sunao; Hiraiwa, Shinichiro; Endo, Jun; Hashida, Kazunobu; Tomonaga, Tetsuro; Nakano, Mayura; Sugiyama, Tomoko; Tajiri, Takuma; Terachi, Toshiro; Uchida, Toyoaki

2015-02-01

To report our early experience with manually controlled targeted biopsy with real-time multiparametric magnetic resonance imaging and transrectal ultrasound fusion images for the diagnosis of prostate cancer. A total of 20 consecutive patients suspicious of prostate cancer at the multiparametric magnetic resonance imaging scan were recruited prospectively. Targeted biopsies were carried out for each cancer-suspicious lesion, and 12 systematic biopsies using the BioJet system. Pathological findings of targeted and systematic biopsies were analyzed. The median age of the patients was 70 years (range 52-83 years). The median preoperative prostate-specific antigen value was 7.4 ng/mL (range 3.54-19.9 ng/mL). Median preoperative prostate volume was 38 mL (range 24-68 mL). The number of cancer-detected cases was 14 (70%). The median Gleason score was 6.5 (range 6-8). Cancer-detected rates of the systematic and targeted biopsy cores were 6.7 and 31.8%, respectively (P < 0.0001). In six patients who underwent radical prostatectomy, the geographic locations and pathological grades of clinically significant cancers and index lesions corresponded to the pathological results of the targeted biopsies. Prostate cancers detected by targeted biopsies with manually controlled targeted biopsy using real-time multiparametric magnetic resonance imaging and transrectal ultrasound fusion imaging have significantly higher grades and longer length compared with those detected by systematic biopsies. Further studies and comparison with the pathological findings of whole-gland specimens have the potential to determine the role of this biopsy methodology in patients selected for focal therapy and those under active surveillance. © 2014 The Japanese Urological Association.

New inverse synthetic aperture radar algorithm for translational motion compensation

NASA Astrophysics Data System (ADS)

Bocker, Richard P.; Henderson, Thomas B.; Jones, Scott A.; Frieden, B. R.

1991-10-01

Inverse synthetic aperture radar (ISAR) is an imaging technique that shows real promise in classifying airborne targets in real time under all weather conditions. Over the past few years a large body of ISAR data has been collected and considerable effort has been expended to develop algorithms to form high-resolution images from this data. One important goal of workers in this field is to develop software that will do the best job of imaging under the widest range of conditions. The success of classifying targets using ISAR is predicated upon forming highly focused radar images of these targets. Efforts to develop highly focused imaging computer software have been challenging, mainly because the imaging depends on and is affected by the motion of the target, which in general is not precisely known. Specifically, the target generally has both rotational motion about some axis and translational motion as a whole with respect to the radar. The slant-range translational motion kinematic quantities must be first accurately estimated from the data and compensated before the image can be focused. Following slant-range motion compensation, the image is further focused by determining and correcting for target rotation. The use of the burst derivative measure is proposed as a means to improve the computational efficiency of currently used ISAR algorithms. The use of this measure in motion compensation ISAR algorithms for estimating the slant-range translational motion kinematic quantities of an uncooperative target is described. Preliminary tests have been performed on simulated as well as actual ISAR data using both a Sun 4 workstation and a parallel processing transputer array. Results indicate that the burst derivative measure gives significant improvement in processing speed over the traditional entropy measure now employed.

Multimodal Hierarchical Imaging of Serial Sections for Finding Specific Cellular Targets within Large Volumes

PubMed Central

Wacker, Irene U.; Veith, Lisa; Spomer, Waldemar; Hofmann, Andreas; Thaler, Marlene; Hillmer, Stefan; Gengenbach, Ulrich; Schröder, Rasmus R.

2018-01-01

Targeting specific cells at ultrastructural resolution within a mixed cell population or a tissue can be achieved by hierarchical imaging using a combination of light and electron microscopy. Samples embedded in resin are sectioned into arrays consisting of ribbons of hundreds of ultrathin sections and deposited on pieces of silicon wafer or conductively coated coverslips. Arrays are imaged at low resolution using a digital consumer like smartphone camera or light microscope (LM) for a rapid large area overview, or a wide field fluorescence microscope (fluorescence light microscopy (FLM)) after labeling with fluorophores. After post-staining with heavy metals, arrays are imaged in a scanning electron microscope (SEM). Selection of targets is possible from 3D reconstructions generated by FLM or from 3D reconstructions made from the SEM image stacks at intermediate resolution if no fluorescent markers are available. For ultrastructural analysis, selected targets are finally recorded in the SEM at high-resolution (a few nanometer image pixels). A ribbon-handling tool that can be retrofitted to any ultramicrotome is demonstrated. It helps with array production and substrate removal from the sectioning knife boat. A software platform that allows automated imaging of arrays in the SEM is discussed. Compared to other methods generating large volume EM data, such as serial block-face SEM (SBF-SEM) or focused ion beam SEM (FIB-SEM), this approach has two major advantages: (1) The resin-embedded sample is conserved, albeit in a sliced-up version. It can be stained in different ways and imaged with different resolutions. (2) As the sections can be post-stained, it is not necessary to use samples strongly block-stained with heavy metals to introduce contrast for SEM imaging or render the tissue blocks conductive. This makes the method applicable to a wide variety of materials and biological questions. Particularly prefixed materials e.g., from biopsy banks and pathology labs, can directly be embedded and reconstructed in 3D. PMID:29630046

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study

NASA Astrophysics Data System (ADS)

Bowen, S. R.; Nyflot, M. J.; Herrmann, C.; Groh, C. M.; Meyer, J.; Wollenweber, S. D.; Stearns, C. W.; Kinahan, P. E.; Sandison, G. A.

2015-05-01

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [18F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study.

PubMed

Bowen, S R; Nyflot, M J; Herrmann, C; Groh, C M; Meyer, J; Wollenweber, S D; Stearns, C W; Kinahan, P E; Sandison, G A

2015-05-07

Effective positron emission tomography / computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [(18)F]FDG. The lung lesion insert was driven by six different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses, and 2%-2 mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10-20%, treatment planning errors were 5-10%, and treatment delivery errors were 5-30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5-10% in PET/CT imaging, <5% in treatment planning, and <2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery.

Imaging and dosimetric errors in 4D PET/CT-guided radiotherapy from patient-specific respiratory patterns: a dynamic motion phantom end-to-end study

PubMed Central

Bowen, S R; Nyflot, M J; Hermann, C; Groh, C; Meyer, J; Wollenweber, S D; Stearns, C W; Kinahan, P E; Sandison, G A

2015-01-01

Effective positron emission tomography/computed tomography (PET/CT) guidance in radiotherapy of lung cancer requires estimation and mitigation of errors due to respiratory motion. An end-to-end workflow was developed to measure patient-specific motion-induced uncertainties in imaging, treatment planning, and radiation delivery with respiratory motion phantoms and dosimeters. A custom torso phantom with inserts mimicking normal lung tissue and lung lesion was filled with [18F]FDG. The lung lesion insert was driven by 6 different patient-specific respiratory patterns or kept stationary. PET/CT images were acquired under motionless ground truth, tidal breathing motion-averaged (3D), and respiratory phase-correlated (4D) conditions. Target volumes were estimated by standardized uptake value (SUV) thresholds that accurately defined the ground-truth lesion volume. Non-uniform dose-painting plans using volumetrically modulated arc therapy (VMAT) were optimized for fixed normal lung and spinal cord objectives and variable PET-based target objectives. Resulting plans were delivered to a cylindrical diode array at rest, in motion on a platform driven by the same respiratory patterns (3D), or motion-compensated by a robotic couch with an infrared camera tracking system (4D). Errors were estimated relative to the static ground truth condition for mean target-to-background (T/Bmean) ratios, target volumes, planned equivalent uniform target doses (EUD), and 2%-2mm gamma delivery passing rates. Relative to motionless ground truth conditions, PET/CT imaging errors were on the order of 10–20%, treatment planning errors were 5–10%, and treatment delivery errors were 5–30% without motion compensation. Errors from residual motion following compensation methods were reduced to 5–10% in PET/CT imaging, < 5% in treatment planning, and < 2% in treatment delivery. We have demonstrated that estimation of respiratory motion uncertainty and its propagation from PET/CT imaging to RT planning, and RT delivery under a dose painting paradigm is feasible within an integrated respiratory motion phantom workflow. For a limited set of cases, the magnitude of errors was comparable during PET/CT imaging and treatment delivery without motion compensation. Errors were moderately mitigated during PET/CT imaging and significantly mitigated during RT delivery with motion compensation. This dynamic motion phantom end-to-end workflow provides a method for quality assurance of 4D PET/CT-guided radiotherapy, including evaluation of respiratory motion compensation methods during imaging and treatment delivery. PMID:25884892

Photoacoustic imaging of tumor targeting with biotin conjugated nanostructured phthalocyanine assemblies

NASA Astrophysics Data System (ADS)

Lee, Seunghyun; Li, Xingshu; Lee, Dayoung; Yoon, Juyoung; Kim, Chulhong

2018-02-01

Visualizing biological markers and delivering bioactive agents to living organisms are important to biological research. In recent decades, photoacoustic imaging (PAI) has been significantly improved in the area of molecular imaging, which provides high-resolution volume imaging with high optical absorption contrast. To demonstrate the ability of nanoprobes to target tumors using PAI, we synthesize convertible nanostructured agents with strong photothermal and photoacoustic properties and linked the nanoprobe with biotin to target tumors in small animal model. Interestingly, these nanoprobes allow partial to disassemble in the presence of targeted proteins that switchable photoactivity, thus the nanoprobes provides a fluorescent-cancer imaging with high signal-to-background ratios. The proposed nanoprobe produce a much stronger PA signal compared to the same concentration of methylene blue (MB), which is widely used in clinical study and contrast agent for PAI. The biotin conjugated nanoprobe has high selectivity for biotin receptor positive cancer cells such as A549 (human lung cancer). Then we subsequently examined the PA properties of the nanoprobe that are inherently suitable for in vivo PAI. After injecting of the nanoprobe via intravenous method, we observed the mice's whole body by PA imaging and acquired the PA signal near the cancer. The PA signal increased linearly with time after injection and the fluorescence signal near the cancer was confirmed by fluorescence imaging. The ability to target a specific cancer of the nanoprobe was well verified by PA imaging. This study provides valuable perspective on the advancement of clinical translations and in the design of tumor-targeting phototheranostic agents that could act as new nanomedicines.

Development of anti-HER2 conjugated ICG-loaded polymeric nanoparticles for targeted optical imaging of ovarian cancer

NASA Astrophysics Data System (ADS)

Bahmani, Baharak; Vullev, Valentine; Anvari, Bahman

2012-03-01

Targeted delivery of therapeutic and imaging agents using surface modified nanovectors has been explored immensely in recent years. The growing demand for site-specific and efficient delivery of nanovectors entails stable surface conjugation of targeting moieties. We have developed a polymeric nanocapsule doped with Indocyanine green (ICG) with potential for targeted and deep tissue optical imaging and phototherapy. Our ICG-loaded nanocapsules (ICG-NCs) have potential for covalent coupling of various targeting moieties and materials due to presence of amine groups on the surface. Here, we covalently bioconjugate polyethylene glycol(PEG)-coated ICG-NCs with monoclonal antibody against HER2 through reductive amination-mediated procedures. The irreversible and stable bonds are formed between anti- EGFR and aldehyde termini of PEG chains on the surface of ICG-NCs. We confirm the uptake of conjugated ICG-NCs by ovarian cancer cells over-expressing HER2 using fluorescent confocal microscopy. The proposed process for covalent attachment of anti-HER2 to PEGylated ICG-NCs can be used as a methodology for bioconjugation of various antibodies to such nano-constrcuts, and provides the capability to use these optically active nano-probes for targeted optical imaging of ovarian and other cancer types.

Frequency Domain Fluorescent Molecular Tomography and Molecular Probes for Small Animal Imaging

NASA Astrophysics Data System (ADS)

Kujala, Naresh Gandhi

Fluorescent molecular tomography (FMT) is a noninvasive biomedical optical imaging that enables 3-dimensional quantitative determination of fluorochromes distributed in biological tissues. There are three methods for imaging large volume tissues based on different light sources: (a) using a light source of constant intensity, through a continuous or constant wave, (b) using a light source that is intensity modulated with a radio frequency (RF), and (c) using ultrafast pulses in the femtosecond range. In this study, we have developed a frequency domain fluorescent molecular tomographic system based on the heterodyne technique, using a single source and detector pair that can be used for small animal imaging. In our system, the intensity of the laser source is modulated with a RF frequency to produce a diffuse photon density wave in the tissue. The phase of the diffuse photon density wave is measured by comparing the reference signal with the signal from the tissue using a phasemeter. The data acquisition was performed by using a Labview program. The results suggest that we can measure the phase change from the heterogeneous inside tissue. Combined with fiber optics and filter sets, the system can be used to sensitively image the targeted fluorescent molecular probes, allowing the detection of cancer at an early stage. We used the system to detect the tumor-targeting molecular probe Alexa Fluor 680 and Alexa Fluor 750 bombesin peptide conjugates in phantoms as well as mouse tissues. We also developed and evaluated fluorescent Bombesin (BBN) probes to target gastrin-releasing peptide (GRP) receptors for optical molecular imaging. GRP receptors are over-expressed in several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. BBN is a 14 amino acid peptide that is an analogue to human gastrin-releasing peptide that binds specifically to GRPr receptors. BBN conjugates are significant in cancer detection and therapy. The optical molecular probe AF750 BBN peptide exhibits optimal pharmacokinetic properties for targeting GRPr in mice. Fluorescent microscopic imaging of the molecular probe in PC-3 prostate and T-47D breast cancer cell lines indicated specific uptake, internalization, and receptor blocking of these probes. In vivo investigations in severely compromised immunodeficient (SCID) mice bearing xenografted PC-3 prostate and T47-D breast cancer lesions demonstrated the ability of this new molecular probe to specifically target tumor tissue with high selectively and affinity.

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer.

PubMed

Ahrens, Bradley J; Li, Lin; Ciminera, Alexandra K; Chea, Junie; Poku, Erasmus; Bading, James R; Weist, Michael R; Miller, Marcia M; Colcher, David M; Shively, John E

2017-09-01

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64 Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64 Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64 Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague-Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64 Cu-DOTA-alendronate. Results: 64 Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64 Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64 Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64 Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64 Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as the differentiation of malignant versus benign tumors based on absolute labeling uptake. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Novel Peptide Sequence (“IQ-tag”) with High Affinity for NIR Fluorochromes Allows Protein and Cell Specific Labeling for In Vivo Imaging

PubMed Central

McCarthy, Jason R.; Weissleder, Ralph

2007-01-01

Background Probes that allow site-specific protein labeling have become critical tools for visualizing biological processes. Methods Here we used phage display to identify a novel peptide sequence with nanomolar affinity for near infrared (NIR) (benz)indolium fluorochromes. The developed peptide sequence (“IQ-tag”) allows detection of NIR dyes in a wide range of assays including ELISA, flow cytometry, high throughput screens, microscopy, and optical in vivo imaging. Significance The described method is expected to have broad utility in numerous applications, namely site-specific protein imaging, target identification, cell tracking, and drug development. PMID:17653285

Noninvasive imaging of multiple myeloma using near infrared fluorescent molecular probe

NASA Astrophysics Data System (ADS)

Hathi, Deep; Zhou, Haiying; Bollerman-Nowlis, Alex; Shokeen, Monica; Akers, Walter J.

2016-03-01

Multiple myeloma is a plasma cell malignancy characterized by monoclonal gammopathy and osteolytic bone lesions. Multiple myeloma is most commonly diagnosed in late disease stages, presenting with pathologic fracture. Early diagnosis and monitoring of disease status may improve quality of life and long-term survival for multiple myeloma patients from what is now a devastating and fatal disease. We have developed a near-infrared targeted fluorescent molecular probe with high affinity to the α4β1 integrin receptor (VLA-4)overexpressed by a majority of multiple myeloma cells as a non-radioactive analog to PET/CT tracer currently being developed for human diagnostics. A near-infrared dye that emits about 700 nm was conjugated to a high affinity peptidomimmetic. Binding affinity and specificity for multiple myeloma cells was investigated in vitro by tissue staining and flow cytometry. After demonstration of sensitivity and specificity, preclinical optical imaging studies were performed to evaluate tumor specificity in murine subcutaneous and metastatic multiple myeloma models. The VLA-4-targeted molecular probe showed high affinity for subcutaneous MM tumor xenografts. Importantly, tumor cells specific accumulation in the bone marrow of metastatic multiple myeloma correlated with GFP signal from transfected cells. Ex vivo flow cytometry of tumor tissue and bone marrow further corroborated in vivo imaging data, demonstrating the specificity of the novel agent and potential for quantitative imaging of multiple myeloma burden in these models.

Rapid optical imaging of EGF receptor expression with a single-chain antibody SNAP-tag fusion protein.

PubMed

Kampmeier, Florian; Niesen, Judith; Koers, Alexander; Ribbert, Markus; Brecht, Andreas; Fischer, Rainer; Kiessling, Fabian; Barth, Stefan; Thepen, Theo

2010-10-01

The epidermal growth factor receptor (EGFR) is overexpressed in several types of cancer and its inhibition can effectively inhibit tumour progression. The purpose of this study was to design an EGFR-specific imaging probe that combines efficient tumour targeting with rapid systemic clearance to facilitate non-invasive assessment of EGFR expression. Genetic fusion of a single-chain antibody fragment with the SNAP-tag produced a 48-kDa antibody derivative that can be covalently and site-specifically labelled with substrates containing 0 (6)-benzylguanine. The EGFR-specific single-chain variable fragment (scFv) fusion protein 425(scFv)SNAP was labelled with the near infrared (NIR) dye BG-747, and its accumulation, specificity and kinetics were monitored using NIR fluorescence imaging in a subcutaneous pancreatic carcinoma xenograft model. The 425(scFv)SNAP fusion protein accumulates rapidly and specifically at the tumour site. Its small size allows efficient renal clearance and a high tumour to background ratio (TBR) of 33.2 +/- 6.3 (n = 4) 10 h after injection. Binding of the labelled antibody was efficiently competed with a 20-fold excess of unlabelled probe, resulting in an average TBR of 6 +/- 1.35 (n = 4), which is similar to that obtained with a non-tumour-specific probe (5.44 +/- 1.92, n = 4). When compared with a full-length antibody against EGFR (cetuximab), 425(scFv)SNAP-747 showed significantly higher TBRs and complete clearance 72 h post-injection. The 425(scFv)SNAP fusion protein combines rapid and specific targeting of EGFR-positive tumours with a versatile and robust labelling technique that facilitates the attachment of fluorophores for use in optical imaging. The same approach could be used to couple a chelating agent for use in nuclear imaging.

Homing peptide guiding optical molecular imaging for the diagnosis of bladder cancer

NASA Astrophysics Data System (ADS)

Yang, Xiao-feng; Pang, Jian-zhi; Liu, Jie-hao; Zhao, Yang; Jia, Xing-you; Li, Jun; Liu, Reng-xin; Wang, Wei; Fan, Zhen-wei; Zhang, Zi-qiang; Yan, San-hua; Luo, Jun-qian; Zhang, Xiao-lei

2014-11-01

Background: The limitations of primary transurethral resection of bladder tumor (TURBt) have led the residual tumors rates as high as 75%. The intraoperative fluorescence imaging offers a great potential for improving TURBt have been confirmed. So we aim to distinguish the residual tumors and normal mucosa using fluorescence molecular imaging formed by conjugated molecule of the CSNRDARRC bladder cancer homing peptide with fluorescent dye. The conjugated molecule was abbreviated FIuo-ACP. In our study, we will research the image features of FIuo-ACP probe targeted bladder cancer for fluorescence molecular imaging diagnosis for bladder cancer in vivo and ex vivo. Methods: After the FIuo-ACP probe was synthetized, the binding sites, factors affecting binding rates, the specificity and the targeting of Fluo-ACP labeled with bladder cancer cells were studied respectively by laser scanning confocal microscope (LSCM), immunofluorescence and multispectral fluorescence ex vivo optical molecular imaging system. Results: The binding sites were located in nucleus and the binding rates were correlated linearly with the dose of probe and the grade of pathology. Moreover, the probe has a binding specificity with bladder cancer in vivo and ex vivo. Tumor cells being labeled by the Fluo-ACP, bright green spots were observed under LSCM. The tissue samples and tumor cells can be labeled and identified by fluorescence microscope. Optical molecular imaging of xenograft tumor tissues was exhibited as fluorescent spots under EMCCD. Conclusion: The CSNRDARRC peptides might be a useful bladder cancer targeting vector. The FIuo-ACP molecular probe was suitable for fluorescence molecular imaging diagnosis for bladder cancer in vivo and ex vivo.

Long-range and depth-selective imaging of macroscopic targets using low-coherence and wide-field interferometry (Conference Presentation)

NASA Astrophysics Data System (ADS)

Woo, Sungsoo; Kang, Sungsam; Yoon, Changhyeong; Choi, Wonshik

2016-03-01

With the advancement of 3D display technology, 3D imaging of macroscopic objects has drawn much attention as they provide the contents to display. The most widely used imaging methods include a depth camera, which measures time of flight for the depth discrimination, and various structured illumination techniques. However, these existing methods have poor depth resolution, which makes imaging complicated structures a difficult task. In order to resolve this issue, we propose an imaging system based upon low-coherence interferometry and off-axis digital holographic imaging. By using light source with coherence length of 200 micro, we achieved the depth resolution of 100 micro. In order to map the macroscopic objects with this high axial resolution, we installed a pair of prisms in the reference beam path for the long-range scanning of the optical path length. Specifically, one prism was fixed in position, and the other prism was mounted on a translation stage and translated in parallel to the first prism. Due to the multiple internal reflections between the two prisms, the overall path length was elongated by a factor of 50. In this way, we could cover a depth range more than 1 meter. In addition, we employed multiple speckle illuminations and incoherent averaging of the acquired holographic images for reducing the specular reflections from the target surface. Using this newly developed system, we performed imaging targets with multiple different layers and demonstrated imaging targets hidden behind the scattering layers. The method was also applied to imaging targets located around the corner.

New chemical probe technologies: applications to imaging and drug discovery (Conference Presentation)

NASA Astrophysics Data System (ADS)

Bogyo, Matthew

2017-02-01

Proteases are enzymes that play pathogenic roles in many common human diseases such as cancer, asthma, arthritis, atherosclerosis and infection by pathogens. Tools to dynamically monitor their activity can be used as diagnostic agents, as imaging contrast agents for intra-operative image guidance and for the identification of novel classes of protease-targeted drugs. I will describe our efforts to design and synthesize small molecule probes that produce a fluorescent signal upon binding to a protease target. We have identified probes that show tumor-specific retention, fast activation kinetics, and rapid systemic distribution making them useful for real-time fluorescence guided tumor resection and other diagnostic imaging applications.

Ultrahigh sensitivity endoscopic camera using a new CMOS image sensor: providing with clear images under low illumination in addition to fluorescent images.

PubMed

Aoki, Hisae; Yamashita, Hiromasa; Mori, Toshiyuki; Fukuyo, Tsuneo; Chiba, Toshio

2014-11-01

We developed a new ultrahigh-sensitive CMOS camera using a specific sensor that has a wide range of spectral sensitivity characteristics. The objective of this study is to present our updated endoscopic technology that has successfully integrated two innovative functions; ultrasensitive imaging as well as advanced fluorescent viewing. Two different experiments were conducted. One was carried out to evaluate the function of the ultrahigh-sensitive camera. The other was to test the availability of the newly developed sensor and its performance as a fluorescence endoscope. In both studies, the distance from the endoscopic tip to the target was varied and those endoscopic images in each setting were taken for further comparison. In the first experiment, the 3-CCD camera failed to display the clear images under low illumination, and the target was hardly seen. In contrast, the CMOS camera was able to display the targets regardless of the camera-target distance under low illumination. Under high illumination, imaging quality given by both cameras was quite alike. In the second experiment as a fluorescence endoscope, the CMOS camera was capable of clearly showing the fluorescent-activated organs. The ultrahigh sensitivity CMOS HD endoscopic camera is expected to provide us with clear images under low illumination in addition to the fluorescent images under high illumination in the field of laparoscopic surgery.

Exogenous Molecular Probes for Targeted Imaging in Cancer: Focus on Multi-modal Imaging

PubMed Central

Joshi, Bishnu P.; Wang, Thomas D.

2010-01-01

Cancer is one of the major causes of mortality and morbidity in our healthcare system. Molecular imaging is an emerging methodology for the early detection of cancer, guidance of therapy, and monitoring of response. The development of new instruments and exogenous molecular probes that can be labeled for multi-modality imaging is critical to this process. Today, molecular imaging is at a crossroad, and new targeted imaging agents are expected to broadly expand our ability to detect and manage cancer. This integrated imaging strategy will permit clinicians to not only localize lesions within the body but also to manage their therapy by visualizing the expression and activity of specific molecules. This information is expected to have a major impact on drug development and understanding of basic cancer biology. At this time, a number of molecular probes have been developed by conjugating various labels to affinity ligands for targeting in different imaging modalities. This review will describe the current status of exogenous molecular probes for optical, scintigraphic, MRI and ultrasound imaging platforms. Furthermore, we will also shed light on how these techniques can be used synergistically in multi-modal platforms and how these techniques are being employed in current research. PMID:22180839

Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIF1α/OATPs signaling axis

PubMed Central

Wu, Jason Boyang; Shao, Chen; Li, Xiangyan; Shi, Changhong; Li, Qinlong; Hu, Peizhen; Chen, Yi-Ting; Dou, Xiaoliang; Sahu, Divya; Li, Wei; Harada, Hiroshi; Zhang, Yi; Wang, Ruoxiang; Zhau, Haiyen E.; Chung, Leland W.K.

2014-01-01

Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1α (HIF1α). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1α was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1α/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy. PMID:24957295

Using In-vivo Fluorescence Imaging in Personalized Cancer Diagnostics and Therapy, an Image and Treat Paradigm

PubMed Central

Ardeshirpour, Yasaman; Chernomordik, Victor; Capala, Jacek; Hassan, Moinuddin; Zielinsky, Rafal; Griffiths, Gary; Achilefu, Samuel; Smith, Paul; Gandjbakhckhe, Amir

2013-01-01

The major goal in developing drugs targeting specific tumor receptors, such as Monoclonal AntiBodies (MAB), is to make a drug compound that targets selectively the cancer-causing biomarkers, inhibits their functionality, and/or delivers the toxin specifically to the malignant cells. Recent advances in MABs show that their efficacy depends strongly on characterization of tumor biomarkers. Therefore, one of the main tasks in cancer diagnostics and treatment is to develop non-invasive in-vivo imaging techniques for detection of cancer biomarkers and monitoring their down regulation during the treatment. Such methods can potentially result in a new imaging and treatment paradigm for cancer therapy. In this article we have reviewed fluorescence imaging approaches, including those developed in our group, to detect and monitor Human Epidermal Growth Factor 2 (HER2) receptors before and during therapy. Transition of these techniques from the bench to bedside is the ultimate goal of our project. Similar approaches can be used potentially for characterization of other cancer related cell biomarkers. PMID:22066595

A dual-targeting liposome conjugated with transferrin and arginine-glycine-aspartic acid peptide for glioma-targeting therapy.

PubMed

Qin, Li; Wang, Cheng-Zheng; Fan, Hui-Jie; Zhang, Chong-Jian; Zhang, Heng-Wei; Lv, Min-Hao; Cui, Shu-DE

2014-11-01

The treatment of a brain glioma remains one of the most difficult challenges in oncology. In the present study a delivery system was developed for targeted drug delivery across the blood-brain barrier (BBB) to the brain cancer cells. A cyclic arginine-glycine-aspartic acid (RGD) peptide and transferrin (TF) were utilized as targeting ligands. Cyclic RGD peptides are specific targeting ligands of cancer cells and TFs are ligands that specifically target the BBB and cancer cells. Liposome (LP) was used to conjugate the cyclic RGD and TFs to establish the brain glioma cascade delivery system (RGD/TF-LP). The LPs were prepared by the thin film hydration method and physicochemical characterization was conducted. In vitro cell uptake and three-dimensional tumor spheroid penetration studies demonstrated that the system could target endothelial and tumor cells, as well as penetrate the tumor cells to reach the core of the tumor spheroids. The results of the in vivo imaging further demonstrated that the RGD/TF-LP provided the highest brain distribution. As a result, the paclitaxel-loaded RGD/TF-LP presents the best antiproliferative activity against C6 cells and tumor spheroids. In conclusion, the RGD/TF-LP may precisely target brain glioma, which may be valuable for glioma imaging and therapy.

Online updating of context-aware landmark detectors for prostate localization in daily treatment CT images

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dai, Xiubin; Gao, Yaozong; Shen, Dinggang, E-mail: dgshen@med.unc.edu

2015-05-15

Purpose: In image guided radiation therapy, it is crucial to fast and accurately localize the prostate in the daily treatment images. To this end, the authors propose an online update scheme for landmark-guided prostate segmentation, which can fully exploit valuable patient-specific information contained in the previous treatment images and can achieve improved performance in landmark detection and prostate segmentation. Methods: To localize the prostate in the daily treatment images, the authors first automatically detect six anatomical landmarks on the prostate boundary by adopting a context-aware landmark detection method. Specifically, in this method, a two-layer regression forest is trained as amore » detector for each target landmark. Once all the newly detected landmarks from new treatment images are reviewed or adjusted (if necessary) by clinicians, they are further included into the training pool as new patient-specific information to update all the two-layer regression forests for the next treatment day. As more and more treatment images of the current patient are acquired, the two-layer regression forests can be continually updated by incorporating the patient-specific information into the training procedure. After all target landmarks are detected, a multiatlas random sample consensus (multiatlas RANSAC) method is used to segment the entire prostate by fusing multiple previously segmented prostates of the current patient after they are aligned to the current treatment image. Subsequently, the segmented prostate of the current treatment image is again reviewed (or even adjusted if needed) by clinicians before including it as a new shape example into the prostate shape dataset for helping localize the entire prostate in the next treatment image. Results: The experimental results on 330 images of 24 patients show the effectiveness of the authors’ proposed online update scheme in improving the accuracies of both landmark detection and prostate segmentation. Besides, compared to the other state-of-the-art prostate segmentation methods, the authors’ method achieves the best performance. Conclusions: By appropriate use of valuable patient-specific information contained in the previous treatment images, the authors’ proposed online update scheme can obtain satisfactory results for both landmark detection and prostate segmentation.« less

Cell and Tissue Imaging with Molecularly Imprinted Polymers.

PubMed

Panagiotopoulou, Maria; Kunath, Stephanie; Haupt, Karsten; Tse Sum Bui, Bernadette

2017-01-01

Advanced tools for cell imaging are of particular interest as they can detect, localize and quantify molecular targets like abnormal glycosylation sites that are biomarkers of cancer and infection. Targeting these biomarkers is often challenging due to a lack of receptor materials. Molecularly imprinted polymers (MIPs) are promising artificial receptors; they can be tailored to bind targets specifically, be labeled easily, and are physically and chemically stable. Herein, we demonstrate the application of MIPs as artificial antibodies for selective labeling and imaging of cellular targets, on the example of hyaluronan and sialylation moieties on fixated human skin cells and tissues. Thus, fluorescently labeled MIP nanoparticles templated with glucuronic acid (MIPGlcA) and N-acetylneuraminic acid (MIPNANA) are respectively applied. Two different fluorescent probes are used: (1) MIPGlcA particles, ~400 nm in size are labeled with the dye rhodamine that target the extracellular hyaluronan on cells and tissue specimens and (2) MIP-coated InP/ZnS quantum dots (QDs) of two different colors, ~125 nm in size that target the extracellular and intracellular hyaluronan and sialylation sites. Green and red emitting QDs are functionalized with MIPGlcA and MIPNANA respectively, enabling multiplexed cell imaging. This is a general approach that can also be adapted to other target molecules on and in cells.

Antibody Conjugated, Raman Tagged Hollow Gold-Silver Nanospheres for Specific Targeting and Multimodal Dark-Field/SERS/Two Photon-FLIM Imaging of CD19(+) B Lymphoblasts.

PubMed

Nagy-Simon, Timea; Tatar, Andra-Sorina; Craciun, Ana-Maria; Vulpoi, Adriana; Jurj, Maria-Ancuta; Florea, Adrian; Tomuleasa, Ciprian; Berindan-Neagoe, Ioana; Astilean, Simion; Boca, Sanda

2017-06-28

In this Research Article, we propose a new class of contrast agents for the detection and multimodal imaging of CD19(+) cancer lymphoblasts. The agents are based on NIR responsive hollow gold-silver nanospheres conjugated with antiCD19 monoclonal antibodies and marked with Nile Blue (NB) SERS active molecules (HNS-NB-PEG-antiCD19). Proof of concept experiments on specificity of the complex for the investigated cells was achieved by transmission electron microscopy (TEM). The microspectroscopic investigations via dark field (DF), surface-enhanced Raman spectroscopy (SERS), and two-photon excited fluorescence lifetime imaging microscopy (TPE-FLIM) corroborate with TEM and demonstrate successful and preferential internalization of the antibody-nanocomplex. The combination of the microspectroscopic techniques enables contrast and sensitivity that competes with more invasive and time demanding cell imaging modalities, while depth sectioning images provide real time localization of the nanoparticles in the whole cytoplasm at the entire depth of the cells. Our findings prove that HNS-NB-PEG-antiCD19 represent a promising type of new contrast agents with great possibility of being detected by multiple, non invasive, rapid and accessible microspectroscopic techniques and real applicability for specific targeting of CD19(+) cancer cells. Such versatile nanocomplexes combine in one single platform the detection and imaging of cancer lymphoblasts by DF, SERS, and TPE-FLIM microspectroscopy.

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides

PubMed Central

Liu, Shuang

2008-01-01

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

EDB Fibronectin Specific Peptide for Prostate Cancer Targeting.

PubMed

Han, Zheng; Zhou, Zhuxian; Shi, Xiaoyue; Wang, Junpeng; Wu, Xiaohui; Sun, Da; Chen, Yinghua; Zhu, Hui; Magi-Galluzzi, Cristina; Lu, Zheng-Rong

2015-05-20

Extradomain-B fibronectin (EDB-FN), one of the oncofetal fibronectin (onfFN) isoforms, is a high-molecular-weight glycoprotein that mediates cell adhesion and migration. The expression of EDB-FN is associated with a number of cancer-related biological processes such as tumorigenesis, angiogenesis, and epithelial-to-mesenchymal transition (EMT). Here, we report the development of a small peptide specific to EDB-FN for targeting prostate cancer. A cyclic nonapeptide, CTVRTSADC (ZD2), was identified using peptide phage display. A ZD2-Cy5 conjugate was synthesized to accomplish molecular imaging of prostate cancer in vitro and in vivo. ZD2-Cy5 demonstrated effective binding to up-regulated EDB-FN secreted by TGF-β-induced PC3 cancer cells following EMT. Following intravenous injections, the targeted fluorescent probe specifically bound to and delineated PC3-GFP prostate tumors in nude mice bearing the tumor xenografts. ZD2-Cy5 also showed stronger binding to human prostate tumor specimens with a higher Gleason score (GS9) compared to those with a lower score (GS 7), with no binding in benign prostatic hyperplasia (BPH). Thus, the ZD2 peptide is a promising strategy for molecular imaging and targeted therapy of prostate cancer.

A Potent, Imaging Adenoviral Vector Driven by the Cancer-selective Mucin-1 Promoter That Targets Breast Cancer Metastasis

PubMed Central

Huyn, Steven T.; Burton, Jeremy B.; Sato, Makoto; Carey, Michael; Gambhir, Sanjiv S.; Wu, Lily

2009-01-01

Purpose With breast cancer, early detection and proper staging are critical, and will often influence both the treatment regimen and the therapeutic outcome for those affected with this disease. Improvements in these areas will play a profound role in reducing mortality from breast cancer. Experimental Design In this work we developed a breast cancer – targeted serotype 5 adenoviral vector, utilizing the tumor-specific mucin-1 promoter in combination with the two-step transcriptional amplification system, a system used to augment the activity of weak tissue – specific promoters. Results We showed the strong specificity of this tumor-selective adenovirus to express the luciferase optical imaging gene, leading to diagnostic signals that enabled detection of sentinel lymph node metastasis of breast cancer. Furthermore, we were able to target hepatic metastases following systemic administration of this mucin-1 selective virus. Conclusions Collectively, we showed that the amplified mucin-1 promoter – driven vector is able to deliver to and selectively express a desirable transgene in metastatic lesions of breast tumors. This work has strong clinical relevance to current diagnostic staging approaches, and could add to targeted therapeutic strategies to advance the fight against breast cancer. PMID:19366829

Poster - Thurs Eve-12: A needle-positioning robot co-registered with volumetric x-ray micro-computed tomography images for minimally-invasive small-animal interventions.

PubMed

Waspe, A C; Holdsworth, D W; Lacefield, J C; Fenster, A

2008-07-01

Preclinical research protocols often require the delivery of biological substances to specific targets in small animal disease models. To target biologically relevant locations in mice accurately, the needle positioning error needs to be < 200 μm. If targeting is inaccurate, experimental results can be inconclusive or misleading. We have developed a robotic manipulator that is capable of positioning a needle with a mean error < 100 μm. An apparatus and method were developed for integrating the needle-positioning robot with volumetric micro-computed tomography image guidance for interventions in small animals. Accurate image-to-robot registration is critical for integration as it enables targets identified in the image to be mapped to physical coordinates inside the animal. Registration is accomplished by injecting barium sulphate into needle tracks as the robot withdraws the needle from target points in a tissue-mimicking phantom. Registration accuracy is therefore affected by the positioning error of the robot and is assessed by measuring the point-to-line fiducial and target registration errors (FRE, TRE). Centroid points along cross-sectional slices of the track are determined using region growing segmentation followed by application of a center-of-mass algorithm. The centerline points are registered to needle trajectories in robot coordinates by applying an iterative closest point algorithm between points and lines. Implementing this procedure with four fiducial needle tracks produced a point-to-line FRE and TRE of 246 ± 58 μm and 194 ± 18 μm, respectively. The proposed registration technique produced a TRE < 200 μm, in the presence of robot positioning error, meeting design specification. © 2008 American Association of Physicists in Medicine.

Targeted systemic gene therapy and molecular imaging of cancer contribution of the vascular-targeted AAVP vector.

PubMed

Hajitou, Amin

2010-01-01

Gene therapy and molecular-genetic imaging have faced a major problem: the lack of an efficient systemic gene delivery vector. Unquestionably, eukaryotic viruses have been the vectors of choice for gene delivery to mammalian cells; however, they have had limited success in systemic gene therapy. This is mainly due to undesired uptake by the liver and reticuloendothelial system, broad tropism for mammalian cells causing toxicity, and their immunogenicity. On the other hand, prokaryotic viruses such as bacteriophage (phage) have no tropism for mammalian cells, but can be engineered to deliver genes to these cells. However, phage-based vectors have inherently been considered poor vectors for mammalian cells. We have reported a new generation of vascular-targeted systemic hybrid prokaryotic-eukaryotic vectors as chimeras between an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV/phage; AAVP). In this hybrid vector, the targeted bacteriophage serves as a shuttle to deliver the AAV transgene cassette inserted in an intergenomic region of the phage DNA genome. As a proof of concept, we assessed the in vivo efficacy of vector in animal models of cancer by displaying on the phage capsid the cyclic Arg-Gly-Asp (RGD-4C) ligand that binds to alphav integrin receptors specifically expressed on the angiogenic blood vessels of tumors. The ligand-directed vector was able to specifically deliver imaging and therapeutic transgenes to tumors in mice, rats, and dogs while sparing the normal organs. This chapter reviews some gene transfer strategies and the potential of the vascular-targeted AAVP vector for enhancing the effectiveness of existing systemic gene delivery and genetic-imaging technologies. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Preclinical evaluation of a bispecific low-molecular heterodimer targeting both PSMA and GRPR for improved PET imaging and therapy of prostate cancer.

PubMed

Eder, Matthias; Schäfer, Martin; Bauder-Wüst, Ulrike; Haberkorn, Uwe; Eisenhut, Michael; Kopka, Klaus

2014-05-01

It has recently been reported that metastases of prostate cancer usually show highly heterogeneous or partly lost prostate-specific membrane antigen (PSMA) expression. In order to image and treat both PSMA positive and negative tissues PSMA targeting probes need to be extended by a further specificity. Since prostate cancer cells usually express both PSMA and gastrin-releasing peptide receptor (GRPR) a bispecific low-molecular heterodimeric molecule, addressing both targets at the same time, may significantly improve prostate cancer imaging and therapy. The nonapeptide BZH3 representing the GRPR binding part was combined with the urea-based PSMA inhibitor Glu-urea-Lys(Ahx)-HBED-CC. The syntheses of the compounds were performed according to standard Fmoc-solid phase peptide synthesis. The binding properties were analyzed by competitive cell binding and internalization experiments. The in vivo targeting properties were investigated by means of biodistribution studies. Cell binding experiments revealed high binding affinities to both GRPR and PSMA expressing cell lines. The heterodimer bound with IC50 -values essentially matching the IC50 values of the respective monomers (25.0 ± 5.4 nM for PSMA and 9.0 ± 1.8 nM for GRPR, respectively). In vivo, the heterodimer showed dual targeting of PSMA (5.4%ID/g for PSMA-positive tumors) and GRPR receptors (3.3% ID/g for GRPR-positive tumors) while exhibiting fast pharmacokinetic properties. The clearance from background was comparable to the monomeric PSMA-targeting reference. The heterodimeric molecule is a promising agent for PET imaging of primary and recurrent prostate cancer covering two receptor entities which might lead to an improved diagnostic sensitivity and therapeutic efficiency. © 2014 Wiley Periodicals, Inc.

Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

PubMed Central

Sun, Hongguang; Zhu, Xun; Lu, Patrick Y; Rosato, Roberto R; Tan, Wen; Zu, Youli

2014-01-01

Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy. PMID:25093706

Novel EGFR-specific immunotoxins based on panitumumab and cetuximab show in vitro and ex vivo activity against different tumor entities.

PubMed

Niesen, Judith; Stein, Christoph; Brehm, Hannes; Hehmann-Titt, Grit; Fendel, Rolf; Melmer, Georg; Fischer, Rainer; Barth, Stefan

2015-12-01

The epidermal growth factor receptor (EGFR) is overexpressed in many solid tumors. EGFR-specific monoclonal antibodies (mAbs), such as cetuximab and panitumumab, have been approved for the treatment of colorectal and head and neck cancer. To increase tissue penetration, we constructed single-chain fragment variable (scFv) antibodies derived from these mAbs and evaluated their potential for targeted cancer therapy. The resulting scFv-based EGFR-specific immunotoxins (ITs) combine target specificity of the full-size mAb with the cell-killing activity of a toxic effector domain, a truncated version of Pseudomonas exotoxin A (ETA'). The ITs and corresponding imaging probes were tested in vitro against four solid tumor entities (rhabdomyosarcoma, breast, prostate and pancreatic cancer). Specific binding and internalization of the ITs scFv2112-ETA' (from cetuximab) and scFv1711-ETA' (from panitumumab) were demonstrated by flow cytometry and for the scFv-SNAP-tag imaging probes by live cell imaging. Cytotoxic potential of the ITs was analyzed in cell viability and apoptosis assays. Binding of the ITs was proofed ex vivo on rhabdomyosarcoma, prostate and breast cancer formalin-fixed paraffin-embedded biopsies. Both novel ITs showed significant pro-apoptotic and anti-proliferative effects toward the target cells, achieving IC50 values of 4 pM (high EGFR expression) to 460 pM (moderate EGFR expression). Additionally, rapid internalization and specific in vitro and ex vivo binding on patient tissue were confirmed. These data demonstrate the potent therapeutic activity of two novel EGFR-specific ETA'-based ITs. Both molecules are promising candidates for further development toward clinical use in the treatment of various solid tumors to supplement the existing therapeutic regimes.

Molecular image-directed biopsies: improving clinical biopsy selection in patients with multiple tumors

NASA Astrophysics Data System (ADS)

Harmon, Stephanie A.; Tuite, Michael J.; Jeraj, Robert

2016-10-01

Site selection for image-guided biopsies in patients with multiple lesions is typically based on clinical feasibility and physician preference. This study outlines the development of a selection algorithm that, in addition to clinical requirements, incorporates quantitative imaging data for automatic identification of candidate lesions for biopsy. The algorithm is designed to rank potential targets by maximizing a lesion-specific score, incorporating various criteria separated into two categories: (1) physician-feasibility category including physician-preferred lesion location and absolute volume scores, and (2) imaging-based category including various modality and application-specific metrics. This platform was benchmarked in two clinical scenarios, a pre-treatment setting and response-based setting using imaging from metastatic prostate cancer patients with high disease burden (multiple lesions) undergoing conventional treatment and receiving whole-body [18F]NaF PET/CT scans pre- and mid-treatment. Targeting of metastatic lesions was robust to different weighting ratios and candidacy for biopsy was physician confirmed. Lesion ranked as top targets for biopsy remained so for all patients in pre-treatment and post-treatment biopsy selection after sensitivity testing was completed for physician-biased or imaging-biased scenarios. After identifying candidates, biopsy feasibility was evaluated by a physician and confirmed for 90% (32/36) of high-ranking lesions, of which all top choices were confirmed. The remaining cases represented lesions with high anatomical difficulty for targeting, such as proximity to sciatic nerve. This newly developed selection method was successfully used to quantitatively identify candidate lesions for biopsies in patients with multiple lesions. In a prospective study, we were able to successfully plan, develop, and implement this technique for the selection of a pre-treatment biopsy location.

Recent advances in aptamer-armed multimodal theranostic nanosystems for imaging and targeted therapy of cancer.

PubMed

Vandghanooni, Somayeh; Eskandani, Morteza; Barar, Jaleh; Omidi, Yadollah

2018-05-30

The side effects of chemotherapeutics during the course of cancer treatment limit their clinical outcomes. The most important mission of the modern cancer therapy modalities is the delivery of anticancer drugs specifically to the target cells/tissue in order to avoid/reduce any inadvertent non-specific impacts on the healthy normal cells. Nanocarriers decorated with a designated targeting ligand such as aptamers (Aps) and antibodies (Abs) are able to deliver cargo molecules to the target cells/tissue without affecting other neighboring cells, resulting in an improved treatment of cancer. For targeted therapy of cancer, different ligands (e.g., protein, peptide, Abs, Aps and small molecules) have widely been used in the development of different targeting drug delivery systems (DDSs). Of these homing agents, nucleic acid Aps show unique targeting potential with high binding affinity to a variety of biological targets (e.g., genes, peptides, proteins, and even cells and organs). Aps have widely been used as the targeting agent, in large part due to their unique 3D structure, simplicity in synthesis and functionalization, high chemical flexibility, low immunogenicity and toxicity, and cell/tissue penetration capability in some cases. Here, in this review, we provide important insights on Ap-decorated multimodal nanosystems (NSs) and discuss their applications in targeted therapy and imaging of cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging.

PubMed

Bhaskar, Sonu; Tian, Furong; Stoeger, Tobias; Kreyling, Wolfgang; de la Fuente, Jesús M; Grazú, Valeria; Borm, Paul; Estrada, Giovani; Ntziachristos, Vasilis; Razansky, Daniel

2010-03-03

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered.

Optical and nuclear imaging of glioblastoma with phosphatidylserine-targeted nanovesicles.

PubMed

Blanco, Víctor M; Chu, Zhengtao; LaSance, Kathleen; Gray, Brian D; Pak, Koon Yan; Rider, Therese; Greis, Kenneth D; Qi, Xiaoyang

2016-05-31

Multimodal tumor imaging with targeted nanoparticles potentially offers both enhanced specificity and sensitivity, leading to more precise cancer diagnosis and monitoring. We describe the synthesis and characterization of phenol-substituted, lipophilic orange and far-red fluorescent dyes and a simple radioiodination procedure to generate a dual (optical and nuclear) imaging probe. MALDI-ToF analyses revealed high iodination efficiency of the lipophilic reporters, achieved by electrophilic aromatic substitution using the chloramide 1,3,4,6-tetrachloro-3α,6α-diphenyl glycoluril (Iodogen) as the oxidizing agent in an organic/aqueous co-solvent mixture. Upon conjugation of iodine-127 or iodine-124-labeled reporters to tumor-targeting SapC-DOPS nanovesicles, optical (fluorescent) and PET imaging was performed in mice bearing intracranial glioblastomas. In addition, tumor vs non-tumor (normal brain) uptake was compared using iodine-125. These data provide proof-of-principle for the potential value of SapC-DOPS for multimodal imaging of glioblastoma, the most aggressive primary brain tumor.

Imaging of targeted lipid microbubbles to detect cancer cells using third harmonic generation microscopy

PubMed Central

Harpel, Kaitlin; Baker, Robert Dawson; Amirsolaimani, Babak; Mehravar, Soroush; Vagner, Josef; Matsunaga, Terry O.; Banerjee, Bhaskar; Kieu, Khanh

2016-01-01

The use of receptor-targeted lipid microbubbles imaged by ultrasound is an innovative method of detecting and localizing disease. However, since ultrasound requires a medium between the transducer and the object being imaged, it is impractical to apply to an exposed surface in a surgical setting where sterile fields need be maintained and ultrasound gel may cause the bubbles to collapse. Multiphoton microscopy (MPM) is an emerging tool for accurate, label-free imaging of tissues and cells with high resolution and contrast. We have recently determined a novel application of MPM to be used for detecting targeted microbubble adherence to the upregulated plectin-receptor on pancreatic tumor cells. Specifically, the third-harmonic generation response can be used to detect bound microbubbles to various cell types presenting MPM as an alternative and useful imaging method. This is an interesting technique that can potentially be translated as a diagnostic tool for the early detection of cancer and inflammatory disorders. PMID:27446711

Correlation based efficient face recognition and color change detection

NASA Astrophysics Data System (ADS)

Elbouz, M.; Alfalou, A.; Brosseau, C.; Alam, M. S.; Qasmi, S.

2013-01-01

Identifying the human face via correlation is a topic attracting widespread interest. At the heart of this technique lies the comparison of an unknown target image to a known reference database of images. However, the color information in the target image remains notoriously difficult to interpret. In this paper, we report a new technique which: (i) is robust against illumination change, (ii) offers discrimination ability to detect color change between faces having similar shape, and (iii) is specifically designed to detect red colored stains (i.e. facial bleeding). We adopt the Vanderlugt correlator (VLC) architecture with a segmented phase filter and we decompose the color target image using normalized red, green, and blue (RGB), and hue, saturation, and value (HSV) scales. We propose a new strategy to effectively utilize color information in signatures for further increasing the discrimination ability. The proposed algorithm has been found to be very efficient for discriminating face subjects with different skin colors, and those having color stains in different areas of the facial image.

Rapid PD-L1 detection in tumors with PET using a highly specific peptide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chatterjee, Samit; Lesniak, Wojciech G.; Miller, Michelle S.

Molecular imaging can report on the status of the tumor immune microenvironment and guide immunotherapeutic strategies to enhance the efficacy of immune modulation therapies. Imaging agents that can rapidly report on targets of immunomodulatory therapies are few. The programmed death ligand 1 (PD-L1) is an immune checkpoint protein over-expressed in several cancers and contributes to tumor immune suppression. Tumor PD-L1 expression is indicative of tumor response to PD-1 and PD-L1 targeted therapies. Herein, we report a highly specific peptide-based positron emission tomography (PET) imaging agent for PD-L1. We assessed the binding modes of the peptide WL12 to PD-L1 by dockingmore » studies, developed a copper-64 labeled WL12 ([{sup 64}Cu]WL12), and performed its evaluation in vitro, and in vivo by PET imaging, biodistribution and blocking studies. Our results show that [{sup 64}Cu]WL12 can be used to detect tumor PD-L1 expression specifically and soon after injection of the radiotracer, to fit within the standard clinical workflow of imaging within 60 min of administration. - Highlights: • A highly specific PD-L1 binding peptide, WL12, was developed as a PET imaging agent. • [{sup 64}Cu]WL12 demonstrates specific binding to PD-L1 in vitro and in vivo. • [{sup 64}Cu]WL12-PET allows PD-L1 detection in cancers within 60 min of administration. • WL12 binding interactions with PD-L1 overlaps with that of PD-1.« less

Kit formulated asialoglycoprotein receptor targeting tracer based on copolymer for liver SPECT imaging.

PubMed

Liu, Chang; Guo, Zhide; Zhang, Pu; Song, Manli; Zhao, Zuoquan; Wu, Xiaowei; Zhang, Xianzhong

2014-08-01

Specific targeting of galactose-carrying molecule to ASGP-R in normal hepatocytes has been demonstrated before. In this study, galactosyl polystyrene was synthesized from controllable ratio of functional monomers and radio-labelled with (99m)Tc by formulated kit for SPECT imaging of hepatic function. p(VLA-co-VNI)(46:54) was synthesized by free-radical copolymerization initiated by AIBN, purified by dialysis, lyophilized to kit with Tricine and TPPTS as co-ligands for (99m)Tc labeling. Radiotracer (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was prepared and evaluated by in vitro stability, in vivo metabolism, ex vivo biodistribution and microSPECT/CT imaging in normal KM mice. MicroSPECT/CT and microMRI imaging were also performed in C57BL/b6 mice with xenograft hepatic carcinoma for hepatic function evaluation. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) was obtained in high radio chemical purity (RCP) (>99%) by using instant kit without further purification and excellent in vitro and in vivo stability. The result of biodistribution showed that liver had high uptake (90.49±10.68 ID%/g) at 30 min after injection and was blocked significantly by cold copolymer. MicroSPECT imaging in normal KM mice at 1h and 4h after injection showed good liver retention and targeting properties. Significant defect of activity was observed in the tumor site which was confirmed by MRI imaging. (99m)Tc-p(VLA-co-VNI)(46:54)(Tricine)(TPPTS) with lower ratio of targeting moiety has no observable effect on the specific binding affinity and liver uptake. This makes it possible to introduce more imaging units for multi-modality imaging. Furthermore, the instant kit preparation of (99m)Tc-labeling provides great potential for the evaluation of hepatocyte function in clinical application. Copyright © 2014 Elsevier Inc. All rights reserved.

Activateable Imaging Probes Light Up Inside Cancer Cells | Center for Cancer Research

Cancer.gov

Imaging can be used to help diagnose cancer as well as monitor tumor progression and response to treatment. The field of molecular imaging focuses on techniques capable of detecting specific molecular targets associated with cancer; the agents used for molecular imaging—often called probes—are multifunctional, with components that allow them to both interact with their

In vivo molecular and genomic imaging: new challenges for imaging physics.

PubMed

Cherry, Simon R

2004-02-07

The emerging and rapidly growing field of molecular and genomic imaging is providing new opportunities to directly visualize the biology of living organisms. By combining our growing knowledge regarding the role of specific genes and proteins in human health and disease, with novel ways to target these entities in a manner that produces an externally detectable signal, it is becoming increasingly possible to visualize and quantify specific biological processes in a non-invasive manner. All the major imaging modalities are contributing to this new field, each with its unique mechanisms for generating contrast and trade-offs in spatial resolution, temporal resolution and sensitivity with respect to the biological process of interest. Much of the development in molecular imaging is currently being carried out in animal models of disease, but as the field matures and with the development of more individualized medicine and the molecular targeting of new therapeutics, clinical translation is inevitable and will likely forever change our approach to diagnostic imaging. This review provides an introduction to the field of molecular imaging for readers who are not experts in the biological sciences and discusses the opportunities to apply a broad range of imaging technologies to better understand the biology of human health and disease. It also provides a brief review of the imaging technology (particularly for x-ray, nuclear and optical imaging) that is being developed to support this new field.

TOPICAL REVIEW: In vivo molecular and genomic imaging: new challenges for imaging physics

NASA Astrophysics Data System (ADS)

Cherry, Simon R.

2004-02-01

The emerging and rapidly growing field of molecular and genomic imaging is providing new opportunities to directly visualize the biology of living organisms. By combining our growing knowledge regarding the role of specific genes and proteins in human health and disease, with novel ways to target these entities in a manner that produces an externally detectable signal, it is becoming increasingly possible to visualize and quantify specific biological processes in a non-invasive manner. All the major imaging modalities are contributing to this new field, each with its unique mechanisms for generating contrast and trade-offs in spatial resolution, temporal resolution and sensitivity with respect to the biological process of interest. Much of the development in molecular imaging is currently being carried out in animal models of disease, but as the field matures and with the development of more individualized medicine and the molecular targeting of new therapeutics, clinical translation is inevitable and will likely forever change our approach to diagnostic imaging. This review provides an introduction to the field of molecular imaging for readers who are not experts in the biological sciences and discusses the opportunities to apply a broad range of imaging technologies to better understand the biology of human health and disease. It also provides a brief review of the imaging technology (particularly for x-ray, nuclear and optical imaging) that is being developed to support this new field.

Tumor-targeting peptides from combinatorial libraries.

PubMed

Liu, Ruiwu; Li, Xiaocen; Xiao, Wenwu; Lam, Kit S

2017-02-01

Cancer is one of the major and leading causes of death worldwide. Two of the greatest challenges in fighting cancer are early detection and effective treatments with no or minimum side effects. Widespread use of targeted therapies and molecular imaging in clinics requires high affinity, tumor-specific agents as effective targeting vehicles to deliver therapeutics and imaging probes to the primary or metastatic tumor sites. Combinatorial libraries such as phage-display and one-bead one-compound (OBOC) peptide libraries are powerful approaches in discovering tumor-targeting peptides. This review gives an overview of different combinatorial library technologies that have been used for the discovery of tumor-targeting peptides. Examples of tumor-targeting peptides identified from each combinatorial library method will be discussed. Published tumor-targeting peptide ligands and their applications will also be summarized by the combinatorial library methods and their corresponding binding receptors. Copyright © 2017. Published by Elsevier B.V.

Precision Modeling Of Targets Using The VALUE Computer Program

NASA Astrophysics Data System (ADS)

Hoffman, George A.; Patton, Ronald; Akerman, Alexander

1989-08-01

The 1976-vintage LASERX computer code has been augmented to produce realistic electro-optical images of targets. Capabilities lacking in LASERX but recently incorporated into its VALUE successor include: •Shadows cast onto the ground •Shadows cast onto parts of the target •See-through transparencies (e.g.,canopies) •Apparent images due both to atmospheric scattering and turbulence •Surfaces characterized by multiple bi-directional reflectance functions VALUE provides not only realistic target modeling by its precise and comprehensive representation of all target attributes, but additionally VALUE is very user friendly. Specifically, setup of runs is accomplished by screen prompting menus in a sequence of queries that is logical to the user. VALUE also incorporates the Optical Encounter (OPEC) software developed by Tricor Systems,Inc., Elgin, IL.

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

PubMed Central

2015-01-01

Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [11C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [11C]6 for human epigenetic imaging. PMID:25203558

Super-contrast photoacoustic resonance imaging

NASA Astrophysics Data System (ADS)

Gao, Fei; Zhang, Ruochong; Feng, Xiaohua; Liu, Siyu; Zheng, Yuanjin

2018-02-01

In this paper, a new imaging modality, named photoacoustic resonance imaging (PARI), is proposed and experimentally demonstrated. Being distinct from conventional single nanosecond laser pulse induced wideband PA signal, the proposed PARI method utilizes multi-burst modulated laser source to induce PA resonant signal with enhanced signal strength and narrower bandwidth. Moreover, imaging contrast could be clearly improved than conventional single-pulse laser based PA imaging by selecting optimum modulation frequency of the laser source, which originates from physical properties of different materials beyond the optical absorption coefficient. Specifically, the imaging steps is as follows: 1: Perform conventional PA imaging by modulating the laser source as a short pulse to identify the location of the target and the background. 2: Shine modulated laser beam on the background and target respectively to characterize their individual resonance frequency by sweeping the modulation frequency of the CW laser source. 3: Select the resonance frequency of the target as the modulation frequency of the laser source, perform imaging and get the first PARI image. Then choose the resonance frequency of the background as the modulation frequency of the laser source, perform imaging and get the second PARI image. 4: subtract the first PARI image from the second PARI image, then we get the contrast-enhanced PARI results over the conventional PA imaging in step 1. Experimental validation on phantoms have been performed to show the merits of the proposed PARI method with much improved image contrast.

A philosophy for CNS radiotracer design

DOE PAGES

Van de Bittner, Genevieve C.; Ricq, Emily L.; Hooker, Jacob M.

2014-10-01

Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfallsmore » of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Lastly, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible.« less

A Philosophy for CNS Radiotracer Design

PubMed Central

2015-01-01

Conspectus Decades after its discovery, positron emission tomography (PET) remains the premier tool for imaging neurochemistry in living humans. Technological improvements in radiolabeling methods, camera design, and image analysis have kept PET in the forefront. In addition, the use of PET imaging has expanded because researchers have developed new radiotracers that visualize receptors, transporters, enzymes, and other molecular targets within the human brain. However, of the thousands of proteins in the central nervous system (CNS), researchers have successfully imaged fewer than 40 human proteins. To address the critical need for new radiotracers, this Account expounds on the decisions, strategies, and pitfalls of CNS radiotracer development based on our current experience in this area. We discuss the five key components of radiotracer development for human imaging: choosing a biomedical question, selection of a biological target, design of the radiotracer chemical structure, evaluation of candidate radiotracers, and analysis of preclinical imaging. It is particularly important to analyze the market of scientists or companies who might use a new radiotracer and carefully select a relevant biomedical question(s) for that audience. In the selection of a specific biological target, we emphasize how target localization and identity can constrain this process and discuss the optimal target density and affinity ratios needed for binding-based radiotracers. In addition, we discuss various PET test–retest variability requirements for monitoring changes in density, occupancy, or functionality for new radiotracers. In the synthesis of new radiotracer structures, high-throughput, modular syntheses have proved valuable, and these processes provide compounds with sites for late-stage radioisotope installation. As a result, researchers can manage the time constraints associated with the limited half-lives of isotopes. In order to evaluate brain uptake, a number of methods are available to predict bioavailability, blood–brain barrier (BBB) permeability, and the associated issues of nonspecific binding and metabolic stability. To evaluate the synthesized chemical library, researchers need to consider high-throughput affinity assays, the analysis of specific binding, and the importance of fast binding kinetics. Finally, we describe how we initially assess preclinical radiotracer imaging, using brain uptake, specific binding, and preliminary kinetic analysis to identify promising radiotracers that may be useful for human brain imaging. Although we discuss these five design components separately and linearly in this Account, in practice we develop new PET-based radiotracers using these design components nonlinearly and iteratively to develop new compounds in the most efficient way possible. PMID:25272291

Diagnostic PET Imaging of Mammary Microcalcifications Using 64Cu-DOTA-Alendronate in a Rat Model of Breast Cancer

PubMed Central

Ahrens, Bradley J.; Li, Lin; Ciminera, Alexandra K.; Chea, Junie; Poku, Erasmus; Bading, James R.; Weist, Michael R.; Miller, Marcia M.; Colcher, David M.

2017-01-01

The development of improved breast cancer screening methods is hindered by a lack of cancer-specific imaging agents and effective small-animal models to test them. The purpose of this study was to evaluate 64Cu-DOTA-alendronate as a mammary microcalcification-targeting PET imaging agent, using an ideal rat model. Our long-term goal is to develop 64Cu-DOTA-alendronate for the detection and noninvasive differentiation of malignant versus benign breast tumors with PET. Methods: DOTA-alendronate was synthesized, radiolabeled with 64Cu, and administered to normal or tumor-bearing aged, female, retired breeder Sprague–Dawley rats for PET imaging. Mammary tissues were subsequently labeled and imaged with light, confocal, and electron microscopy to verify microcalcification targeting specificity of DOTA-alendronate and elucidate the histologic and ultrastructural characteristics of the microcalcifications in different mammary tumor types. Tumor uptake, biodistribution, and dosimetry studies were performed to evaluate the efficacy and safety of 64Cu-DOTA-alendronate. Results: 64Cu-DOTA-alendronate was radiolabeled with a 98% yield. PET imaging using aged, female, retired breeder rats showed specific binding of 64Cu-DOTA-alendronate in mammary glands and mammary tumors. The highest uptake of 64Cu-DOTA-alendronate was in malignant tumors and the lowest uptake in benign tumors and normal mammary tissue. Confocal analysis with carboxyfluorescein-alendronate confirmed the microcalcification binding specificity of alendronate derivatives. Biodistribution studies revealed tissue alendronate concentrations peaking within the first hour, then decreasing over the next 48 h. Our dosimetric analysis demonstrated a 64Cu effective dose within the acceptable range for clinical PET imaging agents and the potential for translation into human patients. Conclusion: 64Cu-DOTA-alendronate is a promising PET imaging agent for the sensitive and specific detection of mammary tumors as well as the differentiation of malignant versus benign tumors based on absolute labeling uptake. PMID:28450564

Multispectral image fusion for target detection

NASA Astrophysics Data System (ADS)

Leviner, Marom; Maltz, Masha

2009-09-01

Various different methods to perform multi-spectral image fusion have been suggested, mostly on the pixel level. However, the jury is still out on the benefits of a fused image compared to its source images. We present here a new multi-spectral image fusion method, multi-spectral segmentation fusion (MSSF), which uses a feature level processing paradigm. To test our method, we compared human observer performance in an experiment using MSSF against two established methods: Averaging and Principle Components Analysis (PCA), and against its two source bands, visible and infrared. The task that we studied was: target detection in the cluttered environment. MSSF proved superior to the other fusion methods. Based on these findings, current speculation about the circumstances in which multi-spectral image fusion in general and specific fusion methods in particular would be superior to using the original image sources can be further addressed.

Selective targeting of melanoma by PEG-masked protein-based multifunctional nanoparticles

PubMed Central

Vannucci, Luca; Falvo, Elisabetta; Fornara, Manuela; Di Micco, Patrizio; Benada, Oldrich; Krizan, Jiri; Svoboda, Jan; Hulikova-Capkova, Katarina; Morea, Veronica; Boffi, Alberto; Ceci, Pierpaolo

2012-01-01

Background Nanoparticle-based systems are promising for the development of imaging and therapeutic agents. The main advantage of nanoparticles over traditional systems lies in the possibility of loading multiple functionalities onto a single molecule, which are useful for therapeutic and/or diagnostic purposes. These functionalities include targeting moieties which are able to recognize receptors overexpressed by specific cells and tissues. However, targeted delivery of nanoparticles requires an accurate system design. We present here a rationally designed, genetically engineered, and chemically modified protein-based nanoplatform for cell/tissue-specific targeting. Methods Our nanoparticle constructs were based on the heavy chain of the human protein ferritin (HFt), a highly symmetrical assembly of 24 subunits enclosing a hollow cavity. HFt-based nanoparticles were produced using both genetic engineering and chemical functionalization methods to impart several functionalities, ie, the α-melanocyte-stimulating hormone peptide as a melanoma-targeting moiety, stabilizing and HFt-masking polyethylene glycol molecules, rhodamine fluorophores, and magnetic resonance imaging agents. The constructs produced were extensively characterized by a number of physicochemical techniques, and assayed for selective melanoma-targeting in vitro and in vivo. Results Our HFt-based nanoparticle constructs functionalized with the α-melanocyte-stimulating hormone peptide moiety and polyethylene glycol molecules were specifically taken up by melanoma cells but not by other cancer cell types in vitro. Moreover, experiments in melanoma-bearing mice indicate that these constructs have an excellent tumor-targeting profile and a long circulation time in vivo. Conclusion By masking human HFt with polyethylene glycol and targeting it with an α-melanocyte-stimulating hormone peptide, we developed an HFt-based melanoma-targeting nanoplatform for application in melanoma diagnosis and treatment. These results could be of general interest, because the same strategy can be exploited to develop ad hoc nanoplatforms for specific delivery towards any cell/tissue type for which a suitable targeting moiety is available. PMID:22619508

Design of peptide-conjugated glycol chitosan nanoparticles for near infrared fluorescent (NIRF) in vivo imaging of bladder tumors

NASA Astrophysics Data System (ADS)

Key, Jaehong; Dhawan, Deepika; Knapp, Deborah W.; Kim, Kwangmeyung; Kwon, Ick Chan; Choi, Kuiwon; Leary, James F.

2012-03-01

Enhanced permeability and retention (EPR) effects for tumor treatment have been utilized as a representative strategy to accumulate untargeted nanoparticles in the blood vessels around tumors. However, the EPR effect itself was not sufficient for the nanoparticles to penetrate into cancer cells. For the improvement of diagnosis and treatment of cancer using nanoparticles, many more nanoparticles need to specifically enter cancer cells. Otherwise, can leave the tumor area and not contribute to treatment. In order to enhance the internalization process, specific ligands on nanoparticles can help their specific internalization in cancer cells by receptor-mediated endocytosis. We previously developed glycol chitosan based nanoparticles that suggested a promising possibility for in vivo tumor imaging using the EPR effect. The glycol chitosan nanoparticles showed a long circulation time beyond 1 day and they were accumulated predominantly in tumor. In this study, we evaluated two peptides for specific targeting and better internalization into urinary bladder cancer cells. We conjugated the peptides on to the glycol chitosan nanoparticles; the peptide-conjugated nanoparticles were also labeling with near infrared fluorescent (NIRF) dye, Cy5.5, to visualize them by optical imaging in vivo. Importantly real-time NIRF imaging can also be used for fluorescence (NIRF)-guided surgery of tumors beyond normal optical penetration depths. The peptide conjugated glycol chitosan nanoparticles were characterized with respect to size, stability and zeta-potential and compared with previous nanoparticles without ligands in terms of their internalization into bladder cancer cells. This study demonstrated the possibility of our nanoparticles for tumor imaging and emphasized the importance of specific targeting peptides.

THz imaging system for in vivo human cornea.

PubMed

Sung, Shijun; Selvin, Skyler; Bajwa, Neha; Chantra, Somporn; Nowroozi, Bryan; Garritano, James; Goell, Jacob; Li, Alex; Deng, Sophie X; Brown, Elliott; Grundfest, Warren S; Taylor, Zachary D

2018-01-01

Terahertz (THz) imaging of corneal tissue water content (CTWC) is a proposed method for early, accurate detection and study of corneal diseases. Despite promising results from ex vivo and in vivo cornea studies, interpretation of the reflectivity data is confounded by the contact between corneal tissue and rigid dielectric window used to flatten the imaging field. This work develops a novel imaging system and image reconstruction methods specifically for nearly spherical targets such as human cornea. A prototype system was constructed using a 650 GHz multiplier source and Schottky diode detector. Resolution and imaging field strength measurement from characterization targets correlate well with those predicted by the quasioptical theory and physical optics analysis. Imaging experiments with corneal phantoms and ex vivo corneas demonstrate the hydration sensitivity of the imaging system and reliable measurement of CTWC. We present successful acquisition of non-contact THz images of in vivo human cornea, and discuss strategies for optimizing the imaging system design for clinical use.

Improving Sensitivity in Ultrasound Molecular Imaging by Tailoring Contrast Agent Size Distribution: In Vivo Studies

PubMed Central

Streeter, Jason E.; Gessner, Ryan; Miles, Iman; Dayton, Paul A.

2010-01-01

Molecular imaging with ultrasound relies on microbubble contrast agents (MCAs) selectively adhering to a ligand-specific target. Prior studies have shown that only small quantities of microbubbles are retained at their target sites, therefore, enhancing contrast sensitivity to low concentrations of microbubbles is essential to improve molecular imaging techniques. In order to assess the effect of MCA diameter on imaging sensitivity, perfusion and molecular imaging studies were performed with microbubbles of varying size distributions. To assess signal improvement and MCA circulation time as a function of size and concentration, blood perfusion was imaged in rat kidneys using nontargeted size-sorted MCAs with a Siemens Sequoia ultrasound system (Siemans, Mountain View, CA) in cadence pulse sequencing (CPS) mode. Molecular imaging sensitivity improvements were studied with size-sorted αvβ3-targeted bubbles in both fibrosarcoma and R3230 rat tumor models. In perfusion imaging studies, video intensity and contrast persistence was ≈8 times and ≈3 times greater respectively, for “sorted 3-micron” MCAs (diameter, 3.3 ± 1.95 μm) when compared to “unsorted” MCAs (diameter, 0.9 ± 0.45 μm) at low concentrations. In targeted experiments, application of sorted 3-micron MCAs resulted in a ≈20 times video intensity increase over unsorted populations. Tailoring size-distributions results in substantial imaging sensitivity improvement over unsorted populations, which is essential in maximizing sensitivity to small numbers of MCAs for molecular imaging. PMID:20236606

Intravascular optical imaging of high-risk plaques in vivo by targeting macrophage mannose receptors

PubMed Central

Kim, Ji Bak; Park, Kyeongsoon; Ryu, Jiheun; Lee, Jae Joong; Lee, Min Woo; Cho, Han Saem; Nam, Hyeong Soo; Park, Ok Kyu; Song, Joon Woo; Kim, Tae Shik; Oh, Dong Joo; Gweon, DaeGab; Oh, Wang-Yuhl; Yoo, Hongki; Kim, Jin Won

2016-01-01

Macrophages mediate atheroma expansion and disruption, and denote high-risk arterial plaques. Therefore, they are substantially gaining importance as a diagnostic imaging target for the detection of rupture-prone plaques. Here, we developed an injectable near-infrared fluorescence (NIRF) probe by chemically conjugating thiolated glycol chitosan with cholesteryl chloroformate, NIRF dye (cyanine 5.5 or 7), and maleimide-polyethylene glycol-mannose as mannose receptor binding ligands to specifically target a subset of macrophages abundant in high-risk plaques. This probe showed high affinity to mannose receptors, low toxicity, and allowed the direct visualization of plaque macrophages in murine carotid atheroma. After the scale-up of the MMR-NIRF probe, the administration of the probe facilitated in vivo intravascular imaging of plaque inflammation in coronary-sized vessels of atheromatous rabbits using a custom-built dual-modal optical coherence tomography (OCT)-NIRF catheter-based imaging system. This novel imaging approach represents a potential imaging strategy enabling the identification of high-risk plaques in vivo and holds promise for future clinical implications. PMID:26948523

Theranostic Gold Nanoantennas for Simultaneous Multiplexed Raman Imaging of Immunomarkers and Photothermal Therapy.

PubMed

Webb, Joseph A; Ou, Yu-Chuan; Faley, Shannon; Paul, Eden P; Hittinger, Joseph P; Cutright, Camden C; Lin, Eugene C; Bellan, Leon M; Bardhan, Rizia

2017-07-31

In this study, we demonstrate the theranostic capability of actively targeted, site-specific multibranched gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells in vitro. By utilizing multiplexed surface-enhanced Raman scattering (SERS) imaging, enabled by the narrow peak widths of Raman signatures, we simultaneously targeted immune checkpoint receptor programmed death ligand 1 (PDL1) and the epidermal growth factor receptor (EGFR) overexpressed in TNBC cells. A 1:1 mixture of MGNs functionalized with anti-PDL1 antibodies and Raman tag 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB) and MGNs functionalized with anti-EGFR antibodies and Raman tag para -mercaptobenzoic acid ( p MBA) were incubated with the cells. SERS imaging revealed a cellular traffic map of MGN localization by surface binding and receptor-mediated endocytosis, enabling targeted diagnosis of both biomarkers. Furthermore, cells incubated with anti-EGFR- p MBA-MGNs and illuminated with an 808 nm laser for 15 min at 4.7 W/cm 2 exhibited photothermal cell death only within the laser spot (indicated by live/dead cell fluorescence assay). Therefore, this study not only provides an optical imaging platform that can track immunomarkers with spatiotemporal control but also demonstrates an externally controlled light-triggered therapeutic approach enabling receptor-specific treatment with biocompatible theranostic nanoprobes.

Theranostic Gold Nanoantennas for Simultaneous Multiplexed Raman Imaging of Immunomarkers and Photothermal Therapy

PubMed Central

2017-01-01

In this study, we demonstrate the theranostic capability of actively targeted, site-specific multibranched gold nanoantennas (MGNs) in triple-negative breast cancer (TNBC) cells in vitro. By utilizing multiplexed surface-enhanced Raman scattering (SERS) imaging, enabled by the narrow peak widths of Raman signatures, we simultaneously targeted immune checkpoint receptor programmed death ligand 1 (PDL1) and the epidermal growth factor receptor (EGFR) overexpressed in TNBC cells. A 1:1 mixture of MGNs functionalized with anti-PDL1 antibodies and Raman tag 5,5-dithio-bis-(2-nitrobenzoic acid) (DTNB) and MGNs functionalized with anti-EGFR antibodies and Raman tag para-mercaptobenzoic acid (pMBA) were incubated with the cells. SERS imaging revealed a cellular traffic map of MGN localization by surface binding and receptor-mediated endocytosis, enabling targeted diagnosis of both biomarkers. Furthermore, cells incubated with anti-EGFR–pMBA–MGNs and illuminated with an 808 nm laser for 15 min at 4.7 W/cm2 exhibited photothermal cell death only within the laser spot (indicated by live/dead cell fluorescence assay). Therefore, this study not only provides an optical imaging platform that can track immunomarkers with spatiotemporal control but also demonstrates an externally controlled light-triggered therapeutic approach enabling receptor-specific treatment with biocompatible theranostic nanoprobes. PMID:28782050

Optical Imaging and Gene Therapy with Neuroblastoma-Targeting Polymeric Nanoparticles for Potential Theranostic Applications.

PubMed

Lee, Jangwook; Jeong, Eun Ju; Lee, Yeon Kyung; Kim, Kwangmeyung; Kwon, Ick Chan; Lee, Kuen Yong

2016-03-02

Recently, targeted delivery systems based on functionalized polymeric nanoparticles have attracted a great deal of attention in cancer diagnosis and therapy. Specifically, as neuroblastoma occurs in infancy and childhood, targeted delivery may be critical to reduce the side effects that can occur with conventional approaches, as well as to achieve precise diagnosis and efficient therapy. Thus, biocompatible poly(d,l-lactide-co-glycolide) (PLG) nanoparticles containing an imaging probe and therapeutic gene are prepared, followed by modification with rabies virus glycoprotein (RVG) peptide for neuroblastoma-targeting delivery. RVG peptide is a well-known neuronal targeting ligand and is chemically conjugated to PLG nanoparticles without changing their size or shape. RVG-modified nanoparticles are effective in specifically targeting neuroblastoma both in vitro and in vivo. RVG-modified nanoparticles loaded with a fluorescent probe are useful to detect the tumor site in a neuroblastoma-bearing mouse model, and those encapsulating a therapeutic gene cocktail (siMyc, siBcl-2, and siVEGF) significantly suppressed tumor growth in the mouse model. This approach to designing and tailoring of polymeric nanoparticles for targeted delivery may be useful in the development of multimodality systems for theranostic approaches. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

LAT1 targeted delivery of methionine based imaging probe derived from M(III) metal ions for early diagnosis of proliferating tumours using molecular imaging modalities.

PubMed

Hazari, Puja Panwar; Prakash, Surbhi; Meena, Virendra K; Jaswal, Ambika; Khurana, Harleen; Mishra, Surabhi Kirti; Bhonsle, Hemanth Kumar; Singh, Lokendra; Mishra, Anil K

2015-01-01

We investigated the potential of DTPA-bis(Methionine), a target specific amino acid based probe for detection of L-type amino acid transporters (LAT1) known to over express in proliferating tumours using multimodality imaging. The ligand, DTPA-bis(Met) was readily converted to lanthanide complexes and was found capable of targeting cancer cells using multimodality imaging. DTPA-bis(Met) complexes were synthesized and characterized by mass spectroscopy. MR longitudinal relaxivity, r₁ = 4.067 ± 0.31 mM⁻¹s⁻¹ and transverse relaxivity, r₂ = 8.61 ± 0.07 mM⁻¹s⁻¹ of Gd(III)-DTPA-bis(Met) were observed at pH 7.4 at 7 T. Bright, localized fluorescence of Eu(III)-DTPA-bis(Met) was observed with standard microscopy and displacement studies indicated ligand functionality. K(D) value determined for Eu(III)-DTPA-bis(Met) on U-87 MG cells was found to be 17.3 pM and showed appreciable fluorescence within the cells. Radio HPLC showed a radiochemical purity more than 95% (specific activity = 400-500 MBq/μmol, labelling efficiency 78 %) for ⁶⁸Ga(III)-DTPA-bis(Met). Pre-treatment of xenografted U-87 MG athymic mice with ⁶⁸Ga(III)-DTPA-bis(Met) following unlabelled L-methionine administration reduced tumour uptake by 10-folds in Micro PET. These data support the specific binding of ⁶⁸Ga(III)-DTPA-bis(Met) to the LAT1 transporter. To summarize, this agent possesses high stability in biological environment and exhibits effective interaction with its LAT1 transporters giving high accumulation in tumour area, excellent tumour/non-tumour ratio and low non-specific retention in vivo.

EGFR Overexpressed in Colonic Neoplasia Can be Detected on Wide-Field Endoscopic Imaging.

PubMed

Zhou, Juan; Joshi, Bishnu P; Duan, Xiyu; Pant, Asha; Qiu, Zhen; Kuick, Rork; Owens, Scott R; Wang, Thomas D

2015-07-16

Colorectal cancer initially lies dormant as dysplasia, a premalignant state that provides an opportunity for early cancer detection. Dysplasia can be flat in morphology, focal in size, and patchy in distribution, and thus it appears "invisible" on conventional wide-field endoscopy. We aim to develop and validate a peptide that is specific for epidermal growth factor receptor (EGFR), a cell surface target that is overexpressed in colonic adenomas and is readily accessible for imaging. We expressed and purified the extracellular domain of EGFR for use with phage display to identify a peptide QRHKPRE that binds to domain 2 of this target. A near-infrared fluorescence endoscope was used to perform in vivo imaging to validate specific peptide binding to spontaneous colonic adenomas in a mouse model with topical administration. We also validated specific peptide binding to human colonic adenomas on immunohistochemistry and immunofluorescence. After labeling with Cy5.5, we validated specific peptide binding to EGFR on knockdown and competition studies. Peptide binding to cells occurred within 2.46 min and had an affinity of 50 nm. No downstream signaling was observed. We measured a target-to-background ratio of 4.0±1.7 and 2.7±0.7, for polyps and flat lesions, respectively. On immunofluorescence of human colonic specimens, greater intensity from peptide binding to dysplasia than normal was found with a 19.4-fold difference. We have selected and validated a peptide that can be used as a specific contrast agent to identify colonic adenomas that overexpress EGFR in vivo on fluorescence endoscopy.

In vivo fluorescence imaging of hepatocellular carcinoma xenograft using near-infrared labeled epidermal growth factor receptor (EGFR) peptide

PubMed Central

Li, Z.; Zhou, Q.; Zhou, J.; Duan, X.; Zhu, J.; Wang, T. D.

2016-01-01

Minimally-invasive surgery of hepatocellular carcinoma (HCC) can be limited by poor tumor visualization with white light. We demonstrate systemic administration of a Cy5.5-labeled peptide specific for epidermal growth factor receptor (EGFR) to target HCC in vivo in a mouse xenograft model. We attached a compact imaging module to the proximal end of a medical laparoscope to collect near-infrared fluorescence and reflectance images concurrently at 15 frames/sec. We measured a mean target-to-background ratio of 2.99 ± 0.22 from 13 surgically exposed subcutaneous human HCC tumors in vivo in 5 mice. This integrated imaging methodology is promising to guide laparoscopic resection of HCC. PMID:27699089

Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy.

PubMed

Chen, Dan; Li, Bowen; Cai, Songhua; Wang, Peng; Peng, Shuwen; Sheng, Yuanzhi; He, Yuanyuan; Gu, Yueqing; Chen, Haiyan

2016-09-01

Dual targeting towards both extracellular and intracellular receptors specific to tumor is a significant approach for cancer diagnosis and therapy. In the present study, a novel nano-platform (AuNC-cRGD-Apt) with dual targeting function was initially established by conjugating gold nanocluster (AuNC) with cyclic RGD (cRGD) that is specific to αvβ3integrins over-expressed on the surface of tumor tissues and aptamer AS1411 (Apt) that is of high affinity to nucleolin over-expressed in the cytoplasm and nucleus of tumor cells. Then, AuNC-cRGD-Apt was further functionalized with near infrared (NIR) fluorescence dye (MPA), giving a NIR fluorescent dual-targeting probe AuNC-MPA-cRGD-Apt. AuNC-MPA-cRGD-Apt displays low cytotoxicity and favorable tumor-targeting capability at both in vitro and in vivo level, suggesting its clinical potential for tumor imaging. Additionally, Doxorubicin (DOX), a widely used clinical chemotherapeutic drug that kill cancer cells by intercalating DNA in cellular nucleus, was immobilized onto AuNC-cRGD-Apt forming a pro-drug, AuNC-DOX-cRGD-Apt. The enhanced tumor affinity, deep tumor penetration and improved anti-tumor activity of this pro-drug were demonstrated in different tumor cell lines, tumor spheroid and tumor-bearing mouse models. Results in this study suggest not only the prospect of non-toxic AuNC modified with two targeting ligands for tumor targeted imaging, but also confirm the promising future of dual targeting AuNC as a core for the design of prodrug in the field of cancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Affibody Modified and Radiolabeled Gold-Iron Oxide Hetero-nanostructures for Tumor PET, Optical and MR Imaging

PubMed Central

Yang, Meng; Cheng, Kai; Qi, Shibo; Liu, Hongguang; Jiang, Yuxin; Jiang, Han; Li, Jinbo; Chen, Kai; Zhang, Huimao; Cheng, Zhen

2013-01-01

A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe3O4, IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T2 reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero-nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal 64Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications. PMID:23343632

Image-guided laser projection for port placement in minimally invasive surgery.

PubMed

Marmurek, Jonathan; Wedlake, Chris; Pardasani, Utsav; Eagleson, Roy; Peters, Terry

2006-01-01

We present an application of an augmented reality laser projection system in which procedure-specific optimal incision sites, computed from pre-operative image acquisition, are superimposed on a patient to guide port placement in minimally invasive surgery. Tests were conducted to evaluate the fidelity of computed and measured port configurations, and to validate the accuracy with which a surgical tool-tip can be placed at an identified virtual target. A high resolution volumetric image of a thorax phantom was acquired using helical computed tomography imaging. Oriented within the thorax, a phantom organ with marked targets was visualized in a virtual environment. A graphical interface enabled marking the locations of target anatomy, and calculation of a grid of potential port locations along the intercostal rib lines. Optimal configurations of port positions and tool orientations were determined by an objective measure reflecting image-based indices of surgical dexterity, hand-eye alignment, and collision detection. Intra-operative registration of the computed virtual model and the phantom anatomy was performed using an optical tracking system. Initial trials demonstrated that computed and projected port placement provided direct access to target anatomy with an accuracy of 2 mm.

A computational imaging target specific detectivity metric

NASA Astrophysics Data System (ADS)

Preece, Bradley L.; Nehmetallah, George

2017-05-01

Due to the large quantity of low-cost, high-speed computational processing available today, computational imaging (CI) systems are expected to have a major role for next generation multifunctional cameras. The purpose of this work is to quantify the performance of theses CI systems in a standardized manner. Due to the diversity of CI system designs that are available today or proposed in the near future, significant challenges in modeling and calculating a standardized detection signal-to-noise ratio (SNR) to measure the performance of these systems. In this paper, we developed a path forward for a standardized detectivity metric for CI systems. The detectivity metric is designed to evaluate the performance of a CI system searching for a specific known target or signal of interest, and is defined as the optimal linear matched filter SNR, similar to the Hotelling SNR, calculated in computational space with special considerations for standardization. Therefore, the detectivity metric is designed to be flexible, in order to handle various types of CI systems and specific targets, while keeping the complexity and assumptions of the systems to a minimum.

In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles

PubMed Central

Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F.; Shi, Sixiang; Kwon, Glen S.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

2013-01-01

Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and 64Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that 64Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy. PMID:24083623

Multispectral photoacoustic decomposition with localized regularization for detecting targeted contrast agent

NASA Astrophysics Data System (ADS)

Tavakoli, Behnoosh; Chen, Ying; Guo, Xiaoyu; Kang, Hyun Jae; Pomper, Martin; Boctor, Emad M.

2015-03-01

Targeted contrast agents can improve the sensitivity of imaging systems for cancer detection and monitoring the treatment. In order to accurately detect contrast agent concentration from photoacoustic images, we developed a decomposition algorithm to separate photoacoustic absorption spectrum into components from individual absorbers. In this study, we evaluated novel prostate-specific membrane antigen (PSMA) targeted agents for imaging prostate cancer. Three agents were synthesized through conjugating PSMA-targeting urea with optical dyes ICG, IRDye800CW and ATTO740 respectively. In our preliminary PA study, dyes were injected in a thin wall plastic tube embedded in water tank. The tube was illuminated with pulsed laser light using a tunable Q-switch ND-YAG laser. PA signal along with the B-mode ultrasound images were detected with a diagnostic ultrasound probe in orthogonal mode. PA spectrums of each dye at 0.5 to 20 μM concentrations were estimated using the maximum PA signal extracted from images which are obtained at illumination wavelengths of 700nm-850nm. Subsequently, we developed nonnegative linear least square optimization method along with localized regularization to solve the spectral unmixing. The algorithm was tested by imaging mixture of those dyes. The concentration of each dye was estimated with about 20% error on average from almost all mixtures albeit the small separation between dyes spectrums.

The Multifaceted Uses and Therapeutic Advantages of Nanoparticles for Atherosclerosis Research.

PubMed

DiStasio, Nicholas; Lehoux, Stephanie; Khademhosseini, Ali; Tabrizian, Maryam

2018-05-08

Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents. In fact, roughly 60% of articles from an initial search for this review included examples of imaging applications of nanoparticles. Thus, this review focuses on experimental therapy interventions applied to and observed in animal models. Particular emphasis is placed on how nanoparticle materials and properties allow researchers to learn a great deal about atherosclerosis. The objective of this review was to provide an update for nanoparticle use in imaging and drug delivery studies and to illustrate how nanoparticles can be used for sensing and modelling, for studying fundamental biological mechanisms, and for the delivery of biotherapeutics such as proteins, peptides, nucleic acids, and even cells all with the goal of attenuating atherosclerosis. Furthermore, the various atherosclerosis processes targeted mainly for imaging studies have been summarized in the hopes of inspiring new and exciting targeted therapeutic and/or imaging strategies.

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI†

PubMed Central

Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing

2017-01-01

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 ± 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 ± 0.1 × 10−22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM−1 s−1 and r2 of 37.9 mM−1 s−1 per Gd (55.2 and 75.8 mM−1 s−1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM−1 s−1 per Gd (188.0 mM−1 s−1 per molecule) and r1 of 18.6 mM−1 s−1 per Gd (37.2 mM−1 s−1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI. PMID:26961235

Highly versatile SPION encapsulated PLGA nanoparticles as photothermal ablators of cancer cells and as multimodal imaging agents.

PubMed

Sivakumar, Balasubramanian; Aswathy, Ravindran Girija; Romero-Aburto, Rebeca; Mitcham, Trevor; Mitchel, Keith A; Nagaoka, Yutaka; Bouchard, Richard R; Ajayan, Pulickel M; Maekawa, Toru; Sakthikumar, Dasappan Nair

2017-02-28

We have designed versatile polymeric nanoparticles with cancer cell specific targeting capabilities via aptamer conjugation after the successful encapsulation of curcumin and superparamagnetic iron oxide nanoparticles (SPIONs) inside a PLGA nanocapsule. These targeted nanocomposites were selectively taken up by tumor cells, under in vitro conditions, demonstrating the effectiveness of the aptamer targeting mechanism. Moreover, the nanocomposite potentially functioned as efficient multiprobes for optical, magnetic resonance imaging (MRI) and photoacoustic imaging contrast agents in the field of cancer diagnostics. The hyperthermic ability of these nanocomposites was mediated by SPIONs upon NIR-laser irradiation. In vitro cytotoxicity was shown by curcumin-loaded nanoparticles as well as the photothermal ablation of cancer cells mediated by the drug-encapsulated nanocomposite demonstrated the potential therapeutic effect of the nanocomposite. In short, we portray the aptamer-conjugated nanocomposite as a multimodal material capable of serving as a contrast agent for MR, photoacoustic and optical imaging. Furthermore, the nanocomposite functions as a targetable drug nanocarrier and a NIR-laser inducible hyperthermic material that is capable of ablating PANC-1 and MIA PaCa-2 cancer cell lines.

Arginine-glycine-aspartic acid-conjugated dendrimer-modified quantum dots for targeting and imaging melanoma.

PubMed

Li, Zhiming; Huang, Peng; Lin, Jing; He, Rong; Liu, Bing; Zhang, Xiaomin; Yang, Sen; Xi, Peng; Zhang, Xuejun; Ren, Qiushi; Cui, Daxiang

2010-08-01

Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. Quantum dots have been broadly investigated for their potential application in cancer molecular imaging. In present work, CdSe quantum dots were synthesized, polyamidoamine dendrimers were used to modify surface of quantum dots and improve their solubility in water solution. Then, dendrimer-modified CdSe quantum dots were conjugated with arginine-glycine-aspartic acid (RGD) peptides. These prepared nanoprobes were injected into nude mice loaded with melanoma (A375) tumor xenografts via tail vessels, IVIS imaging system was used to image the targeting and bio-distribution of as-prepared nanoprobes. The dendrimer-modified quantum dots exhibit water-soluble, high quantum yield, and good biocompatibility. RGD-conjugated quantum dots can specifically target human umbilical vein endothelial cells (HUVEC) and A375 melanoma cells, as well as nude mice loaded with A735 melanoma cells. High-performance RGD-conjugated dendrimers modified quantum dot-based nanoprobes have great potential in application such as tumor diagnosis and therapy.

Targeting Cell Surface Proteins in Molecular Photoacoustic Imaging to Detect Ovarian Cancer Early

DTIC Science & Technology

2013-07-01

biology, nanotechnology, and imaging technology, molecular imaging utilizes specific probes as contrast agents to visualize cellular processes at the...This reagent was covalently coupled to the oligosaccharides attached to polypeptide side-chains of extracellular membrane proteins on living cells...website. The normal tissue gene expression profile dataset was modified and processed as described by Fang (8) and mean intensities and standard

Activatable clinical fluorophore-quencher antibody pairs as dual molecular probes for the enhanced specificity of image-guided surgery

NASA Astrophysics Data System (ADS)

Obaid, Girgis; Spring, Bryan Q.; Bano, Shazia; Hasan, Tayyaba

2017-12-01

The emergence of fluorescently labeled therapeutic antibodies has given rise to molecular probes for image-guided surgery. However, the extraneous interstitial presence of an unbound and nonspecifically accumulated probe gives rise to false-positive detection of tumor tissue and margins. Thus, the concept of tumor-cell activation of smart probes provides a potentially superior mechanism of delineating tumor margins as well as small tumor deposits. The combination of molecular targeting with intracellular activation circumvents the presence of extracellular, nonspecific signals of targeted probe accumulation. Here, we present a demonstration of the clinical antibodies cetuximab (cet, anti-EGFR mAb) and trastuzumab (trast, anti-HER-2 mAb) conjugated to Alexa Fluor molecules and IRDye QC-1 quencher optimized at the ratio of 1∶2∶6 to provide the greatest degree of proteolytic fluorescence activation, synonymous with intracellular lysosomal degradation. The cet-AF-Q-C1 conjugate (1∶2∶6) provides up to 9.8-fold proteolytic fluorescence activation. By preparing a spectrally distinct, irrelevant sham IgG-AF-QC-1 conjugate, a dual-activatable probe approach is shown to enhance the specificity of imaging within an orthotopic AsPC-1 pancreatic cancer xenograft model. The dual-activatable approach warrants expedited clinical translation to improve the specificity of image-guided surgery by spectrally decomposing specific from nonspecific probe accumulation, binding, and internalization.

[Preparation, quality control and thyroid molecule imaging of solid-target based radionuclide ioine-124].

PubMed

Zhu, H; Wang, F; Guo, X Y; Li, L Q; Duan, D B; Liu, Z B; Yang, Z

2018-04-18

To provide useful information for the further production and application of this novel radio-nuclide for potential clinical application. 124 Te (p,n) 124 I nuclide reaction was used for the 124 I production. Firstly, the target material, 124 TeO 2 (200 mg) and Al2O3 (30 mg) mixture, were compressed into the round platinum based solid target by tablet device. HM-20 medical cyclotron was applied to irradiate the solid target slice for 6-10 h with helium and water cooling. Then, the radiated solid target was placed for 12 h (overnight) to decay the radioactive impurity; finally, 124 I was be purified by dry distillation using 1 mL/min nitrogen for about 6 hours and radiochemical separation methods. Micro-PET imaging studies were performed to investigate the metabolism properties and thyroid imaging ability of 124 I.After 740 kBq 124 I was injected intravenously into the tail vein of the normal mice, the animals were imaged with micro-PET and infused with CT. The micro-PET/CT infusion imaging revealed actual state 124 I's metabolism in the mice. It was been successfully applied for 200 mg 124 TeO 2 plating by the tablet device on the surface of platinum. It showed smooth, dense surface and without obviously pits and cracks. The enriched 124 Te target was irradiated for 6 to 10 hours at about 12.0 MeV with 20 μA current on HM-20 cyclotron. Then 370-1 110 MBq 124 I could be produced on the solid target after irradiation and 370-740 MBq high specific activity could be collected afterdry distillation separation and radio-chemical purification. 124 I product was finally dissolved in 0.01 mol/L NaOH for the future distribution. The gamma spectrum of the produced 124 I-solution showed that radionuclide purity was over 80.0%. The micro-PET imaging of 124 I in the normal mice exhibited the thyroid and stomach accumulations and kidney metabolism, the bladder could also be clearly visible, which was in accordance with what was previously reported. To the best of our knowledge, it was the first production of 124 I report in China. In this study, the preparation of 124 TeO 2 solid target was successfully carried out by using the tablet device. After irradiation of the 124 TeO 2 solid target and radio-chemical purification, we successfully produced 370-740 MBq high specific activity 124 I by a cyclotron for biomedical application, and micro-PET imaging of 124 I in normal mice exhibited the thyroid accumulations. Also, slight uptake in stomach were also monitored with almost nonuptake in other organs in the micro-PET imaging. The production of 124 I is expected to provide a new solid target radionuclide for the scientific research and potential clinical application of our country.

The Kepler Full Frame Images

NASA Technical Reports Server (NTRS)

Dotson, Jessie L.; Batalha, Natalie; Bryson, Stephen T.; Caldwell, Douglas A.; Clarke, Bruce D.

2010-01-01

NASA's exoplanet discovery mission Kepler provides uninterrupted 1-min and 30-min optical photometry of a 100 square degree field over a 3.5 yr nominal mission. Downlink bandwidth is filled at these short cadences by selecting only detector pixels specific to 105 preselected stellar targets. The majority of the Kepler field, comprising 4 x 10(exp 6) m_v < 20 sources, is sampled at much lower 1-month cadence in the form of a full-frame image. The Full Frame Images (FFIs) are calibrated by the Science Operations Center at NASA Ames Research Center. The Kepler Team employ these images for astrometric and photometric reference but make the images available to the astrophysics community through the Multimission Archive at STScI (MAST). The full-frame images provide a resource for potential Kepler Guest Observers to select targets and plan observing proposals, while also providing a freely-available long-cadence legacy of photometric variation across a swathe of the Galactic disk.

Nanoparticles for Biomedical Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nune, Satish K.; Gunda, Padmaja; Thallapally, Praveen K.

2009-11-01

Background: Synthetic nanoparticles are emerging as versatile tools in biomedical applications, particularly in the area of biomedical imaging. Nanoparticles 1 to 100 nm in diameter possess dimensions comparable to biological functional units. Diverse surface chemistries, unique magnetic properties, tunable absorption and emission properties, and recent advances in the synthesis and engineering of various nanoparticles suggest their potential as probes for early detection of diseases such as cancer. Surface functionalization has further expanded the potential of nanoparticles as probes for molecular imaging. Objective: To summarize emerging research of nanoparticles for biomedical imaging with increased selectivity and reduced non-specific uptake with increasedmore » spatial resolution containing stabilizers conjugated with targeting ligands. Methods: This review summarizes recent technological advances in the synthesis of various nanoparticle probes, and surveys methods to improve the targeting of nanoparticles for their applications in biomedical imaging. Conclusion: Structural design of nanomaterials for biomedical imaging continues to expand and diversify. Synthetic methods have aimed to control the size and surface characteristics of nanoparticles to control distribution, half-life and elimination. Although molecular imaging applications using nanoparticles are advancing into clinical applications, challenges such as storage stability and long-term toxicology should continue to be addressed. Keywords: nanoparticle synthesis, surface modification, targeting, molecular imaging, and biomedical imaging.« less

Should Low Molecular Weight PSMA Targeted Ligands Get Bigger and Use Albumin Ligands for PSMA Targeting?

PubMed

Huang, Steve S; Heston, Warren D W

2017-01-01

Prostate Specific Membrane Antigen (PSMA) is strongly expressed in prostate cancer. Recently a number of low-molecular-weight inhibitors have demonstrated excellent PSMA targeting activity for both imaging as well as Lutecium-177 radiotherapy in human trials. The paper by Choy et al raises the question of whether we can further increase the effectiveness of PSMA targeted therapy by adding an albumin-binding entity to low-molecular-weight agents.

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: what should be the policy?

PubMed

Kateb, Babak; Chiu, Katherine; Black, Keith L; Yamamoto, Vicky; Khalsa, Bhavraj; Ljubimova, Julia Y; Ding, Hui; Patil, Rameshwar; Portilla-Arias, Jose Antonio; Modo, Mike; Moore, David F; Farahani, Keyvan; Okun, Michael S; Prakash, Neal; Neman, Josh; Ahdoot, Daniel; Grundfest, Warren; Nikzad, Shouleh; Heiss, John D

2011-01-01

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines. Copyright © 2010 Elsevier Inc. All rights reserved.

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: What should be the policy?

PubMed Central

Kateb, Babak; Chiu, Katherine; Black, Keith L.; Yamamoto, Vicky; Khalsa, Bhavraj; Ljubimova, Julia Y.; Ding, Hui; Patil, Rameshwar; Portilla-Arias, Jose Antonio; Modo, Mike; Moore, David F.; Farahani, Keyvan; Okun, Michael S.; Prakash, Neal; Neman, Josh; Ahdoot, Daniel; Grundfest, Warren; Nikzad, Shouleh; Heiss, John D.

2012-01-01

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1–100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law–healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines. PMID:20149882

Quantification of cell surface receptor expression in live tissue culture media using a dual-tracer stain and rinse approach

NASA Astrophysics Data System (ADS)

Xu, Xiaochun; Sinha, Lagnojita; Singh, Aparna; Yang, Cynthia; Xiang, Jialing; Tichauer, Kenneth M.

2015-03-01

Immunofluorescence staining is a robust way to visualize the distribution of targeted biomolecules invasively in in fixed tissues and tissue culture. Despite the fact that these methods has been a well-established method in fixed tissue imaging for over 70 years, quantification of receptor concentration still simply assumes that the signal from the targeted fluorescent marker after incubation and sufficient rinsing is directly proportional to the concentration of targeted biomolecules, thus neglecting the experimental inconsistencies in incubation and rinsing procedures and assuming no, nonspecific binding of the fluorescent markers. This work presents the first imaging approach capable of quantifying the concentration of cell surface receptor on cancer cells grown in vitro based on compartment modeling in a nondestructive way. The approach utilizes a dual-tracer protocol where any non-specific retention or variability in incubation and rinsing of a receptor-targeted imaging agent is corrected by simultaneously imaging the retention of a chemically similar, "untargeted" imaging agent. Various different compartment models were used to analyze the data in order to find the optimal procedure for extracting estimates of epidermal growth factor receptor (EGFR) concentration (a receptor overexpressed in many cancers and a key target for emerging molecular therapies) in tissue cultures with varying concentrations of human glioma cells (U251). Preliminary results demonstrated a need to model nonspecific binding of both the targeted and untargeted imaging agents used. The approach could be used to carry out the first repeated measures of cell surface receptor dynamics during 3D tumor mass development, in addition to the receptor response to therapies.

In vivo cation exchange in quantum dots for tumor-specific imaging.

PubMed

Liu, Xiangyou; Braun, Gary B; Qin, Mingde; Ruoslahti, Erkki; Sugahara, Kazuki N

2017-08-24

In vivo tumor imaging with nanoprobes suffers from poor tumor specificity. Here, we introduce a nanosystem, which allows selective background quenching to gain exceptionally tumor-specific signals. The system uses near-infrared quantum dots and a membrane-impermeable etchant, which serves as a cation donor. The etchant rapidly quenches the quantum dots through cation exchange (ionic etching), and facilitates renal clearance of metal ions released from the quantum dots. The quantum dots are intravenously delivered into orthotopic breast and pancreas tumors in mice by using the tumor-penetrating iRGD peptide. Subsequent etching quenches excess quantum dots, leaving a highly tumor-specific signal provided by the intact quantum dots remaining in the extravascular tumor cells and fibroblasts. No toxicity is noted. The system also facilitates the detection of peritoneal tumors with high specificity upon intraperitoneal tumor targeting and selective etching of excess untargeted quantum dots. In vivo cation exchange may be a promising strategy to enhance specificity of tumor imaging.The imaging of tumors in vivo using nanoprobes has been challenging due to the lack of sufficient tumor specificity. Here, the authors develop a tumor-specific quantum dot system that permits in vivo cation exchange to achieve selective background quenching and high tumor-specific imaging.

Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI

NASA Astrophysics Data System (ADS)

Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing; Yang, Jenny J.

2016-06-01

Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 × 10-22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM-1 s-1 and r2 of 37.9 mM-1 s-1 per Gd (55.2 and 75.8 mM-1 s-1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM-1 s-1 per Gd (188.0 mM-1 s-1 per molecule) and r1 of 18.6 mM-1 s-1 per Gd (37.2 mM-1 s-1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 × 10-22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM-1 s-1 and r2 of 37.9 mM-1 s-1 per Gd (55.2 and 75.8 mM-1 s-1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM-1 s-1 per Gd (188.0 mM-1 s-1 per molecule) and r1 of 18.6 mM-1 s-1 per Gd (37.2 mM-1 s-1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr09071g

PHASTpep: Analysis Software for Discovery of Cell-Selective Peptides via Phage Display and Next-Generation Sequencing

PubMed Central

Dasa, Siva Sai Krishna; Kelly, Kimberly A.

2016-01-01

Next-generation sequencing has enhanced the phage display process, allowing for the quantification of millions of sequences resulting from the biopanning process. In response, many valuable analysis programs focused on specificity and finding targeted motifs or consensus sequences were developed. For targeted drug delivery and molecular imaging, it is also necessary to find peptides that are selective—targeting only the cell type or tissue of interest. We present a new analysis strategy and accompanying software, PHage Analysis for Selective Targeted PEPtides (PHASTpep), which identifies highly specific and selective peptides. Using this process, we discovered and validated, both in vitro and in vivo in mice, two sequences (HTTIPKV and APPIMSV) targeted to pancreatic cancer-associated fibroblasts that escaped identification using previously existing software. Our selectivity analysis makes it possible to discover peptides that target a specific cell type and avoid other cell types, enhancing clinical translatability by circumventing complications with systemic use. PMID:27186887

Carbon nanotubes as in vivo bacterial probes.

PubMed

Bardhan, Neelkanth M; Ghosh, Debadyuti; Belcher, Angela M

2014-09-17

With the rise in antibiotic-resistant infections, non-invasive sensing of infectious diseases is increasingly important. Optical imaging, although safer and simpler, is less developed than other modalities such as radioimaging, due to low availability of target-specific molecular probes. Here we report carbon nanotubes (SWNTs) as bacterial probes for fluorescence imaging of pathogenic infections. We demonstrate that SWNTs functionalized using M13 bacteriophage (M13-SWNT) can distinguish between F'-positive and F'-negative bacterial strains. Moreover, through one-step modification, we attach an anti-bacterial antibody on M13-SWNT, making it easily tunable for sensing specific F'-negative bacteria. We illustrate detection of Staphylococcus aureus intramuscular infections, with ~3.4 × enhancement in fluorescence intensity over background. SWNT imaging presents lower signal spread ~0.08 × and higher signal amplification ~1.4 × , compared with conventional dyes. We show the probe offers greater ~5.7 × enhancement in imaging of S. aureus infective endocarditis. These biologically functionalized, aqueous-dispersed, actively targeted, modularly tunable SWNT probes offer new avenues for exploration of deeply buried infections.

Carbon nanotubes as in vivo bacterial probes

NASA Astrophysics Data System (ADS)

Bardhan, Neelkanth M.; Ghosh, Debadyuti; Belcher, Angela M.

2014-09-01

With the rise in antibiotic-resistant infections, non-invasive sensing of infectious diseases is increasingly important. Optical imaging, although safer and simpler, is less developed than other modalities such as radioimaging, due to low availability of target-specific molecular probes. Here we report carbon nanotubes (SWNTs) as bacterial probes for fluorescence imaging of pathogenic infections. We demonstrate that SWNTs functionalized using M13 bacteriophage (M13-SWNT) can distinguish between F‧-positive and F‧-negative bacterial strains. Moreover, through one-step modification, we attach an anti-bacterial antibody on M13-SWNT, making it easily tunable for sensing specific F‧-negative bacteria. We illustrate detection of Staphylococcus aureus intramuscular infections, with ~3.4 × enhancement in fluorescence intensity over background. SWNT imaging presents lower signal spread ~0.08 × and higher signal amplification ~1.4 × , compared with conventional dyes. We show the probe offers greater ~5.7 × enhancement in imaging of S. aureus infective endocarditis. These biologically functionalized, aqueous-dispersed, actively targeted, modularly tunable SWNT probes offer new avenues for exploration of deeply buried infections.

Selective imaging of cancer cells with a pH-activatable lysosome-targeting fluorescent probe.

PubMed

Shi, Rongguang; Huang, Lu; Duan, Xiaoxue; Sun, Guohao; Yin, Gui; Wang, Ruiyong; Zhu, Jun-Jie

2017-10-02

Fluorescence imaging with tumor-specific fluorescent probe has emerged as a tool to aid surgeons in the identification and removal of tumor tissue. We report here a new lysosome-targeting fluorescent probe (NBOH) with BODIPY fluorephore to distinguish tumor tissue out of normal tissue based on different pH environment. The probe exhibited remarkable pH-dependent fluorescence behavior in a wide pH range from 3.0 to 11.0, especially a sensitive pH-dependent fluorescence change at pH range between 3.5 and 5.5, corresponding well to the acidic microenvironment of tumor cells, in aqueous solution. The response time of NBOH was extremely short and the photostability was proved to be good. Toxicity test and fluorescence cell imaging together with a sub-cellular localization study were carried out revealing its low biotoxicity and good cell membrane permeability. And NBOH was successfully applied to the imaging of tumor tissue in tumor-bearing mice suggesting potential application to surgery as a tumor-specific probe. Copyright © 2017 Elsevier B.V. All rights reserved.

Carbon Nanotubes as in vivo Bacterial Probes

PubMed Central

Bardhan, Neelkanth M.; Ghosh, Debadyuti; Belcher, Angela M.

2014-01-01

With the rise in antibiotic-resistant infections, noninvasive sensing of infectious diseases is increasingly important. Optical imaging, while safer and simpler, is less developed than other modalities like radioimaging; due to low availability of target-specific molecular probes. Here, we report carbon nanotubes (SWNTs) as bacterial probes for fluorescence imaging of pathogenic infections. We demonstrate that SWNTs functionalized using M13 bacteriophage (M13-SWNT) can distinguish between F'-positive and F'-negative bacterial strains. Moreover, through one-step modification, we attach an anti-bacterial antibody on M13-SWNT, making it easily tunable for sensing specific F’-negative bacteria. We illustrate detection of Staphylococcus aureus intramuscular infections, with ~3.4× enhancement in fluorescence intensity over background. SWNT imaging presents lower signal spread ~0.08×, and higher signal amplification ~1.4×, compared to conventional dyes. We show the probe offers greater ~5.7× enhancement in imaging of S. aureus infective endocarditis. These biologically-functionalized, aqueous-dispersed, actively-targeted, modularly-tunable SWNT probes offer new avenues for exploration of deeply-buried infections. PMID:25230005

Imaging Pancreatic Cancer Using Bioconjugated InP Quantum Dots

PubMed Central

Yong, Ken-Tye; Ding, Hong; Roy, Indrajit; Law, Wing-Cheung; Bergey, Earl J.; Maitra, Anirban; Prasad, Paras N.

2009-01-01

In this paper, we report the successful use of non-cadmium based quantum dots (QDs) as highly efficient and non-toxic optical probes for imaging live pancreatic cancer cells. Indium phosphide (core)-zinc sulphide (shell), or InP/ZnS, QDs with high quality and bright luminescence were prepared by a hot colloidal synthesis method in non-aqueous media. The surfaces of these QDs were then functionalized with mercaptosuccinic acid to make them highly dispersible in aqueous media. Further bioconjugation with pancreatic cancer specific monoclonal antibodies, such as anti-claudin 4 and anti-prostate stem cell antigen (anti-PSCA), to the functionalized InP/ZnS QDs, allowed specific in vitro targeting of pancreatic cancer cell lines (both immortalized and low passage ones). The receptor mediated delivery of the bioconjugates was further confirmed by the observation of poor in vitro targeting in non-pancreatic cancer based cell lines which are negative for the claudin-4-receptor. These observations suggest the immense potential of InP/ZnS QDs as non-cadmium based safe and efficient optical imaging nanoprobes in diagnostic imaging, particularly for early detection of cancer. PMID:19243145

Imaging pancreatic cancer using bioconjugated InP quantum dots.

PubMed

Yong, Ken-Tye; Ding, Hong; Roy, Indrajit; Law, Wing-Cheung; Bergey, Earl J; Maitra, Anirban; Prasad, Paras N

2009-03-24

In this paper, we report the successful use of non-cadmium-based quantum dots (QDs) as highly efficient and nontoxic optical probes for imaging live pancreatic cancer cells. Indium phosphide (core)-zinc sulfide (shell), or InP/ZnS, QDs with high quality and bright luminescence were prepared by a hot colloidal synthesis method in nonaqueous media. The surfaces of these QDs were then functionalized with mercaptosuccinic acid to make them highly dispersible in aqueous media. Further bioconjugation with pancreatic cancer specific monoclonal antibodies, such as anticlaudin 4 and antiprostate stem cell antigen (anti-PSCA), to the functionalized InP/ZnS QDs, allowed specific in vitro targeting of pancreatic cancer cell lines (both immortalized and low passage ones). The receptor-mediated delivery of the bioconjugates was further confirmed by the observation of poor in vitro targeting in nonpancreatic cancer based cell lines which are negative for the claudin-4-receptor. These observations suggest the immense potential of InP/ZnS QDs as non-cadmium-based safe and efficient optical imaging nanoprobes in diagnostic imaging, particularly for early detection of cancer.

Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers.

PubMed

Jiang, Qiongchao; Hao, Shaoyun; Xiao, Xiaoyun; Yao, Jiyi; Ou, Bing; Zhao, Zizhuo; Liu, Fengtao; Pan, Xin; Luo, Baoming; Zhi, Hui

2016-05-01

There is an unmet need for specific and sensitive imaging techniques to assess the efficacy of breast cancer therapy, particularly Her-2-expressing cancers. Ultrasonic microbubbles are being developed for use as diagnostic and therapeutic tools. However, nanobubbles circulate longer, are smaller, and diffuse into extravascular tissue to specifically bind target molecules. Here, we characterize a novel Herceptin-conjugated nanobubble for use against Her-2-expressing tumors. Phospholipid-shelled nanobubbles conjugated with Herceptin (NBs-Her) were fabricated using a thin-film hydration method and characterized in vitro in breast cancer cell lines and in vivo in a mouse model. The average size of the unconjugated nanobubbles (NBs-Blank) and NBs-Her was 447.1 ± 18.4 and 613.0 ± 25.4 nm, respectively. In cell culture, the NBs-Her adhered to Her-2-positive cells significantly better than to Her-2-negative cells (p < 0.05). In vivo, the peak intensity and the half-time to washout of the NBs-Her were significantly greater than those of the NBs-Blank (p < 0.05). In addition, contrast-enhanced ultrasound imaging quality was improved through the use of the NBs-Her. The nanobubbles were able to penetrate into tumor tissue to allow extravascular imaging, but did not penetrate normal skeletal muscle. The Herceptin-conjugated nanobubble had many properties that made it useful for in vivo imaging, including longer circulation time and better tumor selectivity. This platform may be able to provide targeted delivery of therapeutic drugs or genes.

Non-Invasive Monitoring of CNS MHC-I Molecules in Ischemic Stroke Mice.

PubMed

Xia, Jing; Zhang, Ying; Zhao, Huanhuan; Wang, Jie; Gao, Xueren; Chen, Jinpeng; Fu, Bo; Shen, Yuqing; Miao, Fengqin; Zhang, Jianqiong; Teng, Gaojun

2017-01-01

Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. The expression of major histocompatibility complex class I (MHC-I) molecules in the central nervous system, which are silenced under normal physiological conditions, have been reported to be induced by injury stimulation. The purpose of this study was to determine whether MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke and to assess whether a high-affinity peptide specific for MHC-I molecules could be applied in the near-infrared imaging of cerebral ischemic mice. Quantitative real-time PCR and Western blotting were used to detect the expression of MHC-I molecules in two mouse models of cerebral ischemic stroke and an in vitro model of ischemia. The NetMHC 4.0 server was used to screen a high-affinity peptide specific for mouse MHC-I molecules. The Rosetta program was used to identify the specificity and affinity of the screened peptide (histocompatibility-2 binding peptide, H2BP). The results demonstrated that MHC-I molecules could serve as molecular targets for the acute phase of ischemic stroke. Cy5.5-H2BP molecular probes could be applied in the near-infrared imaging of cerebral ischemic mice. Research on the expression of MHC-I molecules in the acute phase after ischemia and MHC-I-targeted imaging may not only be helpful for understanding the mechanism of ischemic and hypoxic brain injury and repair but also has potential application value in the imaging of ischemic stroke.

A near-infrared phthalocyanine dye-labeled agent for integrin αvβ6-targeted theranostics of pancreatic cancer.

PubMed

Gao, Duo; Gao, Liquan; Zhang, Chenran; Liu, Hao; Jia, Bing; Zhu, Zhaohui; Wang, Fan; Liu, Zhaofei

2015-06-01

Integrin αvβ6 is widely upregulated in variant malignant cancers but is undetectable in normal organs, making it a promising target for cancer diagnostic imaging and therapy. Using streptavidin-biotin chemistry, we synthesized an integrin αvβ6-targeted near-infrared phthalocyanine dye-labeled agent, termed Dye-SA-B-HK, and investigated whether it could be used for cancer imaging, optical imaging-guided surgery, and phototherapy in pancreatic cancer mouse models. Dye-SA-B-HK specifically bound to integrin αvβ6 in vitro and in vivo with high receptor binding affinity. Using small-animal optical imaging, we detected subcutaneous and orthotopic BxPC-3 human pancreatic cancer xenografts in vivo. Upon optical image-guidance, the orthotopically growing pancreatic cancer lesions could be successfully removed by surgery. Using light irradiation, Dye-SA-B-HK manifested remarkable antitumor effects both in vitro and in vivo. (18)F-FDG positron emission tomography (PET) imaging and ex vivo fluorescence staining validated the observed decrease in proliferation of treated tumors by Dye-DA-B-HK phototherapy. Tissue microarray results revealed overexpression of integrin αvβ6 in over 95% cases of human pancreatic cancer, indicating that theranostic application of Dye-DA-B-HK has clear translational potential. Overall, the results of this study demonstrated that integrin αvβ6-specific Dye-SA-B-HK is a promising theranostic agent for the management of pancreatic cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

In vivo fluorescence lifetime imaging for monitoring the efficacy of the cancer treatment.

PubMed

Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Zielinski, Rafal; Capala, Jacek; Gandjbakhche, Amir

2014-07-01

Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in vivo fluorescence lifetime imaging with HER2-targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pretreatment size. Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (∼0.13 ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment), the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03 ns. The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. ©2014 American Association for Cancer Research.

In-vivo fluorescence lifetime imaging for monitoring the efficacy of the cancer treatment

PubMed Central

Ardeshirpour, Yasaman; Chernomordik, Victor; Hassan, Moinuddin; Zielinski, Rafal; Capala, Jacek; Gandjbakhche, Amir

2015-01-01

Purpose Advances in tumor biology created a foundation for targeted therapy aimed at inactivation of specific molecular mechanisms responsible for cell malignancy. In this paper, we used in-vivo fluorescence lifetime imaging with HER2 targeted fluorescent probes as an alternative imaging method to investigate the efficacy of targeted therapy with 17-DMAG (an HSP90 inhibitor) on tumors with high expression of HER2 receptors. Experimental Design HER2-specific Affibody, conjugated to Alexafluor 750, was injected into nude mice, bearing HER2-positive tumor xenograft. The fluorescence lifetime was measured before treatment and monitored after the probe injections at 12 hours after the last treatment dose, when the response to the 17-DMAG therapy was the most pronounced as well as a week after the last treatment when the tumors grew back almost to their pre-treatment size. Results Imaging results showed significant difference between the fluorescence lifetimes at the tumor and the contralateral site (~0.13ns) in the control group (before treatment) and 7 days after the last treatment when the tumors grew back to their pretreatment dimensions. However, at the time frame that the treatment had its maximum effect (12 hours after the last treatment) the difference between the fluorescence lifetime at the tumor and contralateral site decreased to 0.03ns. Conclusions The results showed a good correlation between fluorescence lifetime and the efficacy of the treatment. These findings show that in-vivo fluorescence lifetime imaging can be used as a promising molecular imaging tool for monitoring the treatment outcome in preclinical models and potentially in patients. PMID:24671949

There's Waldo! A Normalization Model of Visual Search Predicts Single-Trial Human Fixations in an Object Search Task

PubMed Central

Miconi, Thomas; Groomes, Laura; Kreiman, Gabriel

2016-01-01

When searching for an object in a scene, how does the brain decide where to look next? Visual search theories suggest the existence of a global “priority map” that integrates bottom-up visual information with top-down, target-specific signals. We propose a mechanistic model of visual search that is consistent with recent neurophysiological evidence, can localize targets in cluttered images, and predicts single-trial behavior in a search task. This model posits that a high-level retinotopic area selective for shape features receives global, target-specific modulation and implements local normalization through divisive inhibition. The normalization step is critical to prevent highly salient bottom-up features from monopolizing attention. The resulting activity pattern constitues a priority map that tracks the correlation between local input and target features. The maximum of this priority map is selected as the locus of attention. The visual input is then spatially enhanced around the selected location, allowing object-selective visual areas to determine whether the target is present at this location. This model can localize objects both in array images and when objects are pasted in natural scenes. The model can also predict single-trial human fixations, including those in error and target-absent trials, in a search task involving complex objects. PMID:26092221

Clickable and imageable multiblock polymer micelles with magnetically guided and PEG-switched targeting and release property for precise tumor theranosis.

PubMed

Wei, Jing; Shuai, Xiaoyu; Wang, Rui; He, Xueling; Li, Yiwen; Ding, Mingming; Li, Jiehua; Tan, Hong; Fu, Qiang

2017-11-01

Targeted delivery of therapeutics and diagnostics using nanotechnology holds great promise to minimize the side effects of conventional chemotherapy and enable specific and real-time detection of diseases. To realize this goal, we report a clickable and imageable nanovehicle assembled from multiblock polyurethanes (MPUs). The soft segments of the polymers are based on detachable poly(ethylene glycol) (PEG) and degradable poly(ε-caprolactone) (PCL), and the hard segments are constructed from lysine- and cystine-derivatives bearing reduction-responsive disulfide linkages and click-active alkynyl moieties, allowing for post-conjugation of targeting ligands via a click chemistry. It was found that the cleavage of PEG corona bearing a pH-sensitive benzoic-imine linkage (BPEG) could act as an on-off switch, which is capable of activating the clicked targeting ligands under extracellular acidic condition, followed by triggering the core degradation and payload release within tumor cells. In combination with superparamagnetic iron oxide nanoparticles (SPION) clustered within the micellar core, the MPUs exhibit excellent magnetic resonance imaging (MRI) contrast effects and T 2 relaxation in vitro, as well as magnetically guided MR imaging and multimodal targeting of therapeutics to tumor precisely, leading to significant inhibition of cancer with minimal side effect. This work provides a safe and versatile platform for the further development of smart theranostic systems for potential magnetically-targeted and imaging-guided personalized medicine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Current application and future perspectives of PSMA PET imaging in prostate cancer.

PubMed

Ceci, Francesco; Castellucci, Paolo; Fanti, Stefano

2018-03-08

As precision medicine evolves, the contribution of molecular imaging to the management of prostate cancer (PCa) patients, especially for Positron Emission Tomography (PET) imaging, is gaining importance. Highly successful approaches to measure the expression of the prostate specific membrane antigen (PSMA) have been introduced recently. PSMA, the glutamate carboxypeptidase II (GCP-II), is a membrane bound metallo-peptidase that is overexpressed in 90-100% of PCa cells. Due to its selective over-expression, PSMA is a reliable tissue marker for prostate cancer and is considered an ideal target for tumor specific imaging and therapy. A variety of PET and SPECT probes targeting this peptide receptor have been introduced. These are undergoing extensive clinical evaluations. Initial results attest to a high accuracy for disease detection compared conventional radiology (CT or MRI) and other nuclear medicine procedure (choline PET or fluciclovine PET). However, prospective evaluation of the impact on patient management for PSMA-ligand PET and its impact on patient outcome is currently missing. Finally, PSMA inhibitors can be radio-labeled with diagnostic (68Ga-PSMA-11), or therapeutic nuclides (177Lu/225Ac PSMA-617) to be used as theranostic agent. Initial results showed that PSMA-targeted radioligand therapy (RLT) can potentially delay disease progression in metastatic castrate-resistant PCa. This review aims to explore the current application of PSMA based imaging in prostate cancer, reporting about main advantages and limitations of this new theranostic procedure. The future perspectives and potential the applications of this agent will be also discussed.

Affibody Molecules for In vivo Characterization of HER2-Positive Tumors by Near-Infrared Imaging

PubMed Central

Lee, Sang Bong; Hassan, Moinuddin; Fisher, Robert; Chertov, Oleg; Chernomordik, Victor; Kramer-Marek, Gabriela; Gandjbakhche, Amir; Capala, Jacek

2012-01-01

Purpose HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. We are developing molecular probes for in vivo quantitative imaging of HER2 receptors using near-infrared optical imaging. The goal is to provide probes that will minimally interfere with the studied system, i.e., whose binding does not interfere with the binding of the therapeutic agents, and whose effect on the target cells is minimal. Experimental Design We used three different types of HER2-specific Affibody molecules [monomer ZHER2:342, dimer (ZHER2:477)2, and albumin-binding domain-fused-(ZHER2:342)2] as targeting agents, and labeled them with Alexa Fluor dyes. Trastuzumab was also conjugated, using commercially available kits, as a standard control. The resulting conjugates were characterized in vitro by toxicity assays, Biacore affinity measurements, flow cytometry, and confocal microscopy. Semi-uantitative in vivo near-infrared optical imaging studies were carried out using mice with subcutaneous xenografts of HER2-positive tumors. Results The HER2-specific Affibody molecules were not toxic to HER2-overexpressing cells and their binding to HER2 did interfere with neither binding nor effectives of trastuzumab. The binding affinities and specificities of the Affibody-Alexa Fluor fluorescent conjugates to HER2 were unchanged or minimally affected by the modifications. Pharmacokinetics and biodistribution studies showed the albumin-binding domain-fused-(ZHER2:342)2-Alexa Fluor 750 conjugate to be an optimal probe for optical imaging of HER2 in vivo. Conclusion Our results suggest that Affibody-Alexa Fluor conjugates may be used as a specific near-infrared probe for the non-invasive semi-quantitative imaging of HER2 expression in vivo. PMID:18559604

Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery

NASA Astrophysics Data System (ADS)

Smith, Bryan Ronain; Ghosn, Eliver Eid Bou; Rallapalli, Harikrishna; Prescher, Jennifer A.; Larson, Timothy; Herzenberg, Leonore A.; Gambhir, Sanjiv Sam

2014-06-01

In cancer imaging, nanoparticle biodistribution is typically visualized in living subjects using `bulk' imaging modalities such as magnetic resonance imaging, computerized tomography and whole-body fluorescence. Accordingly, nanoparticle influx is observed only macroscopically, and the mechanisms by which they target cancer remain elusive. Nanoparticles are assumed to accumulate via several targeting mechanisms, particularly extravasation (leakage into tumour). Here, we show that, in addition to conventional nanoparticle-uptake mechanisms, single-walled carbon nanotubes are almost exclusively taken up by a single immune cell subset, Ly-6Chi monocytes (almost 100% uptake in Ly-6Chi monocytes, below 3% in all other circulating cells), and delivered to the tumour in mice. We also demonstrate that a targeting ligand (RGD) conjugated to nanotubes significantly enhances the number of single-walled carbon nanotube-loaded monocytes reaching the tumour (P < 0.001, day 7 post-injection). The remarkable selectivity of this tumour-targeting mechanism demonstrates an advanced immune-based delivery strategy for enhancing specific tumour delivery with substantial penetration.

A Selective Impairment in Attentional Disengagement from Erotica in Obsessive-Compulsive Disorder

PubMed Central

Olatunji, Bunmi O.; Ciesielski, Bethany G.; Zald, David H.

2011-01-01

Although an attentional bias for threat has been implicated in obsessive-compulsive disorder (OCD), evidence supporting such a bias has been inconsistent. Furthermore, few studies have made distinctions between attentional capture vs. attentional disengagement and the extent to which different emotional content modulates attention in OCD also remains unclear. To address these issues, we examined patients with OCD (n = 30) and controls (n = 30) during an emotional attentional blink paradigm in which participants searched for a target embedded within a series of rapidly presented images. Critically, an erotic, fear, disgust, or neutral distracter image appeared 200 ms or 800 ms before the target. Impaired target detection was observed among OCD patients relative to controls following erotic distracters, but only when presented 800 ms, and not 200 ms, prior to the target, indicating difficulty with attentional disengagement. Difficulty disengaging from erotic images was significantly correlated with OCD symptoms in the full sample but not with symptoms of trait anxiety. These data delineate a specific information processing abnormality in OCD. PMID:21801779

Molecular imaging of photodynamic therapy

NASA Astrophysics Data System (ADS)

Chang, Sung K.; Errabelli, Divya; Rizvi, Imran; Solban, Nicolas; O'Riordan, Katherine; Hasan, Tayyaba

2006-02-01

Recent advances in light sources, detectors and other optical imaging technologies coupled with the development of novel optical contrast agents have enabled real-time, high resolution, in vivo monitoring of molecular targets. Noninvasive monitoring of molecular targets is particularly relevant to photodynamic therapy (PDT), including the delivery of photosensitizer in the treatment site and monitoring of molecular and physiological changes following treatment. Our lab has developed optical imaging technologies to investigate these various aspects of photodynamic therapy (PDT). We used a laser scanning confocal microscope to monitor the pharmacokinetics of various photosensitizers in in vitro as well as ex vivo samples, and developed an intravital fluorescence microscope to monitor photosensitizer delivery in vivo in small animals. A molecular specific contrast agent that targets the vascular endothelial growth factor (VEGF) was developed to monitor the changes in the protein expression following PDT. We were then able to study the physiological changes due to post-treatment VEGF upregulation by quantifying vascular permeability with in vivo imaging.

Biosensing of BCR/ABL fusion gene using an intensity-interrogation surface plasmon resonance imaging system

NASA Astrophysics Data System (ADS)

Wu, Jiangling; Huang, Yu; Bian, Xintong; Li, DanDan; Cheng, Quan; Ding, Shijia

2016-10-01

In this work, a custom-made intensity-interrogation surface plasmon resonance imaging (SPRi) system has been developed to directly detect a specific sequence of BCR/ABL fusion gene in chronic myelogenous leukemia (CML). The variation in the reflected light intensity detected from the sensor chip composed of gold islands array is proportional to the change of refractive index due to the selective hybridization of surface-bound DNA probes with target ssDNA. SPRi measurements were performed with different concentrations of synthetic target DNA sequence. The calibration curve of synthetic target sequence shows a good relationship between the concentration of synthetic target and the change of reflected light intensity. The detection limit of this SPRi measurement could approach 10.29 nM. By comparing SPRi images, the target ssDNA and non-complementary DNA sequence are able to be distinguished. This SPRi system has been applied for assay of BCR/ABL fusion gene extracted from real samples. This nucleic acid-based SPRi biosensor therefore offers an alternative high-effective, high-throughput label-free tool for DNA detection in biomedical research and molecular diagnosis.

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers

PubMed Central

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Noninvasive Imaging of Early Venous Thrombosis by 19F Magnetic Resonance Imaging With Targeted Perfluorocarbon Nanoemulsions.

PubMed

Temme, Sebastian; Grapentin, Christoph; Quast, Christine; Jacoby, Christoph; Grandoch, Maria; Ding, Zhaoping; Owenier, Christoph; Mayenfels, Friederike; Fischer, Jens W; Schubert, Rolf; Schrader, Jürgen; Flögel, Ulrich

2015-04-21

Noninvasive detection of deep venous thrombi and subsequent pulmonary thromboembolism is a serious medical challenge, since both incidences are difficult to identify by conventional ultrasound techniques. Here, we report a novel technique for the sensitive and specific identification of developing thrombi using background-free 19F magnetic resonance imaging, together with α2-antiplasmin peptide (α2AP)-targeted perfluorocarbon nanoemulsions (PFCs) as contrast agent, which is cross-linked to fibrin by active factor XIII. Ligand functionality was ensured by mild coupling conditions using the sterol-based postinsertion technique. Developing thrombi with a diameter<0.8 mm could be visualized unequivocally in the murine inferior vena cava as hot spots in vivo by simultaneous acquisition of anatomic matching 1H and 19F magnetic resonance images at 9.4 T with both excellent signal-to-noise and contrast-to-noise ratios (71±22 and 17±5, respectively). Furthermore, α2AP-PFCs could be successfully applied for the diagnosis of experimentally induced pulmonary thromboembolism. In line with the reported half-life of factor XIIIa, application of α2AP-PFCs>60 minutes after thrombus induction no longer resulted in detectable 19F magnetic resonance imaging signals. Corresponding results were obtained in ex vivo generated human clots. Thus, α2AP-PFCs can visualize freshly developed thrombi that might still be susceptible to pharmacological intervention. Our results demonstrate that 1H/19F magnetic resonance imaging, together with α2AP-PFCs, is a sensitive, noninvasive technique for the diagnosis of acute deep venous thrombi and pulmonary thromboemboli. Furthermore, ligand coupling by the sterol-based postinsertion technique represents a unique platform for the specific targeting of PFCs for in vivo 19F magnetic resonance imaging. © 2015 American Heart Association, Inc.

Microbubble Compositions, Properties and Biomedical Applications

PubMed Central

Sirsi, Shashank

2010-01-01

Over the last decade, there has been significant progress towards the development of microbubbles as theranostics for a wide variety of biomedical applications. The unique ability of microbubbles to respond to ultrasound makes them useful agents for contrast ultrasound imaging, molecular imaging, and targeted drug and gene delivery. The general composition of a microbubble is a gas core stabilized by a shell comprised of proteins, lipids or polymers. Each type of microbubble has its own unique advantages and can be tailored for specialized functions. In this review, different microbubbles compositions and physiochemical properties are discussed in the context of current progress towards developing novel constructs for biomedical applications, with specific emphasis on molecular imaging and targeted drug/gene delivery. PMID:20574549

Radiolabeled inorganic nanoparticles for positron emission tomography imaging of cancer: an overview

PubMed Central

CHAKRAVARTY, Rubel; GOEL, Shreya; DASH, Ashutosh; CAI, Weibo

2017-01-01

Over the last few years, a plethora of radiolabeled inorganic nanoparticles have been developed and evaluated for their potential use as probes in positron emission tomography (PET) imaging of a wide variety of cancers. Inorganic nanoparticles represent an emerging paradigm in molecular imaging probe design, allowing the incorporation of various imaging modalities, targeting ligands, and therapeutic payloads into a single vector. A major challenge in this endeavor is to develop disease-specific nanoparticles with facile and robust radiolabeling strategies. Also, the radiolabeled nanoparticles should demonstrate adequate in vitro and in vivo stability, enhanced sensitivity for detection of disease at an early stage, optimized in vivo pharmacokinetics for reduced non-specific organ uptake, and improved targeting for achieving high efficacy. Owing to these challenges and other technological and regulatory issues, only a single radiolabeled nanoparticle formulation, namely “C-dots” (Cornell dots), has found its way into clinical trials thus far. This review describes the available options for radiolabeling of nanoparticles and summarizes the recent developments in PET imaging of cancer in preclinical and clinical settings using radiolabeled nanoparticles as probes. The key considerations toward clinical translation of these novel PET imaging probes are discussed, which will be beneficial for advancement of the field. PMID:28124549

Echographic imaging of tumoral cells through novel nanosystems for image diagnosis

PubMed Central

Di Paola, Marco; Chiriacò, Fernanda; Soloperto, Giulia; Conversano, Francesco; Casciaro, Sergio

2014-01-01

Since the recognition of disease molecular basis, it has become clear that the keystone moments of medical practice, namely early diagnosis, appropriate therapeutic treatment and patient follow-up, must be approached at a molecular level. These objectives will be in the near future more effectively achievable thanks to the impressive developments in nanotechnologies and their applications to the biomedical field, starting-up the nanomedicine era. The continuous advances in the development of biocompatible smart nanomaterials, in particular, will be crucial in several aspects of medicine. In fact, the possibility of manufacturing nanoparticle contrast agents that can be selectively targeted to specific pathological cells has extended molecular imaging applications to non-ionizing techniques and, at the same time, has made reachable the perspective of combining highly accurate diagnoses and personalized therapies in a single theranostic intervention. Main developing applications of nanosized theranostic agents include targeted molecular imaging, controlled drug release, therapeutic monitoring, guidance of radiation-based treatments and surgical interventions. Here we will review the most recent findings in nanoparticles contrast agents and their applications in the field of cancer molecular imaging employing non-ionizing techniques and disease-specific contrast agents, with special focus on recent findings on those nanomaterials particularly promising for ultrasound molecular imaging and simultaneous treatment of cancer. PMID:25071886

Enabling automated magnetic resonance imaging-based targeting assessment during dipole field navigation

NASA Astrophysics Data System (ADS)

Latulippe, Maxime; Felfoul, Ouajdi; Dupont, Pierre E.; Martel, Sylvain

2016-02-01

The magnetic navigation of drugs in the vascular network promises to increase the efficacy and reduce the secondary toxicity of cancer treatments by targeting tumors directly. Recently, dipole field navigation (DFN) was proposed as the first method achieving both high field and high navigation gradient strengths for whole-body interventions in deep tissues. This is achieved by introducing large ferromagnetic cores around the patient inside a magnetic resonance imaging (MRI) scanner. However, doing so distorts the static field inside the scanner, which prevents imaging during the intervention. This limitation constrains DFN to open-loop navigation, thus exposing the risk of a harmful toxicity in case of a navigation failure. Here, we are interested in periodically assessing drug targeting efficiency using MRI even in the presence of a core. We demonstrate, using a clinical scanner, that it is in fact possible to acquire, in specific regions around a core, images of sufficient quality to perform this task. We show that the core can be moved inside the scanner to a position minimizing the distortion effect in the region of interest for imaging. Moving the core can be done automatically using the gradient coils of the scanner, which then also enables the core to be repositioned to perform navigation to additional targets. The feasibility and potential of the approach are validated in an in vitro experiment demonstrating navigation and assessment at two targets.

Up Periscope! Designing a New Perceptual Metric for Imaging System Performance

NASA Technical Reports Server (NTRS)

Watson, Andrew B.

2016-01-01

Modern electronic imaging systems include optics, sensors, sampling, noise, processing, compression, transmission and display elements, and are viewed by the human eye. Many of these elements cannot be assessed by traditional imaging system metrics such as the MTF. More complex metrics such as NVTherm do address these elements, but do so largely through parametric adjustment of an MTF-like metric. The parameters are adjusted through subjective testing of human observers identifying specific targets in a set of standard images. We have designed a new metric that is based on a model of human visual pattern classification. In contrast to previous metrics, ours simulates the human observer identifying the standard targets. One application of this metric is to quantify performance of modern electronic periscope systems on submarines.

PSMA-PET based radiotherapy: a review of initial experiences, survey on current practice and future perspectives.

PubMed

Zschaeck, Sebastian; Lohaus, Fabian; Beck, Marcus; Habl, Gregor; Kroeze, Stephanie; Zamboglou, Constantinos; Koerber, Stefan Alexander; Debus, Jürgen; Hölscher, Tobias; Wust, Peter; Ganswindt, Ute; Baur, Alexander D J; Zöphel, Klaus; Cihoric, Nikola; Guckenberger, Matthias; Combs, Stephanie E; Grosu, Anca Ligia; Ghadjar, Pirus; Belka, Claus

2018-05-11

68 Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography (PET) is an increasingly used imaging modality in prostate cancer, especially in cases of tumor recurrence after curative intended therapy. Owed to the novelty of the PSMA-targeting tracers, clinical evidence on the value of PSMA-PET is moderate but rapidly increasing. State of the art imaging is pivotal for radiotherapy treatment planning as it may affect dose prescription, target delineation and use of concomitant therapy.This review summarizes the evidence on PSMA-PET imaging from a radiation oncologist's point of view. Additionally a short survey containing twelve examples of patients and 6 additional questions was performed in seven mayor academic centers with experience in PSMA ligand imaging and the findings are reported here.

PTBS segmentation scheme for synthetic aperture radar

NASA Astrophysics Data System (ADS)

Friedland, Noah S.; Rothwell, Brian J.

1995-07-01

The Image Understanding Group at Martin Marietta Technologies in Denver, Colorado has developed a model-based synthetic aperture radar (SAR) automatic target recognition (ATR) system using an integrated resource architecture (IRA). IRA, an adaptive Markov random field (MRF) environment, utilizes information from image, model, and neighborhood resources to create a discrete, 2D feature-based world description (FBWD). The IRA FBWD features are peak, target, background and shadow (PTBS). These features have been shown to be very useful for target discrimination. The FBWD is used to accrue evidence over a model hypothesis set. This paper presents the PTBS segmentation process utilizing two IRA resources. The image resource (IR) provides generic (the physics of image formation) and specific (the given image input) information. The neighborhood resource (NR) provides domain knowledge of localized FBWD site behaviors. A simulated annealing optimization algorithm is used to construct a `most likely' PTBS state. Results on simulated imagery illustrate the power of this technique to correctly segment PTBS features, even when vehicle signatures are immersed in heavy background clutter. These segmentations also suppress sidelobe effects and delineate shadows.

Self-presentational persona: simultaneous management of multiple impressions.

PubMed

Leary, Mark R; Allen, Ashley Batts

2011-11-01

Most research on self-presentation has examined how people convey images of themselves on only 1 or 2 dimensions at a time. In everyday interactions, however, people often manage their impressions on several image-relevant dimensions simultaneously. By examining people's self-presentations to several targets across multiple dimensions, these 2 studies offer new insights into the nature of self-presentation and provide a novel paradigm for studying impression management. Results showed that most people rely on a relatively small number of basic self-presentational personas in which they convey particular profiles of impressions as a set and that these personas reflect both normative influences to project images that are appropriate to a particular target and distinctive influences by which people put an idiosyncratic spin on these normative images. Furthermore, although people's self-presentational profiles correlate moderately with their self-views, they tailor their public images to specific targets. The degree to which participants' self-presentations were normative and distinctive, as well as the extent to which they reflected their own self-views, were moderated by individual differences in agreeableness, self-esteem, authenticity, and Machiavellianism.

PH-sensitive fluorescence detection by diffuse fluorescence tomography

NASA Astrophysics Data System (ADS)

Li, Jiao; Gao, Feng; Duan, Linjing; Wang, Xin; Zhang, Limin; Zhao, Huijuan

2012-03-01

The importance of cellular pH has been shown clearly in the study of cell activity, pathological feature, drug metabolism, etc. Monitoring pH changes of living cells and imaging the regions with abnormal pH values in vivo could provide the physiologic and pathologic information for the research of the cell biology, pharmacokinetics, diagnostics and therapeutics of certain diseases such as cancer. Thus, pH-sensitive fluorescence imaging of bulk tissues has been attracting great attention in the regime of near-infrared diffuse fluorescence tomography (DFT), an efficient small-animal imaging tool. In this paper, the feasibility of quantifying pH-sensitive fluorescence targets in turbid medium is investigated using both time-domain and steady-state DFT methods. By use of the specifically designed time-domain and continuous-wave systems and the previously proposed image reconstruction scheme, we validate the method through 2-dimensional imaging experiments on a small-animal-sized phantom with multiply targets of distinct pH values. The results show that the approach can localize the targets with reasonable accuracy and achieve quantitative reconstruction of the pH-sensitive fluorescent yield.

Acoustical imaging of high-frequency elastic responses of targets

NASA Astrophysics Data System (ADS)

Morse, Scot F.; Hefner, Brian T.; Marston, Philip L.

2002-05-01

Acoustical imaging was used to investigate high-frequency elastic responses to sound of two targets in water. The backscattering of broadband bipolar acoustic pulses by a truncated cylindrical shell was recorded over a wide range of tilt angles [S. F. Morse and P. L. Marston, ``Backscattering of transients by tilted truncated cylindrical shells: time-frequency identification of ray contributions from measurements,'' J. Acoust. Soc. Am. (in press)]. This data set was used to form synthetic aperture images of the target based on the data within different angular apertures. Over a range of viewing angles, the visibility of the cylinder's closest rear corner was significantly enhanced by the meridional flexural wave contribution to the backscattering. In another experiment, the time evolution of acoustic holographic images was used to explore the response of tilted elastic circular disks to tone bursts having frequencies of 250 and 300 kHz. For different tilt angles, specific responses that enhance the backscattering were identified from the time evolution of the images [B. T. Hefner and P. L. Marston, Acoust. Res. Lett. Online 2, 55-60 (2001)]. [Work supported by ONR.

Real-time non-rigid target tracking for ultrasound-guided clinical interventions

NASA Astrophysics Data System (ADS)

Zachiu, C.; Ries, M.; Ramaekers, P.; Guey, J.-L.; Moonen, C. T. W.; de Senneville, B. Denis

2017-10-01

Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of  ˜1.5 mm and submillimeter precision. This, together with a computational performance of 20 images per second make the proposed method an attractive solution for real-time target tracking during US-guided clinical interventions.

Real-time non-rigid target tracking for ultrasound-guided clinical interventions.

PubMed

Zachiu, C; Ries, M; Ramaekers, P; Guey, J-L; Moonen, C T W; de Senneville, B Denis

2017-10-04

Biological motion is a problem for non- or mini-invasive interventions when conducted in mobile/deformable organs due to the targeted pathology moving/deforming with the organ. This may lead to high miss rates and/or incomplete treatment of the pathology. Therefore, real-time tracking of the target anatomy during the intervention would be beneficial for such applications. Since the aforementioned interventions are often conducted under B-mode ultrasound (US) guidance, target tracking can be achieved via image registration, by comparing the acquired US images to a separate image established as positional reference. However, such US images are intrinsically altered by speckle noise, introducing incoherent gray-level intensity variations. This may prove problematic for existing intensity-based registration methods. In the current study we address US-based target tracking by employing the recently proposed EVolution registration algorithm. The method is, by construction, robust to transient gray-level intensities. Instead of directly matching image intensities, EVolution aligns similar contrast patterns in the images. Moreover, the displacement is computed by evaluating a matching criterion for image sub-regions rather than on a point-by-point basis, which typically provides more robust motion estimates. However, unlike similar previously published approaches, which assume rigid displacements in the image sub-regions, the EVolution algorithm integrates the matching criterion in a global functional, allowing the estimation of an elastic dense deformation. The approach was validated for soft tissue tracking under free-breathing conditions on the abdomen of seven healthy volunteers. Contact echography was performed on all volunteers, while three of the volunteers also underwent standoff echography. Each of the two modalities is predominantly specific to a particular type of non- or mini-invasive clinical intervention. The method demonstrated on average an accuracy of  ∼1.5 mm and submillimeter precision. This, together with a computational performance of 20 images per second make the proposed method an attractive solution for real-time target tracking during US-guided clinical interventions.

Can we develop pathology-specific MRI contrast for "MR-negative" epilepsy?

PubMed

Feindel, Kirk W

2013-05-01

Recent improvements in magnetic resonance imaging (MRI) hardware, software, and analysis routines are helping to put cases of "MR-negative" epilepsy on the decline. However, most standard-of-care MRI relies on careful manipulation and presentation of T1, T2, and diffusion-weighted contrast, which characterize the behavior of water in "bulk" tissue rather than providing pathology-specific contrast. Research efforts in MR physics continue to identify and develop novel theory, and methods such as diffusional kurtosis imaging (DKI) and temporal diffusion spectroscopy that can better characterize tissue substructure, and chemical exchange saturation transfer (CEST) that can target underlying biochemical processes. The potential role of each technique in targeting pathologies implicated in "MR-negative" epilepsy is outlined herein. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

The new frontiers of multimodality and multi-isotope imaging

NASA Astrophysics Data System (ADS)

Behnam Azad, Babak; Nimmagadda, Sridhar

2014-06-01

Technological advances in imaging systems and the development of target specific imaging tracers has been rapidly growing over the past two decades. Recent progress in "all-in-one" imaging systems that allow for automated image coregistration has significantly added to the growth of this field. These developments include ultra high resolution PET and SPECT scanners that can be integrated with CT or MR resulting in PET/CT, SPECT/CT, SPECT/PET and PET/MRI scanners for simultaneous high resolution high sensitivity anatomical and functional imaging. These technological developments have also resulted in drastic enhancements in image quality and acquisition time while eliminating cross compatibility issues between modalities. Furthermore, the most cutting edge technology, though mostly preclinical, also allows for simultaneous multimodality multi-isotope image acquisition and image reconstruction based on radioisotope decay characteristics. These scientific advances, in conjunction with the explosion in the development of highly specific multimodality molecular imaging agents, may aid in realizing simultaneous imaging of multiple biological processes and pave the way towards more efficient diagnosis and improved patient care.

Highly specific spectroscopic photoacoustic molecular imaging of dynamic optical absorption shifts of an antibody-ICG contrast agent (Conference Presentation)

NASA Astrophysics Data System (ADS)

Wilson, Katheryne E.; Bachawal, Sunitha; Abou-Elkacem, Lotfi; Jensen, Kristen C.; Machtaler, Steven; Tian, Lu; Willmann, Juergen K.

2017-03-01

Improved techniques for breast cancer screening are critically needed as current methods lack diagnostic accuracy. Using spectroscopic photoacoustic (sPA) molecular imaging with a priori knowledge of optical absorption spectra allows suppression of endogenous background signal, increasing the overall sensitivity and specificity of the modality to exogenous contrast agents. Here, sPA imaging was used to monitor antibody-indocyanine green (ICG) conjugates as they undergo optical absorption spectrum shifts after cellular endocytosis and degradation to allow differentiation between normal murine mammary glands from breast cancer by enhancing molecular imaging signal from target (B7-H3)-bound antibody-ICG. First, B7-H3 was shown to have highly specific (AUC of 0.93) expression on both vascular endothelium and tumor stroma in malignant lesions through quantitative immunohistochemical staining of B7-H3 on 279 human samples (normal (n=53), benign lesions (11 subtypes, n=182), breast cancers (4 subtypes, n=97)), making B7-H3 a promising target for sPA imaging. Second, absorption spectra of intracellular and degraded B7-H3-ICG and Isotype control (Iso-ICG) were characterized through in vitro and in vivo experiments. Finally, a transgenic murine breast cancer model (FVB/N-Tg(MMTVPyMT)634Mul) was imaged, and sPA imaging in found a 3.01 (IQR 2.63, 3.38, P<0.001) fold increase in molecular B7-H3-ICG signal in tumors (n=80) compared to control conditions (B7-H3-ICG in tumor negative animals (n=60), Iso-ICG (n=30), blocking B7-H3+B7-H3-ICG (n=20), and free ICG (n=20)) despite significant tumor accumulation of Iso-ICG, confirmed through ex vivo histology. Overall, leveraging anti-B7-H3 antibody-ICG contrast agents, which have dynamic optical absorption spectra representative of molecular interactions, allows for highly specific sPA imaging of murine breast cancer.

Multimodality Imaging with Silica-Based Targeted Nanoparticle Platforms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jason S. Lewis

2012-04-09

Objectives: To synthesize and characterize a C-Dot silica-based nanoparticle containing 'clickable' groups for the subsequent attachment of targeting moieties (e.g., peptides) and multiple contrast agents (e.g., radionuclides with high specific activity) [1,2]. These new constructs will be tested in suitable tumor models in vitro and in vivo to ensure maintenance of target-specificity and high specific activity. Methods: Cy5 dye molecules are cross-linked to a silica precursor which is reacted to form a dye-rich core particle. This core is then encapsulated in a layer of pure silica to create the core-shell C-Dot (Figure 1) [2]. A 'click' chemistry approach has beenmore » used to functionalize the silica shell with radionuclides conferring high contrast and specific activity (e.g. 64Cu and 89Zr) and peptides for tumor targeting (e.g. cRGD and octreotate) [3]. Based on the selective Diels-Alder reaction between tetrazine and norbornene, the reaction is bioorthogonal, highyielding, rapid, and water-compatible. This radiolabeling approach has already been employed successfully with both short peptides (e.g. octreotate) and antibodies (e.g. trastuzumab) as model systems for the ultimate labeling of the nanoparticles [1]. Results: PEGylated C-Dots with a Cy5 core and labeled with tetrazine have been synthesized (d = 55 nm, zeta potential = -3 mV) reliably and reproducibly and have been shown to be stable under physiological conditions for up to 1 month. Characterization of the nanoparticles revealed that the immobilized Cy5 dye within the C-Dots exhibited fluorescence intensities over twice that of the fluorophore alone. The nanoparticles were successfully radiolabeled with Cu-64. Efforts toward the conjugation of targeting peptides (e.g. cRGD) are underway. In vitro stability, specificity, and uptake studies as well as in vivo imaging and biodistribution investigations will be presented. Conclusions: C-Dot silica-based nanoparticles offer a robust, versatile, and multi-functional platform to enhance in vivo detection sensitivity and non-invasively assay receptor expression/status of tumor cellular targets, including those of low abundance, using nuclear-NIR fluorescence imaging approaches [2]. Improvements in molecular diagnostics, refined by the availability of nanotechnology platforms, will be a key determinant in driving early-stage disease detection and prevention, ultimately leading to decreases in mortality.« less

Extended morphological processing: a practical method for automatic spot detection of biological markers from microscopic images.

PubMed

Kimori, Yoshitaka; Baba, Norio; Morone, Nobuhiro

2010-07-08

A reliable extraction technique for resolving multiple spots in light or electron microscopic images is essential in investigations of the spatial distribution and dynamics of specific proteins inside cells and tissues. Currently, automatic spot extraction and characterization in complex microscopic images poses many challenges to conventional image processing methods. A new method to extract closely located, small target spots from biological images is proposed. This method starts with a simple but practical operation based on the extended morphological top-hat transformation to subtract an uneven background. The core of our novel approach is the following: first, the original image is rotated in an arbitrary direction and each rotated image is opened with a single straight line-segment structuring element. Second, the opened images are unified and then subtracted from the original image. To evaluate these procedures, model images of simulated spots with closely located targets were created and the efficacy of our method was compared to that of conventional morphological filtering methods. The results showed the better performance of our method. The spots of real microscope images can be quantified to confirm that the method is applicable in a given practice. Our method achieved effective spot extraction under various image conditions, including aggregated target spots, poor signal-to-noise ratio, and large variations in the background intensity. Furthermore, it has no restrictions with respect to the shape of the extracted spots. The features of our method allow its broad application in biological and biomedical image information analysis.

Imaging efficacy of a targeted imaging agent for fluorescence endoscopy

NASA Astrophysics Data System (ADS)

Healey, A. J.; Bendiksen, R.; Attramadal, T.; Bjerke, R.; Waagene, S.; Hvoslef, A. M.; Johannesen, E.

2008-02-01

Colorectal cancer is a major cause of cancer death. A significant unmet clinical need exists in the area of screening for earlier and more accurate diagnosis and treatment. We have identified a fluorescence imaging agent targeted to an early stage molecular marker for colorectal cancer. The agent is administered intravenously and imaged in a far red imaging channel as an adjunct to white light endoscopy. There is experimental evidence of preclinical proof of mechanism for the agent. In order to assess potential clinical efficacy, imaging was performed with a prototype fluorescence endoscope system designed to produce clinically relevant images. A clinical laparoscope system was modified for fluorescence imaging. The system was optimised for sensitivity. Images were recorded at settings matching those expected with a clinical endoscope implementation (at video frame rate operation). The animal model was comprised of a HCT-15 xenograft tumour expressing the target at concentration levels expected in early stage colorectal cancer. Tumours were grown subcutaneously. The imaging agent was administered intravenously at a dose of 50nmol/kg body weight. The animals were killed 2 hours post administration and prepared for imaging. A 3-4mm diameter, 1.6mm thick slice of viable tumour was placed over the opened colon and imaged with the laparoscope system. A receiver operator characteristic analysis was applied to imaging results. An area under the curve of 0.98 and a sensitivity of 87% [73, 96] and specificity of 100% [93, 100] were obtained.

Mucin-1-Antibody-Conjugated Mesoporous Silica Nanoparticles for Selective Breast Cancer Detection in a Mucin-1 Transgenic Murine Mouse Model.

PubMed

Dréau, Didier; Moore, Laura Jeffords; Alvarez-Berrios, Merlis P; Tarannum, Mubin; Mukherjee, Pinku; Vivero-Escoto, Juan L

2016-12-01

Mucin-1 (MUC1), a transmembrane glycoprotein is aberrantly expressed on ~90% of breast cancer and is an excellent target for nanoparticulate targeted imaging. In this study, the development of a dye-doped NIR emitting mesoporous silica nanoparticles platform conjugated to tumor-specific MUC1 antibody (ab-tMUC1-NIR-MSN) for in vivo optical detection of breast adenocarcinoma tissue is reported. The structural properties, the in vitro and in vivo performance of this nanoparticle-based probe were evaluated. In vitro studies showed that the MSN-based optical imaging nanoprobe is non-cytotoxic and targets efficiently mammary cancer cells overexpressing human tMUC1 protein. In vivo experiments with female C57BL/6 mice indicated that this platform accumulates mainly in the liver and did not induce short-term toxicity. In addition, we demonstrated that the ab-tMUC1-NIR-MSN nanoprobe specifically detects mammary gland tumors overexpressing human tMUC1 in a human MUC1 transgenic mouse model.

Proceedings of the Open Sessions of the Workshop on Imaging Trackers and Autonomous Acquisition Applications for Missile Guidance Held at Redstone Arsenal, Alabama on 19-20 November 1979

DTIC Science & Technology

1979-11-01

a generalized cooccurrence matrix. Describing image texture is an important problem in the design of image understanding systems . Applications as...display system design optimization and video signal processing. Based on a study by Southern Research Institute , a number of options were identified...Specification for Target Acquisition Designation System (U), RFP # AMC-DP-AAH-H4020, i2 Apr 77. 4. Terminal Homing Applications of Solid State Image

Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging

PubMed Central

Zhang, Liang; Thurber, Greg M.

2016-01-01

Purpose Quantitative molecular imaging of beta cell mass (BCM) would enable early detection and treatment monitoring of type-1 diabetes. The glucagon like peptide-1 (GLP-1) receptor is an attractive target due to its beta cell specificity and cell surface location. We quantitatively investigated the impact of plasma clearance and receptor internalization on targeting efficiency in healthy B6 mice. Procedures Four exenatide-based probes were synthesized that varied in molecular weight, binding affinity, and plasma clearance. The GLP-1 receptor internalization rate and in vivo receptor expression were quantified. Results Receptor internalization (54,000 receptors/cell in vivo) decreased significantly within minutes, reducing the benefit of a slower clearing agent. The multimers and albumin binding probes had higher kidney and liver uptake, respectively. Conclusions Slow plasma clearance is beneficial for GLP-1 receptor peptide therapeutics. However, for exendin-based imaging of islets, downregulation of the GLP-1 receptor and non-specific background uptake result in a higher TBR for fast-clearing agents. PMID:26194012

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

PubMed

Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

Optimized computational imaging methods for small-target sensing in lens-free holographic microscopy

NASA Astrophysics Data System (ADS)

Xiong, Zhen; Engle, Isaiah; Garan, Jacob; Melzer, Jeffrey E.; McLeod, Euan

2018-02-01

Lens-free holographic microscopy is a promising diagnostic approach because it is cost-effective, compact, and suitable for point-of-care applications, while providing high resolution together with an ultra-large field-of-view. It has been applied to biomedical sensing, where larger targets like eukaryotic cells, bacteria, or viruses can be directly imaged without labels, and smaller targets like proteins or DNA strands can be detected via scattering labels like micro- or nano-spheres. Automated image processing routines can count objects and infer target concentrations. In these sensing applications, sensitivity and specificity are critically affected by image resolution and signal-to-noise ratio (SNR). Pixel super-resolution approaches have been shown to boost resolution and SNR by synthesizing a high-resolution image from multiple, partially redundant, low-resolution images. However, there are several computational methods that can be used to synthesize the high-resolution image, and previously, it has been unclear which methods work best for the particular case of small-particle sensing. Here, we quantify the SNR achieved in small-particle sensing using regularized gradient-descent optimization method, where the regularization is based on cardinal-neighbor differences, Bayer-pattern noise reduction, or sparsity in the image. In particular, we find that gradient-descent with sparsity-based regularization works best for small-particle sensing. These computational approaches were evaluated on images acquired using a lens-free microscope that we assembled from an off-the-shelf LED array and color image sensor. Compared to other lens-free imaging systems, our hardware integration, calibration, and sample preparation are particularly simple. We believe our results will help to enable the best performance in lens-free holographic sensing.

Structure-activity relationships of succinimidyl-Cys-C(O)-Glu derivatives with different near-infrared fluorophores as optical imaging probes for prostate-specific membrane antigen.

PubMed

Matsuoka, Daiko; Watanabe, Hiroyuki; Shimizu, Yoichi; Kimura, Hiroyuki; Yagi, Yusuke; Kawai, Ryoko; Ono, Masahiro; Saji, Hideo

2018-05-15

Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure-activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold. Copyright © 2018 Elsevier Ltd. All rights reserved.

Multiple-Targeted Graphene-based Nanocarrier for Intracellular Imaging of mRNAs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Ying; Li, Zhaohui; Liu, Misha

Simultaneous detection and imaging of multiple intracellular messenger RNA (mRNAs) hold great significant for early cancer diagnostics and preventive medicine development. Herein, we propose a multiple-targeted graphene oxide (GO) nanocarrier that can simultaneously detect and image different type mRNAs in living cells. First of all, in vitro detection of multiple targets have been realized successfully based on the multiple-targeted GO nanocarrier with linear relationship ranging from 3 nM to 200 nM, as well as sensitive detection limit of 1.84 nM for manganese superoxide dismutase (Mn-SOD) mRNA and 2.45 nM for β-actin mRNA. Additionally, this nanosensing platform composed of fluorescent labeledmore » single strand DNA probes and GO nanocarrier can identify Mn-SOD mRNA and endogenous mRNA of β-actin in living cancer cells, showing rapid response, high specificity, nuclease stability, and good biocompatibility during the cell imaging. Thirdly, changes of the expression levels of mRNA in living cells before or after the drug treatment can be monitored successfully. By using multiple ssDNA as probes and GO nanocarrier as the cellular delivery cargo, the proposed simultaneous multiple-targeted sensing platform will be of great potential as a powerful tool for intracellular trafficking process from basic research to clinical diagnosis.« less

Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle

PubMed Central

Dekempeneer, Yana; Keyaerts, Marleen; Krasniqi, Ahmet; Puttemans, Janik; Muyldermans, Serge; Lahoutte, Tony; D’huyvetter, Matthias; Devoogdt, Nick

2016-01-01

ABSTRACT Introduction: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue. Areas covered: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT. Expert opinion: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies’ pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease. PMID:27145158

RGD-conjugated iron oxide magnetic nanoparticles for magnetic resonance imaging contrast enhancement and hyperthermia.

PubMed

Zheng, S W; Huang, M; Hong, R Y; Deng, S M; Cheng, L F; Gao, B; Badami, D

2014-03-01

The purpose of this study was to develop a specific targeting magnetic nanoparticle probe for magnetic resonance imaging and therapy in the form of local hyperthermia. Carboxymethyl dextran-coated ultrasmall superparamagnetic iron oxide nanoparticles with carboxyl groups were coupled to cyclic arginine-glycine-aspartic peptides for integrin α(v)β₃ targeting. The particle size, magnetic properties, heating effect, and stability of the arginine-glycine-aspartic-ultrasmall superparamagnetic iron oxide were measured. The arginine-glycine-aspartic-ultrasmall superparamagnetic iron oxide demonstrates excellent stability and fast magneto-temperature response. Magnetic resonance imaging signal intensity of Bcap37 cells incubated with arginine-glycine-aspartic-ultrasmall superparamagnetic iron oxide was significantly decreased compared with that incubated with plain ultrasmall superparamagnetic iron oxide. The preferential uptake of arginine-glycine-aspartic-ultrasmall superparamagnetic iron oxide by target cells was further confirmed by Prussian blue staining and confocal laser scanning microscopy.

Nanodiamond Landmarks for Subcellular Multimodal Optical and Electron Imaging

PubMed Central

Zurbuchen, Mark A.; Lake, Michael P.; Kohan, Sirus A.; Leung, Belinda; Bouchard, Louis-S.

2013-01-01

There is a growing need for biolabels that can be used in both optical and electron microscopies, are non-cytotoxic, and do not photobleach. Such biolabels could enable targeted nanoscale imaging of sub-cellular structures, and help to establish correlations between conjugation-delivered biomolecules and function. Here we demonstrate a sub-cellular multi-modal imaging methodology that enables localization of inert particulate probes, consisting of nanodiamonds having fluorescent nitrogen-vacancy centers. These are functionalized to target specific structures, and are observable by both optical and electron microscopies. Nanodiamonds targeted to the nuclear pore complex are rapidly localized in electron-microscopy diffraction mode to enable “zooming-in” to regions of interest for detailed structural investigations. Optical microscopies reveal nanodiamonds for in-vitro tracking or uptake-confirmation. The approach is general, works down to the single nanodiamond level, and can leverage the unique capabilities of nanodiamonds, such as biocompatibility, sensitive magnetometry, and gene and drug delivery. PMID:24036840

Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands.

PubMed

Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M

2015-02-18

Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel α-helix-stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enable this technique to potentially be used as a general method for labeling α helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents.

A Dual-Purpose Linker for Alpha Helix Stabilization and Imaging Agent Conjugation to Glucagon-Like Peptide-1 Receptor Ligands

PubMed Central

Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M.

2016-01-01

Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using the glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel alpha helix stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enables this technique to potentially be used as a general method for labeling alpha helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents. PMID:25594741

Multi-Stage System for Automatic Target Recognition

NASA Technical Reports Server (NTRS)

Chao, Tien-Hsin; Lu, Thomas T.; Ye, David; Edens, Weston; Johnson, Oliver

2010-01-01

A multi-stage automated target recognition (ATR) system has been designed to perform computer vision tasks with adequate proficiency in mimicking human vision. The system is able to detect, identify, and track targets of interest. Potential regions of interest (ROIs) are first identified by the detection stage using an Optimum Trade-off Maximum Average Correlation Height (OT-MACH) filter combined with a wavelet transform. False positives are then eliminated by the verification stage using feature extraction methods in conjunction with neural networks. Feature extraction transforms the ROIs using filtering and binning algorithms to create feature vectors. A feedforward back-propagation neural network (NN) is then trained to classify each feature vector and to remove false positives. The system parameter optimizations process has been developed to adapt to various targets and datasets. The objective was to design an efficient computer vision system that can learn to detect multiple targets in large images with unknown backgrounds. Because the target size is small relative to the image size in this problem, there are many regions of the image that could potentially contain the target. A cursory analysis of every region can be computationally efficient, but may yield too many false positives. On the other hand, a detailed analysis of every region can yield better results, but may be computationally inefficient. The multi-stage ATR system was designed to achieve an optimal balance between accuracy and computational efficiency by incorporating both models. The detection stage first identifies potential ROIs where the target may be present by performing a fast Fourier domain OT-MACH filter-based correlation. Because threshold for this stage is chosen with the goal of detecting all true positives, a number of false positives are also detected as ROIs. The verification stage then transforms the regions of interest into feature space, and eliminates false positives using an artificial neural network classifier. The multi-stage system allows tuning the detection sensitivity and the identification specificity individually in each stage. It is easier to achieve optimized ATR operation based on its specific goal. The test results show that the system was successful in substantially reducing the false positive rate when tested on a sonar and video image datasets.

Neural images of pursuit targets in the photoreceptor arrays of male and female houseflies Musca domestica.

PubMed

Burton, Brian G; Laughlin, Simon B

2003-11-01

Male houseflies use a sex-specific frontal eye region, the lovespot, to detect and pursue mates. We recorded the electrical responses of photoreceptors to optical stimuli that simulate the signals received by a male or female photoreceptor as a conspecific passes through its field of view. We analysed the ability of male and female frontal photoreceptors to code conspecifics over the range of speeds and distances encountered during pursuit, and reconstructed the neural images of these targets in photoreceptor arrays. A male's lovespot photoreceptor detects a conspecific at twice the distance of a female photoreceptor, largely through better optics. This detection distance greatly exceeds those reported in previous behavioural studies. Lovespot photoreceptors respond more strongly than female photoreceptors to targets tracked during pursuit, with amplitudes reaching 25 mV. The male photoreceptor also has a faster response, exhibits a unique preference for stimuli of 20-30 ms duration that selects for conspecifics and deblurs moving images with response transients. White-noise analysis substantially underestimates these improvements. We conclude that in the lovespot, both optics and phototransduction are specialised to enhance and deblur the neural images of moving targets, and propose that analogous mechanisms may sharpen the neural image still further as it is transferred to visual interneurones.

Sparsity based target detection for compressive spectral imagery

NASA Astrophysics Data System (ADS)

Boada, David Alberto; Arguello Fuentes, Henry

2016-09-01

Hyperspectral imagery provides significant information about the spectral characteristics of objects and materials present in a scene. It enables object and feature detection, classification, or identification based on the acquired spectral characteristics. However, it relies on sophisticated acquisition and data processing systems able to acquire, process, store, and transmit hundreds or thousands of image bands from a given area of interest which demands enormous computational resources in terms of storage, computationm, and I/O throughputs. Specialized optical architectures have been developed for the compressed acquisition of spectral images using a reduced set of coded measurements contrary to traditional architectures that need a complete set of measurements of the data cube for image acquisition, dealing with the storage and acquisition limitations. Despite this improvement, if any processing is desired, the image has to be reconstructed by an inverse algorithm in order to be processed, which is also an expensive task. In this paper, a sparsity-based algorithm for target detection in compressed spectral images is presented. Specifically, the target detection model adapts a sparsity-based target detector to work in a compressive domain, modifying the sparse representation basis in the compressive sensing problem by means of over-complete training dictionaries and a wavelet basis representation. Simulations show that the presented method can achieve even better detection results than the state of the art methods.

Folate-bovine serum albumin functionalized polymeric micelles loaded with superparamagnetic iron oxide nanoparticles for tumor targeting and magnetic resonance imaging.

PubMed

Li, Huan; Yan, Kai; Shang, Yalei; Shrestha, Lochan; Liao, Rufang; Liu, Fang; Li, Penghui; Xu, Haibo; Xu, Zushun; Chu, Paul K

2015-03-01

Polymeric micelles functionalized with folate conjugated bovine serum albumin (FA-BSA) and loaded with superparamagnetic iron oxide nanoparticles (SPIONs) are investigated as a specific contrast agent for tumor targeting and magnetic resonance imaging (MRI) in vitro and in vivo. The SPIONs-loaded polymeric micelles are produced by self-assembly of amphiphilic poly(HFMA-co-MOTAC)-g-PEGMA copolymers and oleic acid modified Fe3O4 nanoparticles and functionalized with FA-BSA by electrostatic interaction. The FA-BSA modified magnetic micelles have a hydrodynamic diameter of 196.1 nm, saturation magnetization of 5.5 emu/g, and transverse relaxivity of 167.0 mM(-1) S(-1). In vitro MR imaging, Prussian blue staining, and intracellular iron determination studies demonstrate that the folate-functionalized magnetic micelles have larger cellular uptake against the folate-receptor positive hepatoma cells Bel-7402 than the unmodified magnetic micelles. In vivo MR imaging conducted on nude mice bearing the Bel-7402 xenografts after bolus intravenous administration reveals excellent tumor targeting and MR imaging capabilities, especially at 24h post-injection. These findings suggest the potential of FA-BSA modified magnetic micelles as targeting MRI probe in tumor detection. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Red fluorescent zinc oxide nanoparticle: A novel platform for cancer targeting

DOE PAGES

Hong, Hao; Wang, Fei; Zhang, Yin; ...

2015-01-21

Multifunctional zinc oxide (ZnO) nanoparticles (NPs) with well-integrated multimodality imaging capacities have generated increasing research interest in the past decade. However, limited progress has been made in developing ZnO NP-based multimodality tumor-imaging agents. In this paper, we developed novel red fluorescent ZnO NPs and described the successful conjugation of 64Cu ( t 1/2 = 12.7 h) and TRC105, a chimeric monoclonal antibody against CD105, to these ZnO NPs via well-developed surface engineering procedures. The produced dual-modality ZnO NPs were readily applicable for positron emission tomography (PET) imaging and fluorescence imaging of the tumor vasculature. Their pharmacokinetics and tumor-targeting efficacy/specificity inmore » mice bearing murine breast 4T1 tumor were thoroughly investigated. In conclusion, ZnO NPs with dual-modality imaging properties can serve as an attractive candidate for future cancer theranostics.« less

Quantitative Imaging in Cancer Clinical Trials

PubMed Central

Yankeelov, Thomas E.; Mankoff, David A.; Schwartz, Lawrence H.; Lieberman, Frank S.; Buatti, John M.; Mountz, James M.; Erickson, Bradley J.; Fennessy, Fiona M.M.; Huang, Wei; Kalpathy-Cramer, Jayashree; Wahl, Richard L.; Linden, Hannah M.; Kinahan, Paul; Zhao, Binsheng; Hylton, Nola M.; Gillies, Robert J.; Clarke, Laurence; Nordstrom, Robert; Rubin, Daniel L.

2015-01-01

As anti-cancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. While traditional, anatomic CT and MRI exams are useful in many settings, there is increasing evidence that these methods cannot answer the fundamental biological and physiological questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients, and to provide a more efficient path for the development of improved targeted therapies. PMID:26773162

Ultrasound molecular imaging of acute cellular cardiac allograft rejection in rat with T-cell-specific nanobubbles.

PubMed

Wu, Wei; Zhang, Zhe; Zhuo, Lisha; Zhou, Lina; Liu, Ping; He, Yun; Gao, Yunhua; Li, Rui; Chen, Qinghai; Hua, Xing

2013-09-01

Acute rejection (AR) is one of the main obstacles of cardiac transplantation; however, a noninvasive diagnostic method, which reflects its pathologic nature, has not been developed yet. In this study, we prepared a specific nanobubbles targeting to the activated T cells and applied it in the ultrasound molecular imaging of AR in heart transplantation by myocardial contrast echocardiography (MCE). Nanobubbles loading anti-CD25 antibody (NB(specific)) or isotype control antibody (NB(nonspecific)) were prepared and then applied in the ultrasound molecular imaging by MCE in a rat model. MCE was performed in 24 allografts and 18 isografts that were divided into three groups, including days 2, 4, and 6 after transplantation. Confocal laser scanning microscopy was used to evaluate the binding of nanobubbles and T cells in four allografts and four isografts. MCE with NB(specific) in allograft showed a "delayed enhancement," and the time-intensity curve presented a second peak. The intensity and time of second peak were both positively correlated with the transplant time (P<0.01) and the pathologic grade of AR (P<0.01). Confocal laser scanning microscopy demonstrated the binding of nanobubbles and lymphocytes in myocardium post-MCE with NB(specific). Ultrasound molecular imaging of AR after heart transplantation can be achieved by using MCE with the nanobubbles targeted to T cells. The appearance of delayed enhancement indicates the occurrence of AR, and the intensity and time of the second peak in time-intensity curve provide potential quantitative indications for diagnosis and severity of AR.

(99m)Tc-labeled SWL specific peptide for targeting EphA2 receptor.

PubMed

Liu, Yu; Lan, Xiaoli; Wu, Tao; Lang, Juntao; Jin, Xueyan; Sun, Xun; Wen, Qiong; An, Rui

2014-07-01

EphA2, one member of the Eph receptor family, is widely expressed in multiple aggressive cancers. SWL, a small peptide identified by phage display, has high binding affinity to EphA2, suggesting that it could be exploited for targeted molecular imaging. Therefore, a novel peptide-based probe, (99m)Tc-HYNIC-SWL, was developed and its potential to specifically target EphA2-positive tumors was investigated. The SWL peptide was labeled with hydrazinonicotinic acid (HYNIC), followed by (99m)Tc labeling. Immunofluorescence staining was carried out to detect the expression of EphA2 in A549 lung cancer cells and OCM-1 melanoma cells. Saturation binding experiments were performed by incubating A549 cells with increasing concentrations of radiolabeled peptide in vitro. To test the probe in vivo, nude mice bearing either A549 or OCM-1 derived tumors were established, injected with (99m)Tc-HYNIC-SWL, and subjected to SPECT imaging. Mice injected with excess unlabeled SWL were used as a specific control. Ex vivo γ-counting of dissected tissues from the mice was also performed to evaluate biodistribution. Immunofluorescence staining showed that A549 cells intensively expressed EphA2, while OCM-1 cells had little expression. (99m)Tc-HYNIC-SWL displayed high binding affinity with A549 cells (KD=2.6±0.7nM). From the SPECT images and the results of the biodistribution study, significantly higher uptake of the tracer was seen in A549 tumors (1.44±0.12 %ID/g) than in OCM-1 tumors (0.43±0.20 %ID/g) at 1h after injection. Pre-injection with excess unlabeled peptide in A549-bearing nude mice, significantly reduced tumor uptake of the radiolabeled probe (0.58±0.20 %ID/g) was seen. These data suggest that (99m)Tc-HYNIC-SWL specifically targets EphA2 in tumors. The expression of EphA2 can be noninvasively investigated using (99m)Tc-HYNIC-SWL by SPECT imaging. The in vitro and in vivo characteristics of (99m)Tc-HYNIC-SWL make it a promising probe for EphA2-positive tumor imaging. Copyright © 2014 Elsevier Inc. All rights reserved.

Development and Evaluation of a Fluorescent Antibody-Drug Conjugate for Molecular Imaging and Targeted Therapy of Pancreatic Cancer

PubMed Central

Knutson, Steve; Raja, Erum; Bomgarden, Ryan; Nlend, Marie; Chen, Aoshuang; Kalyanasundaram, Ramaswamy; Desai, Surbhi

2016-01-01

Antibodies are widely available and cost-effective research tools in life science, and antibody conjugates are now extensively used for targeted therapy, immunohistochemical staining, or in vivo diagnostic imaging of cancer. Significant advances in site-specific antibody labeling technologies have enabled the production of highly characterized and homogenous conjugates for biomedical purposes, and some recent studies have utilized site-specific labeling to synthesize bifunctional antibody conjugates with both imaging and drug delivery properties. While these advances are important for the clinical safety and efficacy of such biologics, these techniques can also be difficult, expensive, and time-consuming. Furthermore, antibody-drug conjugates (ADCs) used for tumor treatment generally remain distinct from conjugates used for diagnosis. Thus, there exists a need to develop simple dual-labeling methods for efficient therapeutic and diagnostic evaluation of antibody conjugates in pre-clinical model systems. Here, we present a rapid and simple method utilizing commercially available reagents for synthesizing a dual-labeled fluorescent ADC. Further, we demonstrate the fluorescent ADC’s utility for simultaneous targeted therapy and molecular imaging of cancer both in vitro and in vivo. Employing non-site-specific, amine-reactive chemistry, our novel biopharmaceutical theranostic is a monoclonal antibody specific for a carcinoembryonic antigen (CEA) biomarker conjugated to both paclitaxel and a near-infrared (NIR), polyethylene glycol modified (PEGylated) fluorophore (DyLight™ 680-4xPEG). Using in vitro systems, we demonstrate that this fluorescent ADC selectively binds a CEA-positive pancreatic cancer cell line (BxPC-3) in immunofluorescent staining and flow cytometry, exhibits efficient internalization kinetics, and is cytotoxic. Model studies using a xenograft of BxPC-3 cells in athymic mice also show the fluorescent ADC’s efficacy in detecting tumors in vivo and inhibiting tumor growth more effectively than equimolar amounts of unconjugated drug. Overall, our results demonstrate that non-selective, amine-targeting chemistry is an effective dual-labeling method for synthesizing and evaluating a bifunctional fluorescent antibody-drug conjugate, allowing concurrent detection, monitoring and treatment of cancer. PMID:27336622

Prospective treatment plan-specific action limits for real-time intrafractional monitoring in surface image guided radiosurgery.

PubMed

Yock, Adam D; Pawlicki, Todd; Kim, Gwe-Ya

2016-07-01

In surface image guided radiosurgery, action limits are created to determine at what point intrafractional motion exhibited by the patient is large enough to warrant intervention. Action limit values remain constant across patients despite the fact that patient motion affects the target coverage of brain metastases differently depending on the planning technique and other treatment plan-specific factors. The purpose of this work was twofold. The first purpose was to characterize the sensitivity of single-met per iso and multimet per iso treatment plans to uncorrected patient motion. The second purpose was to describe a method to prospectively determine treatment plan-specific action limits considering this sensitivity. In their surface image guided radiosurgery technique, patient positioning is achieved with a thermoplastic mask that does not cover the patient's face. The patient's exposed face is imaged by a stereoscopic photogrammetry system. It is then compared to a reference surface and monitored throughout treatment. Seventy-two brain metastases (representing 29 patients) were used for this study. Twenty-five mets were treated individually ("single-met per iso plans"), and 47 were treated in a plan simultaneously with at least one other met ("multimet per iso plans"). For each met, the proportion of the gross tumor volume that remained within the 100% prescription isodose line was estimated under the influence of combinations of translations and rotations (0.0-3.0 mm and 0.0°-3.0°, respectively). The target volume and the prescription dose-volume were considered concentric spheres that each encompassed a volume determined from the treatment plan. Plan-specific contour plots and DVHs were created to illustrate the sensitivity of a specific lesion to uncorrected patient motion. Both single-met per iso and multimet per iso plans exhibited compromised target coverage under translations and rotations, though multimet per iso plans were considerably more sensitive to these transformations (2.3% and 39.8%, respectively). Plan-specific contour plots and DVHs were used to illustrate how size, distance from isocenter, and planning technique affect a particular met's sensitivity to motion. Stereotactic radiosurgery treatment plans that treat multiple brain metastases using a common isocenter are particularly susceptible to compromised target coverage as a result of uncorrected patient motion. The use of such a planning technique along with other treatment plan-specific factors should influence patient motion management. A graphical representation of the effect of translations and rotations on any particular plan can be generated to inform clinicians of the appropriate action limit when monitoring intrafractional motion.

Design and Modular Construction of A Polymeric Nanoparticle for Targeted Atherosclerosis Positron Emission Tomography Imaging: A Story of 25% 64Cu-CANF-Comb

PubMed Central

Woodard, Pamela K.; Liu, Yongjian; Pressly, Eric D.; Luehmann, Hannah P.; Detering, Lisa; Sultan, Deborah; Laforest, Richard; McGrath, Alaina J.; Gropler, Robert J.; Hawker, Craig J.

2016-01-01

Purpose To assess the physicochemical properties, pharmacokinetic profiles, and in vivo positron emission tomography (PET) imaging of natriuretic peptide clearance receptors (NPRC) expressed on atherosclerotic plaque of a series of targeted, polymeric nanoparticles. Methods To control their structure, non-targeted and targeted polymeric (comb) nanoparticles, conjugated with various amounts of c-atrial natriuretic peptide (CANF, 0, 5, 10 and 25%), were synthesized by controlled and modular chemistry. In vivo pharmacokinetic evaluation of these nanoparticles was performed in wildtype (WT) C57BL/6 mice after 64Cu radiolabeling. PET imaging was performed on an apolipoprotein E–deficient (ApoE−/−) mouse atherosclerosis model to assess the NPRC targeting efficiency. For comparison, an in vivo blood metabolism study was carried out in WT mice. Results All three 64Cu-CANF-comb nanoparticles showed improved biodistribution profiles, including significantly reduced accumulation in both liver and spleen, compared to the non-targeted 64Cu-comb. Of the three nanoparticles, the 25% 64Cu-CANF-comb demonstrated the best NPRC targeting specificity and sensitivity in ApoE−/− mice. Metabolism studies showed that the radiolabeled CANF-comb was stable in blood up to 9 days. Histopathological analyses confirmed the up-regulation of NPRC along the progression of atherosclerosis. Conclusion The 25% 64Cu-CANF-comb demonstrated its potential as a PET imaging agent to detect atherosclerosis progression and status. PMID:27286872

225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.

PubMed

Kratochwil, Clemens; Bruchertseifer, Frank; Giesel, Frederik L; Weis, Mirjam; Verburg, Frederik A; Mottaghy, Felix; Kopka, Klaus; Apostolidis, Christos; Haberkorn, Uwe; Morgenstern, Alfred

2016-12-01

Prostate-specific membrane antigen (PSMA) is a promising target in prostate cancer. Recently, we started the first-in-human treatment with an α-radionuclide-labeled PSMA ligand. Although the case series is still ongoing, we here report in advance about two patients in highly challenging clinical situations who showed a complete response to 225 Ac-PSMA-617 therapy. 68 Ga-PSMA-11 PET/CT validated the presence of the PSMA-positive tumor phenotype. A 100-kBq activity of 225 Ac-PSMA-617 per kilogram of body weight was administered bimonthly. Prostate-specific antigen response and hematologic toxicity were measured at least every 4 wk. Restaging was performed with 68 Ga-PSMA-11 PET/CT. Both patients experienced a prostate-specific antigen decline to below the measurable level and showed a complete response on imaging. No relevant hematologic toxicity was observed. Xerostomia was the only mentionable clinical side effect. Targeted α-therapy with 225 Ac-PSMA-617, although still experimental, obviously has strong potential to significantly benefit advanced-stage prostate cancer patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Numerical simulation of magnetic nano drug targeting in patient-specific lower respiratory tract

NASA Astrophysics Data System (ADS)

Russo, Flavia; Boghi, Andrea; Gori, Fabio

2018-04-01

Magnetic nano drug targeting, with an external magnetic field, can potentially improve the drug absorption in specific locations of the body. However, the effectiveness of the procedure can be reduced due to the limitations of the magnetic field intensity. This work investigates this technique with the Computational Fluid Dynamics (CFD) approach. A single rectangular coil generates the external magnetic field. A patient-specific geometry of the Trachea, with its primary and secondary bronchi, is reconstructed from Digital Imaging and Communications in Medicine (DICOM) formatted images, throughout the Vascular Modelling Tool Kit (VMTK) software. A solver, coupling the Lagrangian dynamics of the magnetic nanoparticles with the Eulerian dynamics of the air, is used to perform the simulations. The resistive pressure, the pulsatile inlet velocity and the rectangular coil magnetic field are the boundary conditions. The dynamics of the injected particles is investigated without and with the magnetic probe. The flow field promotes particles adhesion to the tracheal wall. The particles volumetric flow rate in both cases has been calculated. The magnetic probe is shown to increase the particles flow in the target region, but at a limited extent. This behavior has been attributed to the small particle size and the probe configuration.

Attentional biases toward body images in males at high risk of muscle dysmorphia

PubMed Central

Jin, Xinhong; Zhou, Shi; Chang, Shuzhi; Li, Hui

2018-01-01

Objective Although research on muscle dysmorphia (MD), a body dysmorphic disorder subtype, has recently increased, the causes and mechanisms underlying this disorder remain unclear. Results from studies examining disorders associated with body image suggest the involvement of self-schema in biasing attention toward specific body information. The present study examined whether individuals at higher risk of MD also display attentional biases toward specific types of body images. Methods The validated Chinese version of the Muscle Appearance Satisfaction Scale was used to distinguish men at higher and lower risk of MD. Sixty-five adult Chinese men at higher (HRMD, n = 33) and lower risk of MD (LRMD, n = 32) performed a visual probe task. Initially, an image of a bodybuilder with either larger or smaller musculature was presented on one side of a central point, with a neutral image of a car exterior presented on the other side along the horizontal plane for 2,000 ms. The paired images were removed, and a visual target (a dot) was displayed in the location of one of the previously shown images. Participants were asked to indicate the location of the target, and their eye movements were recorded during the entire visual presentation. Participant reaction time and three eye movement measurements (gaze direction, first saccade latency, and first fixation duration) were recorded for use in determining attentional bias. Results The HRMD group revealed biases in orienting and maintaining their attention on images of bodybuilders with larger musculatures. Participants in this group consequently had a shorter reaction time in identifying the target that appeared at the location in which an image of a bodybuilder with a larger musculature had been previously displayed. They also directed their initial gaze more frequently, had shorter saccade latency, and had longer first fixation duration on images of bodybuilders with larger musculatures (all p < .0001). In comparison, the LRMD group had longer reaction times, slower attention orientation toward body images, and shorter fixation duration for images of bodybuilders with larger musculatures (all p < .0001), indicating weaker or mixed responses. Discussion Adult Chinese men at higher risk of MD displayed biases in orienting and maintaining their visual attention toward images of bodybuilders with larger musculatures, and these biases facilitated their information processing. These results suggest that development of MD may be due in part to attentional biases associated with established negative self-schema of specific body information. These findings provide insight into understanding and identifying the cognitive characteristics of MD in an Asian population. PMID:29362698

Attentional biases toward body images in males at high risk of muscle dysmorphia.

PubMed

Jin, Xinhong; Jin, Yahong; Zhou, Shi; Yang, Shun-Nan; Chang, Shuzhi; Li, Hui

2018-01-01

Although research on muscle dysmorphia (MD), a body dysmorphic disorder subtype, has recently increased, the causes and mechanisms underlying this disorder remain unclear. Results from studies examining disorders associated with body image suggest the involvement of self-schema in biasing attention toward specific body information. The present study examined whether individuals at higher risk of MD also display attentional biases toward specific types of body images. The validated Chinese version of the Muscle Appearance Satisfaction Scale was used to distinguish men at higher and lower risk of MD. Sixty-five adult Chinese men at higher (HRMD, n  = 33) and lower risk of MD (LRMD, n  = 32) performed a visual probe task. Initially, an image of a bodybuilder with either larger or smaller musculature was presented on one side of a central point, with a neutral image of a car exterior presented on the other side along the horizontal plane for 2,000 ms. The paired images were removed, and a visual target (a dot) was displayed in the location of one of the previously shown images. Participants were asked to indicate the location of the target, and their eye movements were recorded during the entire visual presentation. Participant reaction time and three eye movement measurements (gaze direction, first saccade latency, and first fixation duration) were recorded for use in determining attentional bias. The HRMD group revealed biases in orienting and maintaining their attention on images of bodybuilders with larger musculatures. Participants in this group consequently had a shorter reaction time in identifying the target that appeared at the location in which an image of a bodybuilder with a larger musculature had been previously displayed. They also directed their initial gaze more frequently, had shorter saccade latency, and had longer first fixation duration on images of bodybuilders with larger musculatures (all p  < .0001). In comparison, the LRMD group had longer reaction times, slower attention orientation toward body images, and shorter fixation duration for images of bodybuilders with larger musculatures (all p  < .0001), indicating weaker or mixed responses. Adult Chinese men at higher risk of MD displayed biases in orienting and maintaining their visual attention toward images of bodybuilders with larger musculatures, and these biases facilitated their information processing. These results suggest that development of MD may be due in part to attentional biases associated with established negative self-schema of specific body information. These findings provide insight into understanding and identifying the cognitive characteristics of MD in an Asian population.

Fluorescence imaging with multifunctional polyglycerol sulfates: novel polymeric near-IR probes targeting inflammation.

PubMed

Licha, Kai; Welker, Pia; Weinhart, Marie; Wegner, Nicole; Kern, Sylvia; Reichert, Stefanie; Gemeinhardt, Ines; Weissbach, Carmen; Ebert, Bernd; Haag, Rainer; Schirner, Michael

2011-12-21

We present a highly selective approach for the targeting of inflammation with a multivalent polymeric probe. Dendritic polyglycerol was employed to synthesize a polyanionic macromolecular conjugate with a near-infrared fluorescent dye related to Indocyanine Green (ICG). On the basis of the dense assembly of sulfate groups which were generated from the polyol core, the resulting polyglycerol sulfate (molecular weight 12 kD with ~70 sulfate groups) targets factors of inflammation (IC(50) of 3-6 nM for inhibition of L-selectin binding) and is specifically transported into inflammatory cells. The in vivo accumulation studied by near-IR fluorescence imaging in an animal model of rheumatoid arthritis demonstrated fast and selective uptake which enabled the differentiation of diseased joints (score 1-3) with a 3.5-fold higher fluorescence level and a signal maximum at 60 min post injection. Localization in tissues using fluorescence histology showed that the conjugates are deposited in the inflammatory infiltrate in the synovial membrane, whereas nonsulfated control was not detected in association with disease. Hence, this type of polymeric imaging probe is an alternative to current bioconjugates and provides future options for targeted imaging and drug delivery.

Efficacy of NGR peptide-modified PEGylated quantum dots for crossing the blood-brain barrier and targeted fluorescence imaging of glioma and tumor vasculature.

PubMed

Huang, Ning; Cheng, Si; Zhang, Xiang; Tian, Qi; Pi, Jiangli; Tang, Jun; Huang, Qing; Wang, Feng; Chen, Jin; Xie, Zongyi; Xu, Zhongye; Chen, Weifu; Zheng, Huzhi; Cheng, Yuan

2017-01-01

Delivery of imaging agents to brain glioma is challenging because the blood-brain barrier (BBB) functions as a physiological checkpoint guarding the central nervous system from circulating large molecules. Moreover, the ability of existing probes to target glioma has been insufficient and needs to be improved. In present study, PEG-based long circulation, CdSe/ZnS quantum dots (QDs)-based nanoscale and fluorescence, asparagines-glycine-arginine peptides (NGR)-based specific CD13 recognition were integrated to design and synthesize a novel nanoprobe by conjugating biotinylated NGR peptides to avidin-PEG-coated QDs. Our data showed that the NGR-PEG-QDs were nanoscale with less than 100 nm and were stable in various pH (4.0~8.0). These nanomaterials with non-toxic concentrations could cross the BBB and target CD13-overexpressing glioma and tumor vasculature in vitro and in vivo, contributing to fluorescence imaging of this brain malignancy. These achievements allowed groundbreaking technological advances in targeted fluorescence imaging for the diagnosis and surgical removal of glioma, facilitating potential transformation toward clinical nanomedicine. Copyright © 2016 Elsevier Inc. All rights reserved.

Emotions' Impact on Viewing Behavior under Natural Conditions

PubMed Central

Kaspar, Kai; Hloucal, Teresa-Maria; Kriz, Jürgen; Canzler, Sonja; Gameiro, Ricardo Ramos; Krapp, Vanessa; König, Peter

2013-01-01

Human overt attention under natural conditions is guided by stimulus features as well as by higher cognitive components, such as task and emotional context. In contrast to the considerable progress regarding the former, insight into the interaction of emotions and attention is limited. Here we investigate the influence of the current emotional context on viewing behavior under natural conditions. In two eye-tracking studies participants freely viewed complex scenes embedded in sequences of emotion-laden images. The latter primes constituted specific emotional contexts for neutral target images. Viewing behavior toward target images embedded into sets of primes was affected by the current emotional context, revealing the intensity of the emotional context as a significant moderator. The primes themselves were not scanned in different ways when presented within a block (Study 1), but when presented individually, negative primes were more actively scanned than positive primes (Study 2). These divergent results suggest an interaction between emotional priming and further context factors. Additionally, in most cases primes were scanned more actively than target images. Interestingly, the mere presence of emotion-laden stimuli in a set of images of different categories slowed down viewing activity overall, but the known effect of image category was not affected. Finally, viewing behavior remained largely constant on single images as well as across the targets' post-prime positions (Study 2). We conclude that the emotional context significantly influences the exploration of complex scenes and the emotional context has to be considered in predictions of eye-movement patterns. PMID:23326353

SU-F-J-176: Development of a Patient-Specific 3D Couplant Pad for Ultrasound IGRT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, H; Chang, A; Ye, S

Purpose: to overcome the several issues of ultrasound image-guided radiation therapy (US IGRT) such as probe pressure and optical tracking disability by using a patient-specific three-dimensional couplant pad (CP) fabricated by a patient’s skin mold using a 3D printing technique. Methods: A CP was then fabricated by pouring gelatin solution into a fixed-shape container accommodating the patient skin mold fabricated by a 3D printer. A breast phantom was fabricated with the compound of gelatin and agarose and a phantom study was carried out. From four patients who underwent US IGRT, total 486 ultrasound images with and without a CP weremore » acquired before treatment. Effectiveness of the use of the CP was evaluated. Results: The positioning accuracies in the phantom study were 0.9 ± 0.3 mm and 1.3 ± 0.4 mm with and without the CP in 3D vector amplitude, respectively. In the patient study, the use of CP reduced the mean target shift from 4.7 mm to 3.7 mm in 3D vector amplitude and the one standard deviation from 2.2 mm to 1.7 mm. It also improved the image contrast around the treatment target by 10 %. The centroid offset of the target volume affected from the US scanning coverage and the target deformation due to the excessive probe pressure was decreased from 4.4 mm to 2.9 mm due to the use of CP. Its difference among three different users was statistically significant (p=0.020) without the use of CP but not significantly different (p=0.133) with the use of CP. Conclusion: Our patient-specific 3D CP using a mold by 3D printing technique is a promising strategy for improving tracking accuracy, image quality, and inter-observer variation for ultrasound-based image guided radiotherapy. In addition to its conventional advantage of non-invasiveness, US can be more facilitated in radiotherapy by the developed CP.« less

Dual-Labeled Near-Infrared/99mTc Imaging Probes Using PAMAM-Coated Silica Nanoparticles for the Imaging of HER2-Expressing Cancer Cells

PubMed Central

Yamaguchi, Haruka; Tsuchimochi, Makoto; Hayama, Kazuhide; Kawase, Tomoyuki; Tsubokawa, Norio

2016-01-01

We sought to develop dual-modality imaging probes using functionalized silica nanoparticles to target human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer cells and achieve efficient target imaging of HER2-expressing tumors. Polyamidoamine-based functionalized silica nanoparticles (PCSNs) for multimodal imaging were synthesized with near-infrared (NIR) fluorescence (indocyanine green (ICG)) and technetium-99m (99mTc) radioactivity. Anti-HER2 antibodies were bound to the labeled PCSNs. These dual-imaging probes were tested to image HER2-overexpressing breast carcinoma cells. In vivo imaging was also examined in breast tumor xenograft models in mice. SK-BR3 (HER2 positive) cells were imaged with stronger NIR fluorescent signals than that in MDA-MB231 (HER2 negative) cells. The increased radioactivity of the SK-BR3 cells was also confirmed by phosphor imaging. NIR images showed strong fluorescent signals in the SK-BR3 tumor model compared to muscle tissues and the MDA-MB231 tumor model. Automatic well counting results showed increased radioactivity in the SK-BR3 xenograft tumors. We developed functionalized silica nanoparticles loaded with 99mTc and ICG for the targeting and imaging of HER2-expressing cells. The dual-imaging probes efficiently imaged HER2-overexpressing cells. Although further studies are needed to produce efficient isotope labeling, the results suggest that the multifunctional silica nanoparticles are a promising vehicle for imaging specific components of the cell membrane in a dual-modality manner. PMID:27399687

Dual-Labeled Near-Infrared/(99m)Tc Imaging Probes Using PAMAM-Coated Silica Nanoparticles for the Imaging of HER2-Expressing Cancer Cells.

PubMed

Yamaguchi, Haruka; Tsuchimochi, Makoto; Hayama, Kazuhide; Kawase, Tomoyuki; Tsubokawa, Norio

2016-07-07

We sought to develop dual-modality imaging probes using functionalized silica nanoparticles to target human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer cells and achieve efficient target imaging of HER2-expressing tumors. Polyamidoamine-based functionalized silica nanoparticles (PCSNs) for multimodal imaging were synthesized with near-infrared (NIR) fluorescence (indocyanine green (ICG)) and technetium-99m ((99m)Tc) radioactivity. Anti-HER2 antibodies were bound to the labeled PCSNs. These dual-imaging probes were tested to image HER2-overexpressing breast carcinoma cells. In vivo imaging was also examined in breast tumor xenograft models in mice. SK-BR3 (HER2 positive) cells were imaged with stronger NIR fluorescent signals than that in MDA-MB231 (HER2 negative) cells. The increased radioactivity of the SK-BR3 cells was also confirmed by phosphor imaging. NIR images showed strong fluorescent signals in the SK-BR3 tumor model compared to muscle tissues and the MDA-MB231 tumor model. Automatic well counting results showed increased radioactivity in the SK-BR3 xenograft tumors. We developed functionalized silica nanoparticles loaded with (99m)Tc and ICG for the targeting and imaging of HER2-expressing cells. The dual-imaging probes efficiently imaged HER2-overexpressing cells. Although further studies are needed to produce efficient isotope labeling, the results suggest that the multifunctional silica nanoparticles are a promising vehicle for imaging specific components of the cell membrane in a dual-modality manner.

GEM-loaded magnetic albumin nanospheres modified with cetuximab for simultaneous targeting, magnetic resonance imaging, and double-targeted thermochemotherapy of pancreatic cancer cells.

PubMed

Wang, Ling; An, Yanli; Yuan, Chenyan; Zhang, Hao; Liang, Chen; Ding, Fengan; Gao, Qi; Zhang, Dongsheng

2015-01-01

Targeted delivery is a promising strategy to improve the diagnostic imaging and therapeutic effect of cancers. In this paper, novel cetuximab (C225)-conjugated, gemcitabine (GEM)-containing magnetic albumin nanospheres (C225-GEM/MANs) were fabricated and applied as a theranostic nanocarrier to conduct simultaneous targeting, magnetic resonance imaging (MRI), and double-targeted thermochemotherapy against pancreatic cancer cells. Fe3O4 nanoparticles (NPs) and GEM co-loaded albumin nanospheres (GEM/MANs) were prepared, and then C225 was further conjugated to synthesize C225-GEM/MANs. Their morphology, mean particle size, GEM encapsulation ratio, specific cell-binding ability, and thermal dynamic profiles were characterized. The effects of discriminating different EGFR-expressing pancreatic cancer cells (AsPC-1 and MIA PaCa-2) and monitoring cellular targeting effects were assessed by targeted MRI. Lastly, the antitumor efficiency of double/C225/magnetic-targeted and nontargeted thermochemotherapy was compared with chemotherapy alone using 3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and flow cytometry (FCM) assay. When treated with targeted nanospheres, AsPC-1 cells showed a significantly less intense MRI T2 signal than MIA PaCa-2 cells, while both cells had similar signal strength when incubated with nontargeted nanospheres. T2 signal intensity was significantly lower when magnetic and C225 targeting were combined, rather than used alone. The inhibitory and apoptotic rates of each thermochemotherapy group were significantly higher than those of the chemotherapy-alone groups. Additionally, both MTT and FCM analysis verified that double-targeted thermochemotherapy had the highest targeted killing efficiency among all groups. The C225-GEM/MANs can distinguish various EGFR-expressing live pancreatic cancer cells, monitor diverse cellular targeting effects using targeted MRI imaging, and efficiently mediate double-targeted thermochemotherapy against pancreatic cancer cells.

Assessment of plaque vulnerability in atherosclerosis via intravascular photoacoustic imaging of targeted liposomal ICG J-aggregates (Conference Presentation)

NASA Astrophysics Data System (ADS)

Harris, Justin T.; Dumani, Diego S.; Cook, Jason R.; Sokolov, Konstantin V.; Emelianov, Stanislav Y.; Homan, Kimberly A.

2017-03-01

While molecular and cellular imaging can be used to visualize the conventional morphology characteristics of vulnerable plaques, there is a need to monitor other physiological factors correlated with high rupture rates; a high M1 activated macrophage concentration is one such indicator of high plaque vulnerability. Here, we present a molecularly targeted contrast agent for intravascular photoacoustic (IVPA) imaging consisting of liposomes loaded with indocyanine green (ICG) J-aggregates with high absorption at 890 nm, allowing for imaging in the presence of blood. This "Lipo-ICG" was targeted to a biomarker of M1 activated macrophages in vulnerable plaques: folate receptor beta (FRβ). The targeted liposomes accumulate in plaques through areas of endothelial dysfunction, while the liposome encapsulation prevents nonspecific interaction with lipids and endothelium. Lipo-ICG specifically interacts with M1 activated macrophages, causing a spectral shift and change in the 890/780 nm photoacoustic intensity ratio upon breakdown of J-aggregates. This sensing mechanism enables assessment of the M1 activated macrophage concentration, providing a measure of plaque vulnerability. In a pilot in vivo study utilizing ApoE deficient mouse models of atherosclerosis, diseased mice showed increased uptake of FRβ targeted Lipo-ICG in the heart and arteries vs. normal mice. Likewise, targeted Lipo-ICG showed increased uptake vs. two non-targeted controls. Thus, we successfully synthesized a contrast agent to detect M1 activated macrophages in high risk atherosclerotic plaques and exhibited targeting both in vitro and in vivo. This biocompatible agent could enable M1 macrophage detection, allowing better clinical decision making in treatment of atherosclerosis.

Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer.

PubMed

Rhee, H; Thomas, P; Shepherd, B; Gustafson, S; Vela, I; Russell, P J; Nelson, C; Chung, E; Wood, G; Malone, G; Wood, S; Heathcote, P

2016-10-01

Positron emission tomography using ligands targeting prostate specific membrane antigen has recently been introduced. Positron emission tomography imaging with (68)Ga-PSMA-HBED-CC has been shown to detect metastatic prostate cancer lesions at a high rate. In this study we compare multiparametric magnetic resonance imaging and prostate specific membrane antigen positron emission tomography of the prostate with whole mount ex vivo prostate histopathology to determine the true sensitivity and specificity of these imaging modalities for detecting and locating tumor foci within the prostate. In a prospective clinical trial setting 20 patients with localized prostate cancer and a planned radical prostatectomy were recruited. All patients underwent multiparametric magnetic resonance imaging and positron emission tomography before surgery, and whole mount histopathology slides were directly compared to the images. European Society of Urogenital Radiology guidelines for reporting magnetic resonance imaging were used as a template for regional units of analysis. The uropathologist and radiologists were blinded to individual components of the study, and the final correlation was performed by visual and deformable registration analysis. A total of 50 clinically significant lesions were identified from the whole mount histopathological analysis. Based on regional analysis the sensitivity, specificity, positive predictive value and negative predictive value for multiparametric magnetic resonance imaging were 44%, 94%, 81% and 76%, respectively. With prostate specific membrane antigen positron emission tomography the sensitivity, specificity, positive predictive value and negative predictive value were 49%, 95%, 85% and 88%, respectively. Prostate specific membrane antigen positron emission tomography yielded a higher specificity and positive predictive value. A significant proportion of cancers are potentially missed and underestimated by both imaging modalities. Prostate specific membrane antigen positron emission tomography may be used in addition to multiparametric magnetic resonance imaging to help improve local staging in those patients undergoing retropubic radical prostatectomy. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases

PubMed Central

Urnauer, Sarah; Müller, Andrea M.; Schug, Christina; Schmohl, Kathrin A.; Tutter, Mariella; Schwenk, Nathalie; Rödl, Wolfgang; Morys, Stephan; Ingrisch, Michael; Bertram, Jens; Bartenstein, Peter; Clevert, Dirk-André; Wagner, Ernst; Spitzweg, Christine

2017-01-01

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of 131I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using 18F-tetrafluoroborate (18F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before 18F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq 131I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease. PMID:29190908

A deep learning model observer for use in alterative forced choice virtual clinical trials

NASA Astrophysics Data System (ADS)

Alnowami, M.; Mills, G.; Awis, M.; Elangovanr, P.; Patel, M.; Halling-Brown, M.; Young, K. C.; Dance, D. R.; Wells, K.

2018-03-01

Virtual clinical trials (VCTs) represent an alternative assessment paradigm that overcomes issues of dose, high cost and delay encountered in conventional clinical trials for breast cancer screening. However, to fully utilize the potential benefits of VCTs requires a machine-based observer that can rapidly and realistically process large numbers of experimental conditions. To address this, a Deep Learning Model Observer (DLMO) was developed and trained to identify lesion targets from normal tissue in small (200 x 200 pixel) image segments, as used in Alternative Forced Choice (AFC) studies. The proposed network consists of 5 convolutional layers with 2x2 kernels and ReLU (Rectified Linear Unit) activations, followed by max pooling with size equal to the size of the final feature maps and three dense layers. The class outputs weights from the final fully connected dense layer are used to consider sets of n images in an n-AFC paradigm to determine the image most likely to contain a target. To examine the DLMO performance on clinical data, a training set of 2814 normal and 2814 biopsy-confirmed malignant mass targets were used. This produced a sensitivity of 0.90 and a specificity of 0.92 when presented with a test data set of 800 previously unseen clinical images. To examine the DLMOs minimum detectable contrast, a second dataset of 630 simulated backgrounds and 630 images with simulated lesion and spherical targets (4mm and 6mm diameter), produced contrast thresholds equivalent to/better than human observer performance for spherical targets, and comparable (12 % difference) for lesion targets.

Tumor-associated macrophages, nanomedicine and imaging: the axis of success in the future of cancer immunotherapy.

PubMed

Zanganeh, Saeid; Spitler, Ryan; Hutter, Gregor; Ho, Jim Q; Pauliah, Mohan; Mahmoudi, Morteza

2017-09-01

The success of any given cancer immunotherapy relies on several key factors. In particular, success hinges on the ability to stimulate the immune system in a controlled and precise fashion, select the best treatment options and appropriate therapeutic agents, and use highly effective tools to accurately and efficiently assess the outcome of the immunotherapeutic intervention. Furthermore, a deep understanding and effective utilization of tumor-associated macrophages (TAMs), nanomedicine and biomedical imaging must be harmonized to improve treatment efficacy. Additionally, a keen appreciation of the dynamic interplay that occurs between immune cells and the tumor microenvironment (TME) is also essential. New advances toward the modulation of the immune TME have led to many novel translational research approaches focusing on the targeting of TAMs, enhanced drug and nucleic acid delivery, and the development of theranostic probes and nanoparticles for clinical trials. In this review, we discuss the key cogitations that influence TME, TAM modulations and immunotherapy in solid tumors as well as the methods and resources of tracking the tumor response. The vast array of current nanomedicine technologies can be readily modified to modulate immune function, target specific cell types, deliver therapeutic payloads and be monitored using several different imaging modalities. This allows for the development of more effective treatments, which can be specifically designed for particular types of cancer or on an individual basis. Our current capacities have allowed for greater use of theranostic probes and multimodal imaging strategies that have led to better image contrast, real-time imaging capabilities leveraging targeting moieties, tracer kinetics and enabling more detailed response profiles at the cellular and molecular levels. These novel capabilities along with new discoveries in cancer biology should drive innovation for improved biomarkers for efficient and individualized cancer therapy.

Multi-brain fusion and applications to intelligence analysis

NASA Astrophysics Data System (ADS)

Stoica, A.; Matran-Fernandez, A.; Andreou, D.; Poli, R.; Cinel, C.; Iwashita, Y.; Padgett, C.

2013-05-01

In a rapid serial visual presentation (RSVP) images are shown at an extremely rapid pace. Yet, the images can still be parsed by the visual system to some extent. In fact, the detection of specific targets in a stream of pictures triggers a characteristic electroencephalography (EEG) response that can be recognized by a brain-computer interface (BCI) and exploited for automatic target detection. Research funded by DARPA's Neurotechnology for Intelligence Analysts program has achieved speed-ups in sifting through satellite images when adopting this approach. This paper extends the use of BCI technology from individual analysts to collaborative BCIs. We show that the integration of information in EEGs collected from multiple operators results in performance improvements compared to the single-operator case.

Simple synthesis of carbon-11 labeled styryl dyes as new potential PET RNA-specific, living cell imaging probes.

PubMed

Wang, Min; Gao, Mingzhang; Miller, Kathy D; Sledge, George W; Hutchins, Gary D; Zheng, Qi-Huang

2009-05-01

A new type of styryl dyes have been developed as RNA-specific, live cell imaging probes for fluorescent microscopy technology to study nuclear structure and function. This study was designed to develop carbon-11 labeled styryl dyes as new probes for biomedical imaging technique positron emission tomography (PET) imaging of RNA in living cells. Precursors (E)-2-(2-(1-(triisopropylsilyl)-1H-indol-3-yl)vinyl)quinoline (2), (E)-2-(2,4,6-trimethoxystyryl)quinoline (3) and (E)-4-(2-(6-methoxyquinolin-2-yl)vinyl)-N,N-diemthylaniline (4), and standards styryl dyes E36 (6), E144 (7) and F22 (9) were synthesized in multiple steps with moderate to high chemical yields. Precursor 2 was labeled by [(11)C]CH(3)OTf, trapped on a cation-exchange CM Sep-Pak cartridge following a quick deprotecting reaction by addition of (n-Bu)(4)NF in THF, and isolated by solid-phase extraction (SPE) purification to provide target tracer [(11)C]E36 ([(11)C]6) in 40-50% radiochemical yields, decay corrected to end of bombardment (EOB), based on [(11)C]CO(2). The target tracers [(11)C]E144 ([(11)C]7) and [(11)C]F22 ([(11)C]9) were prepared by N-[(11)C]methylation of the precursors 3 and 4, respectively, using [(11)C]CH(3)OTf and isolated by SPE method in 50-70% radiochemical yields at EOB. The specific activity of the target tracers [(11)C]6, [(11)C]7 and [(11)C]9 was in a range of 74-111GBq/mumol at the end of synthesis (EOS).

A Lipopeptide-Based αvβ₃ Integrin-Targeted Ultrasound Contrast Agent for Molecular Imaging of Tumor Angiogenesis.

PubMed

Yan, Fei; Xu, Xiuxia; Chen, Yihan; Deng, Zhiting; Liu, Hongmei; Xu, Jianrong; Zhou, Jie; Tan, Guanghong; Wu, Junru; Zheng, Hairong

2015-10-01

The design and fabrication of targeted ultrasound contrast agents are key factors in the success of ultrasound molecular imaging applications. Here, we introduce a transformable αvβ3 integrin-targeted microbubble (MB) by incorporation of iRGD-lipopeptides into the MB membrane for non-invasive ultrasound imaging of tumor angiogenesis. First, the iRGD-lipopeptides were synthesized by conjugating iRGD peptides to distearoylphosphatidylethanolamine-polyethylene glycol 2000-maleimide. The resulting iRGD-lipopeptides were used for fabrication of the iRGD-carrying αvβ3 integrin-targeted MBs (iRGD-MBs). The binding specificity of iRGD-MBs for endothelial cells was found to be significantly stronger than that of control MBs (p < 0.01) under in vitro static and dynamic conditions. The binding of iRGD-MBs on the endothelial cells was competed off by pre-incubation with the anti-αv or anti-β3 antibody (p < 0.01). Ultrasound images taken of mice bearing 4T1 breast tumors after intravenous injections of iRGD-MBs or control MBs revealed strong contrast enhancement within the tumors from iRGD-MBs but not from the control MBs; the mean acoustic signal intensity was 10.71 ± 2.75 intensity units for iRGD-MBs versus 1.13 ± 0.18 intensity units for the control MBs (p < 0.01). The presence of αvβ3 integrin was confirmed by immunofluorescence staining. These data indicate that iRGD-MBs can be used as an ultrasound imaging probe for the non-invasive molecular imaging of tumor angiogenesis, and may have further implications for ultrasound image-guided tumor targeting drug delivery. Copyright © 2015 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

Image-aided Suicide Gene Therapy Utilizing Multifunctional hTERT-targeting Adenovirus for Clinical Translation in Hepatocellular Carcinoma.

PubMed

Kim, Yun-Hee; Kim, Kyung Tae; Lee, Sang-Jin; Hong, Seung-Hee; Moon, Ju Young; Yoon, Eun Kyung; Kim, Sukyoung; Kim, Eun Ok; Kang, Se Hun; Kim, Seok Ki; Choi, Sun Il; Goh, Sung Ho; Kim, Daehong; Lee, Seong-Wook; Ju, Mi Ha; Jeong, Jin Sook; Kim, In-Hoo

2016-01-01

Trans-splicing ribozyme enables to sense and reprogram target RNA into therapeutic transgene and thereby becomes a good sensing device for detection of cancer cells, judging from transgene expression. Previously we proposed PEPCK-Rz-HSVtk (PRT), hTERT targeting trans-splicing ribozyme (Rz) driven by liver-specific promoter phosphoenolpyruvate carboxykinase (PEPCK) with downstream suicide gene, herpes simplex virus thymidine kinase (HSVtk) for hepatocellular carcinoma (HCC) gene therapy. Here, we describe success of a re-engineered adenoviral vector harboring PRT in obtaining greater antitumor activity with less off-target effect for clinical application as a theranostics. We introduced liver-selective apolipoprotein E (ApoE) enhancer to the distal region of PRT unit to augment activity and liver selectivity of PEPCK promoter, and achieved better transduction into liver cancer cells by replacement of serotype 35 fiber knob on additional E4orf1-4 deletion of E1&E3-deleted serotype 5 back bone. We demonstrated that our refined adenovirus harboring PEPCK/ApoE-Rz-HSVtk (Ad-PRT-E) achieved great anti-tumor efficacy and improved ability to specifically target HCC without damaging normal hepatocytes. We also showed noninvasive imaging modalities were successfully employed to monitor both how well a therapeutic gene (HSVtk) was expressed inside tumor and how effectively a gene therapy took an action in terms of tumor growth. Collectively, this study suggests that the advanced therapeutic adenoviruses Ad-PRT-E and its image-aided evaluation system may lead to the powerful strategy for successful clinical translation and the development of clinical protocols for HCC therapy.

Testing and evaluation of tactical electro-optical sensors

NASA Astrophysics Data System (ADS)

Middlebrook, Christopher T.; Smith, John G.

2002-07-01

As integrated electro-optical sensor payloads (multi- sensors) comprised of infrared imagers, visible imagers, and lasers advance in performance, the tests and testing methods must also advance in order to fully evaluate them. Future operational requirements will require integrated sensor payloads to perform missions at further ranges and with increased targeting accuracy. In order to meet these requirements sensors will require advanced imaging algorithms, advanced tracking capability, high-powered lasers, and high-resolution imagers. To meet the U.S. Navy's testing requirements of such multi-sensors, the test and evaluation group in the Night Vision and Chemical Biological Warfare Department at NAVSEA Crane is developing automated testing methods, and improved tests to evaluate imaging algorithms, and procuring advanced testing hardware to measure high resolution imagers and line of sight stabilization of targeting systems. This paper addresses: descriptions of the multi-sensor payloads tested, testing methods used and under development, and the different types of testing hardware and specific payload tests that are being developed and used at NAVSEA Crane.

Identification of reduced-order thermal therapy models using thermal MR images: theory and validation.

PubMed

Niu, Ran; Skliar, Mikhail

2012-07-01

In this paper, we develop and validate a method to identify computationally efficient site- and patient-specific models of ultrasound thermal therapies from MR thermal images. The models of the specific absorption rate of the transduced energy and the temperature response of the therapy target are identified in the reduced basis of proper orthogonal decomposition of thermal images, acquired in response to a mild thermal test excitation. The method permits dynamic reidentification of the treatment models during the therapy by recursively utilizing newly acquired images. Such adaptation is particularly important during high-temperature therapies, which are known to substantially and rapidly change tissue properties and blood perfusion. The developed theory was validated for the case of focused ultrasound heating of a tissue phantom. The experimental and computational results indicate that the developed approach produces accurate low-dimensional treatment models despite temporal and spatial noises in MR images and slow image acquisition rate.

Duplexed sandwich immunoassays on a fiber-optic microarray.

PubMed

Rissin, David M; Walt, David R

2006-03-30

In this paper, we describe a duplexed imaging optical fiber array-based immunoassay for immunoglobulin A (IgA) and lactoferrin. To fabricate the individually addressable array, microspheres were functionalized with highly specific monoclonal antibodies. The microspheres were loaded in microwells etched into the distal face of an imaging optical fiber bundle. Two microsphere-based sandwich immunoassays were developed to simultaneously detect IgA and lactoferrin, two innate immune system proteins found in human saliva. Individual microspheres could be interrogated for the simultaneous measurement of both proteins. The working concentration range for IgA detection was between 700 pM and 100 nM, while the working concentration range for lactoferrin was between 385 pM and 10 nM. The cross-reactivity between detection antibodies and their non-specific targets was relatively low in comparison to the signal generated by the specific binding with their targets. These results suggest that the degree of multiplexing on this fiber-optic array platform can be increased beyond a duplex.

Surface-Engineered Multifunctional Eu:Gd2O3 Nanoplates for Targeted and pH-Responsive Drug Delivery and Imaging Applications.

PubMed

Saha, Arindam; Mohanta, Subas Chandra; Deka, Kashmiri; Deb, Pritam; Devi, Parukuttyamma Sujatha

2017-02-01

In this paper, we report the synthesis of surface-engineered multifunctional Eu:Gd 2 O 3 triangular nanoplates with small size and uniform shape via a high-temperature solvothermal technique. Surface engineering has been performed by a one-step polyacrylate coating, followed by controlled conjugation chemistry. This creates the desired number of surface functional groups that can be used to attach folic acid as a targeting ligand on the nanoparticle surface. To specifically deliver the drug molecules in the nucleus, the folate density on the nanoparticle surface has been kept low. We have also modified the drug molecules with terminal double bond and ester linkage for the easy conjugation of nanoparticles. The nanoparticle surface was further modified with free thiols to specifically attach the modified drug molecules with a pH-responsive feature. High drug loading has been encountered for both hydrophilic drug daunorubicin (∼69% loading) and hydrophobic drug curcumin (∼75% loading) with excellent pH-responsive drug release. These nanoparticles have also been used as imaging probes in fluorescence imaging. Some preliminary experiments to evaluate their application in magnetic resonance imaging have also been explored. A detailed fluorescence imaging study has confirmed the efficient delivery of drugs to the nuclei of cancer cells with a high cytotoxic effect. Synthesized surface-engineered nanomaterials having small hydrodynamic size, excellent colloidal stability, and high drug-loading capacity, along with targeted and pH-responsive delivery of dual drugs to the cancer cells, will be potential nanobiomaterials for various biomedical applications.

In Vivo 18 FDG/18 Choline Mediated Cerenkov Radiation Energy Transfer (CRET) Multiplexed Optical Imaging for Human Prostate Carcinoma Detection and Staging

DTIC Science & Technology

2016-10-01

human prostate cancer xenografts. We have selected peptides from bacteriophage display libraries that target TF and ErbB2/ErbB3. The peptides have been...facilitate biomarker-specific diagnosis. The specific aims of the proposal are to: 1) select peptides that target the ErbB2/3 heterodimer using novel...parallel in vitro/in vivo phage display techniques; 2) generate NIR-QDs decorated with TF- and ErbB2/3-avid peptides for in vivo molecular

Recent Trends in Antibody-based Oncologic Imaging

PubMed Central

Kaur, Sukhwinder; Venktaraman, Ganesh; Jain, Maneesh; Senapati, Shantibhusan; Garg, Pradeep K.; Batra, Surinder K.

2011-01-01

Antibodies, with their unmatched ability for selective binding to any target, are considered as potentially the most specific probes for imaging. Their clinical utility, however, has been limited chiefly due to their slow clearance from the circulation, longer retention in non-targeted tissues and the extensive optimization required for each antibody-tracer. The development of newer contrast agents, combined with improved conjugation strategies and novel engineered forms of antibodies (diabodies, minibodies, single chain variable fragments, and nanobodies), have triggered a new wave of antibody-based imaging approaches. Apart from their conventional use with nuclear imaging probes, antibodies and their modified forms are increasingly being employed with non-radioisotopic contrast agents (MRI and ultrasound) as well as newer imaging modalities, such as quantum dots, near infra red (NIR) probes, nanoshells and surface enhanced Raman spectroscopy (SERS). The review article provides new developments in the usage of antibodies and their modified forms in conjunction with probes of various imaging modalities such as nuclear imaging, optical imaging, ultrasound, MRI, SERS and nanoshells in preclinical and clinical studies on the diagnosis, prognosis and therapeutic responses of cancer. PMID:22104729

The Human Vertical Translation Vestibulo-ocular Reflex (tVOR): Normal and Abnormal Responses

PubMed Central

Liao, Ke; Walker, Mark F.; Joshi, Anand; Reschke, Millard; Strupp, Michael; Leigh, R. John

2010-01-01

Geometric considerations indicate that the human translational vestibulo-ocular reflex (tVOR) should have substantially different properties than the angular vestibulo-ocular reflex (aVOR). Specifically, tVOR cannot simultaneously stabilize images of distant and near objects on the retina. Most studies make the tacit assumption that tVOR acts to stabilize foveal images even though, in humans, tVOR is reported to compensate for less than 60% of foveal image motion. We have determined that the compensation gain (eye rotational velocity / required eye rotational velocity to maintain foveal target fixation) of tVOR is held steady at ~ 0.6 during viewing of either near or distant targets during vertical (bob) translations in ambient illumination. We postulate that tVOR evolved not to stabilize the image of the target on the fovea, but rather to minimize retinal image motion between objects lying in different depth planes, in order to optimize motion parallax information. Such behavior is optimized when binocular visual cues of both far and distant targets are available in ambient light. Patients with progressive supranuclear palsy or cerebellar ataxia show impaired ability to increase tVOR responses appropriately when they view near targets. In cerebellar patients, impaired ability to adjust tVOR responses to viewing conditions occurs despite intact ability to converge at near. Loss of the ability to adjust tVOR according to viewing conditions appears to represent a distinct disorder of vestibular function. PMID:19645882

Image-derived arterial input function for quantitative fluorescence imaging of receptor-drug binding in vivo

PubMed Central

Elliott, Jonathan T.; Samkoe, Kimberley S.; Davis, Scott C.; Gunn, Jason R.; Paulsen, Keith D.; Roberts, David W.; Pogue, Brian W.

2017-01-01

Receptor concentration imaging (RCI) with targeted-untargeted optical dye pairs has enabled in vivo immunohistochemistry analysis in preclinical subcutaneous tumors. Successful application of RCI to fluorescence guided resection (FGR), so that quantitative molecular imaging of tumor-specific receptors could be performed in situ, would have a high impact. However, assumptions of pharmacokinetics, permeability and retention, as well as the lack of a suitable reference region limit the potential for RCI in human neurosurgery. In this study, an arterial input graphic analysis (AIGA) method is presented which is enabled by independent component analysis (ICA). The percent difference in arterial concentration between the image-derived arterial input function (AIFICA) and that obtained by an invasive method (ICACAR) was 2.0 ± 2.7% during the first hour of circulation of a targeted-untargeted dye pair in mice. Estimates of distribution volume and receptor concentration in tumor bearing mice (n = 5) recovered using the AIGA technique did not differ significantly from values obtained using invasive AIF measurements (p=0.12). The AIGA method, enabled by the subject-specific AIFICA, was also applied in a rat orthotopic model of U-251 glioblastoma to obtain the first reported receptor concentration and distribution volume maps during open craniotomy. PMID:26349671

Evaluation of Liver Ischemia-Reperfusion Injury in Rabbits Using a Nanoscale Ultrasound Contrast Agent Targeting ICAM-1.

PubMed

Xie, Fang; Li, Zhi-Ping; Wang, Hong-Wei; Fei, Xiang; Jiao, Zi-Yu; Tang, Wen-Bo; Tang, Jie; Luo, Yu-Kun

2016-01-01

To assess the feasibility of ultrasound molecular imaging in the early diagnosis of liver ischemia-reperfusion injury (IRI) using a nanoscale contrast agent targeting anti-intracellular adhesion molecule-1 (anti-ICAM-1). The targeted nanobubbles containing anti-ICAM-1 antibody were prepared using the avidin-biotin binding method. Human hepatic sinusoidal endothelial cells (HHSECs) were cultured at the circumstances of hypoxia/reoxygenation (H/R) and low temperature. The rabbit liver IRI model (I/R group) was established using the Pringle's maneuver. The time-intensity curve of the liver contrast ultrasonographic images was plotted and the peak intensity, time to peak, and time of duration were calculated. The size of the targeted nanobubbles were 148.15 ± 39.75 nm and the concentration was 3.6-7.4 × 109/ml, and bound well with the H/R HHSECs. Animal contrast enhanced ultrasound images showed that the peak intensity and time of duration of the targeted nanobubbles were significantly higher than that of common nanobubbles in the I/R group, and the peak intensity and time of duration of the targeted nanobubbles in the I/R group were also significantly higher than that in the SO group. The targeted nanobubbles have small particle size, stable characteristic, and good targeting ability, which can assess hepatic ischemia-reperfusion injury specifically, noninvasively, and quantitatively at the molecular level.

RGD-functionalized ultrasmall iron oxide nanoparticles for targeted T1-weighted MR imaging of gliomas

NASA Astrophysics Data System (ADS)

Luo, Yu; Yang, Jia; Yan, Yu; Li, Jingchao; Shen, Mingwu; Zhang, Guixiang; Mignani, Serge; Shi, Xiangyang

2015-08-01

We report a convenient approach to prepare ultrasmall Fe3O4 nanoparticles (NPs) functionalized with an arginylglycylaspartic acid (RGD) peptide for in vitro and in vivo magnetic resonance (MR) imaging of gliomas. In our work, stable sodium citrate-stabilized Fe3O4 NPs were prepared by a solvothermal route. Then, the carboxylated Fe3O4 NPs stabilized with sodium citrate were conjugated with polyethylene glycol (PEG)-linked RGD. The formed ultrasmall RGD-functionalized nanoprobe (Fe3O4-PEG-RGD) was fully characterized using different techniques. We show that these Fe3O4-PEG-RGD particles with a size of 2.7 nm are water-dispersible, stable, cytocompatible and hemocompatible in a given concentration range, and display targeting specificity to glioma cells overexpressing αvβ3 integrin in vitro. With the relatively high r1 relaxivity (r1 = 1.4 mM-1 s-1), the Fe3O4-PEG-RGD particles can be used as an efficient nanoprobe for targeted T1-weighted positive MR imaging of glioma cells in vitro and the xenografted tumor model in vivo via an active RGD-mediated targeting pathway. The developed RGD-functionalized Fe3O4 NPs may hold great promise to be used as a nanoprobe for targeted T1-weighted MR imaging of different αvβ3 integrin-overexpressing cancer cells or biological systems.We report a convenient approach to prepare ultrasmall Fe3O4 nanoparticles (NPs) functionalized with an arginylglycylaspartic acid (RGD) peptide for in vitro and in vivo magnetic resonance (MR) imaging of gliomas. In our work, stable sodium citrate-stabilized Fe3O4 NPs were prepared by a solvothermal route. Then, the carboxylated Fe3O4 NPs stabilized with sodium citrate were conjugated with polyethylene glycol (PEG)-linked RGD. The formed ultrasmall RGD-functionalized nanoprobe (Fe3O4-PEG-RGD) was fully characterized using different techniques. We show that these Fe3O4-PEG-RGD particles with a size of 2.7 nm are water-dispersible, stable, cytocompatible and hemocompatible in a given concentration range, and display targeting specificity to glioma cells overexpressing αvβ3 integrin in vitro. With the relatively high r1 relaxivity (r1 = 1.4 mM-1 s-1), the Fe3O4-PEG-RGD particles can be used as an efficient nanoprobe for targeted T1-weighted positive MR imaging of glioma cells in vitro and the xenografted tumor model in vivo via an active RGD-mediated targeting pathway. The developed RGD-functionalized Fe3O4 NPs may hold great promise to be used as a nanoprobe for targeted T1-weighted MR imaging of different αvβ3 integrin-overexpressing cancer cells or biological systems. Electronic supplementary information (ESI) available: Additional experimental results. See DOI: 10.1039/c5nr04003e

PET Imaging of 64Cu-DOTA-scFv-Anti-PSMA Lipid Nanoparticles (LNPs): Enhanced Tumor Targeting over Anti-PSMA scFv or Untargeted LNPs

PubMed Central

Wong, Patty; Li, Lin; Chea, Junie; Delgado, Melissa K.; Crow, Desiree; Poku, Erasmus; Szpikowska, Barbara; Bowles, Nicole; Channappa, Divya; Colcher, David; Wong, Jeffrey Y.C.; Shively, John E.; Yazaki, Paul J.

2017-01-01

Introduction Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance. Methods An anti-prostate membrane antigen (PSMA) scFv with a site-specific cysteine was expressed and evaluated in a prostate cancer xenograft model by Cu-64 PET imaging. To enhance tumor accumulation, the scFv-cys was conjugated to the co-polymer DSPE-PEG-maleimide that spontaneously assembled into a homogeneous multivalent lipid nanoparticle (LNP). Results The targeted LNP exhibited a 2-fold increase in tumor uptake compared to the scFv alone using two different thiol ester chemistries. The anti-PSMA scFv-LNP exhibited a 1.6 fold increase in tumor targeting over the untargeted LNP. Conclusions The targeted anti-PSMA scFv-LNP showed enhanced tumor accumulation over the scFv alone or the untargeted DOTA-micelle providing evidence for the development of this system for drug delivery. Advances in Knowledge and implications for patient care Anti-tumor scFv antibody fragments have not achieved their therapeutic potential due to their fast blood clearance. Conjugation to a LNP enables multivalency to the tumor antigen as well as increased molecular size for chemotherapy drug delivery. PMID:28126683

Characterization of target camouflage structures by means of different microwave imaging procedures

NASA Astrophysics Data System (ADS)

Inaebnit, Christian; John, Marc-Andre; Aulenbacher, Uwe; Akyol, Zeynrep; Hueppi, Rudolf; Wellig, Peter

2009-05-01

This paper presents two different test methods for camouflage layers (CL) like nets or foam based structures. The effectiveness of CL in preventing radar detection and recognition of targets depends on the interaction of CL properties as absorption and diffuse scattering with target specific scattering properties. This fact is taken into account by representing target backscattering as interference of different types of GTD contributions and evaluating the impact of CL onto these individual contributions separately. The first method investigates how a CL under test alters these individual scattering contributions and which "new" contributions are produced by "self-scattering" at the CL. This information is gained by applying ISAR imaging technique to a test structure with different types of scattering contributions. The second test method aims for separating the effects of absorption and "diffuse scattering" in case of a planar metallic plate covered by CL. For this, the equivalent source distribution in the plane of the CL is reconstructed from bistatic scattering data. Both test methods were verified by experimental results obtained from X-band measurements at different CL and proved to be well suited for an application specific evaluation of camouflage structures from different manufacturers.

Multi-scale image segmentation method with visual saliency constraints and its application

NASA Astrophysics Data System (ADS)

Chen, Yan; Yu, Jie; Sun, Kaimin

2018-03-01

Object-based image analysis method has many advantages over pixel-based methods, so it is one of the current research hotspots. It is very important to get the image objects by multi-scale image segmentation in order to carry out object-based image analysis. The current popular image segmentation methods mainly share the bottom-up segmentation principle, which is simple to realize and the object boundaries obtained are accurate. However, the macro statistical characteristics of the image areas are difficult to be taken into account, and fragmented segmentation (or over-segmentation) results are difficult to avoid. In addition, when it comes to information extraction, target recognition and other applications, image targets are not equally important, i.e., some specific targets or target groups with particular features worth more attention than the others. To avoid the problem of over-segmentation and highlight the targets of interest, this paper proposes a multi-scale image segmentation method with visually saliency graph constraints. Visual saliency theory and the typical feature extraction method are adopted to obtain the visual saliency information, especially the macroscopic information to be analyzed. The visual saliency information is used as a distribution map of homogeneity weight, where each pixel is given a weight. This weight acts as one of the merging constraints in the multi- scale image segmentation. As a result, pixels that macroscopically belong to the same object but are locally different can be more likely assigned to one same object. In addition, due to the constraint of visual saliency model, the constraint ability over local-macroscopic characteristics can be well controlled during the segmentation process based on different objects. These controls will improve the completeness of visually saliency areas in the segmentation results while diluting the controlling effect for non- saliency background areas. Experiments show that this method works better for texture image segmentation than traditional multi-scale image segmentation methods, and can enable us to give priority control to the saliency objects of interest. This method has been used in image quality evaluation, scattered residential area extraction, sparse forest extraction and other applications to verify its validation. All applications showed good results.

Localized Chemical Remodeling for Live Cell Imaging of Protein-Specific Glycoform.

PubMed

Hui, Jingjing; Bao, Lei; Li, Siqiao; Zhang, Yi; Feng, Yimei; Ding, Lin; Ju, Huangxian

2017-07-03

Live cell imaging of protein-specific glycoforms is important for the elucidation of glycosylation mechanisms and identification of disease states. The currently used metabolic oligosaccharide engineering (MOE) technology permits routinely global chemical remodeling (GCM) for carbohydrate site of interest, but can exert unnecessary whole-cell scale perturbation and generate unpredictable metabolic efficiency issue. A localized chemical remodeling (LCM) strategy for efficient and reliable access to protein-specific glycoform information is reported. The proof-of-concept protocol developed for MUC1-specific terminal galactose/N-acetylgalactosamine (Gal/GalNAc) combines affinity binding, off-on switchable catalytic activity, and proximity catalysis to create a reactive handle for bioorthogonal labeling and imaging. Noteworthy assay features associated with LCM as compared with MOE include minimum target cell perturbation, short reaction timeframe, effectiveness as a molecular ruler, and quantitative analysis capability. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

A pretargeting system for tumor PET imaging and radioimmunotherapy

PubMed Central

Kraeber-Bodéré, Françoise; Rousseau, Caroline; Bodet-Milin, Caroline; Frampas, Eric; Faivre-Chauvet, Alain; Rauscher, Aurore; Sharkey, Robert M.; Goldenberg, David M.; Chatal, Jean-François; Barbet, Jacques

2015-01-01

Labeled antibodies, as well as their fragments and antibody-derived recombinant constructs, have long been proposed as general vectors to target radionuclides to tumor lesions for imaging and therapy. They have indeed shown promise in both imaging and therapeutic applications, but they have not fulfilled the original expectations of achieving sufficient image contrast for tumor detection or sufficient radiation dose delivered to tumors for therapy. Pretargeting was originally developed for tumor immunoscintigraphy. It was assumed that directly-radiolabled antibodies could be replaced by an unlabeled immunoconjugate capable of binding both a tumor-specific antigen and a small molecular weight molecule. The small molecular weight molecule would carry the radioactive payload and would be injected after the bispecific immunoconjugate. It has been demonstrated that this approach does allow for both antibody-specific recognition and fast clearance of the radioactive molecule, thus resulting in improved tumor-to-normal tissue contrast ratios. It was subsequently shown that pretargeting also held promise for tumor therapy, translating improved tumor-to-normal tissue contrast ratios into more specific delivery of absorbed radiation doses. Many technical approaches have been proposed to implement pretargeting, and two have been extensively documented. One is based on the avidin-biotin system, and the other on bispecific antibodies binding a tumor-specific antigen and a hapten. Both have been studied in preclinical models, as well as in several clinical studies, and have shown improved targeting efficiency. This article reviews the historical and recent preclinical and clinical advances in the use of bispecific-antibody-based pretargeting for radioimmunodetection and radioimmunotherapy of cancer. The results of recent evaluation of pretargeting in PET imaging also are discussed. PMID:25873896

A new imaging technique to detect recurrent prostate cancer is tested in new clinical trial | Center for Cancer Research

Cancer.gov

Standard imaging techniques cannot accurately locate sites of prostate cancer metastasis. The use of 18F-DCFPyL, a second-generation PET agent, aims to improve doctors’ ability to assess high-risk primary tumors, detect sites of recurrent prostate cancer and target therapies to specific sites of recurrence. Read more...

Mixture-Tuned, Clutter Matched Filter for Remote Detection of Subpixel Spectral Signals

NASA Technical Reports Server (NTRS)

Thompson, David R.; Mandrake, Lukas; Green, Robert O.

2013-01-01

Mapping localized spectral features in large images demands sensitive and robust detection algorithms. Two aspects of large images that can harm matched-filter detection performance are addressed simultaneously. First, multimodal backgrounds may thwart the typical Gaussian model. Second, outlier features can trigger false detections from large projections onto the target vector. Two state-of-the-art approaches are combined that independently address outlier false positives and multimodal backgrounds. The background clustering models multimodal backgrounds, and the mixture tuned matched filter (MT-MF) addresses outliers. Combining the two methods captures significant additional performance benefits. The resulting mixture tuned clutter matched filter (MT-CMF) shows effective performance on simulated and airborne datasets. The classical MNF transform was applied, followed by k-means clustering. Then, each cluster s mean, covariance, and the corresponding eigenvalues were estimated. This yields a cluster-specific matched filter estimate as well as a cluster- specific feasibility score to flag outlier false positives. The technology described is a proof of concept that may be employed in future target detection and mapping applications for remote imaging spectrometers. It is of most direct relevance to JPL proposals for airborne and orbital hyperspectral instruments. Applications include subpixel target detection in hyperspectral scenes for military surveillance. Earth science applications include mineralogical mapping, species discrimination for ecosystem health monitoring, and land use classification.

Hetero-bivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen (PSMA) and Hepsin

DTIC Science & Technology

2012-09-01

functions of PSMA for PCa, we have designed and prepared PSMA-based imaging probes to evaluate its biological activity in vivo in a variety of...nucleophilic functional group to be coupled with radionuclides, i.e., 125I or 18F, or optical dyes. C. Accomplishments in Year 2 1...position of the lysine or N-terminus isoleucine with the imaging prosthetic groups such as optical dyes and radionuclides. The alloc group was

Proposed Optimal Fluoroscopic Targets for Cooled Radiofrequency Neurotomy of the Sacral Lateral Branches to Improve Clinical Outcomes: An Anatomical Study.

PubMed

Stout, Alison; Dreyfuss, Paul; Swain, Nathan; Roberts, Shannon; Loh, Eldon; Agur, Anne

2017-11-23

Current sacroiliac joint (SIJ) cooled radiofrequency (RF) is based on fluoroscopic anatomy of lateral branches (LBs) in three specimens. Recent studies confirm significant variation in LB positions. To determine if common fluoroscopic needle placements for cooled SIJ RF are adequate to lesion all S1-3 LBs. If not, would different targets improve lesion accuracy? The LBs of 20 cadavers were dissected bilaterally (40 SIJs), and 26 G radiopaque wires were sutured to the LBs. With a 10-mm radius ruler centered at each foramen, standard targets were assessed, as judged by a clockface on the right, for S1 and S2 at 2:30, 4:00, and 5:30 positions and at S3 at 2:30 and 4:00. Mirror image targets were assessed on the left. Assuming an 8-mm lesion diameter, the percentage of LBs that would not be ablated for each level was determined. Imaging through the superior end plate of S1 was compared against segment specific (SS) imaging. Nine point four percent of LBs would not be ablated at S1 vs 0.99% at S2 vs 35% at S3, and 60% of the 40 SIJs would be completely denervated using current targets. SS imaging did not improve results. Alternate target locations could improve the miss rate to 2.8% at S1 and 0% at S3 and would ablate all LBs in 95% of SIJs. Using a conservative 8-mm lesion measurement, contemporary cooled RF needle targets are inadequate to lesion all target LBs. Modifications to current targets are recommended to increase the effectiveness of the procedure. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Ions doped melanin nanoparticle as a multiple imaging agent.

PubMed

Ha, Shin-Woo; Cho, Hee-Sang; Yoon, Young Il; Jang, Moon-Sun; Hong, Kwan Soo; Hui, Emmanuel; Lee, Jung Hee; Yoon, Tae-Jong

2017-10-10

Multimodal nanomaterials are useful for providing enhanced diagnostic information simultaneously for a variety of in vivo imaging methods. According to our research findings, these multimodal nanomaterials offer promising applications for cancer therapy. Melanin nanoparticles can be used as a platform imaging material and they can be simply produced by complexation with various imaging active ions. They are capable of specifically targeting epidermal growth factor receptor (EGFR)-expressing cancer cells by being anchored with a specific antibody. Ion-doped melanin nanoparticles were found to have high bioavailability with long-term stability in solution, without any cytotoxicity in both in vitro and in vivo systems. By combining different imaging modalities with melanin particles, we can use the complexes to obtain faster diagnoses by computed tomography deep-body imaging and greater detailed pathological diagnostic information by magnetic resonance imaging. The ion-doped melanin nanoparticles also have applications for radio-diagnostic treatment and radio imaging-guided surgery, warranting further proof of concept experimental.

Molecular Imaging of Atherothrombotic Diseases: Seeing Is Believing.

PubMed

Wang, Xiaowei; Peter, Karlheinz

2017-06-01

Molecular imaging, with major advances in the development of both innovative targeted contrast agents/particles and radiotracers, as well as various imaging technologies, is a fascinating, rapidly growing field with many preclinical and clinical applications, particularly for personalized medicine. Thrombosis in either the venous or the arterial system, the latter typically caused by rupture of unstable atherosclerotic plaques, is a major determinant of mortality and morbidity in patients. However, imaging of the various thrombotic complications and the identification of plaques that are prone to rupture are at best indirect, mostly unreliable, or not available at all. The development of molecular imaging toward diagnosis and prevention of thrombotic disease holds promise for major advance in this clinically important field. Here, we review the medical need and clinical importance of direct molecular imaging of thrombi and unstable atherosclerotic plaques that are prone to rupture, thereby causing thrombotic complications such as myocardial infarction and ischemic stroke. We systematically compare the advantages/disadvantages of the various molecular imaging modalities, including X-ray computed tomography, magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, fluorescence imaging, and ultrasound. We further systematically discuss molecular targets specific for thrombi and those characterizing unstable, potentially thrombogenic atherosclerotic plaques. Finally, we provide examples for first theranostic approaches in thrombosis, combining diagnosis, targeted therapy, and monitoring of therapeutic success or failure. Overall, molecular imaging is a rapidly advancing field that holds promise of major benefits to many patients with atherothrombotic diseases. © 2017 American Heart Association, Inc.

Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yi, Jianbing, E-mail: yijianbing8@163.com; Yang, Xuan, E-mail: xyang0520@263.net; Li, Yan-Ran, E-mail: lyran@szu.edu.cn

2015-10-15

Purpose: Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. Methods: An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered atmore » points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. Results: The performances of the authors’ method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors’ method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors’ method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors’ method ranks 24 of 39. According to the index of the maximum shear stretch, the authors’ method is also efficient to describe the discontinuous motion at the lung boundaries. Conclusions: By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors’ method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy.« less

Lung motion estimation using dynamic point shifting: An innovative model based on a robust point matching algorithm.

PubMed

Yi, Jianbing; Yang, Xuan; Chen, Guoliang; Li, Yan-Ran

2015-10-01

Image-guided radiotherapy is an advanced 4D radiotherapy technique that has been developed in recent years. However, respiratory motion causes significant uncertainties in image-guided radiotherapy procedures. To address these issues, an innovative lung motion estimation model based on a robust point matching is proposed in this paper. An innovative robust point matching algorithm using dynamic point shifting is proposed to estimate patient-specific lung motion during free breathing from 4D computed tomography data. The correspondence of the landmark points is determined from the Euclidean distance between the landmark points and the similarity between the local images that are centered at points at the same time. To ensure that the points in the source image correspond to the points in the target image during other phases, the virtual target points are first created and shifted based on the similarity between the local image centered at the source point and the local image centered at the virtual target point. Second, the target points are shifted by the constrained inverse function mapping the target points to the virtual target points. The source point set and shifted target point set are used to estimate the transformation function between the source image and target image. The performances of the authors' method are evaluated on two publicly available DIR-lab and POPI-model lung datasets. For computing target registration errors on 750 landmark points in six phases of the DIR-lab dataset and 37 landmark points in ten phases of the POPI-model dataset, the mean and standard deviation by the authors' method are 1.11 and 1.11 mm, but they are 2.33 and 2.32 mm without considering image intensity, and 1.17 and 1.19 mm with sliding conditions. For the two phases of maximum inhalation and maximum exhalation in the DIR-lab dataset with 300 landmark points of each case, the mean and standard deviation of target registration errors on the 3000 landmark points of ten cases by the authors' method are 1.21 and 1.04 mm. In the EMPIRE10 lung registration challenge, the authors' method ranks 24 of 39. According to the index of the maximum shear stretch, the authors' method is also efficient to describe the discontinuous motion at the lung boundaries. By establishing the correspondence of the landmark points in the source phase and the other target phases combining shape matching and image intensity matching together, the mismatching issue in the robust point matching algorithm is adequately addressed. The target registration errors are statistically reduced by shifting the virtual target points and target points. The authors' method with consideration of sliding conditions can effectively estimate the discontinuous motion, and the estimated motion is natural. The primary limitation of the proposed method is that the temporal constraints of the trajectories of voxels are not introduced into the motion model. However, the proposed method provides satisfactory motion information, which results in precise tumor coverage by the radiation dose during radiotherapy.

Breast imaging technology: Recent advances in imaging endogenous or transferred gene expression utilizing radionuclide technologies in living subjects - applications to breast cancer

PubMed Central

Berger, Frank; Sam Gambhir, Sanjiv

2001-01-01

A variety of imaging technologies is being investigated as tools for studying gene expression in living subjects. Two technologies that use radiolabeled isotopes are single photon emission computed tomography (SPECT) and positron emission tomography (PET). A relatively high sensitivity, a full quantitative tomographic capability, and the ability to extend small animal imaging assays directly into human applications characterize radionuclide approaches. Various radiolabeled probes (tracers) can be synthesized to target specific molecules present in breast cancer cells. These include antibodies or ligands to target cell surface receptors, substrates for intracellular enzymes, antisense oligodeoxynucleotide probes for targeting mRNA, probes for targeting intracellular receptors, and probes for genes transferred into the cell. We briefly discuss each of these imaging approaches and focus in detail on imaging reporter genes. In a PET reporter gene system for in vivo reporter gene imaging, the protein products of the reporter genes sequester positron emitting reporter probes. PET subsequently measures the PET reporter gene dependent sequestration of the PET reporter probe in living animals. We describe and review reporter gene approaches using the herpes simplex type 1 virus thymidine kinase and the dopamine type 2 receptor genes. Application of the reporter gene approach to animal models for breast cancer is discussed. Prospects for future applications of the transgene imaging technology in human gene therapy are also discussed. Both SPECT and PET provide unique opportunities to study animal models of breast cancer with direct application to human imaging. Continued development of new technology, probes and assays should help in the better understanding of basic breast cancer biology and in the improved management of breast cancer patients. PMID:11250742

Effect of Dye and Conjugation Chemistry on the Biodistribution Profile of Near-Infrared-Labeled Nanobodies as Tracers for Image-Guided Surgery.

PubMed

Debie, Pieterjan; Van Quathem, Jannah; Hansen, Inge; Bala, Gezim; Massa, Sam; Devoogdt, Nick; Xavier, Catarina; Hernot, Sophie

2017-04-03

Advances in optical imaging technologies have stimulated the development of near-infrared (NIR) fluorescently labeled targeted probes for use in image-guided surgery. As nanobodies have already proven to be excellent candidates for molecular imaging, we aimed in this project to design NIR-conjugated nanobodies targeting the tumor biomarker HER2 for future applications in this field and to evaluate the effect of dye and dye conjugation chemistry on their pharmacokinetics during development. IRDye800CW or IRdye680RD were conjugated either randomly (via lysines) or site-specifically (via C-terminal cysteine) to the anti-HER2 nanobody 2Rs15d. After verification of purity and functionality, the biodistribution and tumor targeting of the NIR-nanobodies were assessed in HER2-positive and -negative xenografted mice. Site-specifically IRDye800CW- and IRdye680RD-labeled 2Rs15d as well as randomly labeled 2Rs15d-IRDye680RD showed rapid tumor accumulation and low nonspecific uptake, resulting in high tumor-to-muscle ratios at early time points (respectively 6.6 ± 1.0, 3.4 ± 1.6, and 3.5 ± 0.9 for HER2-postive tumors at 3 h p.i., while <1.0 for HER2-negative tumors at 3 h p.i., p < 0.05). Contrarily, using the randomly labeled 2Rs15d-IRDye800CW, HER2-positive and -negative tumors could only be distinguished after 24 h due to high nonspecific signals. Moreover, both randomly labeled 2Rs15d nanobodies were not only cleared via the kidneys but also partially via the hepatobiliary route. In conclusion, near-infrared fluorescent labeling of nanobodies allows rapid, specific, and high contrast in vivo tumor imaging. Nevertheless, the fluorescent dye as well as the chosen conjugation strategy can affect the nanobodies' properties and consequently have a major impact on their pharmacokinetics.

Positron Emission Tomography Imaging Using Radiolabeled Inorganic Nanomaterials

PubMed Central

Sun, Xiaolian; Cai, Weibo; Chen, Xiaoyuan

2015-01-01

CONSPECTUS Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochemical) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clinical research, only very few have moved to humans. One major reason is the lack of understanding of the biological behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal molecular imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time. PMID:25635467

Protein Cage Nanoparticles Bearing the LyP-1 Peptide for Enhanced Imaging of Macrophage-Rich Vascular Lesions

PubMed Central

Uchida, Masaki; Kosuge, Hisanori; Terashima, Masahiro; Willits, Deborah A.; Liepold, Lars O.; Young, Mark J.; McConnell, Michael V.; Douglas, Trevor

2011-01-01

Cage-like protein nano particles are promising platforms for cell and tissue specific targeted delivery of imaging and therapeutic agents. Here, we have successfully modified the 12 nm small heat shock protein from Methanococcus jannaschii (MjHsp) to detect atherosclerotic plaque lesions in a mouse model system. As macrophages are centrally involved in the initiation and progression of atherosclerosis, targeted imaging of macrophages is valuable to assess the biologic status of the blood vessel wall. LyP-1, a nine residue peptide, has been shown to target tumor-associated macrophages. Thus, LyP-1 was genetically incorporated onto the exterior surface of MjHsp, while a fluorescent molecule (Cy5.5) was conjugated on the interior cavity. This bioengineered protein cage, LyP-Hsp, exhibited enhanced affinity to macrophage in vitro. Furthermore, in vivo injection of LyP-Hsp allowed visualization of macrophage-rich murine carotid lesions by in situ and ex vivo fluorescence imaging. These results demonstrate the potential of LyP-1-conjugated protein cages as nano-scale platforms for delivery of imaging agents for the diagnosis of atherosclerosis. PMID:21391720

Detection and Delineation of Oral Cancer With a PARP1-Targeted Optical Imaging Agent.

PubMed

Kossatz, Susanne; Weber, Wolfgang; Reiner, Thomas

2017-01-01

More sensitive and specific methods for early detection are imperative to improve survival rates in oral cancer. However, oral cancer detection is still largely based on visual examination and histopathology of biopsy material, offering no molecular selectivity or spatial resolution. Intuitively, the addition of optical contrast could improve oral cancer detection and delineation, but so far no molecularly targeted approach has been translated. Our fluorescently labeled small-molecule inhibitor PARPi-FL binds to the DNA repair enzyme poly(ADP-ribose)polymerase 1 (PARP1) and is a potential diagnostic aid for oral cancer delineation. Based on our preclinical work, a clinical phase I/II trial opened in March 2017 to evaluate PARPi-FL as a contrast agent for oral cancer imaging. In this commentary, we discuss why we chose PARP1 as a biomarker for tumor detection and which particular characteristics make PARPi-FL an excellent candidate to image PARP1 in optically guided applications. We also comment on the potential benefits of our molecularly targeted PARPi-FL-guided imaging approach in comparison to existing oral cancer screening adjuncts and mention the adaptability of PARPi-FL imaging to other environments and tumor types.

Near infrared fluorescence for image-guided surgery

PubMed Central

2012-01-01

Near infrared (NIR) image-guided surgery holds great promise for improved surgical outcomes. A number of NIR image-guided surgical systems are currently in preclinical and clinical development with a few approved for limited clinical use. In order to wield the full power of NIR image-guided surgery, clinically available tissue and disease specific NIR fluorophores with high signal to background ratio are necessary. In the current review, the status of NIR image-guided surgery is discussed along with the desired chemical and biological properties of NIR fluorophores. Lastly, tissue and disease targeting strategies for NIR fluorophores are reviewed. PMID:23256079

Folate and Heptamethine Cyanine Modified Chitosan-Based Nanotheranostics for Tumor Targeted Near-Infrared Fluorescence Imaging and Photodynamic Therapy.

PubMed

Zhang, Yingying; Lv, Tingting; Zhang, Huijuan; Xie, Xiaodong; Li, Ziying; Chen, Haijun; Gao, Yu

2017-07-10

Folate (FA) and heptamethine cyanine (Cy7)-modified chitosan (CF7) was synthesized by click chemistry and its self-assembled nanoparticles (CF7Ns) were developed for tumor-specific imaging and photodynamic therapy. The characterization spectrum confirmed CF7 had a good FA and Cy7 conjugation efficacy. The diameter of CF7Ns measured by DLS was about 291.6 nm, and the morphology observed with AFM showed filamentous clusters of particles. The results of targeting ability of CF7Ns demonstrated enhanced targeting behaviors of CF7Ns compared with non-FA-modified nanoparticles C7Ns in FA receptor-positive HeLa cells. The cytotoxicity and cell apoptosis assay showed that CF7Ns under near-infrared light irradiation led to more apoptotic cell death in HeLa cells to improve the therapeutic efficacy. The mechanisms of the photodynamic effects of CF7Ns were demonstrated through measurement of intracellular reactive oxygen species and the apoptosis-related cytokines. These results suggested that CF7Ns are promising tumor targeting carriers for simultaneous fluorescence imaging and photodynamic therapy.

Microbubble Enzyme-Linked Immunosorbent Assay for the Detection of Targeted Microbubbles in in Vitro Static Binding Assays.

PubMed

Wischhusen, Jennifer; Padilla, Frederic

2017-07-01

Targeted microbubbles (MBs) are ultrasound contrast agents that are functionalized with a ligand for ultrasound molecular imaging of endothelial markers. Novel targeted MBs are characterized in vitro by incubation in protein-coated wells, followed by binding quantification by microscopy or ultrasound imaging. Both methods provide operator-dependent results: Between 3 and 20 fields of view from a heterogeneous sample are typically selected for analysis by microscopy, and in ultrasound imaging, different acoustic settings affect signal intensities. This study proposes a new method to reproducibly quantify MB binding based on enzyme-linked immunosorbent assay (ELISA), in which bound MBs are revealed with an enzyme-linked antibody. MB-ELISA was adapted to in vitro static binding assays, incubating the MBs in inverted position or by agitation, and compared with microscopy. The specificity and sensitivity of MB-ELISA enable the reliable quantification of MB binding in a rapid, high-throughput and whole-well analysis, facilitating the characterization of new targeted contrast agents. Copyright © 2017 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Effects of partner beauty on opposite-sex attractiveness judgments.

PubMed

Little, Anthony C; Caldwell, Christine A; Jones, Benedict C; DeBruine, Lisa M

2011-12-01

Many studies show mate choice copying effects on mate preferences in non-human species in which individuals follow or copy the mate choices of same-sex conspecifics. Recent studies suggest that social learning also influences mate preferences in humans. Studies on heterosexual humans have focused on rating the attractiveness of potential mates (targets) presented alongside individuals of the opposite sex to the target (models). Here, we examined several different types of pairing to examine how specific social learning is to mate preferences. In Study 1, we replicated a previous effect whereby target faces of the opposite sex to the subject were rated as more attractive when paired with attractive than unattractive partner models of the same sex as the subject. Using the same paired stimuli, Study 2 demonstrated no effect of a paired model if subjects were asked to rate targets who were the same sex as themselves. In Study 3, we used pairs of the same sex, stating the pair were friends, and subjects rated targets of the opposite sex to themselves. Attractive models decreased targets' attractiveness, opposite to the effect in Study 1. Finally, Study 4 examined if attractive versus unattractive non-face stimuli might influence attraction. Unlike in Study 1, pairing with attractive stimuli either had no effect or decreased the attractiveness of paired target face images. These data suggest that social transmission of preferences via pairing with attractive/unattractive images is relatively specific to learning about mate preferences but does not influence attractiveness judgments more generally.

Nanocarriers for nuclear imaging and radiotherapy of cancer.

PubMed

Mitra, Amitava; Nan, Anjan; Line, Bruce R; Ghandehari, Hamidreza

2006-01-01

Several nanoscale carriers (nanoparticles, liposomes, water-soluble polymers, micelles and dendrimers) have been developed for targeted delivery of cancer diagnostic and therapeutic agents. These carriers can selectively target cancer sites and carry large payloads, thereby improving cancer detection and therapy effectiveness. Further, the combination of newer nuclear imaging techniques providing high sensitivity and spatial resolution such as dual modality imaging with positron emission tomography/computed tomography (PET/CT) and use of nanoscale devices to carry diagnostic and therapeutic radionuclides with high target specificity can enable more accurate detection, staging and therapy planning of cancer. The successful clinical applications of radiolabeled monoclonal antibodies for cancer detection and therapy bode well for the future of nanoscale carrier systems in clinical oncology. Several radiolabeled multifunctional nanocarriers have been effective in detecting and treating cancer in animal models. Nonetheless, further preclinical, clinical and long-term toxicity studies will be required to translate this technology to the care of patients with cancer. The objective of this review is to present a brief but comprehensive overview of the various nuclear imaging techniques and the use of nanocarriers to deliver radionuclides for the diagnosis and therapy of cancer.

Targeted nano analysis of water and ions using cryocorrelative light and scanning transmission electron microscopy.

PubMed

Nolin, Frédérique; Ploton, Dominique; Wortham, Laurence; Tchelidze, Pavel; Balossier, Gérard; Banchet, Vincent; Bobichon, Hélène; Lalun, Nathalie; Terryn, Christine; Michel, Jean

2012-11-01

Cryo fluorescence imaging coupled with the cryo-EM technique (cryo-CLEM) avoids chemical fixation and embedding in plastic, and is the gold standard for correlated imaging in a close to native state. This multi-modal approach has not previously included elementary nano analysis or evaluation of water content. We developed a new approach allowing analysis of targeted in situ intracellular ions and water measurements at the nanoscale (EDXS and STEM dark field imaging) within domains identified by examination of specific GFP-tagged proteins. This method allows both water and ions- fundamental to cell biology- to be located and quantified at the subcellular level. We illustrate the potential of this approach by investigating changes in water and ion content in nuclear domains identified by GFP-tagged proteins in cells stressed by Actinomycin D treatment and controls. The resolution of our approach was sufficient to distinguish clumps of condensed chromatin from surrounding nucleoplasm by fluorescence imaging and to perform nano analysis in this targeted compartment. Copyright © 2012 Elsevier Inc. All rights reserved.

Self-assembled polymeric nanoparticles as new, smart contrast agents for cancer early detection using magnetic resonance imaging.

PubMed

Mouffouk, Fouzi; Simão, Teresa; Dornelles, Daniel F; Lopes, André D; Sau, Pablo; Martins, Jorge; Abu-Salah, Khalid M; Alrokayan, Salman A; Rosa da Costa, Ana M; dos Santos, Nuno R

2015-01-01

Early cancer detection is a major factor in the reduction of mortality and cancer management cost. Here we developed a smart and targeted micelle-based contrast agent for magnetic resonance imaging (MRI), able to turn on its imaging capability in the presence of acidic cancer tissues. This smart contrast agent consists of pH-sensitive polymeric micelles formed by self-assembly of a diblock copolymer (poly(ethyleneglycol-b-trimethylsilyl methacrylate)), loaded with a gadolinium hydrophobic complex ((t)BuBipyGd) and exploits the acidic pH in cancer tissues. In vitro MRI experiments showed that (t)BuBipyGd-loaded micelles were pH-sensitive, as they turned on their imaging capability only in an acidic microenvironment. The micelle-targeting ability toward cancer cells was enhanced by conjugation with an antibody against the MUC1 protein. The ability of our antibody-decorated micelles to be switched on in acidic microenvironments and to target cancer cells expressing specific antigens, together with its high Gd(III) content and its small size (35-40 nm) reveals their potential use for early cancer detection by MRI.

Target-induced Catalytic Assembly of Y-Shaped DNA and Its Application for In Situ Imaging of MicroRNAs.

PubMed

Xue, Chang; Zhang, Shu-Xin; Ouyang, Chang-He; Chang, Dingran; Salena, Bruno J; Li, Yingfu; Wu, Zai-Sheng

2018-06-14

DNA is a highly programmable material that can be configured into unique high-order structures, such as DNA branched junctions containing multiple helical arms converging at a center. Herein we show that DNA programmability can deliver in situ growth of a 3-way junction-based DNA structure (denoted Y-shaped DNA) with the use of three hairpin-shaped DNA molecules as precursors, a specific microRNA target as a recyclable trigger, and a DNA polymerase as a driver. We demonstrate that the Y-shaped configuration comes with the benefit of restricted freedom of movement in confined cellular environment, which makes the approach ideally suited for in situ imaging of small RNA targets, such as microRNAs. Comparative analysis illustrates that the proposed imaging technique is superior to both the classic fluorescence in situ hybridization (FISH) method and an analogous amplified imaging method via programmed growth of a double-stranded DNA (rather than Y-shaped DNA) product. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetically targeted 3D visualisation of Drosophila neurons under Electron Microscopy and X-Ray Microscopy using miniSOG

PubMed Central

Ng, Julian; Browning, Alyssa; Lechner, Lorenz; Terada, Masako; Howard, Gillian; Jefferis, Gregory S. X. E.

2016-01-01

Large dimension, high-resolution imaging is important for neural circuit visualisation as neurons have both long- and short-range patterns: from axons and dendrites to the numerous synapses at terminal endings. Electron Microscopy (EM) is the favoured approach for synaptic resolution imaging but how such structures can be segmented from high-density images within large volume datasets remains challenging. Fluorescent probes are widely used to localise synapses, identify cell-types and in tracing studies. The equivalent EM approach would benefit visualising such labelled structures from within sub-cellular, cellular, tissue and neuroanatomical contexts. Here we developed genetically-encoded, electron-dense markers using miniSOG. We demonstrate their ability in 1) labelling cellular sub-compartments of genetically-targeted neurons, 2) generating contrast under different EM modalities, and 3) segmenting labelled structures from EM volumes using computer-assisted strategies. We also tested non-destructive X-ray imaging on whole Drosophila brains to evaluate contrast staining. This enabled us to target specific regions for EM volume acquisition. PMID:27958322

Serial Magnetic Resonance Imaging in Active Surveillance of Prostate Cancer: Incremental Value.

PubMed

Felker, Ely R; Wu, Jason; Natarajan, Shyam; Margolis, Daniel J; Raman, Steven S; Huang, Jiaoti; Dorey, Fred; Marks, Leonard S

2016-05-01

We assessed whether changes in serial multiparametric magnetic resonance imaging can help predict the pathological progression of prostate cancer in men on active surveillance. A retrospective cohort study was conducted of 49 consecutive men with Gleason 6 prostate cancer who underwent multiparametric magnetic resonance imaging at baseline and again more than 6 months later, each followed by a targeted prostate biopsy, between January 2011 and May 2015. We evaluated whether progression on multiparametric magnetic resonance imaging (an increase in index lesion suspicion score, increase in index lesion volume or decrease in index lesion apparent diffusion coefficient) could predict pathological progression (Gleason 3 + 4 or greater on subsequent biopsy, in systematic or targeted cores). Diagnostic performance of multiparametric magnetic resonance imaging was determined with and without clinical data using a binary logistic regression model. The mean interval between baseline and followup multiparametric magnetic resonance imaging was 28.3 months (range 11 to 43). Pathological progression occurred in 19 patients (39%). The sensitivity, specificity, positive predictive value and negative predictive value of multiparametric magnetic resonance imaging was 37%, 90%, 69% and 70%, respectively. Area under the receiver operating characteristic curve was 0.63. A logistic regression model using clinical information (maximum cancer core length greater than 3 mm on baseline biopsy or a prostate specific antigen density greater than 0.15 ng/ml(2) at followup biopsy) had an AUC of 0.87 for predicting pathological progression. The addition of serial multiparametric magnetic resonance imaging data significantly improved the AUC to 0.91 (p=0.044). Serial multiparametric magnetic resonance imaging adds incremental value to prostate specific antigen density and baseline cancer core length for predicting Gleason 6 upgrading in men on active surveillance. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

An improved 99mTc-HYNIC-(Ser)3-LTVSPWY peptide with EDDA/tricine as co-ligands for targeting and imaging of HER2 overexpression tumor.

PubMed

Khodadust, Fatemeh; Ahmadpour, Sajjad; Aligholikhamseh, Nazan; Abedi, Seyed Mohammad; Hosseinimehr, Seyed Jalal

2018-01-20

Overexpression of human epidermal receptor 2 (HER2) has given the opportunity for targeting and delivering of imaging radiotracers. The aim of this study was to evaluate the 99m Tc-HYNIC-(EDDA/tricine)-(Ser) 3 -LTVSPWY peptide for tumor targeting and imaging of tumor with overexpression of HER2. The HYNIC-(Ser) 3 -LTVSPWY was labeled with 99m Tc in presence of EDDA/tricine mixture as co-ligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular specific binding and tumor targeting. The high radiochemical purity of 99m Tc-HYNIC (EDDA/tricine)-(Ser) 3 -LTVSPWY was obtained to be 99%. It exhibited high stability in normal saline and human serum. In HER2 binding affinity study, a significant reduction in uptake of radiolabeled peptide (7.7 fold) was observed by blocking SKOV-3 cells receptors with unlabeled peptide. The K D and B max values for this radiolabeled peptide were determined as 3.3 ± 1.0 nM and 2.9 ± 0.3 × 10 6 CPM/pMol, respectively. Biodistribution study revealed tumor to blood and tumor to muscle ratios about 6.9 and 4 respectively after 4 h. Tumor imaging by gamma camera demonstrated considerable high contrast tumor uptake. This developed 99m Tc-HYNIC-(Ser) 3 -LTVSPWY peptide selectively targeted on HER2 tumor and exhibited a high target uptake combined with acceptable low background activity for tumor imaging in mice. The results of this study and its comparison with another study showed that 99m Tc-HYNIC-(EDDA/tricine)-(Ser) 3 -LTVSPWY is much better than previously reported radiolabeled peptide as 99m Tc-CSSS-LTVSPWY for HER2 overexpression tumor targeting and imaging. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chlorotoxin-Conjugated Multifunctional Dendrimers Labeled with Radionuclide 131I for Single Photon Emission Computed Tomography Imaging and Radiotherapy of Gliomas.

PubMed

Zhao, Lingzhou; Zhu, Jingyi; Cheng, Yongjun; Xiong, Zhijuan; Tang, Yueqin; Guo, Lilei; Shi, Xiangyang; Zhao, Jinhua

2015-09-09

Chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I were synthesized and utilized for targeted single photon emission computed tomography (SPECT) imaging and radiotherapy of cancer. In this study, generation five amine-terminated poly(amidoamine) dendrimers were used as a platform to be sequentially conjugated with polyethylene glycol (PEG), targeting agent chlorotoxin (CTX), and 3-(4'-hydroxyphenyl)propionic acid-OSu (HPAO). This was followed by acetylation of the remaining dendrimer terminal amines and radiolabeling with 131I to form the targeted theranostic dendrimeric nanoplatform. We show that the dendrimer platform possessing approximately 7.7 CTX and 21.1 HPAO moieties on each dendrimer displays excellent cytocompatibility in a given concentration range (0-20 μM) and can specifically target cancer cells overexpressing matrix metallopeptidase 2 (MMP2) due to the attached CTX. With the attached HPAO moiety having the phenol group, the dendrimer platform can be effectively labeled with radioactive 131I with good stability and high radiochemical purity. Importantly, the 131I labeling renders the dendrimer platform with an ability to be used for targeted SPECT imaging and radiotherapy of an MMP2-overexpressing glioma model in vivo. The developed radiolabeled multifunctional dendrimeric nanoplatform may hold great promise to be used for targeted theranostics of human gliomas.

Imaging of Nonprostate Cancers Using PSMA-Targeted Radiotracers: Rationale, Current State of the Field, and a Call to Arms.

PubMed

Salas Fragomeni, Roberto A; Amir, Tali; Sheikhbahaei, Sara; Harvey, Susan C; Javadi, Mehrbod S; Solnes, Lilja B; Kiess, Ana P; Allaf, Mohamad E; Pomper, Martin G; Gorin, Michael A; Rowe, Steven P

2018-06-01

Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly overexpressed on prostate cancer epithelial cells and for which there is a growing body of literature examining the role of small-molecule and antibody radiotracers targeted against this protein for prostate cancer detection and therapy. Despite its name, PSMA is also expressed, to varying degrees, in the neovasculature of a wide variety of nonprostate cancers; indeed, the pathology literature is replete with promising immunohistochemistry findings. Several groups have begun to correlate those pathology-level results with in vivo imaging and therapy in nonprostate cancers using the same PSMA-targeted agents that have been so successful in prostate cancer. The potential to leverage radiotracers targeted to PSMA beyond prostate cancer is a promising approach for many cancers, and PSMA-targeted agents may be able to supplement or fill gaps left by other agents. However, to date, most of the reported findings with PSMA-targeted radiotracers in nonprostate malignancies have been in case reports and small case series, and the field must adopt a more thorough approach to the design and execution of larger prospective trials to realize the potential of these promising agents outside prostate cancer. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

Echogenic Glycol Chitosan Nanoparticles for Ultrasound-Triggered Cancer Theranostics

PubMed Central

Min, Hyun Su; You, Dong Gil; Son, Sejin; Jeon, Sangmin; Park, Jae Hyung; Lee, Seulki; Kwon, Ick Chan; Kim, Kwangmeyung

2015-01-01

Theranostic nanoparticles hold great promise for simultaneous diagnosis of diseases, targeted drug delivery with minimal toxicity, and monitoring of therapeutic efficacy. However, one of the current challenges in developing theranostic nanoparticles is enhancing the tumor-specific targeting of both imaging probes and anticancer agents. Herein, we report the development of tumor-homing echogenic glycol chitosan-based nanoparticles (Echo-CNPs) that concurrently execute cancer-targeted ultrasound (US) imaging and US-triggered drug delivery. To construct this novel Echo-CNPs, an anticancer drug and bioinert perfluoropentane (PFP), a US gas precursor, were simultaneously encapsulated into glycol chitosan nanoparticles using the oil in water (O/W) emulsion method. The resulting Echo-CNPs had a nano-sized particle structure, composing of hydrophobic anticancer drug/PFP inner cores and a hydrophilic glycol chitosan polymer outer shell. The Echo-CNPs had a favorable hydrodynamic size of 432 nm, which is entirely different from the micro-sized core-empty conventional microbubbles (1-10 μm). Furthermore, Echo-CNPs showed the prolonged echogenicity via the sustained microbubble formation process of liquid-phase PFP at the body temperature and they also presented a US-triggered drug release profile through the external US irradiation. Interestingly, Echo-CNPs exhibited significantly increased tumor-homing ability with lower non-specific uptake by other tissues in tumor-bearing mice through the nanoparticle's enhanced permeation and retention (EPR) effect. Conclusively, theranostic Echo-CNPs are highly useful for simultaneous cancer-targeting US imaging and US-triggered delivery in cancer theranostics. PMID:26681985

Study on feasibility of laser reflective tomography with satellite-accompany

NASA Astrophysics Data System (ADS)

Gu, Yu; Hu, Yi-hua; Hao, Shi-qi; Gu, You-lin; Zhao, Nan-xiang; Wang, Yang-yang

2015-10-01

Laser reflective tomography is a long-range, high-resolution active detection technology, whose advantage is that the spatial resolution is unrelated with the imaging distance. Accompany satellite is a specific satellite around the target spacecraft with encircling movement. When using the accompany satellite to detect the target aircraft, multi-angle echo data can be obtained with the application of reflective tomography imaging. The feasibility of such detection working mode was studied in this article. Accompany orbit model was established with horizontal circular fleet and the parameters of accompany flight was defined. The simulation of satellite-to-satellite reflective tomography imaging with satellite-accompany was carried out. The operating mode of reflective tomographic data acquisition from monostatic laser radar was discussed and designed. The flight period, which equals to the all direction received data consuming time, is one of the important accompany flight parameters. The azimuth angle determines the plane of image formation while the elevation angle determines the projection direction. Both of the azimuth and elevation angles guide the satellite attitude stability controller in order to point the laser radar spot on the target. The influences of distance between accompany satellite and target satellite on tomographic imaging consuming time was analyzed. The influences of flight period, azimuth angle and elevation angle on tomographic imaging were analyzed as well. Simulation results showed that the satellite-accompany laser reflective tomography is a feasible and effective method to the satellite-to-satellite detection.

Superpixel Based Factor Analysis and Target Transformation Method for Martian Minerals Detection

NASA Astrophysics Data System (ADS)

Wu, X.; Zhang, X.; Lin, H.

2018-04-01

The Factor analysis and target transformation (FATT) is an effective method to test for the presence of particular mineral on Martian surface. It has been used both in thermal infrared (Thermal Emission Spectrometer, TES) and near-infrared (Compact Reconnaissance Imaging Spectrometer for Mars, CRISM) hyperspectral data. FATT derived a set of orthogonal eigenvectors from a mixed system and typically selected first 10 eigenvectors to least square fit the library mineral spectra. However, minerals present only in a limited pixels will be ignored because its weak spectral features compared with full image signatures. Here, we proposed a superpixel based FATT method to detect the mineral distributions on Mars. The simple linear iterative clustering (SLIC) algorithm was used to partition the CRISM image into multiple connected image regions with spectral homogeneous to enhance the weak signatures by increasing their proportion in a mixed system. A least square fitting was used in target transformation and performed to each region iteratively. Finally, the distribution of the specific minerals in image was obtained, where fitting residual less than a threshold represent presence and otherwise absence. We validate our method by identifying carbonates in a well analysed CRISM image in Nili Fossae on Mars. Our experimental results indicate that the proposed method work well both in simulated and real data sets.

Nanoparticle-enabled, image-guided treatment planning of target specific RNAi therapeutics in an orthotopic prostate cancer model.

PubMed

Lin, Qiaoya; Jin, Cheng S; Huang, Huang; Ding, Lili; Zhang, Zhihong; Chen, Juan; Zheng, Gang

2014-08-13

The abilities to deliver siRNA to its intended action site and assess the delivery efficiency are challenges for current RNAi therapy, where effective siRNA delivery will join force with patient genetic profiling to achieve optimal treatment outcome. Imaging could become a critical enabler to maximize RNAi efficacy in the context of tracking siRNA delivery, rational dosimetry and treatment planning. Several imaging modalities have been used to visualize nanoparticle-based siRNA delivery but rarely did they guide treatment planning. We report a multimodal theranostic lipid-nanoparticle, HPPS(NIR)-chol-siRNA, which has a near-infrared (NIR) fluorescent core, enveloped by phospholipid monolayer, intercalated with siRNA payloads, and constrained by apoA-I mimetic peptides to give ultra-small particle size (<30 nm). Using fluorescence imaging, we demonstrated its cytosolic delivery capability for both NIR-core and dye-labeled siRNAs and its structural integrity in mice through intravenous administration, validating the usefulness of NIR-core as imaging surrogate for non-labeled therapeutic siRNAs. Next, we validated the targeting specificity of HPPS(NIR)-chol-siRNA to orthotopic tumor using sequential four-steps (in vivo, in situ, ex vivo and frozen-tissue) fluorescence imaging. The image co-registration of computed tomography and fluorescence molecular tomography enabled non-invasive assessment and treatment planning of siRNA delivery into the orthotopic tumor, achieving efficacious RNAi therapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeted detection of murine colonic dysplasia in vivo with flexible multispectral scanning fiber endoscopy

NASA Astrophysics Data System (ADS)

Joshi, Bishnu P.; Miller, Sharon J.; Lee, Cameron; Gustad, Adam; Seibel, Eric J.; Wang, Thomas D.

2012-02-01

We demonstrate a multi-spectral scanning fiber endoscope (SFE) that collects fluorescence images in vivo from three target peptides that bind specifically to murine colonic adenomas. This ultrathin endoscope was demonstrated in a genetically engineered mouse model of spontaneous colorectal adenomas based on somatic Apc (adenomatous polyposis coli) gene inactivation. The SFE delivers excitation at 440, 532, 635 nm with <2 mW per channel. The target 7-mer peptides were conjugated to visible organic dyes, including 7-Diethylaminocoumarin-3-carboxylic acid (DEAC) (λex=432 nm, λem=472 nm), 5-Carboxytetramethylrhodamine (5-TAMRA) (λex=535 nm, λem=568 nm), and CF-633 (λex=633 nm, λem=650 nm). Target peptides were first validated using techniques of pfu counting, flow cytometry and previously established methods of fluorescence endoscopy. Peptides were applied individually or in combination and detected with fluorescence imaging. The ability to image multiple channels of fluorescence concurrently was successful for all three channels in vitro, while two channels were resolved simultaneously in vivo. Selective binding of the peptide was evident to adenomas and not to adjacent normal-appearing mucosa. Multispectral wide-field fluorescence detection using the SFE is achievable, and this technology has potential to advance early cancer detection and image-guided therapy in human patients by simultaneously visualizing multiple over expressed molecular targets unique to dysplasia.

Multifunctional Poly(L-lactide)-Polyethylene Glycol-Grafted Graphene Quantum Dots for Intracellular MicroRNA Imaging and Combined Specific-Gene-Targeting Agents Delivery for Improved Therapeutics.

PubMed

Dong, Haifeng; Dai, Wenhao; Ju, Huangxian; Lu, Huiting; Wang, Shiyan; Xu, Liping; Zhou, Shu-Feng; Zhang, Yue; Zhang, Xueji

2015-05-27

Photoluminescent (PL) graphene quantum dots (GQDs) with large surface area and superior mechanical flexibility exhibit fascinating optical and electronic properties and possess great promising applications in biomedical engineering. Here, a multifunctional nanocomposite of poly(l-lactide) (PLA) and polyethylene glycol (PEG)-grafted GQDs (f-GQDs) was proposed for simultaneous intracellular microRNAs (miRNAs) imaging analysis and combined gene delivery for enhanced therapeutic efficiency. The functionalization of GQDs with PEG and PLA imparts the nanocomposite with super physiological stability and stable photoluminescence over a broad pH range, which is vital for cell imaging. Cell experiments demonstrate the f-GQDs excellent biocompatibility, lower cytotoxicity, and protective properties. Using the HeLa cell as a model, we found the f-GQDs effectively delivered a miRNA probe for intracellular miRNA imaging analysis and regulation. Notably, the large surface of GQDs was capable of simultaneous adsorption of agents targeting miRNA-21 and survivin, respectively. The combined conjugation of miRNA-21-targeting and survivin-targeting agents induced better inhibition of cancer cell growth and more apoptosis of cancer cells, compared with conjugation of agents targeting miRNA-21 or survivin alone. These findings highlight the promise of the highly versatile multifunctional nanocomposite in biomedical application of intracellular molecules analysis and clinical gene therapeutics.

Targeted detection of murine colonic dysplasia in vivo with flexible multispectral scanning fiber endoscopy

NASA Astrophysics Data System (ADS)

Miller, Sharon J.; Lee, Cameron M.; Joshi, Bishnu P.; Gaustad, Adam; Seibel, Eric J.; Wang, Thomas D.

2012-02-01

Gastrointestinal cancers are heterogeneous and can overexpress several protein targets that can be imaged simultaneously on endoscopy using multiple molecular probes. We aim to demonstrate a multispectral scanning fiber endoscope for wide-field fluorescence detection of colonic dysplasia. Excitation at 440, 532, and 635 nm is delivered into a single spiral scanning fiber, and fluorescence is collected by a ring of light-collecting optical fibers placed around the instrument periphery. Specific-binding peptides are selected with phage display technology using the CPC;Apc mouse model of spontaneous colonic dysplasia. Validation of peptide specificity is performed on flow cytometry and in vivo endoscopy. The peptides KCCFPAQ, AKPGYLS, and LTTHYKL are selected and labeled with 7-diethylaminocoumarin-3-carboxylic acid (DEAC), 5-carboxytetramethylrhodamine (TAMRA), and CF633, respectively. Separate droplets of KCCFPAQ-DEAC, AKPGYLS-TAMRA, and LTTHYKL-CF633 are distinguished at concentrations of 100 and 1 μM. Separate application of the fluorescent-labeled peptides demonstrate specific binding to colonic adenomas. The average target/background ratios are 1.71+/-0.19 and 1.67+/-0.12 for KCCFPAQ-DEAC and AKPGYLS-TAMRA, respectively. Administration of these two peptides together results in distinct binding patterns in the blue and green channels. Specific binding of two or more peptides can be distinguished in vivo using a novel multispectral endoscope to localize colonic dysplasia on real-time wide-field imaging.

Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

PubMed

Hamel, Wolfgang; Köppen, Johannes A; Alesch, François; Antonini, Angelo; Barcia, Juan A; Bergman, Hagai; Chabardes, Stephan; Contarino, Maria Fiorella; Cornu, Philippe; Demmel, Walter; Deuschl, Günther; Fasano, Alfonso; Kühn, Andrea A; Limousin, Patricia; McIntyre, Cameron C; Mehdorn, H Maximilian; Pilleri, Manuela; Pollak, Pierre; Rodríguez-Oroz, Maria C; Rumià, Jordi; Samuel, Michael; Timmermann, Lars; Valldeoriola, Francesc; Vesper, Jan; Visser-Vandewalle, Veerle; Volkmann, Jens; Lozano, Andres M

2017-03-01

Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Gold-manganese nanoparticles for targeted diagnostic and imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Murph, Simona Hunyadi

Imagine the possibility of non-invasive, non-radiation based Magnetic resonance imaging (MRI) in combating cardiac disease. Researchers at the Savannah River National Laboratory (SRNL) are developing a process that would use nanotechnology in a novel, targeted approach that would allow MRIs to be more descriptive and brighter, and to target specific organs. Researchers at SRNL have discovered a way to use multifunctional metallic gold-manganese nanoparticles to create a unique, targeted positive contrast agent. SRNL Senior Scientist Dr. Simona Hunyadi Murph says she first thought of using the nanoparticles for cardiac disease applications after learning that people who survive an infarct exhibitmore » up to 15 times higher rate of developing chronic heart failure, arrhythmias and/or sudden death compared to the general population. Without question, nanotechnology will revolutionize the future of technology. The development of functional nanomaterials with multi-detection modalities opens up new avenues for creating multi-purpose technologies for biomedical applications.« less

MRI-guided targeting delivery of doxorubicin with reduction-responsive lipid-polymer hybrid nanoparticles.

PubMed

Wu, Bo; Lu, Shu-Ting; Deng, Kai; Yu, Hui; Cui, Can; Zhang, Yang; Wu, Ming; Zhuo, Ren-Xi; Xu, Hai-Bo; Huang, Shi-Wen

2017-01-01

In recent years, there has been increasing interest in developing a multifunctional nanoscale platform for cancer monitoring and chemotherapy. However, there is still a big challenge for current clinic contrast agents to improve their poor tumor selectivity and response. Herein, we report a new kind of Gd complex and folate-coated redox-sensitive lipid-polymer hybrid nanoparticle (Gd-FLPNP) for tumor-targeted magnetic resonance imaging and therapy. Gd-FLPNPs can simultaneously accomplish diagnostic imaging, and specific targeting and controlled release of doxorubicin (DOX). They exhibit good monodispersity, excellent size stability, and a well-defined core-shell structure. Paramagnetic nanoparticles based on gadolinium-diethylenetriaminepentaacetic acid-bis-cetylamine have paramagnetic properties with an approximately two-fold enhancement in the longitudinal relaxivity compared to clinical used Magnevist. For targeted and reduction-sensitive drug delivery, Gd-FLPNPs released DOX faster and enhanced cell uptake in vitro, and exhibited better antitumor effect both in vitro and in vivo.

Schedule for CT image guidance in treating prostate cancer with helical tomotherapy

PubMed Central

Beldjoudi, G; Yartsev, S; Bauman, G; Battista, J; Van Dyk, J

2010-01-01

The aim of this study was to determine the effect of reducing the number of image guidance sessions and patient-specific target margins on the dose distribution in the treatment of prostate cancer with helical tomotherapy. 20 patients with prostate cancer who were treated with helical tomotherapy using daily megavoltage CT (MVCT) imaging before treatment served as the study population. The average geometric shifts applied for set-up corrections, as a result of co-registration of MVCT and planning kilovoltage CT studies over an increasing number of image guidance sessions, were determined. Simulation of the consequences of various imaging scenarios on the dose distribution was performed for two patients with different patterns of interfraction changes in anatomy. Our analysis of the daily set-up correction shifts for 20 prostate cancer patients suggests that the use of four fractions would result in a population average shift that was within 1 mm of the average obtained from the data accumulated over all daily MVCT sessions. Simulation of a scenario in which imaging sessions are performed at a reduced frequency and the planning target volume margin is adapted provided significantly better sparing of organs at risk, with acceptable reproducibility of dose delivery to the clinical target volume. Our results indicate that four MVCT sessions on helical tomotherapy are sufficient to provide information for the creation of personalised target margins and the establishment of the new reference position that accounts for the systematic error. This simplified approach reduces overall treatment session time and decreases the imaging dose to the patient. PMID:19505966

Bioconjugated Quantum Dots for In Vivo Molecular and Cellular Imaging

PubMed Central

Smith, Andrew M.; Duan, Hongwei; Mohs, Aaron M.; Nie, Shuming

2008-01-01

Semiconductor quantum dots (QDs) are tiny light-emitting particles on the nanometer scale, and are emerging as a new class of fluorescent labels for biology and medicine. In comparison with organic dyes and fluorescent proteins, they have unique optical and electronic properties, with size-tunable light emission, superior signal brightness, resistance to photobleaching, and broad absorption spectra for simultaneous excitation of multiple fluorescence colors. QDs also provide a versatile nanoscale scaffold for designing multifunctional nanoparticles with both imaging and therapeutic functions. When linked with targeting ligands such as antibodies, peptides or small molecules, QDs can be used to target tumor biomarkers as well as tumor vasculatures with high affinity and specificity. Here we discuss the synthesis and development of state-of-the-art QD probes and their use for molecular and cellular imaging. We also examine key issues for in vivo imaging and therapy, such as nanoparticle biodistribution, pharmacokinetics, and toxicology. PMID:18495291

Repetition Blindness for Natural Images of Objects with Viewpoint Changes

PubMed Central

Buffat, Stéphane; Plantier, Justin; Roumes, Corinne; Lorenceau, Jean

2013-01-01

When stimuli are repeated in a rapid serial visual presentation (RSVP), observers sometimes fail to report the second occurrence of a target. This phenomenon is referred to as “repetition blindness” (RB). We report an RSVP experiment with photographs in which we manipulated object viewpoints between the first and second occurrences of a target (0°, 45°, or 90° changes), and spatial frequency (SF) content. Natural images were spatially filtered to produce low, medium, or high SF stimuli. RB was observed for all filtering conditions. Surprisingly, for full-spectrum (FS) images, RB increased significantly as the viewpoint reached 90°. For filtered images, a similar pattern of results was found for all conditions except for medium SF stimuli. These findings suggest that object recognition in RSVP are subtended by viewpoint-specific representations for all spatial frequencies except medium ones. PMID:23346069

Use of a Novel Rover-mounted Fluorescence Imager and Fluorescent Probes to Detect Biological Material in the Atacama Desert in Daylight

NASA Technical Reports Server (NTRS)

Weinstein, S.; Pane, D.; Warren-Rhodes, K.; Cockell, C.; Ernst, L. A.; Minkley, E.; Fisher, G.; Emani, S.; Wettergreen, D. S.; Wagner, M.

2005-01-01

We have developed an imaging system, the Fluorescence Imager (FI), for detecting fluorescence signals from sparse microorganisms and biofilms during autonomous rover exploration. The fluorescence signals arise both from naturally occurring chromophores, such as chlorophyll of cyanobacteria and lichens, and from fluorescent probes applied to soil and rocks. Daylight imaging has been accomplished by a novel use of a high-powered flashlamp synchronized to a CCD camera. The fluorescent probes are cell permanent stains that have extremely low intrinsic fluorescence (quantum yields less than 0.01) and a large fluorescence enhancement (quantum yields greater than 0.4) when bound to the target. Each probe specifically targets either carbohydrates, proteins, nucleic acids or membrane lipids, the four classes of macromolecules found in terrestrial life. The intent of the probes is to interrogate the environment for surface and endolithic life forms.