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Sample records for angiogenesis imaging agent

  1. PET Imaging of Angiogenesis

    PubMed Central

    Niu, Gang; Chen, Xiaoyuan

    2009-01-01

    Synopsis Angiogenesis is a highly-controlled process that is dependent on the intricate balance of both promoting and inhibiting factors, involved in various physiological and pathological processes. A comprehensive understanding of the molecular mechanisms that regulate angiogenesis has resulted in the design of new and more effective therapeutic strategies. Due to insufficient sensitivity to detect therapeutic effects by using standard clinical endpoints or by looking for physiological improvement, a multitude of imaging techniques have been developed to assess tissue vasculature on the structural, functional and molecular level. Imaging is expected to provide a novel approach to noninvasively monitor angiogenesis, to optimize the dose of new antiangiogenic agents and to assess the efficacy of therapies directed at modulation of the angiogenic process. All these methods have been successfully used preclinically and will hopefully aid in antiangiogenic drug development in animal studies. In this review article, the application of PET in angiogenesis imaging at both functional and molecular level will be discussed. For PET imaging of angiogenesis related molecular markers, we emphasize integrin αvβ3, VEGF/VEGFR, and MMPs. PMID:20046926

  2. Spatiotemporal correlation of ultrasound contrast agent dilution curves for angiogenesis localization by dispersion imaging.

    PubMed

    Kuenen, Maarten P J; Saidov, Tamerlan A; Wijkstra, Hessel; de la Rosette, Jean J M C H; Mischi, Massimo

    2013-12-01

    The major role of angiogenesis in cancer development has driven many researchers to investigate the prospects of noninvasive cancer imaging based on assessment of microvascular perfusion. The limited results so far may be caused by the complex and contradictory effects of angiogenesis on perfusion. Alternatively, assessment of ultrasound contrast agent dispersion kinetics, resulting from features such as density and tortuosity, has shown a promising potential to characterize angiogenic effects on the microvascular structure. This method, referred to as contrast-ultrasound dispersion imaging (CUDI), is based on contrast-enhanced ultrasound imaging after an intravenous contrast agent bolus injection. In this paper, we propose a new spatiotemporal correlation analysis to perform CUDI. We provide the rationale for indirect estimation of local dispersion by deriving the analytical relation between dispersion and the correlation coefficient among neighboring time-intensity curves obtained at each pixel. This robust analysis is inherently normalized and does not require curve-fitting. In a preliminary validation of the method for localization of prostate cancer, the results of this analysis show superior cancer localization performance (receiver operating characteristic curve area of 0.89) compared with those of previously reported CUDI implementations and perfusion estimation methods.

  3. Ultrasound Molecular Imaging of Tumor Angiogenesis with an Integrin Targeted Microbubble Contrast Agent

    PubMed Central

    Anderson, Christopher R.; Hu, Xiaowen; Tlaxca, Jose; Decleves, Anne-Emilie; Houghtaling, Robert; Sharma, Kumar; Lawrence, Michael; Ferrara, Katherine; Rychak, Joshua J.

    2010-01-01

    Rationale and Objectives Ultrasound molecular imaging is an emerging technique for sensitive detection of intravascular targets. Molecular imaging of angiogenesis has strong potential for both clinical use and as a research tool in tumor biology and the development of anti-angiogenic therapies. Our objective is to develop a robust microbubble (MB) ultrasound contrast agent platform to which targeting ligands can be conjugated by biocompatible, covalent conjugation chemistry, and to develop a pure low mechanical index imaging processing method and corresponding quantifying method. The microbubbles and the imaging methods were evaluated in a mouse model of breast cancer in vivo. Materials and Methods We utilized a cyclic RGD (cRGD) pentapeptide containing a terminal cysteine group conjugated to the surface of MB bearing pyridyldithio-propionate (PDP) for targeting αvβ3 integrins. As negative controls, MB without a ligand or MB bearing a scrambled sequence (cRAD) were prepared. To enable characterization of peptides bound to MB surfaces, the cRGD peptide was labeled with FITC and detected by plate fluorometry, flow cytometry, and fluorescence microscopy. Targeted adhesion of cRGD-MB was demonstrated in an in vitro flow adhesion assay against recombinant murine αvβ3 integrin protein and αvβ3 integrin-expressing endothelial cells (bEnd.3). The specificity of cRGD-MB for αvβ3 integrin was demonstrated by treating bEnd.3 EC with a blocking antibody. A murine model of mammary carcinoma was used to assess targeted adhesion and ultrasound molecular imaging in vivo. The targeted microbubbles were visualized using a low mechanical index contrast imaging pulse sequence, and quantified by intensity normalization and two-dimensional Fourier transform analysis, Results The cRGD ligand concentration on the MB surface was ~8.2 × 106 molecules/MB. At a wall shear stress of 1.0 dynes/cm2, cRGD-MB exhibited 5-fold higher adhesion to immobilized recombinant αvβ3 integrin

  4. Dynamic contrast-enhanced MR imaging kinetic parameters and molecular weight of dendritic contrast agents in tumor angiogenesis in mice.

    PubMed

    de Lussanet, Quido G; Langereis, Sander; Beets-Tan, Regina G H; van Genderen, Marcel H P; Griffioen, Arjan W; van Engelshoven, Jos M A; Backes, Walter H

    2005-04-01

    To evaluate the relationship between dynamic contrast agent-enhanced magnetic resonance (MR) imaging-derived kinetic parameters and contrast agents of equal chemical composition and configuration but with different molecular weights in a tumor angiogenesis model. This study was approved by the ethical review committee. Maintenance and care of animals was in compliance with guidelines set by the institutional animal care committee. Dynamic contrast-enhanced MR imaging was performed with dendritic contrast agents in 16 mice with tumor xenografts; mice were placed in groups of four for each molecular weight of the contrast agent. The magnitude and spatial distribution of kinetic parameters (transfer coefficient [K(PS)] and plasma fraction [f(PV)]) were compared with molecular weight of the contrast agent by determining the Spearman correlation coefficient (r) and the quantitative relationship between the endothelial K(PS) and molecular weight. Inverse relationships between molecular weight of contrast agent and K(PS) and f(PV) of tumor rim (r = -0.8, P < .001 and r = -0.5, P = .04, respectively) and core (r = -0.7, P = .004 and r = -0.6, P = .01, respectively) were observed. The quantitative relationship between K(PS) and molecular weight (MW) was K(PS) = 0.4/MW(0.44). A decreasing stepwise pattern in f(PV) was noted between contrast agents with low (0.7- and 3.0-kDa) molecular weight and those with high (12- and 51-kDa) molecular weight. Macromolecular permeability is best measured with high-molecular-weight contrast agents; endothelial K(PS) values measured with low-molecular-weight contrast agents incorporate tissue perfusion and permeability and demonstrate heterogeneous microcirculatory flow. (c) RSNA, 2005.

  5. Radionuclide imaging of tumor angiogenesis.

    PubMed

    Dijkgraaf, Ingrid; Boerman, Otto C

    2009-12-01

    Angiogenesis is a multistep process regulated by pro- and antiangiogenic factors. In order to grow and metastasize, tumors need a constant supply of oxygen and nutrients. For growth beyond 1-2 mm in size, tumors are dependent on angiogenesis. Inhibition of angiogenesis is a new cancer treatment strategy that is now widely investigated clinically. Researchers have begun to search for objective measures that indicate pharmacologic responses to antiangiogenic drugs. Therefore, there is a great interest in techniques to visualize angiogenesis in growing tumors noninvasively. Several markers have been described that are preferentially expressed on newly formed blood vessels in tumors (alpha(v)beta(3) integrin, vascular endothelial growth factor, and its receptor, prostate-specific membrane antigen) and in the extracellular matrix surrounding newly formed blood vessels (extra domain B of fibronectin, Tenascin-C, matrix metalloproteinases, and Robo-4). Several ligands targeting these markers have been tested as a radiotracer for imaging angiogenesis in tumors. The potential of some of these tracers, such as radiolabeled cyclic RGD peptides and radiolabeled anti-PSMA antibodies, has already been tested in cancer patients, while for markers such as Robo-4, the ligand has not yet been identified. In this review, an overview on the currently used nuclear imaging probes for noninvasive visualization of tumor angiogenesis is given.

  6. Science to practice: will contrast agents for molecular imaging of angiogenesis help overcome the limitations of functional vascular imaging?

    PubMed

    Kiessling, Fabian

    2013-08-01

    Schmieder and colleagues introduced a new molecular magnetic resonance (MR) probe with a promising lipophilic gadolinium chelate complex that provides high relaxivity. Results of in vivo experiments clearly demonstrate the excellence of the probe for longitudinally monitoring α(v)β(3) integrin expression in tumors. In addition, the authors have developed a robust nonrelaxometric analysis method with which to quantify the spatial distribution of molecular MR probes. In combination with a molecular probe targeting angiogenesis, this approach may be superior to functional vascular assessments. It has the potential to enable better detection of angiogenic regions in heterogeneous tumors and to improve the monitoring and individualization of antiangiogenic treatments.

  7. 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.

  8. BR55: a lipopeptide-based VEGFR2-targeted ultrasound contrast agent for molecular imaging of angiogenesis.

    PubMed

    Pochon, Sibylle; Tardy, Isabelle; Bussat, Philippe; Bettinger, Thierry; Brochot, Jean; von Wronski, Mathew; Passantino, Lisa; Schneider, Michel

    2010-02-01

    BR55, an ultrasound contrast agent functionalized with a heterodimer peptide targeting the vascular endothelial growth factor receptor 2 (VEGFR2), was evaluated in vitro and in vivo, demonstrating its potential for specific tumor detection. The targeted contrast agent was prepared by incorporation of a biospecific lipopeptide into the microbubble membrane. Experiments were performed in vitro to demonstrate the binding capacities of BR55 microbubbles on immobilized receptor proteins and on various endothelial or transfected cells expressing VEGFR2. The performance of BR55 microbubbles was compared with that of streptavidin-conjugated microbubbles targeted to the same receptor by coupling them to a biotinylated antibody. The specificity of BR55 binding to human and mouse endothelial cells was determined in competition experiments with the free lipopeptide, vascular endothelial growth factor (VEGF), or a VEGFR2-specific antibody. Molecular ultrasound imaging of VEGFR2 was performed in an orthotopic breast tumor model in rats using a nondestructive, contrast-specific imaging mode. BR55 was shown to bind specifically to the immobilized recombinant VEGFR2 under flow (dynamic conditions). BR55 accumulation on the target over time was similar to that of microbubbles bearing a specific antibody. BR55 avidly bound to cells expressing VEGFR2, and the pattern of microbubble distribution was correlated with the pattern of receptor expression determined by immunocytochemistry. The binding of targeted microbubbles on cells was competed off by an excess of free lipopeptide, the natural ligand (VEGF) and by a VEGFR2-specific antibody (P < 0.001). Although selected for the human receptor, the VEGFR2-binding lipopeptide was also shown to recognize the rodent receptor. Tumor perfusion was assessed during the vascular phase of BR55, and then the malignant lesion was highlighted by specific accumulation of the targeted microbubbles on tumoral endothelium. The presence of VEGFR2 was

  9. A novel Tc-99 m and fluorescence labeled peptide as a multimodal imaging agent for targeting angiogenesis in a murine tumor model.

    PubMed

    Kim, Myoung Hyoun; Kim, Chang Guhn; Kim, Seul-Gi; Kim, Dae-Weung

    2016-11-01

    The serine-aspartic acid-valine (SDV) peptide binds specifically to integrin αV β3 . In the present study, we successfully developed a TAMRA-GHEG-ECG-SDV peptide labeled with both Tc-99 m and TAMRA to target the integrin αV β3 of tumor cells; furthermore, we evaluated the diagnostic performance of Tc-99 m TAMRA-GHEG-ECG-SDV as a dual-modality imaging agent for tumor of the murine model. TAMRA-GHEG-ECG-SDV was synthesized using Fmoc solid-phase peptide synthesis. Radiolabeling of TAMRA-GHEG-ECG-SDV with Tc-99 m was done using ligand exchange methods. Labeling stability and cytotoxicity studies were performed. Gamma camera imaging, biodistribution and ex vivo imaging studies were performed in murine models with HT-1080 and HT-29 tumors. A tumor tissue slide was prepared and analyzed using confocal microscopy. After radiolabeling procedures with Tc-99 m, the Tc-99 m TAMRA-GHEG-ECG-SDV complexes were prepared in high yield (>99%). In the gamma camera imaging study, a substantial uptake of Tc-99 m TAMRA-GHEG-ECG-SDV into HT-1080 tumor (integrin αV β3 positive) and low uptake of Tc-99 m TAMRA-GHEG-ECG-SDV into HT-29 tumor (integrin αV β3 negative) were demonstrated. A competition study revealed that HT-1080 tumor uptake was effectively blocked by the co-injection of an excess concentration of SDV. Specific uptake of Tc-99 m TAMRA-GHEG-ECG-SDV was confirmed by biodistribution, ex vivo imaging and confocal microscopy studies. Our in vivo and in vitro studies revealed substantial uptake of Tc-99 m TAMRA-GHEG-ECG-SDV in the integrin αV β3 -positive tumor. Tc-99 m TAMRA-GHEG-ECG-SDV could be a good candidate for a dual-modality imaging agent targeting tumor angiogenesis. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Whole-body distribution and radiation dosimetry of (68)Ga-NOTA-RGD, a positron emission tomography agent for angiogenesis imaging.

    PubMed

    Kim, Joong Hyun; Lee, Jae Sung; Kang, Keon Wook; Lee, Ho-Young; Han, Sae-Won; Kim, Tae-You; Lee, Yun-Sang; Jeong, Jae Min; Lee, Dong Soo

    2012-02-01

    (68)Ga labeled NOTA-RGD was a recently developed positron emission tomography (PET) radiotracer for the visualization of angiogenesis, and is regarded as a promising imaging agent for cancer and several other disorders. In this study, we investigated the whole-body distribution and radiation dosimetry of (68)Ga-NOTA-RGD in humans. Ten cancer patients (53.7 ± 13.5 years; 61.5 ± 7.4  kg) participated in this study. PET scans were performed using a PET/computed tomography (scanner in three-dimensional mode). After an intravenous injection of 172.4 ± 20.5  MBq of (68)Ga-NOTA-RGD, eight serial whole-body scans were performed during 90 minutes. Volumes of interest were drawn manually over the entire volumes of the urinary bladder, the gallbladder, heart, kidneys, liver, lungs, pancreas, spleen, and stomach. Time-activity curves were obtained from serial PET scan data. Residence times were calculated from areas under curve of time-activity curves and used as input to the OLINDA/EXM 1.1 software. The uptake of (68)Ga-NOTA-RGD was highest in the kidneys and urinary bladder. Radiation doses to kidneys and urinary bladder were 71.6 ± 28.4  μ Gy/MBq and 239.6 ± 56.6  μ Gy/MBq. Mean effective doses were 25.0 ± 4.4  μ Sv/MBq using International Commission of Radiation Protection (ICRP) publication 60 and 22.4 ± 3.8  μ Sv/MBq using ICRP publication 103 weighting factor. We evaluated the radiation dosimetry of (68)Ga labeled NOTA-RGD, which has an acceptable effective radiation dose.

  11. MO-F-CAMPUS-I-05: Radiation Dosimetry of 99mTc-IDA-D-[c(RGDfK)]2, a SPECT Agent for Angiogenesis Imaging

    SciTech Connect

    Kim, J

    2015-06-15

    Purpose: Tc-99m labeled IDA-D-[c(RGDfK){sub 2} ( {sup 99m}Tc-RGD) is a recently developed radiotracer for gamma camera or single photon emission computed tomography (SPECT) imaging and promising agent for the visualization of angiogenesis. In this study, we investigated the internal radiation dosimetry of {sup 99m}Tc-RGD in humans. Methods: Six normal controls (F:M=4:2; 68.3±3.2 years; 56.5±10.7 kg) were participated in this study. Simultaneous anterior and posterior scans of whole-body were performed using dual head gamma camera system. Before the emission scan, transmission scan was performed just before injection of {sup 99m}Tc-RGD using Co-57 flood source. After an intravenous injection of 388.7±29.3 MBq of {sup 99m}Tc-RGD, six serial emission scans were performed at 0, 1, 2, 4, 8 and 24 hours post-injection. The anterior and posterior images were geometrically averaged and attenuation correction was applied using transmission scan image. Regions of interest (ROIs) were drawn on liver, gallbladder, kidneys, urinary bladder, spleen, brain, and large intestine. Time activity curves were obtained from serial emission scan and ROIs. The number of disintegrations per unit activity administered (residence time) were calculated from the area under the curve of time activity curves and injected dose of each patient. Finally, the radiation dose for each organ and effective doses were obtained using OLINDA/EXM 1.1 software and residence time. Results: High radiation doses were reported on renal and biliary excretion tracks such as urinary bladder wall, upper large intestine, kidneys, liver and gallbladder wall and their doses were 19.15±6.84, 19.28±4.78, 15.67±0.90, 9.13±1.71 and 9.09±2.03 µGy/MBq, respectively. The effective dose and effective dose equivalent were 5.08±0.53 and 7.11±0.58 µSv/MBq, respectively. Conclusion: We evaluated the radiation dose of 99mTc-RGD, which has an acceptable effective radiation dose compare to the other Tc-99m labeled radio-tracers.

  12. Molecular Imaging System for Monitoring Tumor Angiogenesis

    NASA Astrophysics Data System (ADS)

    Aytac, Esra; Burcin Unlu, Mehmet

    2012-02-01

    In cancer, non-invasive imaging techniques that monitor molecular processes associated with the tumor angiogenesis could have a central role in the evaluation of novel antiangiogenic and proangiogenic therapies as well as early detection of the disease. Matrix metalloproteinases (MMP) can serve as specific biological targets for imaging of angiogenesis since expression of MMPs is required for angiogenesis and has been found to be upregulated in every type of human cancer and correlates with stage, invasive, metastatic properties and poor prognosis. However, for most cancers it is still unknown when, where and how MMPs are involved in the tumor angiogenesis [1]. Development of high-resolution, high sensitivity imaging techniques in parallel with the tumor models could prove invaluable for assessing the physical location and the time frame of MMP enzymatic acitivity. The goal of this study is to understand where, when and how MMPs are involved in the tumor angiogenesis. We will accomplish this goal by following two objectives: to develop a high sensitivity, high resolution molecular imaging system, to develop a virtual tumor simulator that can predict the physical location and the time frame of the MMP activity. In order to achieve our objectives, we will first develop a PAM system and develop a mathematical tumor model in which the quantitative data obtained from the PAM can be integrated. So, this work will develop a virtual tumor simulator and a molecular imaging system for monitoring tumor angiogenesis. 1.Kessenbrock, K., V. Plaks, and Z. Werb, MMP:regulators of the tumor microenvironment. Cell, 2010. 141(1)

  13. Assessment of tumor angiogenesis using fluorescence contrast agents

    NASA Astrophysics Data System (ADS)

    Chen, Yu; Liu, Qian; Huang, Ping; Hyman, Shay; Intes, Xavier; Lee, William; Chance, Britton

    2003-12-01

    Angiogenesis is an important factor for further tumor growth and thus could be an attractive therapeutic target. Optical imaging can provide a non-invasive way to measure the permeability of tumor blood vessels and assess the tumor vasculature. We have developed a dual-channel near-infrared fluorescence system for simultaneous measurement of the pharmacokinetics of tumorous and normal tissues with exogenous contrast agents. This frequency-domain system consists of the light source (780 nm laser diode), fiber optics, interference filter (830 nm) and the detector (PMT). The fluorescent contrast agent used in this study is Indocyanine Green (ICG), and the normal dosage is 100 μl at a concentration of 5 μM. In vivo animal study is performed on the K1735 melanoma-bearing mouse. The fluorescence signals both tumorous and normal tissues after the bolus injection of ICG through the tail vein are continuously recorded as a function of time. The data is fitted by a double-exponential model to reveal the wash-in and wash-out parameters of different tissues. We observed an elongated wash-out from the tumor compared with normal tissue (leg). The effect of radiation therapy on the tumor vasculature is also discussed.

  14. Pyrazoles as potential anti-angiogenesis agents: a contemporary overview

    PubMed Central

    Kasiotis, Konstantinos M.; Tzanetou, Evangelia N.; Haroutounian, Serkos A.

    2014-01-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently, several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research. PMID:25250310

  15. Pyrazoles as potential anti-angiogenesis agents: A contemporary overview

    NASA Astrophysics Data System (ADS)

    Kasiotis, Konstantinos; Tzanetou, Evangelia; Haroutounian, Serkos

    2014-09-01

    Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research.

  16. MR Molecular Imaging of Aortic Angiogenesis

    PubMed Central

    Cai, Kejia; Caruthers, Shelton D.; Huang, Wenjing; Williams, Todd A.; Zhang, Huiying; Wickline, Samuel A.; Lanza, Gregory M.; Winter, Patrick M.

    2012-01-01

    OBJECTIVES The objectives of this study were to use magnetic resonance (MR) molecular imaging to 1) characterize the aortic neovascular development in a rat model of atherosclerosis and 2) monitor the effects of an appetite suppressant on vascular angiogenesis progression. BACKGROUND The James C. Russell:LA corpulent rat strain (JCR:LA-cp) is a model of metabolic syndrome characterized by obesity, insulin resistance, hyperlipidemia, and vasculopathy, although plaque neovascularity has not been reported in this strain. MR molecular imaging with ανβ3-targeted nanoparticles can serially map angiogenesis in the aortic wall and monitor the progression of atherosclerosis. METHODS Six-week old JCR:LA-cp (+/?; lean, n = 5) and JCR:LA-cp (cp/cp; obese, n = 5) rats received standard chow, and 6 obese rats were fed the appetite suppressant benfluorex over 16 weeks. Body weight and food consumption were recorded at baseline and weeks 4, 8, 12, and 16. MR molecular imaging with ανβ3-targeted paramagnetic nanoparticles was performed at weeks 0, 8, and 16. Fasted plasma triglyceride, cholesterol, and glucose were measured immediately before MR scans. Plasma insulin and leptin levels were assayed at weeks 8 and 16. RESULTS Benfluorex reduced food consumption (p < 0.05) to the same rate as lean animals, but had no effect on serum cholesterol or triglyceride levels. MR (3-T) aortic signal enhancement with ανβ3-targeted nanoparticles was initially equivalent between groups, but increased (p < 0.05) in the untreated obese animals over 16 weeks. No signal change (p > 0.05) was observed in the benfluorex-treated or lean rat groups. MR differences paralleled adventitial microvessel counts, which increased (p < 0.05) among the obese rats and were equivalently low in the lean and benfluorex-treated animals (p > 0.05). Body weight, insulin, and leptin were decreased (p < 0.05) from the untreated obese animals by benfluorex, but not to the lean control levels (p < 0.05). CONCLUSIONS

  17. Angiogenesis in prostate cancer: onset, progression and imaging.

    PubMed

    Russo, Giovanna; Mischi, Massimo; Scheepens, Wout; De la Rosette, Jean J; Wijkstra, Hessel

    2012-12-01

    What's known on the subject? and What does the study add? Today, angiogenesis is known to play a key role in cancer growth and development. Emerging cancer treatments are based on the suppression of angiogenesis, and modern imaging techniques investigate changes in the microvasculature that are caused by angiogenesis. As for other forms of cancers, angiogenesis is well recognised as a fundamental process in the development of prostate cancer. The novelty of this extensive report on angiogenesis in cancer, with particular attention on prostate cancer and the imaging techniques able to detect it, is the new prospective to the subject. In contrast with the other available reviews, this report goes from 'theory' to 'practice', establishing a clear link between angiogenesis development and imaged angiogenesis features. Once the key role of angiogenesis in the development of cancer and in particular prostate cancer has been fully described, attention is turned to the current imaging methods with the potential to assess the angiogenesis process and, as a consequence, to detect and localise prostate cancer. • As confirmed by all available statistics, cancer represents a major clinical and societal problem in the developed world. The form of cancer with the highest incidence in men is prostate cancer. For prostate cancer, as well as for most forms of cancer, detection of the disease at an early stage is critical to reduce mortality and morbidity. • Today, it is well known that pathological angiogenesis represents a crucial step in cancer development and progression. Comparable with most forms of cancer, angiogenesis also plays a fundamental role for prostate cancer growth. • As a consequence, angiogenesis is an ideal target not only for novel anti-angiogenic therapies, but also for modern imaging techniques that aim at cancer localisation by detection of angiogenic microvascular changes. • These techniques are mainly based on magnetic resonance, ultrasound, and

  18. Molecular Imaging of Angiogenesis and Vascular Remodeling in Cardiovascular Pathology

    PubMed Central

    Golestani, Reza; Jung, Jae-Joon; Sadeghi, Mehran M.

    2016-01-01

    Angiogenesis and vascular remodeling are involved in a wide array of cardiovascular diseases, from myocardial ischemia and peripheral arterial disease, to atherosclerosis and aortic aneurysm. Molecular imaging techniques to detect and quantify key molecular and cellular players in angiogenesis and vascular remodeling (e.g., vascular endothelial growth factor and its receptors, αvβ3 integrin, and matrix metalloproteinases) can advance vascular biology research and serve as clinical tools for early diagnosis, risk stratification, and selection of patients who would benefit most from therapeutic interventions. To target these key mediators, a number of molecular imaging techniques have been developed and evaluated in animal models of angiogenesis and vascular remodeling. This review of the state of the art molecular imaging of angiogenesis and vascular (and valvular) remodeling, will focus mostly on nuclear imaging techniques (positron emission tomography and single photon emission tomography) that offer high potential for clinical translation. PMID:27275836

  19. Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

    NASA Astrophysics Data System (ADS)

    Wang, Jinfeng; Zhang, Lin; Pan, Xiaoyan; Dai, Bingling; Sun, Ying; Li, Chuansheng; Zhang, Jie

    2017-03-01

    Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis.

  20. Discovery of multi-target receptor tyrosine kinase inhibitors as novel anti-angiogenesis agents

    PubMed Central

    Wang, Jinfeng; Zhang, Lin; Pan, Xiaoyan; Dai, Bingling; Sun, Ying; Li, Chuansheng; Zhang, Jie

    2017-01-01

    Recently, we have identified a biphenyl-aryl urea incorporated with salicylaldoxime (BPS-7) as an anti-angiogenesis agent. Herein, we disclosed a series of novel anti-angiogenesis agents with BPS-7 as lead compound through combining diarylureas with N-pyridin-2-ylcyclopropane carboxamide. Several title compounds exhibited simultaneous inhibition effects against three pro-angiogenic RTKs (VEGFR-2, TIE-2 and EphB4). Some of them displayed potent anti-proliferative activity against human vascular endothelial cell (EA.hy926). In particular, two potent compounds (CDAU-1 and CDAU-2) could be considered as promising anti-angiogenesis agents with triplet inhibition profile. The biological evaluation and molecular docking results indicate that N-pyridin-2-ylcyclopropane carboxamide could serve as a hinge-binding group (HBG) for the discovery of multi-target anti-angiogenesis agents. CDAU-2 also exhibited promising anti-angiogenic potency in a tissue model for angiogenesis. PMID:28332573

  1. Radiotracer-based strategies to image angiogenesis.

    PubMed

    Haubner, R H; Wester, H J; Weber, W A; Schwaiger, M

    2003-09-01

    Tumour-induced angiogenesis plays an important role in tumour progression. Great efforts are made to develop therapeutic strategies to interfere with this process resulting in the starvation of the tumour. However, strategies to monitor conventional therapies seems to be inappropriate to control these approaches. Thus, there is a keen interest in developing methods supplying information about the corresponding therapeutical effects. Several radiotracer-based approaches focused on different targets in the angiogenic process are currently investigated. One class of tracers is based on matrix metalloproteinases inhibitors. These compounds show promising results in in vitro assays. However, initial data from in vivo studies using murine tumour models could not confirm successful non-invasive monitoring of MMP activity yet. Another strategy uses a radiolabelled single chain fragment against the ED-B domain of fibronectin, an extracellular matrix protein. Promising results demonstrated selective accumulation of the tracer in the tumour vasculature of a murine tumour model. Most of the studies are concentrated on the development of radiolabelled antagonists of the integrin alpha(v)beta(3). This heterodimeric transmembrane glycoprotein is involved in the migration of activated endothelial cells during formation of new vessels. Different compounds have been labelled with (18F), (111)In, (99m)Tc, (90)Y and several iodine isotopes. In in vitro assays most of them revealed high alpha(v)beta(3) affinity and selectivity. Moreover, in different murine tumour models successful non-invasive determination of alpha(v)beta(3) expression has been shown. Some of these approaches indicate that tumour-induced angiogenesis can be monitored in animal studies. Nevertheless, translation of these approaches into clinical settings allowing visualisation of tumour-induced angiogenesis in patients needs still to be demonstrated.

  2. Fluorescence imaging of angiogenesis in green fluorescent protein-expressing tumors

    NASA Astrophysics Data System (ADS)

    Yang, Meng; Baranov, Eugene; Jiang, Ping; Li, Xiao-Ming; Wang, Jin W.; Li, Lingna; Yagi, Shigeo; Moossa, A. R.; Hoffman, Robert M.

    2002-05-01

    The development of therapeutics for the control of tumor angiogenesis requires a simple, reliable in vivo assay for tumor-induced vascularization. For this purpose, we have adapted the orthotopic implantation model of angiogenesis by using human and rodent tumors genetically tagged with Aequorea victoria green fluorescent protein (GFP) for grafting into nude mice. Genetically-fluorescent tumors can be readily imaged in vivo. The non-luminous induced capillaries are clearly visible against the bright tumor fluorescence examined either intravitally or by whole-body luminance in real time. Fluorescence shadowing replaces the laborious histological techniques for determining blood vessel density. High-level GFP-expressing tumor cell lines made it possible to acquire the high-resolution real-time fluorescent optical images of angiogenesis in both primary tumors and their metastatic lesions in various human and rodent tumor models by means of a light-based imaging system. Intravital images of angiogenesis onset and development were acquired and quantified from a GFP- expressing orthotopically-growing human prostate tumor over a 19-day period. Whole-body optical imaging visualized vessel density increasing linearly over a 20-week period in orthotopically-growing, GFP-expressing human breast tumor MDA-MB-435. Vessels in an orthotopically-growing GFP- expressing Lewis lung carcinoma tumor were visualized through the chest wall via a reversible skin flap. These clinically-relevant angiogenesis mouse models can be used for real-time in vivo evaluation of agents inhibiting or promoting tumor angiogenesis in physiological micro- environments.

  3. Photoacoustic imaging of angiogenesis in subdermal islet transplant sites

    NASA Astrophysics Data System (ADS)

    Shi, Wei; Pawlick, Rena; Bruni, Antonio; Rafiei, Yasmin; Pepper, Andrew R.; Gala-Lopez, Boris; Choi, Min; Malcolm, Andrew; Zemp, Roger J.; Shapiro, A. M. James

    2016-03-01

    Exogenous insulin administration is the mainstay treatment therapy for patients with Type-1 diabetes mellitus (T1DM). However, for select patients, clinical islet transplantation is an alternative therapeutic treatment. In this procedure, islets are transplanted into the hepatic portal vein, and despite improved success within the last decade, obstacles are still associated with this approach. It has been discovered that the subcutaneous space may be an effective alternative site for islet transplantation, and may provide advantages of easy access and potential for simple monitoring. The ability to monitor islet viability and the transplant microenvironment may be key to future success in islet transplantation. A subcutaneous device-less technique has been developed to facilitate angiogenesis in the islet transplant site, however, a method for monitoring the potential engraftment site have yet to be explored fully. Here we demonstrate the ability to track angiogenesis in mice with 1, 2, 3 and 4 weeks post-catheter implant on both sides of the abdomen using a FujiFilm VisualSonics Vevo-LAZR system. Quantitative analysis on vessel densities exhibited gradual vessel growth successfully induced by catheter implantation. Our study demonstrates the ability of employing photoacoustic and micro-ultrasound imaging to track angiogenesis around the catheter site prior to islet transplantation.

  4. Micro-CT molecular imaging of tumor angiogenesis using a magnetite nano-cluster probe.

    PubMed

    Liu, Ping; Li, Jing; Zhang, Chunfu; Xu, Lisa X

    2013-06-01

    Due to its high resolution, micro-CT is desirable for molecular imaging of tumor angiogenesis. However, the sensitivity of micro-CT to contrast agents is relatively low. Therefore, the purpose of this study is to develop high micro-CT sensitive molecular imaging probes for direct visualization and dynamic monitoring of tumor angiogenesis. To this end, Arg-Gly-Asp (RGD) peptides conjugated magnetite nano clusters (RGD-MNCs) were developed by assembling individual magnetite nano particles into clusters with amphiphilic (maleimide) methoxypoly(ethylene glycol)-b-poly(lactic acid) ((Mal)mPEG-PLA) copolymer and subsequently encoding RGD peptides onto the clusters for specific targeting alpha(v)beta3 integrin. The hydrodynamic size of RGD-MNCs was about 85 nm. To test its specificity, alpha(v)beta3 positive cells (H1299) were incubated with magnetite nano clusters (MNCs), RGD-MNCs or RGD-MNCs competition with free RGD peptides. Prussian Blue staining and inductively coupled plasma optical emission spectrometer (ICP-OES) measurements indicated that the cell uptake of RGD-MNCs was significantly more than that of MNCs, which could be inhibited by free RGD peptides. For detection of tumor angiogenesis, mice bearing H1299 tumors were injected intravenously with RGD-MNCs at the dose of 400 micro mol Fe/kg. Tumor angiogenic hot spots as well as individual angiogenic vessels could be clearly manifested by micro-CT imaging 12 h post injection, which was dynamically monitored with the extension of probe circulation time. Subsequent histological studies of tumor tissues verified that RGD-MNCs registered tumor angiogenic vessels. Our study demonstrated that RGD-MNC probes fabricated in this study could be used to effectively target alpha(v)beta3 integrin. Using high resolution micro-CT in combination with the probes, tumor angiogenesis could be studied dynamically.

  5. Early Detection of Ovarian Cancer by Molecular Targeted Ultrasound Imaging Together with Serum Markers of Tumor-Associated Nuclear Change and Angiogenesis

    DTIC Science & Technology

    2013-10-01

    ultrasound molecular imaging agents enhances signal intensity and detection of OVCA’ was examined in specific aim 1 described in Year-1 report...improved the detection of OVCA at early stage. This improvement in OVCA detectability was due to the enhanced ultrasound imaging signal intensity ...Molecular Targeted Ultrasound Imaging Together with Serum Markers of Tumor-Associated Nuclear Change and Angiogenesis PRINCIPAL

  6. Clinically Approved Nanoparticle Imaging Agents

    PubMed Central

    Thakor, Avnesh S.; Jokerst, Jesse V.; Ghanouni, Pejman; Campbell, Jos L.; Mittra, Erik

    2016-01-01

    Nanoparticles are a new class of imaging agent used for both anatomic and molecular imaging. Nanoparticle-based imaging exploits the signal intensity, stability, and biodistribution behavior of submicron-diameter molecular imaging agents. This review focuses on nanoparticles used in human medical imaging, with an emphasis on radionuclide imaging and MRI. Newer nanoparticle platforms are also discussed in relation to theranostic and multimodal uses. PMID:27738007

  7. Ultrasound Molecular Imaging of Tumor Angiogenesis with a Neuropilin-1-Targeted Microbubble

    PubMed Central

    Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S.; Mahakian, Lisa M.; Lai, Chun-Yen; Tumbale, Spencer K.; Teesalu, Tambet; Hubbard, Neil E.; Borowsky, Alexander D.; Ferrara, Katherine W.

    2015-01-01

    Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ~6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7–21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis. PMID:25934284

  8. Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble.

    PubMed

    Zhang, Hua; Tam, Sarah; Ingham, Elizabeth S; Mahakian, Lisa M; Lai, Chun-Yen; Tumbale, Spencer K; Teesalu, Tambet; Hubbard, Neil E; Borowsky, Alexander D; Ferrara, Katherine W

    2015-07-01

    Ultrasound molecular imaging has great potential to impact early disease diagnosis, evaluation of disease progression and the development of target-specific therapy. In this paper, two neuropilin-1 (NRP) targeted peptides, CRPPR and ATWLPPR, were conjugated onto the surface of lipid microbubbles (MBs) to evaluate molecular imaging of tumor angiogenesis in a breast cancer model. Development of a molecular imaging agent using CRPPR has particular importance due to the previously demonstrated internalizing capability of this and similar ligands. In vitro, CRPPR MBs bound to an NRP-expressing cell line 2.6 and 15.6 times more than ATWLPPR MBs and non-targeted (NT) MBs, respectively, and the binding was inhibited by pretreating the cells with an NRP antibody. In vivo, the backscattered intensity within the tumor, relative to nearby vasculature, increased over time during the ∼6 min circulation of the CRPPR-targeted contrast agents providing high contrast images of angiogenic tumors. Approximately 67% of the initial signal from CRPPR MBs remained bound after the majority of circulating MBs had cleared (8 min), 8 and 4.5 times greater than ATWLPPR and NT MBs, respectively. Finally, at 7-21 days after the first injection, we found that CRPPR MBs cleared faster from circulation and tumor accumulation was reduced likely due to a complement-mediated recognition of the targeted microbubble and a decrease in angiogenic vasculature, respectively. In summary, we find that CRPPR MBs specifically bind to NRP-expressing cells and provide an effective new agent for molecular imaging of angiogenesis.

  9. A concise review of magnetic resonance molecular imaging of tumor angiogenesis by targeting integrin αvβ3 with magnetic probes.

    PubMed

    Liu, Yajie; Yang, Yi; Zhang, Chunfu

    2013-01-01

    Angiogenesis is an essential step for the growth and spread of malignant tumors. Accurate detection and quantification of tumor angiogenesis is important for early diagnosis of cancers as well as post therapy assessment of antiangiogenic drugs. The cell adhesion molecule integrin αvβ3 is a specific marker of angiogenesis, which is highly expressed on activated and proliferating endothelial cells, but generally not on quiescent endothelial cells. Therefore, in recent years, many different approaches have been developed for imaging αvβ3 expression, for the detection and characterization of tumor angiogenesis. The present review provides an overview of the current status of magnetic resonance molecular imaging of integrin αvβ3, including the new development of high sensitive contrast agents and strategies for improving the specificity of targeting probes and the biological effects of imaging probes on αvβ3 positive cells.

  10. Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks.

    PubMed

    Walpole, J; Chappell, J C; Cluceru, J G; Mac Gabhann, F; Bautch, V L; Peirce, S M

    2015-09-01

    Many biological processes are controlled by both deterministic and stochastic influences. However, efforts to model these systems often rely on either purely stochastic or purely rule-based methods. To better understand the balance between stochasticity and determinism in biological processes a computational approach that incorporates both influences may afford additional insight into underlying biological mechanisms that give rise to emergent system properties. We apply a combined approach to the simulation and study of angiogenesis, the growth of new blood vessels from existing networks. This complex multicellular process begins with selection of an initiating endothelial cell, or tip cell, which sprouts from the parent vessels in response to stimulation by exogenous cues. We have constructed an agent-based model of sprouting angiogenesis to evaluate endothelial cell sprout initiation frequency and location, and we have experimentally validated it using high-resolution time-lapse confocal microscopy. ABM simulations were then compared to a Monte Carlo model, revealing that purely stochastic simulations could not generate sprout locations as accurately as the rule-informed agent-based model. These findings support the use of rule-based approaches for modeling the complex mechanisms underlying sprouting angiogenesis over purely stochastic methods.

  11. Endothelial cell targeted molecular imaging in tumor angiogenesis: strategies and current status.

    PubMed

    Xu, Ye; Zeng, Yun; Liu, Yanhong; Liu, Gang; Ai, Hua

    2013-01-01

    Angiogenesis plays crucial roles in tumor growth, progression and metastasis. Non-invasive in vivo imaging of tumor neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly anti-angiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of cellular/molecular processes before gross pathological changes, leading to better understanding of fundamental biological processes of tumor angiogenesis. In this review, we will summarize recent progresses on molecular imaging of attractive biochemical epitopes in tumor angiogenesis, especially the endothelial cell targets-based imaging probes.

  12. Correlation of ultrasound contrast agent derived blood flow parameters with immunohistochemical angiogenesis markers in murine xenograft tumor models.

    PubMed

    Eisenbrey, John R; Wilson, Christian C; Ro, Raymond J; Fox, Traci B; Liu, Ji-Bin; Chiou, See-Ying; Forsberg, Flemming

    2013-09-01

    In this study we used temporal analysis of ultrasound contrast agent (UCA) estimate blood flow dynamics and demonstrate their improved correlation to angiogenesis markers relative to previously reported, non-temporal fractional vascularity estimates. Breast tumor (NMU) or glioma (C6) cells were implanted in either the abdomen or thigh of 144 rats. After 6, 8 or 10 days, rats received a bolus UCA injection of Optison (GE Healthcare, Princeton, NJ; 0.4 ml/kg) during power Doppler imaging (PDI), harmonic imaging (HI), and microflow imaging (MFI) using an Aplio ultrasound scanner with 7.5 MHz linear array (Toshiba America Medical Systems, Tustin, CA). Time-intensity curves of contrast wash-in were constructed on a pixel-by-pixel basis and averaged to calculate maximum intensity, time to peak, perfusion, and time integrated intensity (TII). Tumors were then stained for four immunohistochemical markers (bFGF, CD31, COX-2, and VEGF). Correlations between temporal parameters and the angiogenesis markers were investigated for each imaging mode. Effects of tumor model and implant location on these correlations were also investigated. Significant correlation over the entire dataset was only observed between TII and VEGF for all three imaging modes (R=-0.35, -0.54, -0.32 for PDI, HI and MFI, respectively; p<0.0001). Tumor type and location affected these correlations, with the strongest correlation of TII to VEGF found to be with implanted C6 cells (R=-0.43, -0.54, -0.52 for PDI, HI and MFI, respectively; p<0.0002). While UCA-derived temporal blood flow parameters were found to correlate strongly with VEGF expression, these correlations were also found to be influenced by both tumor type and implant location. Copyright © 2013 Elsevier B.V. All rights reserved.

  13. High-Resolution SPECT-CT/MR Molecular Imaging of Angiogenesis in the Vx2 Model

    PubMed Central

    Lijowski, Michal; Caruthers, Shelton; Hu, Grace; Zhang, Huiying; Scott, Michael J.; Williams, Todd; Erpelding, Todd; Schmieder, Anne H.; Kiefer, Garry; Gulyas, Gyongyi; Athey, Phillip S.; Gaffney, Patrick J.; Wickline, Samuel A.; Lanza, Gregory M.

    2009-01-01

    Background The use of antiangiogenic therapy in conjunction with traditional chemotherapy is becoming increasingly in cancer management, but the optimal benefit of these targeted pharmaceuticals has been limited to a subset of the population treated. Improved imaging probes that permit sensitive detection and high-resolution characterization of tumor angiogenesis could improve patient risk-benefit stratification. Objectives The overarching objective of these experiments was to develop a dual modality αvβ3-targeted nanoparticle molecular imaging agent that affords sensitive nuclear detection in conjunction with high-resolution MR characterization of tumor angiogenesis. Materials and Methods In part 1, New Zealand white rabbits (n = 21) bearing 14d Vx2 tumor received either αvβ3-targeted 99mTc nanoparticles at doses of 11, 22, or 44 MBq/kg, nontargeted 99mTc nanoparticles at 22 MBq/kg, or αvβ3-targeted 99mTc nanoparticles (22 MBq/kg) competitively inhibited with unlabeled αvβ3-nanoparticles. All animals were imaged dynamically over 2 hours with a planar camera using a pinhole collimator. In part 2, the effectiveness of αvβ3-targeted 99mTc nanoparticles in the Vx2 rabbit model was demonstrated using clinical SPECT-CT imaging techniques. Next, MR functionality was incorporated into αvβ3-targeted 99mTc nanoparticles by inclusion of lipophilic gadolinium chelates into the outer phospholipid layer, and the concept of high sensitivity – high-resolution detection and characterization of tumor angiogenesis was shown using sequential SPECT-CT and MR molecular imaging with 3D neovascular mapping. Results αvβ3-Targeted 99mTc nanoparticles at 22 MBq/kg produced the highest tumor-to-muscle contrast ratio (8.56 ± 0.13, TMR) versus the 11MBq/kg (7.32 ± 0.12) and 44 MBq/kg (6.55 ± 0.07) doses, (P < 0.05). TMR of nontargeted particles at 22.2 MBq/kg (5.48 ± 0.09) was less (P < 0.05) than the equivalent dosage of αvβ3-targeted 99mTc nanoparticles. Competitively

  14. Europium-doped mesoporous silica nanosphere as an immune-modulating osteogenesis/angiogenesis agent.

    PubMed

    Shi, Mengchao; Xia, Lunguo; Chen, Zetao; Lv, Fang; Zhu, Huiying; Wei, Fei; Han, Shengwei; Chang, Jiang; Xiao, Yin; Wu, Chengtie

    2017-11-01

    Although much research has gone into the design of nanomaterials, inflammatory response still impedes the capacity of nanomaterial-induced tissue regeneration. In-situ incorporation of nutrient elements in silica-based biomaterials has emerged as a new option to endow the nanomaterials modulating biological reactions. In this work, europium-doped mesoporous silica nanospheres (Eu-MSNs) were successfully synthesized via a one-pot method. The nanospheres (size of 280-300 nm) possess uniformly spherical morphology and mesoporous structure, and well distributed Eu elements. The nanospheres show distinct fluorescent property at 615 nm for potential bio-labeling. Noticeably, the Eu-MSNs stimulate pro-inflammatory response of macrophages and induce a modulated immune microenvironment, which further activates the osteogenic differentiation of bone marrow stromal cells (BMSCs) as well as angiogenic activity of human umbilical vein endothelial cells (HUVECs). During the process, osteogenesis-related genes (e.g. ALP, OCN, OPN and COL-I) of BMSCs, and angiogenesis-related genes (e.g. CD31, MMP9, VEGFR1/2, and PDGFRα/β) of HUVECs were significantly upregulated by Eu-MSNs modulating immune environment of macrophages. The in vivo study further demonstrated that the Eu-MSNs could not only stimulate osteogenesis by accelerating the new bone formation at critical-sized cranial defect site, but also support the blood vessel formation as well as collagen deposition and re-epithelialization at chronic skin wound sites, showing an improved angiogenesis activity when comparing with MSNs alone. Given the easy handling characteristics and extensive application potential, the results suggest that Eu-MSNs could be used as immunity-modulated osteogenesis/angiogenesis agent for skin and bone regeneration. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Sprouty1, a new target of the angiostatic agent 16K prolactin, negatively regulates angiogenesis

    PubMed Central

    2010-01-01

    Background Disorganized angiogenesis is associated with several pathologies, including cancer. The identification of new genes that control tumor neovascularization can provide novel insights for future anti-cancer therapies. Sprouty1 (SPRY1), an inhibitor of the MAPK pathway, might be one of these new genes. We identified SPRY1 by comparing the transcriptomes of untreated endothelial cells with those of endothelial cells treated by the angiostatic agent 16 K prolactin (16 K hPRL). In the present study, we aimed to explore the potential function of SPRY1 in angiogenesis. Results We confirmed 16 K hPRL induced up-regulation of SPRY1 in primary endothelial cells. In addition, we demonstrated the positive SPRY1 regulation in a chimeric mouse model of human colon carcinoma in which 16 K hPRL treatment was shown to delay tumor growth. Expression profiling by qRT-PCR with species-specific primers revealed that induction of SPRY1 expression by 16 K hPRL occurs only in the (murine) endothelial compartment and not in the (human) tumor compartment. The regulation of SPRY1 expression was NF-κB dependent. Partial SPRY1 knockdown by RNA interference protected endothelial cells from apoptosis as well as increased endothelial cell proliferation, migration, capillary network formation, and adhesion to extracellular matrix proteins. SPRY1 knockdown was also shown to affect the expression of cyclinD1 and p21 both involved in cell-cycle regulation. These findings are discussed in relation to the role of SPRY1 as an inhibitor of ERK/MAPK signaling and to a possible explanation of its effect on cell proliferation. Conclusions Taken together, these results suggest that SPRY1 is an endogenous angiogenesis inhibitor. PMID:20813052

  16. High and low frequency subharmonic imaging of angiogenesis in a murine breast cancer model.

    PubMed

    Dahibawkar, Manasi; Forsberg, Mark A; Gupta, Aditi; Jaffe, Samantha; Dulin, Kelly; Eisenbrey, John R; Halldorsdottir, Valgerdur G; Forsberg, Anya I; Dave, Jaydev K; Marshall, Andrew; Machado, Priscilla; Fox, Traci B; Liu, Ji-Bin; Forsberg, Flemming

    2015-09-01

    This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×10(6) breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180μl/kg) and LF pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by HF imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11-13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast-enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=-0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of breast cancer

  17. High and low frequency subharmonic imaging of angiogenesis in a murine breast cancer model

    PubMed Central

    Dahibawkar, Manasi; Forsberg, Mark A.; Gupta, Aditi; Jaffe, Samantha; Dulin, Kelly; Eisenbrey, John R.; Halldorsdottir, Valgerdur G.; Forsberg, Anya I.; Dave, Jaydev K.; Marshall, Andrew; Machado, Priscilla; Fox, Traci B.; Liu, Ji-Bin; Forsberg, Flemming

    2015-01-01

    This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×106 breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180µl/kg) and low frequency pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by high frequency imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11–13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=−0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of

  18. Imaging Cancer Angiogenesis and Metastasis in a Zebrafish Embryo Model.

    PubMed

    Tulotta, C; He, S; van der Ent, W; Chen, L; Groenewoud, A; Spaink, H P; Snaar-Jagalska, B E

    2016-01-01

    Tumor angiogenesis and metastasis are key steps of cancer progression. In vitro and animal model studies have contributed to partially elucidating the mechanisms involved in these processes and in developing therapies. Besides the improvements in fundamental research and the optimization of therapeutic regimes, cancer still remains a major health threatening condition and therefore the development of new models is needed. The zebrafish is a powerful tool to study tumor angiogenesis and metastasis, because it allows the visualization of fluorescently labelled tumor cells inducing vessel remodeling, disseminating and invading surrounding tissues in a whole transparent embryo. The embryo model has also been used to address the contribution of the tumor stroma in sustaining tumor angiogenesis and spreading. Simultaneously, new anti-angiogenic drugs and compounds affecting malignant cell survival and migration can be tested by simply adding the compound into the water of living embryos. Therefore the zebrafish model offers the opportunity to gain more knowledge on cancer angiogenesis and metastasis in vivo with the final aim of providing new translational insights into therapeutic approaches to help patients.

  19. Angiogenesis Inhibitors

    MedlinePlus

    ... of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6(8):465–477. [ ... mechanisms involved in the toxicity of angiogenesis inhibition. Nature Reviews Cancer 2007; 7(6):475–485. [PubMed ...

  20. In vivo Imaging of Tumor Angiogenesis using Fluorescence Confocal Videomicroscopy

    PubMed Central

    Fitoussi, Victor; Faye, Nathalie; Chamming's, Foucauld; Clement, Olivier; Cuenod, Charles-Andre; Fournier, Laure S.

    2013-01-01

    Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained. We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 μm in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools. The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability. PMID:24056503

  1. In vivo imaging of tumor angiogenesis using fluorescence confocal videomicroscopy.

    PubMed

    Fitoussi, Victor; Faye, Nathalie; Chamming's, Foucauld; Clement, Olivier; Cuenod, Charles-Andre; Fournier, Laure S

    2013-09-11

    Fibered confocal fluorescence in vivo imaging with a fiber optic bundle uses the same principle as fluorescent confocal microscopy. It can excite fluorescent in situ elements through the optical fibers, and then record some of the emitted photons, via the same optical fibers. The light source is a laser that sends the exciting light through an element within the fiber bundle and as it scans over the sample, recreates an image pixel by pixel. As this scan is very fast, by combining it with dedicated image processing software, images in real time with a frequency of 12 frames/sec can be obtained. We developed a technique to quantitatively characterize capillary morphology and function, using a confocal fluorescence videomicroscopy device. The first step in our experiment was to record 5 sec movies in the four quadrants of the tumor to visualize the capillary network. All movies were processed using software (ImageCell, Mauna Kea Technology, Paris France) that performs an automated segmentation of vessels around a chosen diameter (10 μm in our case). Thus, we could quantify the 'functional capillary density', which is the ratio between the total vessel area and the total area of the image. This parameter was a surrogate marker for microvascular density, usually measured using pathology tools. The second step was to record movies of the tumor over 20 min to quantify leakage of the macromolecular contrast agent through the capillary wall into the interstitium. By measuring the ratio of signal intensity in the interstitium over that in the vessels, an 'index leakage' was obtained, acting as a surrogate marker for capillary permeability.

  2. The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.

    PubMed

    Yoshii, J; Yoshiji, H; Kuriyama, S; Ikenaka, Y; Noguchi, R; Okuda, H; Tsujinoue, H; Nakatani, T; Kishida, H; Nakae, D; Gomez, D E; De Lorenzo, M S; Tejera, A M; Fukui, H

    2001-12-15

    Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy. Copyright 2001 Wiley-Liss, Inc.

  3. In Vivo Tumor Angiogenesis Imaging Using Peptide-Based Near-Infrared Fluorescent Probes.

    PubMed

    Huang, Rui; Conti, Peter S; Chen, Kai

    2016-01-01

    Near-infrared fluorescence (NIRF) imaging is an emerging imaging technique for studying diseases at the molecular level. Optical imaging with a near-infrared emitting fluorophore for targeting tumor angiogenesis offers a noninvasive method for early tumor detection and efficient monitoring of tumor response to anti-angiogenesis therapy. CD13 receptor, a zinc-dependent membrane-bound ectopeptidase, plays important roles in regulating tumor angiogenesis and the growth of new blood vessels. In this chapter, we use CD13 receptor as an example to demonstrate how to construct CD13-specific NGR-containing peptides via bioorthogonal click chemistry for visualizing and quantifying the CD13 receptor expression in vivo by means of NIRF optical imaging.

  4. Clinical biomarkers of angiogenesis inhibition

    PubMed Central

    Brown, Aaron P.; Citrin, Deborah E.; Camphausen, Kevin A.

    2009-01-01

    Introduction An expanding understanding of the importance of angiogenesis in oncology and the development of numerous angiogenesis inhibitors are driving the search for biomarkers of angiogenesis. We review currently available candidate biomarkers and surrogate markers of anti-angiogenic agent effect. Discussion A number of invasive, minimally invasive, and non-invasive tools are described with their potential benefits and limitations. Diverse markers can evaluate tumor tissue or biological fluids, or specialized imaging modalities. Conclusions The inclusion of these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, prediction of individual response to an agent, insight into the interaction of chemotherapy and radiation following exposure to these agents, and perhaps most importantly, a better understanding of the complex nature of angiogenesis in human tumors. While many markers have potential for clinical use, it is not yet clear which marker or combination of markers will prove most useful. PMID:18414993

  5. Contrast agents in dynamic contrast-enhanced magnetic resonance imaging

    PubMed Central

    Yan, Yuling; Sun, Xilin; Shen, Baozhong

    2017-01-01

    Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive method to assess angiogenesis, which is widely used in clinical applications including diagnosis, monitoring therapy response and prognosis estimation in cancer patients. Contrast agents play a crucial role in DCE-MRI and should be carefully selected in order to improve accuracy in DCE-MRI examination. Over the past decades, there was much progress in the development of optimal contrast agents in DCE-MRI. In this review, we describe the recent research advances in this field and discuss properties of contrast agents, as well as their advantages and disadvantages. Finally, we discuss the research perspectives for improving this promising imaging method. PMID:28415647

  6. Contrast Enhanced Maximum Intensity Projection Ultrasound Imaging for Assessing Angiogenesis in Murine Glioma and Breast Tumor Models: A Comparative Study

    PubMed Central

    Forsberg, Flemming; Ro, Raymond J.; Fox, Traci B; Liu, Ji-Bin; Chiou, See-Ying; Potoczek, Magdalena; Goldberg, Barry B

    2010-01-01

    The purpose of this study was to prospectively compare noninvasive, quantitative measures of vascularity obtained from 4 contrast enhanced ultrasound (US) techniques to 4 invasive immunohistochemical markers of tumor angiogenesis in a large group of murine xenografts. Glioma (C6) or breast cancer (NMU) cells were implanted in 144 rats. The contrast agent Optison (GE Healthcare, Princeton, NJ) was injected in a tail vein (dose: 0.4ml/kg). Power Doppler imaging (PDI), pulse-subtraction harmonic imaging (PSHI), flash-echo imaging (FEI), and Microflow imaging (MFI; a technique creating maximum intensity projection images over time) was performed with an Aplio scanner (Toshiba America Medical Systems, Tustin, CA) and a 7.5 MHz linear array. Fractional tumor neovascularity was calculated from digital clips of contrast US, while the relative area stained was calculated from specimens. Results were compared using a factorial, repeated measures ANOVA, linear regression and z-tests. The tortuous morphology of tumor neovessels was visualized better with MFI than with the other US modes. Cell line, implantation method and contrast US imaging technique were significant parameters in the ANOVA model (p<0.05). The strongest correlation determined by linear regression in the C6 model was between PSHI and percent area stained with CD31 (r=0.37, p<0.0001). In the NMU model the strongest correlation was between FEI and COX-2 (r=0.46, p<0.0001). There were no statistically significant differences between correlations obtained with the various US methods (p>0.05). In conclusion, the largest study of contrast US of murine xenografts to date has been conducted and quantitative contrast enhanced US measures of tumor neovascularity in glioma and breast cancer xenograft models appear to provide a noninvasive marker for angiogenesis; although the best method for monitoring angiogenesis was not conclusively established. PMID:21144542

  7. Bioluminescence Imaging of Angiogenesis in a Murine Orthotopic Pancreatic Cancer Model

    PubMed Central

    Chen, Monica; Mojadidi, Michelle; Hines, O. Joe; Reber, Howard A.; Eibl, Guido

    2010-01-01

    Purpose Angiogenesis is essential for physiological processes as well as for carcinogenesis. New approaches to cancer therapy include targeting angiogenesis. One target is VEGF-A and its receptor VEGFR2. In this study, we sought to investigate pancreatic cancer angiogenesis in a genetically modified VEGFR2-luc-KI mouse. Procedures Live in vivo bioluminescence imaging of angiogenesis was performed continuously until sacrifice in subcutaneous tumors as well as in orthotopically transplanted tumors. Tumor tissue was immunostained for CD-31 and VEGFR2. Results Peritumoral angiogenesis measured by light emission was detected beginning at week 3 following subcutaneous injection. In the orthotopic model, light emission began at day 4, which likely corresponds to wound healing, and continued throughout the experimental period during tumor growth. Peritumoral CD-31 vessel- and VEGFR2-staining were positive. Conclusions The VEGFR2-luc-KI mouse is a valuable tool to demonstrate tumor angiogenesis and seems to be suitable to evaluate anti-angiogenic approaches in pancreatic cancer. PMID:20376570

  8. Spatiotemporal Analyses of Osteogenesis and Angiogenesis via Intravital Imaging in Cranial Bone Defect Repair

    PubMed Central

    Huang, Chunlan; Ness, Vincent P.; Yang, Xiaochuan; Chen, Hongli; Luo, Jiebo; Brown, Edward B; Zhang, Xinping

    2015-01-01

    Osteogenesis and angiogenesis are two integrated components in bone repair and regeneration. A deeper understanding of osteogenesis and angiogenesis has been hampered by technical difficulties of analyzing bone and neovasculature simultaneously in spatiotemporal scales and in three-dimensional formats. To overcome these barriers, a cranial defect window chamber model was established that enabled high-resolution, longitudinal, and real-time tracking of angiogenesis and bone defect healing via Multiphoton Laser Scanning Microscopy (MPLSM). By simultaneously probing new bone matrix via second harmonic generation (SHG), neovascular networks via intravenous perfusion of fluorophore, and osteoblast differentiation via 2.3kb collagen type I promoter driven GFP (Col2.3GFP), we examined the morphogenetic sequence of cranial bone defect healing and further established the spatiotemporal analyses of osteogenesis and angiogenesis coupling in repair and regeneration. We demonstrated that bone defect closure was initiated in the residual bone around the edge of the defect. The expansion and migration of osteoprogenitors into the bone defect occurred during the first 3 weeks of healing, coupled with vigorous microvessel angiogenesis at the leading edge of the defect. Subsequent bone repair was marked by matrix deposition and active vascular network remodeling within new bone. Implantation of bone marrow stromal cells (BMSCs) isolated from Col2.3GFP mice further showed that donor-dependent bone formation occurred rapidly within the first 3 weeks of implantation, in concert with early angiogenesis. The subsequent bone wound closure was largely host-dependent, associated with localized modest induction of angiogenesis. The establishment of a live imaging platform via cranial window provides a unique tool to understand osteogenesis and angiogenesis in repair and regeneration, enabling further elucidation of the spatiotemporal regulatory mechanisms of osteoprogenitor cell interactions

  9. RGD-Targeted Ultrasound Contrast Agent for Longitudinal Assessment of Hep-2 Tumor Angiogenesis In Vivo

    PubMed Central

    Hu, Qiao; Wang, Xiao-Yan; Kang, Li-Ke; Wei, Hai-Ming; Xu, Chun-Mei; Wang, Tao; Wen, Zong-Hua

    2016-01-01

    Objective To prepare arginine-glycine-aspartate (RGD)-targeted ultrasound contrast microbubbles (MBs) and explore the feasibility of their use in assessing dynamic changes in αvβ3 integrin expression in a murine model of tumor angiogenesis. Methods RGD peptides were conjugated to the surfaces of microbubbles via biotin-avidin linkage. Microbubbles bearing RADfK peptides were prepared as controls. The RGD-MBs were characterized using an Accusizer 780 and optical microscopy. The binding specificity of the RGD-MBs for ανβ3-expressing endothelial cells (bEnd.3) was demonstrated in vitro by a competitive inhibition experiment. In an in vivo study, mice bearing tumors of three different stages were intravenously injected with RGD-MBs and subjected to targeted, contrast-enhanced, high-frequency ultrasound. Subsequently, tumors were harvested and sectioned for immunofluorescence analysis of ανβ3 expression. Results The mean size of the RGD-MBs was 2.36 ± 1.7 μm. The RGD-MBs showed significantly higher adhesion levels to bEnd.3 cells compared to control MBs (P < 0.01). There was rarely binding of RGD-MBs to αvβ3-negative MCF-7 cells. Adhesion of the RGD-MBs to the bEnd.3 cells was significantly inhibited following treatment with anti-alpha(v) antibodies. The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01). Conclusions RGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts. PMID:26862757

  10. Fluorescence imaging agents in cancerology

    PubMed Central

    Paganin-Gioanni, Aurélie; Bellard, Elisabeth; Paquereau, Laurent; Ecochard, Vincent; Golzio, Muriel; Teissié, Justin

    2010-01-01

    Background One of the major challenges in cancer therapy is to improve early detection and prevention using novel targeted cancer diagnostics. Detection requests specific recognition. Tumor markers have to be ideally present on the surface of cancer cells. Their targeting with ligands coupled to imaging agents make them visible/detectable. Conclusions Fluorescence imaging is a newly emerging technology which is becoming a complementary medical method for cancer diagnosis. It allows detection with a high spatio-temporal resolution of tumor markers in small animals and in clinical studies. In this review, we focus on the recent outcome of basic studies in the design of new approaches (probes and devices) used to detect tumor cells by fluorescence imaging. PMID:22933906

  11. The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression.

    PubMed

    Yoshiji, Hitoshi; Kuriyama, Shigeki; Yoshii, Junichi; Ikenaka, Yasuhide; Noguchi, Ryuichi; Yanase, Koji; Namisaki, Tadashi; Yamazaki, Masaharu; Tsujinoue, Hirohisa; Imazu, Hiroo; Fukui, Hiroshi

    2003-01-01

    It has been shown that angiogenesis plays an important role not only in tumor growth, but also in carcinogenesis. We previously reported that the copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited hepatocellular carcinoma (HCC) tumor growth. The aim of the current study was to elucidate the effect of trientine on liver enzyme-altered preneoplastic lesions in rats, especially in conjunction with angiogenesis alteration in the liver. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment, even at a clinically comparable low dose, significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions associated with a decrease in copper content in the liver. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of the preneoplastic lesions. On the contrary, the proliferative cell nuclear antigen (PCNA)-positive cells were not altered with or without trientine treatment. These results suggested that the copper-chelating agent, trientine, exerted chemopreventive effects against rat liver carcinogenesis due to the suppression of angiogenesis, and suggest that it might be useful clinically as a chemopreventive agent of HCC.

  12. FKBPL and Peptide Derivatives: Novel Biological Agents That Inhibit Angiogenesis by a CD44-Dependent Mechanism

    PubMed Central

    Valentine, Andrea; O’Rourke, Martin; Yakkundi, Anita; Worthington, Jenny; Hookham, Michelle; Bicknell, Roy; McCarthy, Helen O.; McClelland, Keeva; McCallum, Lynn; Dyer, Hayder; McKeen, Hayley; Waugh, David; Roberts, Jennifer; McGregor, Joanne; Cotton, Graham; James, Iain; Harrison, Timothy; Hirst, David G.; Robson, Tracy

    2011-01-01

    Purpose Anti-angiogenic therapies can be an important adjunct to the management of many malignancies. Here we investigated a novel protein, FKBPL, and peptide derivative for their anti-angiogenic activity and mechanism of action. Experimental Design Recombinant FKBPL (rFKBPL) and its peptide derivative were assessed in a range of human microvascular endothelial cell (HMEC-1) assays in vitro. Their ability to inhibit proliferation, migration and Matrigel dependent tubule formation was determined. They were further evaluated in an ex-vivo rat model of neo-vascularisation and in two in vivo mouse models of angiogenesis; the sponge implantation and the intra-vital microscopy models. Anti-tumor efficacy was determined in two human tumor xenograft models grown in SCID mice. Finally, the dependence of peptide on CD44 was determined using a CD44 targeted siRNA approach or in cell lines of differing CD44 status. Results rFKBPL inhibited endothelial cell migration, tubule formation and microvessel formation in vitro and in vivo. The region responsible for FKBPL’s anti-angiogenic activity was identified and a 24 amino acid peptide (AD-01) spanning this sequence was synthesised. It was potently anti-angiogenic and inhibited growth in two human tumor xenograft models (DU145 and MDA-231) when administered systemically, either on its own, or in combination with docetaxel. The anti-angiogenic activity of FKBPL and AD-01 was dependent on the cell surface receptor CD44 and signalling downstream of this receptor promoted an anti-migratory phenotype. Conclusion FKBPL and its peptide derivative AD-01 have potent anti-angiogenic activity. Thus, these agents offer the potential of an attractive new approach to anti-angiogenic therapy. PMID:21364036

  13. Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice.

    PubMed

    Yoshiji, Hitoshi; Yoshii, Junichi; Kuriyama, Shigeki; Ikenaka, Yasuhide; Noguchi, Ryuichi; Yanase, Koji; Namisaki, Tadashi; Kitade, Mitsuteru; Yamazaki, Masaharu; Fukui, Hiroshi

    2005-07-01

    Recent studies have suggested that an anti-angiogenic agent could improve the inhibitory effects of standard chemotherapeutic drugs against tumor development. We previously reported that the clinically used copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited tumor growth. The aim of the current study was to examine the combined effect of trientine and methotrexate on the development and angiogenesis of xenograft human colorectal carcinoma (CRC) cells at clinically comparable low doses. When used individually, both trientine and methotrexate significantly suppressed CRC development along with inhibition of neovascularization in the tumor. A combination regimen of trientine and methotrexate exerted the most potent tumoricidal effect and led to 'tumor dormancy.' The combination of these agents also resulted in a marked suppression of the angiogenic factors, in particular the vascular endothelial growth factor and interleukin-8, and an increase of apoptosis in the tumor. In vitro studies revealed that neither trientine nor methotrexate was cytotoxic for tumor cells. On the other hand, the endothelial cell proliferation and tubular formation were significantly suppressed by these agents. The combined treatment of trientine and methotrexate at clinically comparable low doses could inhibit CRC development and angiogenesis, as well as suppress the angiogenic factors. Because both agents are widely used in clinical practice, the combination regimen may represent a potential new strategy for CRC therapy in the future.

  14. In-vivo three-dimensional Doppler variance imaging for tumor angiogenesis on chorioallantoic membrane

    NASA Astrophysics Data System (ADS)

    Qi, Wenjuan; Liu, Gangjun; Chen, Zhongping

    2011-03-01

    Non-invasive tumor microvasculature visualization and characterization play significant roles in the detection of tumors and importantly, for aiding in the development of therapeutic strategies. The feasibility and effectiveness of a Doppler variance standard deviation imaging method for tumor angiogenesis on chorioallantoic membrane were tested in vivo on a rat glioma F98 tumor spheroid. Utilizing a high resolution Doppler Variance Optical Coherence Tomography (DVOCT) system with A-line rate of 20 kHz, three-dimensional mapping of a tumor with a total area of 3×2.5mm2 was completed within 15 seconds. The top-view image clearly visualized the complex vascular perfusion with the detection of capillaries as small as approximately 10μm. The results of the current study demonstrate the capability of the Doppler variance standard deviation imaging method as a non-invasive assessment of tumor angiogenesis, with the potential for its use in clinical settings.

  15. 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

  16. Ultrasound Molecular Imaging of Angiogenesis Using Vascular Endothelial Growth Factor-Conjugated Microbubbles.

    PubMed

    Wang, Jianjun; Qin, Bin; Chen, Xucai; Wagner, William R; Villanueva, Flordeliza S

    2017-03-06

    Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to antiangiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF121 (MBVEGF) bind to the kinase insert domain receptor (KDR) in vitro and angiogenic endothelium in vivo, and that this specific binding can be imaged on a clinical ultrasound system. In this work, targeted adhesion of MBVEGF was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MBVEGF to KDR-coated plates when the amount of VEGF121 on each MB or KDR density on the plate was increased. MBVEGF adhesion to KDR-coated plates decreased with increasing wall shear rate. On intravital microscopic imaging of bFGF-stimulated rat cremaster muscle, there was greater microvascular adhesion of MBVEGF compared to that of isotype IgG-conjugated control MB (MBCTL). To determine if MBVEGF could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MBVEGF. Ultrasound videointensity enhancement in tumor was significantly higher for MBVEGF (17.3 ± 9.7 dB) compared to MBCTL (3.8 ± 4.4 dB, n = 6, p < 0.05). This work demonstrates the feasibility of targeted ultrasound imaging of an angiogenic marker using MBVEGF. This approach offers a noninvasive bedside method for detecting tumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or antiangiogenic therapies in cardiovascular disease or cancer.

  17. Ultrasound Molecular Imaging of Angiogenesis Using Vascular Endothelial Growth Factor-Conjugated Microbubbles

    PubMed Central

    Wang, Jianjun; Qin, Bin; Chen, Xucai; Wagner, William R.; Villanueva, Flordeliza S.

    2017-01-01

    Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to anti-angiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF121 (MBVEGF) bind to the kinase insert domain receptor (KDR) in vitro and angiogenic endothelium in vivo, and that this specific binding can be imaged on a clinical ultrasound system. In this work, targeted adhesion of MBVEGF was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MBVEGF to KDR-coated plates when the amount of VEGF121 on each MB or KDR density on the plate was increased. MBVEGF adhesion to KDR-coated plates decreased with increasing wall shear rate. On intravital microscopic imaging of bFGF-stimulated rat cremaster muscle, there was greater microvascular adhesion of MBVEGF compared to that of isotype IgG-conjugated control MB (MBCTL). To determine if MBVEGF could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MBVEGF. Ultrasound videointensity enhancement in tumor was significantly higher for MBVEGF (17.3±9.7 dB) compared to MBCTL (3.8±4.4 dB, n=6, p<0.05). This work demonstrates the feasibility of targeted ultrasound imaging of an angiogenic marker using MBVEGF. This approach offers a non-invasive bedside method for detecting tumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or anti-angiogenic therapies in cardiovascular disease or cancer. PMID:28165246

  18. Image compression impact on quantitative angiogenesis analysis of ovarian epithelial neoplasms.

    PubMed

    Nicolosi, Jacqueline S; Yoshida, Adriana O; Sarian, Luís O Z; Silva, Cleide A M; Andrade, Liliana A L A; Derchain, Sophie F M; Vassallo, José; Schenka, André Almeida

    2012-01-01

    This study aims to investigate the impact of digital image compression on manual and semiautomatic quantification of angiogenesis in ovarian epithelial neoplasms (including benign, borderline, and malignant specimens). We examined 405 digital images (obtained from a previously validated computer-assisted analysis system), which were equally divided into 5 groups: images captured in Tagged Image File Format (TIFF), low and high compression Joint Photographic Experts Group (JPEG) formats, and low and high compression JPEG images converted from the TIFF files. Microvessel density counts and CD34 endothelial areas manually and semiautomatically determined from TIFF images were compared with those from the other 4 groups. Mostly, the correlations between TIFF and JPEG images were very high (intraclass correlation coefficients >0.8), especially for low compression JPEG images obtained by capture, regardless of the variable considered. The only exception consisted in the use of high compression JPEG files for semiautomatic microvessel density counts, which resulted in intraclass correlation coefficients of <0.7. Nonetheless, even then, interconversion between TIFF and JPEG values could be successfully achieved using prediction models established by linear regression. Image compression does not seem to significantly compromise the accuracy of angiogenesis quantitation in the ovarian epithelial tumors, although low compression JPEG images should always be preferred over high compression ones.

  19. Angiogenesis Imaging Using (68)Ga-RGD PET/CT: Therapeutic Implications.

    PubMed

    Eo, Jae Seon; Jeong, Jae Min

    2016-09-01

    Angiogenesis imaging is important for diagnostic and therapeutic treatment of various malignant and nonmalignant diseases. The Arg-Gly-Asp (RGD) sequence has been known to bind with the αvβ3 integrin that is expressed on the surface of angiogenic blood vessels or tumor cells. Thus, various radiolabeled derivatives of RGD peptides have been developed for angiogenesis imaging. Among the various radionuclides, (68)Ga was the most widely studied for RGD peptide imaging because of its excellent nuclear physical properties, easy-to-label chemical properties, and cost-effectiveness owing to the availability of a (68)Ge-(68)Ga generator. Thus, various (68)Ga-labeled RGD derivatives have been developed and applied for preclinical and clinical studies. Clinical trials were performed for both malignant and nonmalignant diseases. Breast cancer, glioma, and lung cancer were malignant, and myocardial infarction, atherosclerosis, and moyamoya disease were nonmalignant among the investigated diseases. Further, these (68)Ga-labeled RGD derivatives could be applied to assess the effects of antiangiogenic treatment or theragnosis or both, of cancers. In conclusion, the angiogenesis imaging technology using (68)Ga-labeled RGD derivatives might be useful for the development of new therapeutic assessments, and for diagnostic and theragnostic applications. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Photoacoustic imaging of angiogenesis in a subcutaneous islet transplant site in a murine model

    NASA Astrophysics Data System (ADS)

    Shi, Wei; Pawlick, Rena; Bruni, Antonio; Rafiei, Yasmin; Pepper, Andrew R.; Gala-Lopez, Boris; Choi, Min; Malcolm, Andrew; Zemp, Roger J.; Shapiro, A. M. James

    2016-06-01

    Islet transplantation (IT) is an established clinical therapy for select patients with type-1 diabetes. Clinically, the hepatic portal vein serves as the site for IT. Despite numerous advances in clinical IT, limitations remain, including early islet cell loss posttransplant, procedural complications, and the inability to effectively monitor islet grafts. Hence, alternative sites for IT are currently being explored, with the subcutaneous space as one potential option. When left unmodified, the subcutaneous space routinely fails to promote successful islet engraftment. However, when employing the previously developed subcutaneous "deviceless" technique, a favorable microenvironment for islet survival and function is established. In this technique, an angiocatheter was temporarily implanted subcutaneously, which facilitated angiogenesis to promote subsequent islet engraftment. This technique has been employed in preclinical animal models, providing a sufficient means to develop techniques to monitor functional aspects of the graft such as angiogenesis. Here, we utilize photoacoustic imaging to track angiogenesis during the priming of the subcutaneous site by the implanted catheter at 1 to 4 weeks postcatheter. Quantitative analysis on vessel densities shows gradual growth of vasculature in the implant position. These results demonstrate the ability to track angiogenesis, thus facilitating a means to optimize and assess the pretransplant microenvironment.

  1. In Vitro Imaging of Angiogenesis Using Embryonic Stem Cell-Derived Endothelial Cells

    PubMed Central

    Stuhlmann, Heidi

    2012-01-01

    Angiogenesis is an important event during developmental processes, and it plays a key role in neovascularization. The development of an in vitro model that can be used for live imaging of vessel growth will facilitate the study of molecular and cellular mechanisms for the growth of blood vessels. Embryonic stem cells (ESCs) are considered to be a novel renewable source for the derivation of genetically manipulable endothelial cells (ECs). To derive green fluorescence protein (GFP)-expressing ECs, we used a transgenic ESC line in which a GFP reporter was driven by the endothelial-specific promoter fetal liver kinase 1. ESC-ECs were isolated from 11-day embryoid bodies by fluorescence-activated cell sorting. Embedding the aggregated ESC-ECs in a 3-dimensional collagen gel matrix resulted in ESC-EC migration out of the aggregates and coalescence into a capillary network. Time-lapse microscopy revealed EC migration, proliferation, lumen formation, and anastomosis to other capillary vessels during this process, which were reminiscent of angiogenic processes. Vascular endothelial growth factor plays major roles in the induction of ESC-EC angiogenesis in vitro. Blockage of the β1 integrin subunit severely impaired ESC-EC survival and migration. We demonstrate that our in vitro ESC-EC angiogenesis model represents a high-resolution dynamic video-image system for observing the cellular events underlying angiogenic cascades. We also consider this model as an image screening tool for the identification of pro-angiogenic and anti-angiogenic molecules. PMID:21385073

  2. Molecular imaging using contrast-enhanced ultrasound: evaluation of angiogenesis and cell therapy.

    PubMed

    Leong-Poi, Howard

    2009-11-01

    The field of regenerative medicine and its applications for cardiovascular diseases continues to grow rapidly, fuelled by the increasing numbers of symptomatic patients who are not candidates for conventional revascularization procedures and remain refractory to maximal medical therapy. Therapeutic angiogenesis, initially in the form of the administration of growth factor protein or gene therapy and, more recently, in the form of adult progenitor cell therapy, has emerged as a promising new method of treatment for patients with ischaemic heart disease and peripheral arterial disease. There is a growing interest in non-invasive imaging techniques to evaluate the response to angiogenic gene-and cell-based therapies. Contrast-enhanced ultrasound (CEU) techniques using site-specific microbubbles have recently been developed for the molecular imaging of the vascular phenotype that characterizes angiogenesis. These methods have now been modified to allow the imaging of progenitor cell engraftment into neovessels. These molecular imaging techniques using contrast ultrasound and targeted microbubbles have the potential to further characterize the angiogenic response, aid in the optimization of gene- and cell-based strategies of therapeutic neovascularization, and ultimately serve to monitor the therapeutic effects in patients enrolled in clinical trials of regenerative therapies. This review will focus specifically on CEU molecular imaging techniques for the evaluation of angiogenesis and cell therapies in cardiovascular diseases, including: (i) an overview of the techniques and results of pre-clinical studies; (ii) a comparison of CEU molecular imaging techniques with other available molecular imaging modalities; and (iii) a discussion of the future role of CEU molecular imaging in the field of regenerative medicine.

  3. Three-dimensional ultrasound molecular imaging of angiogenesis in colon cancer using a clinical matrix array ultrasound transducer.

    PubMed

    Wang, Huaijun; Kaneko, Osamu F; Tian, Lu; Hristov, Dimitre; Willmann, Jürgen K

    2015-05-01

    We sought to assess the feasibility and reproducibility of 3-dimensional ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer. Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n = 33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) after intravenous injection of either clinical grade VEGFR2-targeted microbubbles or nontargeted control microbubbles. Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24 hours after treatment with either bevacizumab (n = 7) or saline only (n = 7). Three-dimensional USMI data sets were retrospectively reconstructed into multiple consecutive 1-mm-thick USMI data sets to simulate 2-dimensional imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence. Three-dimensional USMI was highly reproducible using both VEGFR2-targeted microbubbles and nontargeted control microbubbles (intraclass correlation coefficient, 0.83). The VEGFR2-targeted USMI signal significantly (P = 0.02) decreased by 57% after antiangiogenic treatment compared with the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (ρ = 0.93, P = 0.003). If only central 1-mm tumor planes were analyzed to assess antiangiogenic treatment response, the USMI signal change was significantly (P = 0.006) overestimated by an average of 27% (range, 2%-73%) compared with 3-dimensional USMI. Three-dimensional USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer.

  4. Three-dimensional Ultrasound Molecular Imaging of Angiogenesis in Colon Cancer using a Clinical Matrix Array Ultrasound Transducer

    PubMed Central

    Wang, Huaijun; Kaneko, Osamu F.; Tian, Lu; Hristov, Dimitre; Willmann, Jürgen K.

    2015-01-01

    Objectives We sought to assess the feasibility and reproducibility of three-dimensional (3D) ultrasound molecular imaging (USMI) of vascular endothelial growth factor receptor 2 (VEGFR2) expression in tumor angiogenesis using a clinical matrix array transducer and a clinical grade VEGFR2-targeted contrast agent in a murine model of human colon cancer. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice with human colon cancer xenografts (n=33) were imaged with a clinical ultrasound system and transducer (Philips iU22; X6-1) following intravenous injection of either clinical grade VEGFR2-targeted microbubbles (MBVEGFR2) or non-targeted control microbubbles (MBControl). Nineteen mice were scanned twice to assess imaging reproducibility. Fourteen mice were scanned both before and 24h after treatment with either bevacizumab (n=7) or saline only (n=7). 3D USMI datasets were retrospectively reconstructed into multiple consecutive 1-mm thick USMI data sets to simulate 2D imaging. Vascular VEGFR2 expression was assessed ex vivo using immunofluorescence. Results 3D USMI was highly reproducible using both MBVEGFR2 and MBControl (ICC=0.83). VEGFR2-targeted USMI signal significantly (P=0.02) decreased by 57% following anti-angiogenic treatment compared to the control group, which correlated well with ex vivo VEGFR2 expression on immunofluorescence (rho=0.93, P=0.003). If only central 1-mm tumor planes were analyzed to assess anti-angiogenic treatment response, the USMI signal change was significantly (P=0.006) overestimated by an average of 27% (range, 2–73%) compared to 3D USMI. Conclusions 3D USMI is feasible and highly reproducible and allows accurate assessment and monitoring of VEGFR2 expression in tumor angiogenesis in a murine model of human colon cancer. PMID:25575176

  5. Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

    PubMed Central

    Bäuerle, Tobias; Komljenovic, Dorde; Berger, Martin R.; Semmler, Wolfhard

    2012-01-01

    Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques. For this purpose, we injected 105 MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US). MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated

  6. Imaging tumor angiogenesis in breast cancer experimental lung metastasis with positron emission tomography, near-infrared fluorescence, and bioluminescence

    PubMed Central

    Zhang, Yin; Hong, Hao; Nayak, Tapas R.; Valdovinos, Hector F.; Myklejord, Duane V.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

    2013-01-01

    The goal of this study was to develop a molecular imaging agent that can allow for both positron emission tomography (PET) and near-infrared fluorescence (NIRF) imaging of CD105 expression in metastatic breast cancer. TRC105, a chimeric anti-CD105 monoclonal antibody, was labeled with both a NIRF dye (i.e., IRDye 800CW) and 64Cu to yield 64Cu-NOTA-TRC105-800CW. Flow cytometry analysis revealed no difference in CD105 binding affinity/specificity between TRC105 and NOTA-TRC105-800CW. Serial bioluminescence imaging (BLI) was carried out to non-invasively monitor the lung tumor burden in BALB/c mice, after intravenous injection of firefly luciferase-transfected 4T1 (i.e., fLuc-4T1) murine breast cancer cells to establish the experimental lung metastasis model. Serial PET imaging revealed that fLuc-4T1 lung tumor uptake of 64Cu-NOTA-TRC105-800CW was 11.9 ± 1.2, 13.9 ± 3.9, and 13.4 ± 2.1 %ID/g at 4, 24, and 48 h post-injection respectively (n = 3). Biodistribution studies, blocking fLuc-4T1 lung tumor uptake with excess TRC105, control experiments with 64Cu-NOTA-cetuximab-800CW (which served as an isotype-matched control), ex vivo BLI/PET/NIRF imaging, autoradiography, and histology all confirmed CD105 specificity of 64Cu-NOTA-TRC105-800CW. Successful PET/NIRF imaging of tumor angiogenesis (i.e., CD105 expression) in the breast cancer experimental lung metastasis model warrants further investigation and clinical translation of dual-labeled TRC105-based agents, which can potentially enable early detection of small metastases and image-guided surgery for tumor removal. PMID:23471463

  7. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1.

    PubMed

    Sagar, S M; Yance, D; Wong, R K

    2006-02-01

    An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as

  8. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 1

    PubMed Central

    Sagar, S.M.; Yance, D.; Wong, R.K.

    2006-01-01

    An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or

  9. Dynamic fluorescence imaging with molecular agents for cancer detection

    NASA Astrophysics Data System (ADS)

    Kwon, Sun Kuk

    Non-invasive dynamic optical imaging of small animals requires the development of a novel fluorescence imaging modality. Herein, fluorescence imaging is demonstrated with sub-second camera integration times using agents specifically targeted to disease markers, enabling rapid detection of cancerous regions. The continuous-wave fluorescence imaging acquires data with an intensified or an electron-multiplying charge-coupled device. The work presented in this dissertation (i) assessed dose-dependent uptake using dynamic fluorescence imaging and pharmacokinetic (PK) models, (ii) evaluated disease marker availability in two different xenograft tumors, (iii) compared the impact of autofluorescence in fluorescence imaging of near-infrared (NIR) vs. red light excitable fluorescent contrast agents, (iv) demonstrated dual-wavelength fluorescence imaging of angiogenic vessels and lymphatics associated with a xenograft tumor model, and (v) examined dynamic multi-wavelength, whole-body fluorescence imaging with two different fluorescent contrast agents. PK analysis showed that the uptake of Cy5.5-c(KRGDf) in xenograft tumor regions linearly increased with doses of Cy5.5-c(KRGDf) up to 1.5 nmol/mouse. Above 1.5 nmol/mouse, the uptake did not increase with doses, suggesting receptor saturation. Target to background ratio (TBR) and PK analysis for two different tumor cell lines showed that while Kaposi's sarcoma (KS1767) exhibited early and rapid uptake of Cy5.5-c(KRGDf), human melanoma tumors (M21) had non-significant TBR differences and early uptake rates similar to the contralateral normal tissue regions. The differences may be due to different compartment location of the target. A comparison of fluorescence imaging with NIR vs. red light excitable fluorescent dyes demonstrates that NIR dyes are associated with less background signal, enabling rapid tumor detection. In contrast, animals injected with red light excitable fluorescent dyes showed high autofluorescence. Dual

  10. Precursors to radiopharmaceutical agents for tissue imaging

    DOEpatents

    Srivastava, Prem C.; Knapp, Jr., Furn F.

    1988-01-01

    A class of radiolabeled compounds to be used in tissue imaging that exhibits rapid brain uptake, good brain:blood radioactivity ratios, and long retention times. The imaging agents are more specifically radioiodinated aromatic amines attached to dihydropyridine carriers, that exhibit heart as well as brain specificity. In addition to the radiolabeled compounds, classes of compounds are also described that are used as precursors and intermediates in the preparation of the imaging agents.

  11. Dynamic Contrast-Enhanced MRI Perfusion Parameters as Imaging Biomarkers of Angiogenesis

    PubMed Central

    2016-01-01

    Hypoxia in the tumor microenvironment is the leading factor in angiogenesis. Angiogenesis can be identified by dynamic contrast-enhanced breast MRI (DCE MRI). Here we investigate the relationship between perfusion parameters on DCE MRI and angiogenic and prognostic factors in patients with invasive ductal carcinoma (IDC). Perfusion parameters (Ktrans, kep and ve) of 81 IDC were obtained using histogram analysis. Twenty-fifth, 50th and 75th percentile values were calculated and were analyzed for association with microvessel density (MVD), vascular endothelial growth factor (VEGF) and conventional prognostic factors. Correlation between MVD and ve50 was positive (r = 0.33). Ktrans50 was higher in tumors larger than 2 cm than in tumors smaller than 2 cm. In multivariate analysis, Ktrans50 was affected by tumor size and MVD with 12.8% explanation. There was significant association between Ktrans50 and tumor size and MVD. Therefore we conclude that DCE MRI perfusion parameters are potential imaging biomarkers for prediction of tumor angiogenesis and aggressiveness. PMID:28036342

  12. Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis

    PubMed Central

    Almutairi, Adah; Rossin, Raffaella; Shokeen, Monica; Hagooly, Aviv; Ananth, Ashwin; Capoccia, Benjamin; Guillaudeu, Steve; Abendschein, Dana; Anderson, Carolyn J.; Welch, Michael J.; Fréchet, Jean M. J.

    2009-01-01

    A biodegradable positron-emitting dendritic nanoprobe targeted at αvβ3 integrin, a biological marker known to modulate angiogenesis, was developed for the noninvasive imaging of angiogenesis. The nanoprobe has a modular multivalent core-shell architecture consisting of a biodegradable heterobifunctional dendritic core chemoselectively functionalized with heterobifunctional polyethylene oxide (PEO) chains that form a protective shell, which imparts biological stealth and dictates the pharmacokinetics. Each of the 8 branches of the dendritic core was functionalized for labeling with radiohalogens. Placement of radioactive moieties at the core was designed to prevent in vivo dehalogenation, a potential problem for radiohalogens in imaging and therapy. Targeting peptides of cyclic arginine–glycine–aspartic acid (RGD) motifs were installed at the terminal ends of the PEO chains to enhance their accessibility to αvβ3 integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to αvβ3 integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC50. Cell-based assays of the 125I-labeled dendritic nanoprobes using αvβ3-positive cells showed a 6-fold increase in αvβ3 receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas αvβ3-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of 76Br-labeled dendritic nanoprobes showed excellent bioavailability for the targeted and nontargeted nanoprobes. In vivo studies in a murine hindlimb ischemia model for angiogenesis revealed high specific accumulation of 76Br-labeled dendritic nanoprobes targeted at αvβ3 integrins in angiogenic muscles, allowing highly selective imaging of this critically important process. PMID:19129498

  13. Neurovascular abnormalities in brain disorders: highlights with angiogenesis and magnetic resonance imaging studies

    PubMed Central

    2013-01-01

    The coupling between neuronal activity and vascular responses is controlled by the neurovascular unit (NVU), which comprises multiple cell types. Many different types of dysfunction in these cells may impair the proper control of vascular responses by the NVU. Magnetic resonance imaging, which is the most powerful tool available to investigate neurovascular structures or functions, will be discussed in the present article in relation to its applications and discoveries. Because aberrant angiogenesis and vascular remodeling have been increasingly reported as being implicated in brain pathogenesis, this review article will refer to this hallmark event when suitable. PMID:23829868

  14. Concanavalin A: A potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis for cancer therapeutics

    SciTech Connect

    Li, Wen-wen; Yu, Jia-ying; Xu, Huai-long; Bao, Jin-ku

    2011-10-22

    Highlights: {yields} ConA induces cancer cell death targeting apoptosis and autophagy. {yields} ConA inhibits cancer cell angiogenesis. {yields} ConA is utilized in pre-clinical and clinical trials. -- Abstract: Concanavalin A (ConA), a Ca{sup 2+}/Mn{sup 2+}-dependent and mannose/glucose-binding legume lectin, has drawn a rising attention for its remarkable anti-proliferative and anti-tumor activities to a variety of cancer cells. ConA induces programmed cell death via mitochondria-mediated, P73-Foxo1a-Bim apoptosis and BNIP3-mediated mitochondrial autophagy. Through IKK-NF-{kappa}B-COX-2, SHP-2-MEK-1-ERK, and SHP-2-Ras-ERK anti-angiogenic pathways, ConA would inhibit cancer cell survival. In addition, ConA stimulates cell immunity and generates an immune memory, resisting to the same genotypic tumor. These biological findings shed light on new perspectives of ConA as a potential anti-neoplastic agent targeting apoptosis, autophagy and anti-angiogenesis in pre-clinical or clinical trials for cancer therapeutics.

  15. Targeted magnetic resonance imaging contrast agents.

    PubMed

    Caruthers, Shelton D; Winter, Patrick M; Wickline, Samuel A; Lanza, Gregory M

    2006-01-01

    The era of personalized medicine is emerging as physicians attempt to diagnose disease in asymptomatic individuals and treat pathology early in its natural history. A novel tool in an emerging armamentarium, molecular imaging will allow noninvasive characterization and segmentation of patients for delivering custom-tailored therapy. Nanoparticulate agents, such as superparamagnetic agents, liposomes, perfluorocarbon nanoparticle emulsions, and dendrimers, are being intensively researched as formulation platforms for various targeted clinical applications. As exemplified by perfluorocarbon nanoparticles, these new agents, in combination with the rapid innovations in imaging hardware and software, will allow the emergence of new medical diagnostic and therapeutic paradigms.

  16. Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention

    PubMed Central

    WANG, YING; MA, WENLI; ZHENG, WENLING

    2013-01-01

    Deguelin is a natural compound of the flavonoid family products isolated from Derris trifoliata Lour. or Mundulea sericea (Leguminosae). It exhibited significant anti-tumorigenesis and anti-proliferative activity in various types of cancer both in vitro and in vivo. Deguelin induced cell apoptosis by blocking anti-apoptotic pathways, such as PI3K-Akt, IKK-IκBα-NF-κB and AMPK-mTOR-survivin, while inhibiting tumor cell propagation and malignant transformation through p27-cyclinE-pRb-E2F1 cell cycle control and HIF-1α-VEGF anti-angiogenic pathways. In pre-clinical trials, deguelin markedly decreased the tumor incidence. These biological findings identified deguelin as a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention and chemotherapy. PMID:24649149

  17. In vivo imaging study of angiogenesis in a channelized porous scaffold.

    PubMed

    Tamplenizza, Margherita; Tocchio, Alessandro; Gerges, Irini; Martello, Federico; Martelli, Cristina; Ottobrini, Luisa; Lucignani, Giovanni; Milani, Paolo; Lenardi, Cristina

    2015-01-01

    The main scientific issue hindering the development of tissue engineering technologies is the lack of proper vascularization. Among the various approaches developed for boosting vascularization, scaffold design has attracted increasing interest over the last few years. The aim of this article is to illustrate a scaffold design strategy for enhancing vascularization based on sacrificial microfabrication of embedded microchannels. This approach was combined with an innovative poly(ether urethane urea) (PEUtU) porous scaffold to provide an alternative graft substitute material for the treatment of tissue defects. Fluorescent and chemiluminescent imaging combined with computed tomography were used to study the behavior of the scaffold composition within living subjects by analyzing angiogenesis and inflammation processes and observing the variation in x-ray absorption, respectively. For this purpose, an IntegriSense 680 probe was used in vivo for the localization and quantification of integrin αvβ3, due to its critical involvement in angiogenesis, and a XenoLight RediJect Inflammation Probe for the study of the decline in inflammation progression during healing. Overall, the collected data suggest the advantages of embedding a synthetic vascular network into a PEUtU porous matrix to enhance in vivo tissue integration, maturation, and regeneration. Moreover, our imaging approach proved to be an efficient and versatile tool for scaffold in vivo testing.

  18. Functional CT imaging of angiogenesis in rabbit VX2 soft-tissue tumour

    NASA Astrophysics Data System (ADS)

    Purdie, Thomas G.; Henderson, Elizabeth; Lee, Ting-Yim

    2001-12-01

    Functional parameters such as blood flow (BF), microvessel permeability surface area product (PS), blood volume (BV) and mean transit time (MTT) are physiological markers related to the changes associated with angiogenesis. In the current study we present a functional CT technique for the simultaneous measurement of these four functional parameters and the display of each parameter as a functional image over an entire tissue slice. New Zealand White rabbits with implanted VX2 thigh tumours were scanned using CT with contrast media injection. The ex vivo method of radioactive microspheres was used to evaluate the accuracy of BF measurements with the functional CT technique. There was a significant linear correlation (R = 0.96) between regional CT and microsphere-measured BF values, with a slope not significantly different from unity (0.98 +/- 0.02, P < 0.0001). The precision of our CT technique was determined by the repeated scanning under steady-state conditions. The precision of CT-measured BF, PS, BV and MTT was 14%, 18%, 20% and 24%, respectively. In conclusion, BF can be measured accurately and BF, PS, BV and MTT reproducibly using our functional CT technique. Functional CT can be readily incorporated into existing imaging protocols to assess tumour angiogenesis.

  19. In vivo imaging of the molecular distribution of the VEGF receptor during angiogenesis in a mouse model of ischemia.

    PubMed

    Hamada, Yoh; Gonda, Kohsuke; Takeda, Motohiro; Sato, Akira; Watanabe, Mika; Yambe, Tomoyuki; Satomi, Susumu; Ohuchi, Noriaki

    2011-09-29

    Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and has been applied to medical therapy. However, because vascular imaging at the molecular level is impossible, the detailed in vivo dynamics of VEGF and its receptor (VEGFR) remain unknown. In this study, to understand the molecular distribution of VEGF and the VEGFR, we prepared ischemic mice with a new surgical method and induced angiogenesis in the gastrocnemius muscle. Then, we made a VEGF-conjugated fluorescence nanoparticle and performed staining of VEGFR-expressing cells with the fluorescent probe, demonstrating the high affinity of the probe for VEGFR. To observe the physiologic molecular distribution of VEGFR, we performed in vivo single-particle imaging of gastrocnemius in the ischemic leg with the fluorescent probe. The results suggested that only a 3-fold difference of VEGFR distribution is involved in the formation of branched vasculature in angiogenesis, although previous ex vivo data showed a 13-fold difference in its distribution, indicating that a method inducing a several-fold local increase of VEGFR concentration may be effective in generating site-specific angiogenesis in ischemic disease. This new in vivo imaging of ischemic mice could make useful contributions to understanding the mechanisms of angiogenesis and to developing a VEGFR-related drug.

  20. Imaging Angiogenesis Using 99mTc-Macroaggregated Albumin Scintigraphy in Patients with Peripheral Artery Disease.

    PubMed

    Takagi, Gen; Miyamoto, Masaaki; Fukushima, Yoshimitsu; Yasutake, Masahiro; Tara, Shuhei; Takagi, Ikuyo; Seki, Naoki; Kumita, Shinichiro; Shimizu, Wataru

    2016-02-01

    One problem of vascular angiogenesis therapy is the lack of reliable methods for evaluating blood flow in the microcirculation. We aimed to assess whether (99m)Tc-macroaggregated albumin perfusion scintigraphy ((99m)Tc-MAA) predicts quantitated blood flow after therapeutic angiogenesis in patients with peripheral artery disease. Forty-six patients with peripheral artery disease were treated with bone marrow mononuclear cell implantation (BMCI). Before and 4 wk after BMCI, blood flow was evaluated via transcutaneous oxygen tension (TcPO2), ankle-brachial index, intravenous (99m)Tc-tetrofosmin perfusion scintigraphy ((99m)Tc-TF), and intraaortic (99m)Tc-MAA. Four weeks after BMCI, TcPO2 improved significantly (20.4 ± 14.4 to 36.0 ± 20.0 mm Hg, P < 0.01), but ankle-brachial index did not (0.65 ± 0.30 to 0.76 ± 0.24, P = 0.07). Improvement in (99m)Tc-TF count (0.60 ± 0.23 to 0.77 ± 0.29 count ratio/pixel, P < 0.01) and (99m)Tc-MAA count (5.21 ± 3.56 to 10.33 ± 7.18 count ratio/pixel, P = 0.02) was observed in the foot region but not the lower limb region, using both methods. When these data were normalized by subtracting the pixel count of the untreated side, the improvements in (99m)Tc-TF count (-0.04 ± 0.26 to 0.08 ± 0.32 count ratio/pixel, P = 0.04) and (99m)Tc-MAA count (1.49 ± 3.64 to 5.59 ± 4.84 count ratio/pixel, P = 0.03) in the foot remained significant. (99m)Tc-MAA indicated that the newly developed arteries were approximately 25 μm in diameter. BMCI induced angiogenesis in the foot, which was detected using (99m)Tc-TF and (99m)Tc-MAA. (99m)Tc-MAA is a useful method to quantitate blood flow, estimate vascular size, and evaluate flow distribution after therapeutic angiogenesis. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  1. Imaging biomarkers of angiogenesis and the microvascular environment in cerebral tumours

    PubMed Central

    Thompson, G; Mills, S J; Coope, D J; O’connor, J P B; Jackson, A

    2011-01-01

    Conventional contrast-enhanced CT and MRI are now in routine clinical use for the diagnosis, treatment and monitoring of diseases in the brain. The presence of contrast enhancement is a proxy for the pathological changes that occur in the normally highly regulated brain vasculature and blood-brain barrier. With recognition of the limitations of these techniques, and a greater appreciation for the nuanced mechanisms of microvascular change in a variety of pathological processes, novel techniques are under investigation for their utility in further interrogating the microvasculature of the brain. This is particularly important in tumours, where the reliance on angiogenesis (new vessel formation) is crucial for tumour growth, and the resulting microvascular configuration and derangement has profound implications for diagnosis, treatment and monitoring. In addition, novel therapeutic approaches that seek to directly modify the microvasculature require more sensitive and specific biological markers of baseline tumour behaviour and response. The currently used imaging biomarkers of angiogenesis and brain tumour microvascular environment are reviewed. PMID:22433824

  2. Quantitative ultrasound molecular imaging by modeling the binding kinetics of targeted contrast agent

    NASA Astrophysics Data System (ADS)

    Turco, Simona; Tardy, Isabelle; Frinking, Peter; Wijkstra, Hessel; Mischi, Massimo

    2017-03-01

    Ultrasound molecular imaging (USMI) is an emerging technique to monitor diseases at the molecular level by the use of novel targeted ultrasound contrast agents (tUCA). These consist of microbubbles functionalized with targeting ligands with high-affinity for molecular markers of specific disease processes, such as cancer-related angiogenesis. Among the molecular markers of angiogenesis, the vascular endothelial growth factor receptor 2 (VEGFR2) is recognized to play a major role. In response, the clinical-grade tUCA BR55 was recently developed, consisting of VEGFR2-targeting microbubbles which can flow through the entire circulation and accumulate where VEGFR2 is over-expressed, thus causing selective enhancement in areas of active angiogenesis. Discrimination between bound and free microbubbles is crucial to assess cancer angiogenesis. Currently, this is done non-quantitatively by looking at the late enhancement, about 10 min after injection, or by calculation of the differential targeted enhancement, requiring the application of a high-pressure ultrasound (US) burst to destroy all the microbubbles in the acoustic field and isolate the signal coming only from bound microbubbles. In this work, we propose a novel method based on mathematical modeling of the binding kinetics during the tUCA first pass, thus reducing the acquisition time and with no need for a destructive US burst. Fitting time-intensity curves measured with USMI by the proposed model enables the assessment of cancer angiogenesis at both the vascular and molecular levels. This is achieved by estimation of quantitative parameters related to the microvascular architecture and microbubble binding. The proposed method was tested in 11 prostate-tumor bearing rats by performing USMI after injection of BR55, and showed good agreement with current USMI methods. The novel information provided by the proposed method, possibly combined with the current non-quantitative methods, may bring deeper insight into

  3. Quantitative ultrasound molecular imaging by modeling the binding kinetics of targeted contrast agent.

    PubMed

    Turco, Simona; Tardy, Isabelle; Frinking, Peter; Wijkstra, Hessel; Mischi, Massimo

    2017-03-21

    Ultrasound molecular imaging (USMI) is an emerging technique to monitor diseases at the molecular level by the use of novel targeted ultrasound contrast agents (tUCA). These consist of microbubbles functionalized with targeting ligands with high-affinity for molecular markers of specific disease processes, such as cancer-related angiogenesis. Among the molecular markers of angiogenesis, the vascular endothelial growth factor receptor 2 (VEGFR2) is recognized to play a major role. In response, the clinical-grade tUCA BR55 was recently developed, consisting of VEGFR2-targeting microbubbles which can flow through the entire circulation and accumulate where VEGFR2 is over-expressed, thus causing selective enhancement in areas of active angiogenesis. Discrimination between bound and free microbubbles is crucial to assess cancer angiogenesis. Currently, this is done non-quantitatively by looking at the late enhancement, about 10 min after injection, or by calculation of the differential targeted enhancement, requiring the application of a high-pressure ultrasound (US) burst to destroy all the microbubbles in the acoustic field and isolate the signal coming only from bound microbubbles. In this work, we propose a novel method based on mathematical modeling of the binding kinetics during the tUCA first pass, thus reducing the acquisition time and with no need for a destructive US burst. Fitting time-intensity curves measured with USMI by the proposed model enables the assessment of cancer angiogenesis at both the vascular and molecular levels. This is achieved by estimation of quantitative parameters related to the microvascular architecture and microbubble binding. The proposed method was tested in 11 prostate-tumor bearing rats by performing USMI after injection of BR55, and showed good agreement with current USMI methods. The novel information provided by the proposed method, possibly combined with the current non-quantitative methods, may bring deeper insight into

  4. Hypoxia imaging agents labeled with positron emitters.

    PubMed

    Hoigebazar, Lathika; Jeong, Jae Min

    2013-01-01

    Imaging hypoxia using positron emission tomography (PET) is of great importance for therapy of cancer. [(18)F]Fluoromisonidazole (FMISO) was the first PET agent for hypoxia imaging, and various radiolabeled nitroimidazole derivatives such as [(18)F]fluoroerythronitroimidazole (FETNIM), [(18)F]1-α-D: -(2-deoxy-2-fluoroarabinofuranosyl)-2-nitroimidazole (FAZA), [(18)F]2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide (EF-5), and [(18)F]fluoroetanidazole (FETA) have been developed successively. To overcome the high cost of cyclotron installation, (68)Ga-labeled nitroimidazole derivatives also have been developed. Another important hypoxia imaging agent is (64)Cu-diacetyl-bis(N (4)-methylthiosemicarbazone) ((64)Cu-ATSM), which can distribute in cancer tissue rapidly due to high lipophilicity. However, its application is limited due to high cost of radionuclide production. Although various hypoxia imaging agents have been reported and tested, hypoxia PET images still have to be improved, because of the low blood flow in hypoxic tissues and resulting low uptake of the agents.

  5. Folate-receptor-targeted radionuclide imaging agents.

    PubMed

    Ke, Chun-Yen; Mathias, Carla J; Green, Mark A

    2004-04-29

    The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including delivery of radiolabeled folate-chelate conjugates for diagnostic imaging. This review surveys the growing literature on tumor imaging with radionuclide agents targeted to the folate receptor. Successful folate-receptor targeting has been reported, both in vitro and in vivo, using a variety of radionuclides that are suitable for clinical diagnostic imaging (67Ga, 111In, 99mTc, 66Ga, and 64Cu). While none of these agents has, to date, been demonstrated to have clinical efficacy as a diagnostic tool, existing data indicates that it is feasible to noninvasively assess (at least qualitatively) tissue folate receptor levels by external radionuclide imaging.

  6. Heterobivalent Imaging Agents Targeting Prostate Cancer Training

    DTIC Science & Technology

    2011-06-01

    has been implicated as a salient player in the pathobiology of cancers of epithelial origin, e.g. prostate, cervix , ovarian, colon and...ANSI Std. Z39.18 W81XWH-10-1-0481 Heterobivalent Imaging Agents Targeting Prostate Cancer Training Aaron LeBeau University of California, San...Francisco San Francisco, CA 94103 Annual Summary 31 MAY 2010 - 1JUN 201101-06-2011 To determine the utility of imaging MT-SP1 in cancer , xenografts of

  7. Imaging agent and method of use

    DOEpatents

    Wieland, Donald M.; Brown, Lawrence E.; Beierwaltes, William H.; Wu, Jiann-long

    1986-04-22

    A new radiopharmaceutical composition for use in nuclear medicine comprises a radioiodinated meta-iodobenzylguanidine. The composition is used as an imaging agent for the heart, adrenal medulla, and tumors of the adrenal medulla and can be used for treatment of tumors of the adrenal medulla.

  8. Imaging agent and method of use

    DOEpatents

    Wieland, D.M.; Brown, L.E.; Beierwaltes, W.H.; Wu, J.L.

    1986-04-22

    A new radiopharmaceutical composition for use in nuclear medicine comprises a radioiodinated meta-iodobenzylguanidine. The composition is used as an imaging agent for the heart, adrenal medulla, and tumors of the adrenal medulla and can be used for treatment of tumors of the adrenal medulla. No Drawings

  9. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer—Part 2

    PubMed Central

    Sagar, S.M.; Yance, D.; Wong, R.K.

    2006-01-01

    The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are expanding the clinical knowledge that is already documented in traditional texts. The herbs that are traditionally used for anti-cancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclo-oxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose–response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies or reducing toxicity. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials may be preferable, smaller studies with appropriate endpoints and

  10. Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 2.

    PubMed

    Sagar, S M; Yance, D; Wong, R K

    2006-06-01

    The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are expanding the clinical knowledge that is already documented in traditional texts. The herbs that are traditionally used for anti-cancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclo-oxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies or reducing toxicity. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials may be preferable, smaller studies with appropriate endpoints and

  11. Modular Strategies for PET Imaging Agents

    PubMed Central

    Hooker, Jacob M

    2009-01-01

    Summary of Recent Advances In recent years, modular and simplified chemical and biological strategies have been developed for the synthesis and implementation of positron emission tomography (PET) radiotracers. New developments in bioconjugation and synthetic methodologies, in combination with advances in macromolecular delivery systems and gene-expression imaging, reflect a need to reduce radiosynthesis burden in order to accelerate imaging agent development. These new approaches, which are often mindful of existing infrastructure and available resources, are anticipated to provide a more approachable entry point for researchers interested in using PET to translate in vitro research to in vivo imaging. PMID:19880343

  12. Microbubble contrast agents: targeted ultrasound imaging and ultrasound-assisted drug-delivery applications.

    PubMed

    Klibanov, Alexander L

    2006-03-01

    The use of microbubble contrast agents for general tissue delineation and perfusion enjoys steady interest in ultrasound imaging. Microbubbles as contrast materials require a small dosage and show excellent detection sensitivity. Targeting ligands on the surface of microbubbles permit the selective accumulation of these particles in the areas of interest, which show an up-regulated level of receptor molecules on vascular endothelium. Selective contrast imaging of inflammation, ischemia-reperfusion injury, angiogenesis, and thrombosis has been achieved in animal models. Ultrasound-assisted drug delivery and activation, performed by combining microbubble agent containing drug substances or coadministered with pharmaceutical agents (including plasmid DNA for transfection), has been achieved in multiple model systems in vitro and in vivo. Ultrasound and microbubbles-based targeted acceleration of the thrombolytic enzyme action already have reached clinical trials. Overall, microbubble targeting and ultrasound-assisted microbubble-based drug-delivery systems will offer a step toward the application of targeted personalized diagnostics and therapy.

  13. Development of an intravenous formulation of SU010382 (prodrug of SU5416, an anti-angiogenesis agent).

    PubMed

    Sistla, Anand; Kertelj, Adriana; Shenoy, Narmada

    2008-01-01

    SU5416, the first in a new class of anti-angiogenesis agents, is an insoluble and neutral molecule which requires a formulation containing Cremophor EL, ethanol, and polyethylene glycol. SU010382, a prodrug of SU5416, was designed as N-Mannich base to provide a basic handle that could be exploited to increase the compound's solubility. Though an increase in solubility was obtained, the inherent hydrolytic instability of SU010382 presented a major challenge in formulation development. The aim of this study is to design a stable intravenous formulation of SU010382 at 2 mg/mL equivalent to the 1.5 mg/mL clinical formulation of SU5416 without a high surfactant/co-solvent content. A stable formulation of SU010382 was successfully designed using a combination of adjusted pH and complexation with sulfobutyl-ether-beta-cyclodextrin. This formulation was designed as a lyophilized product to further increase stability. The lyophilized formulation was stable for at least 6 months at 40 degrees C/75% relative humidity, reconstituted completely within 1 min, and was stable for at least 24 h at 25 degrees C following reconstitution.

  14. Hemodynamic Response Imaging: A Potential Tool for the Assessment of Angiogenesis in Brain Tumors

    PubMed Central

    Ben Ami, Haim; Aizenstein, Orna; Blumenthal, Deborah T.; Bokstein, Felix; Corn, Benjamin W.; Ram, Zvi; Kanner, Avraham A.; Lifschitz-Mercer, Biatris; Solar, Irit; Kolatt, Tsafrir; Palmon, Mika; Edrei, Yifat; Abramovitch, Rinat

    2012-01-01

    Blood oxygenation level dependence (BOLD) imaging under either hypercapnia or hyperoxia has been used to study neuronal activation and for assessment of various brain pathologies. We evaluated the benefit of a combined protocol of BOLD imaging during both hyperoxic and hypercapnic challenges (termed hemodynamic response imaging (HRI)). Nineteen healthy controls and seven patients with primary brain tumors were included: six with glioblastoma (two newly diagnosed and four with recurrent tumors) and one with atypical-meningioma. Maps of percent signal intensity changes (ΔS) during hyperoxia (carbogen; 95%O2+5%CO2) and hypercapnia (95%air+5%CO2) challenges and vascular reactivity mismatch maps (VRM; voxels that responded to carbogen with reduced/absent response to CO2) were calculated. VRM values were measured in white matter (WM) and gray matter (GM) areas of healthy subjects and used as threshold values in patients. Significantly higher response to carbogen was detected in healthy subjects, compared to hypercapnia, with a GM/WM ratio of 3.8 during both challenges. In patients with newly diagnosed/treatment-naive tumors (n = 3), increased response to carbogen was detected with substantially increased VRM response (compared to threshold values) within and around the tumors. In patients with recurrent tumors, reduced/absent response during both challenges was demonstrated. An additional finding in 2 of 4 patients with recurrent glioblastoma was a negative response during carbogen, distant from tumor location, which may indicate steal effect. In conclusion, the HRI method enables the assessment of blood vessel functionality and reactivity. Reference values from healthy subjects are presented and preliminary results demonstrate the potential of this method to complement perfusion imaging for the detection and follow up of angiogenesis in patients with brain tumors. PMID:23209575

  15. An imaging-based computational model for simulating angiogenesis and tumour oxygenation dynamics

    NASA Astrophysics Data System (ADS)

    Adhikarla, Vikram; Jeraj, Robert

    2016-05-01

    Tumour growth, angiogenesis and oxygenation vary substantially among tumours and significantly impact their treatment outcome. Imaging provides a unique means of investigating these tumour-specific characteristics. Here we propose a computational model to simulate tumour-specific oxygenation changes based on the molecular imaging data. Tumour oxygenation in the model is reflected by the perfused vessel density. Tumour growth depends on its doubling time (T d) and the imaged proliferation. Perfused vessel density recruitment rate depends on the perfused vessel density around the tumour (sMVDtissue) and the maximum VEGF concentration for complete vessel dysfunctionality (VEGFmax). The model parameters were benchmarked to reproduce the dynamics of tumour oxygenation over its entire lifecycle, which is the most challenging test. Tumour oxygenation dynamics were quantified using the peak pO2 (pO2peak) and the time to peak pO2 (t peak). Sensitivity of tumour oxygenation to model parameters was assessed by changing each parameter by 20%. t peak was found to be more sensitive to tumour cell line related doubling time (~30%) as compared to tissue vasculature density (~10%). On the other hand, pO2peak was found to be similarly influenced by the above tumour- and vasculature-associated parameters (~30-40%). Interestingly, both pO2peak and t peak were only marginally affected by VEGFmax (~5%). The development of a poorly oxygenated (hypoxic) core with tumour growth increased VEGF accumulation, thus disrupting the vessel perfusion as well as further increasing hypoxia with time. The model with its benchmarked parameters, is applied to hypoxia imaging data obtained using a [64Cu]Cu-ATSM PET scan of a mouse tumour and the temporal development of the vasculature and hypoxia maps are shown. The work underscores the importance of using tumour-specific input for analysing tumour evolution. An extended model incorporating therapeutic effects can serve as a powerful tool for analysing

  16. Molecular magnetic resonance imaging of angiogenesis in vivo using polyvalent cyclic RGD-iron oxide microparticle conjugates.

    PubMed

    Melemenidis, Stavros; Jefferson, Andrew; Ruparelia, Neil; Akhtar, Asim M; Xie, Jin; Allen, Danny; Hamilton, Alastair; Larkin, James R; Perez-Balderas, Francisco; Smart, Sean C; Muschel, Ruth J; Chen, Xiaoyuan; Sibson, Nicola R; Choudhury, Robin P

    2015-01-01

    Angiogenesis is an essential component of tumour growth and, consequently, an important target both therapeutically and diagnostically. The cell adhesion molecule α(v)β(3) integrin is a specific marker of angiogenic vessels and the most prevalent vascular integrin that binds the amino acid sequence arginine-glycine-aspartic acid (RGD). Previous studies using RGD-targeted nanoparticles (20-50 nm diameter) of iron oxide (NPIO) for magnetic resonance imaging (MRI) of tumour angiogenesis, have identified a number of limitations, including non-specific extravasation, long blood half-life (reducing specific contrast) and low targeting valency. The aim of this study, therefore, was to determine whether conjugation of a cyclic RGD variant [c(RGDyK)], with enhanced affinity for α(v)β(3), to microparticles of iron oxide (MPIO) would provide a more sensitive contrast agent for imaging of angiogenic tumour vessels. Cyclic RGD [c(RGDyK)] and RAD [c(RADyK)] based peptides were coupled to 2.8 μm MPIO, and binding efficacy tested both in vitro and in vivo. Significantly greater specific binding of c(RGDyK)-MPIO to S-nitroso-n-acetylpenicillamine (SNAP)-stimulated human umbilical vein endothelial cells in vitro than PBS-treated cells was demonstrated under both static (14-fold increase; P < 0.001) and flow (44-fold increase; P < 0.001) conditions. Subsequently, mice bearing subcutaneous colorectal (MC38) or melanoma (B16F10) derived tumours underwent in vivo MRI pre- and post-intravenous administration of c(RGDyK)-MPIO or c(RADyK)-MPIO. A significantly greater volume of MPIO-induced hypointensities were found in c(RGDyK)-MPIO injected compared to c(RADyK)-MPIO injected mice, in both tumour models (P < 0.05). Similarly, administration of c(RGDyK)-MPIO induced a greater reduction in mean tumour T(2)* relaxation times than the control agent in both tumour models (melanoma P < 0.001; colorectal P < 0.0001). Correspondingly, MPIO density per tumour volume assessed

  17. Ultrasound contrast agents for ultrasound molecular imaging.

    PubMed

    Tranquart, F; Arditi, M; Bettinger, T; Frinking, P; Hyvelin, J M; Nunn, A; Pochon, S; Tardy, I

    2014-11-01

    Ultrasound is a real-time imaging technique which is widely used in many clinical applications for its capacity to provide anatomic information with high spatial and temporal resolution. The advent of ultrasound contrast agents in combination with contrast-specific imaging modes has given access to perfusion assessments at an organ level, leading to an improved diagnostic accuracy. More recently, the development of biologically-targeted ultrasound contrast agents has expanded the role of ultrasound even further into molecular imaging applications. Ultrasound molecular imaging can be used to visualize the expression of intravascular markers, and to assess their local presence over time and/or during therapeutic treatment. Major applications are in the field of inflammation and neoangiogenesis due to the strictly intravascular presence of microbubbles. Various technologies have been investigated for attaching the targeting moiety to the shell from simple biotin-avidin constructs to more elaborated insertion within the shell through attachment to PEG residues. This important improvement has allowed a clinical translation of initial pre-clinical investigations, opening the way for an early detection and an accurate characterization of lesions in patients. The combination of anatomic, functional and molecular information/data provided by contrast ultrasound is a powerful tool which is still in its infancy due to the lack of agents suitable for clinical use. The advantages of ultrasound techniques combined with the molecular signature of lesions will represent a significant advance in imaging in the field of personalized medicine. © Georg Thieme Verlag KG Stuttgart · New York.

  18. Firefly luciferase-based dynamic bioluminescence imaging: a noninvasive technique to assess tumor angiogenesis.

    PubMed

    Sun, Amy; Hou, Lewis; Prugpichailers, Tiffany; Dunkel, Jason; Kalani, Maziyar A; Chen, Xiaoyuan; Kalani, M Yashar S; Tse, Victor

    2010-04-01

    Bioluminescence imaging (BLI) is emerging as a cost-effective, high-throughput, noninvasive, and sensitive imaging modality to monitor cell growth and trafficking. We describe the use of dynamic BLI as a noninvasive method of assessing vessel permeability during brain tumor growth. With the use of stereotactic technique, 10 firefly luciferase-transfected GL26 mouse glioblastoma multiforme cells were injected into the brains of C57BL/6 mice (n = 80). After intraperitoneal injection of D-luciferin (150 mg/kg), serial dynamic BLI was performed at 1-minute intervals (30 seconds exposure) every 2 to 3 days until death of the animals. The maximum intensity was used as an indirect measurement of tumor growth. The adjusted slope of initial intensity (I90/Im) was used as a proxy to monitor the flow rate of blood into the vascular tree. Using a modified Evans blue perfusion protocol, we calculated the relative permeability of the vascular tree at various time points. Daily maximum intensity correlated strongly with tumor volume. At postinjection day 23, histology and BLI demonstrated an exponential growth of the tumor mass. Slopes were calculated to reflect the flow in the vessels feeding the tumor (adjusted slope = I90/Im). The increase in BLI intensity was correlated with a decrease in adjusted slope, reflecting a decrease in the rate of blood flow as tumor volume increased (y = 93.8e-0.49, R2 = 0.63). Examination of calculated slopes revealed a peak in permeability around postinjection day 20 (n = 42, P < .02 by 1-way analysis of variance) and showed a downward trend in relation to both postinjection day and maximum intensity observed; as angiogenesis progressed, tumor vessel caliber increased dramatically, resulting in sluggish but increased flow. This trend was correlated with Evans blue histology, revealing an increase in Evans blue dye uptake into the tumor, as slope calculated by BLI increases. Dynamic BLI is a practical, noninvasive technique that can

  19. Monomolecular multimodal fluorescence-radioisotope imaging agents.

    PubMed

    Zhang, Zongren; Liang, Kexian; Bloch, Sharon; Berezin, Mikhail; Achilefu, Samuel

    2005-01-01

    Diagnosis of diseases by different imaging methods can provide complementary information about the functional status of diseased tissues or organs. To overcome the current difficulties in coregistering images from different imaging modalities with a high degree of accuracy, we prepared near-infrared (NIR) monomolecular multimodal imaging agents (MOMIAs) consisting of a heptamethine carbocyanine and 111In-DOTA chelate that served as antennae for optical and scintigraphic imaging, respectively. Their spectral properties clearly show that coordination of indium to MOMIA increased the fluorescence intensity of the compounds. The MOMIAs are exceptionally stable in biological media and serum up to 24 h at 37 degrees C. Biodistribution of the compounds in mice obtained by fluorescence photon and gamma-counts demonstrated a similar distribution trend of the molecular probe in different tissues, suggesting that the detected fluorescence and gamma-emissions emanated from the same source (MOMIA). At 24 h postinjection, the MOMIAs were excreted by the renal and hepatobiliary systems and the blood level of a representative MOMIA was very low, thereby reducing background noise caused by circulating molecular probes. These findings demonstrate the feasibility of preparing single molecules with the capacity to emit discernible and diagnostic fluorescent and gamma-radiations for optical and nuclear imaging of living organisms.

  20. Optical Imaging with Dynamic Contrast Agents

    PubMed Central

    Wei, Qingshan; Wei, Alexander

    2011-01-01

    Biological imaging applications often employ molecular probes or nanoparticles for enhanced contrast. However, resolution and detection are still often limited by the intrinsic heterogeneity of the Isample, which can produce high levels of background that obscure the signals of interest. In this article we describe approaches to overcome this obstacle based on the concept of dynamic contrast, a strategy for elucidating signals by the suppression or removal of background noise. Dynamic contrast mechanisms can greatly reduce the loading requirement of contrast agents, and may be especially useful for single-probe imaging. Dynamic contrast modalities are also platform-independent, and can enhance the performance of sophisticated biomedical imaging systems or simple optical microscopes alike. Dynamic contrast is performed in two stages: i) a signal modulation scheme to introduce time-dependent changes in amplitude or phase, and ii) a demodulation step for signal recovery. Optical signals can be coupled with magnetic nanoparticles, photoswitchable probes, or plasmon-resonant nanostructures for modulation by magnetomotive, photonic, or photothermal mechanisms respectively. With respect to image demodulation, many of the strategies developed for signal processing in electronics and communication technologies can also be applied toward the editing of digital images. The image processing step can be as simple as differential imaging, or may involve multiple reference points for deconvolution using cross-correlation algorithms. Periodic signals are particularly amenable to image demodulation strategies based on Fourier transform; the contrast of the demodulated signal increases with acquisition time, and modulation frequencies in the kHz range are possible. Dynamic contrast is an emerging topic with considerable room for development, both with respect to molecular or nanoscale probes for signal modulation, and also to methods for more efficient image processing and editing

  1. Optical imaging with dynamic contrast agents.

    PubMed

    Wei, Qingshan; Wei, Alexander

    2011-01-24

    Biological imaging applications often employ molecular probes or nanoparticles for enhanced contrast. However, resolution and detection are still often limited by the intrinsic heterogeneity of the sample, which can produce high levels of background that obscure the signals of interest. Herein, we describe approaches to overcome this obstacle based on the concept of dynamic contrast: a strategy for elucidating signals by the suppression or removal of background noise. Dynamic contrast mechanisms can greatly reduce the loading requirement of contrast agents, and may be especially useful for single-probe imaging. Dynamic contrast modalities are also platform-independent, and can enhance the performance of sophisticated biomedical imaging systems or simple optical microscopes alike. Dynamic contrast is performed in two stages: 1) a signal modulation scheme to introduce time-dependent changes in amplitude or phase, and 2) a demodulation step for signal recovery. Optical signals can be coupled with magnetic nanoparticles, photoswitchable probes, or plasmon-resonant nanostructures for modulation by magnetomotive, photonic, or photothermal mechanisms, respectively. With respect to image demodulation, many of the strategies developed for signal processing in electronics and communication technologies can also be applied toward the editing of digital images. The image-processing step can be as simple as differential imaging, or may involve multiple reference points for deconvolution by using cross-correlation algorithms. Periodic signals are particularly amenable to image demodulation strategies based on Fourier transform; the contrast of the demodulated signal increases with acquisition time, and modulation frequencies in the kHz range are possible. Dynamic contrast is an emerging topic with considerable room for development, both with respect to molecular or nanoscale probes for signal modulation, and also to methods for more efficient image processing and editing

  2. Advances in Magnetic Resonance Imaging Contrast Agents for Biomarker Detection

    NASA Astrophysics Data System (ADS)

    Sinharay, Sanhita; Pagel, Mark D.

    2016-06-01

    Recent advances in magnetic resonance imaging (MRI) contrast agents have provided new capabilities for biomarker detection through molecular imaging. MRI contrast agents based on the T2 exchange mechanism have more recently expanded the armamentarium of agents for molecular imaging. Compared with T1 and T2* agents, T2 exchange agents have a slower chemical exchange rate, which improves the ability to design these MRI contrast agents with greater specificity for detecting the intended biomarker. MRI contrast agents that are detected through chemical exchange saturation transfer (CEST) have even slower chemical exchange rates. Another emerging class of MRI contrast agents uses hyperpolarized 13C to detect the agent with outstanding sensitivity. These hyperpolarized 13C agents can be used to track metabolism and monitor characteristics of the tissue microenvironment. Together, these various MRI contrast agents provide excellent opportunities to develop molecular imaging for biomarker detection.

  3. Advances in Magnetic Resonance Imaging Contrast Agents for Biomarker Detection

    PubMed Central

    Sinharay, Sanhita; Pagel, Mark D.

    2016-01-01

    Recent advances in magnetic resonance imaging (MRI) contrast agents have provided new capabilities for biomarker detection through molecular imaging. MRI contrast agents based on the T2 exchange mechanism have more recently expanded the armamentarium of agents for molecular imaging. Compared with T1 and T2* agents, T2 exchange agents have a slower chemical exchange rate, which improves the ability to design these MRI contrast agents with greater specificity for detecting the intended biomarker. MRI contrast agents that are detected through chemical exchange saturation transfer (CEST) have even slower chemical exchange rates. Another emerging class of MRI contrast agents uses hyperpolarized 13C to detect the agent with outstanding sensitivity. These hyperpolarized 13C agents can be used to track metabolism and monitor characteristics of the tissue microenvironment. Together, these various MRI contrast agents provide excellent opportunities to develop molecular imaging for biomarker detection. PMID:27049630

  4. Magnetoliposomes as magnetic resonance imaging contrast agents.

    PubMed

    Soenen, Stefaan J; Vande Velde, Greetje; Ketkar-Atre, Ashwini; Himmelreich, Uwe; De Cuyper, Marcel

    2011-01-01

    Among the wide variety in iron oxide nanoparticles which are routinely used as magnetic resonance imaging (MRI) contrast agents, magnetoliposomes (MLs) take up a special place. In the present work, the two main types (large and small MLs) are defined and their specific features are commented. For both types of MLs, the flexibility of the lipid coating allows for efficient functionalization, enabling bimodal imaging (e.g., MRI and fluorescence) or the use of MLs as theranostics. These features are especially true for large MLs, where several magnetite cores are encapsulated within a single large liposome, which were found to be highly efficient theranostic agents. By carefully fine-tuning the number of magnetite cores and attaching Gd(3+) -complexes onto the liposomal surface, the large MLs can be efficiently optimized for dynamic MRI. A special type of MLs, biogenic MLs, can also be efficiently used in this regard, with potential applications in cancer treatment and imaging. Small MLs, where the lipid bilayer is immediately attached onto a solid magnetite core, give a very high r2 /r1 ratio. The flexibility of the lipid bilayer allows the incorporation of poly(ethylene glycol)-lipid conjugates to increase blood circulation times and be used as bone marrow contrast agents. Cationic lipids can also be incorporated, leading to high cell uptake and associated strong contrast generation in MRI of implanted cells. Unique for these small MLs is the high resistance the particles exhibit against intracellular degradation compared with dextran- or citrate-coated particles. Additionally, intracellular clustering of the iron oxide cores enhances negative contrast generation and enables longer tracking of labeled cells in time. Copyright © 2011 John Wiley & Sons, Inc.

  5. Intraoperative imaging using intravascular contrast agent

    NASA Astrophysics Data System (ADS)

    Watson, Jeffrey R.; Martirosyan, Nikolay; Garland, Summer; Lemole, G. Michael; Romanowski, Marek

    2016-03-01

    Near-infrared (NIR) contrast agents are becoming more frequently studied in medical imaging due to their advantageous characteristics, most notably the ability to capture near-infrared signal across the tissue and the safety of the technique. This produces a need for imaging technology that can be specific for both the NIR dye and medical application. Indocyanine green (ICG) is currently the primary NIR dye used in neurosurgery. Here we report on using the augmented microscope we described previously for image guidance in a rat glioma resection. Luc-C6 cells were implanted in a rat in the left-frontal lobe and grown for 22 days. Surgical resection was performed by a neurosurgeon using augmented microscopy guidance with ICG contrast. Videos and images were acquired to evaluate image quality and resection margins. ICG accumulated in the tumor tissue due to enhanced permeation and retention from the compromised bloodbrain- barrier. The augmented microscope was capable of guiding the rat glioma resection and intraoperatively highlighted tumor tissue regions via ICG fluorescence under normal illumination of the surgical field.

  6. Family of enhanced photoacoustic imaging agents for high-sensitivity and multiplexing studies in living mice.

    PubMed

    de la Zerda, Adam; Bodapati, Sunil; Teed, Robert; May, Salomón Y; Tabakman, Scott M; Liu, Zhuang; Khuri-Yakub, Butrus T; Chen, Xiaoyuan; Dai, Hongjie; Gambhir, Sanjiv S

    2012-06-26

    Photoacoustic imaging is a unique modality that overcomes to a great extent the resolution and depth limitations of optical imaging while maintaining relatively high contrast. However, since many diseases will not manifest an endogenous photoacoustic contrast, it is essential to develop exogenous photoacoustic contrast agents that can target diseased tissue(s). Here we present a family of novel photoacoustic contrast agents that are based on the binding of small optical dyes to single-walled carbon nanotubes (SWNT-dye). We synthesized five different SWNT-dye contrast agents using different optical dyes, creating five "flavors" of SWNT-dye nanoparticles. In particular, SWNTs that were coated with either QSY(21) (SWNT-QSY) or indocyanine green (SWNT-ICG) exhibited over 100-times higher photoacoustic contrast in living animals compared to plain SWNTs, leading to subnanomolar sensitivities. We then conjugated the SWNT-dye conjugates with cyclic Arg-Gly-Asp peptides to molecularly target the α(v)β(3) integrin, which is associated with tumor angiogenesis. Intravenous administration of these tumor-targeted imaging agents to tumor-bearing mice showed significantly higher photoacoustic signal in the tumor than in mice injected with the untargeted contrast agent. Finally, we were able to spectrally separate the photoacoustic signals of SWNT-QSY and SWNT-ICG in living animals injected subcutaneously with both particles in the same location, opening the possibility for multiplexing in vivo studies.

  7. Photoacoustic molecular imaging of angiogenesis using theranostic ανβ3-targeted copper nanoparticles incorporating a sn-2 lipase-labile fumagillin prodrug

    NASA Astrophysics Data System (ADS)

    Zhang, Ruiying; Cai, Xin; Yang, Xiaoxia; Senpan, Angana; Allen, John S.; Pan, Dipanjan; Lanza, Gregory M.; Wang, Lihong V.

    2014-03-01

    Photoacoustic (PA) tomography imaging is an emerging, versatile, and noninvasive imaging modality, which combines the advantages of both optical imaging and ultrasound imaging. It opens up opportunities for noninvasive imaging of angiogenesis, a feature of skin pathologies including cancers and psoriasis. In this study, high-density copper oleate encapsulated within a phospholipid surfactant (CuNPs) generated a soft nanoparticle with PA contrast comparable to gold. Within the near-infrared window, the copper nanoparticles can provide a signal more than 7 times higher that of blood. ανβ3-targeted of CuNPs in a Matrigel mouse model demonstrated prominent PA contrast enhancement of the neovasculature compared to mice given nontargeted or competitively inhibited CuNPs. Incorporation of a sn-2 lipase-labile fumagillin prodrug into the CuNPs produced marked antiangiogenesis in the same model, demonstrating the theranostic potential of a PA agent for the first time in vivo. With a PA signal comparable to gold-based nanoparticles yet a lower cost and demonstrated drug delivery potential, ανβ3-targeted CuNPs hold great promise for the management of skin pathologies with neovascular features.

  8. VEGF-loaded graphene oxide as theranostics for multi-modality imaging-monitored targeting therapeutic angiogenesis of ischemic muscle

    NASA Astrophysics Data System (ADS)

    Sun, Zhongchan; Huang, Peng; Tong, Guang; Lin, Jing; Jin, Albert; Rong, Pengfei; Zhu, Lei; Nie, Liming; Niu, Gang; Cao, Feng; Chen, Xiaoyuan

    2013-07-01

    Herein we report the design and synthesis of multifunctional VEGF-loaded IR800-conjugated graphene oxide (GO-IR800-VEGF) for multi-modality imaging-monitored therapeutic angiogenesis of ischemic muscle. The as-prepared GO-IR800-VEGF positively targets VEGF receptors, maintains an elevated level of VEGF in ischemic tissues for a prolonged time, and finally leads to remarkable therapeutic angiogenesis of ischemic muscle. Although more efforts are required to further understand the in vivo behaviors and the long-term toxicology of GO, our work demonstrates the success of using GO for efficient VEGF delivery in vivo by intravenous administration and suggests the great promise of using graphene oxide in theranostic applications for treating ischemic disease.Herein we report the design and synthesis of multifunctional VEGF-loaded IR800-conjugated graphene oxide (GO-IR800-VEGF) for multi-modality imaging-monitored therapeutic angiogenesis of ischemic muscle. The as-prepared GO-IR800-VEGF positively targets VEGF receptors, maintains an elevated level of VEGF in ischemic tissues for a prolonged time, and finally leads to remarkable therapeutic angiogenesis of ischemic muscle. Although more efforts are required to further understand the in vivo behaviors and the long-term toxicology of GO, our work demonstrates the success of using GO for efficient VEGF delivery in vivo by intravenous administration and suggests the great promise of using graphene oxide in theranostic applications for treating ischemic disease. Electronic supplementary information (ESI) available. See DOI: 10.1039/c3nr01573d

  9. Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA).

    PubMed

    Hannafon, Bethany N; Carpenter, Karla J; Berry, William L; Janknecht, Ralf; Dooley, William C; Ding, Wei-Qun

    2015-07-16

    Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA's anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA's anticancer action. Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA's anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. We conclude that DHA alters breast

  10. Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor

    PubMed Central

    Li, Xiaoyu; Wu, Meiying; Pan, Limin; Shi, Jianlin

    2016-01-01

    To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID:26766908

  11. Aggretin Venom Polypeptide as a Novel Anti-angiogenesis Agent by Targeting Integrin alpha2beta1

    PubMed Central

    Chung, Ching Hu; Chang, Chien Hsin; Hsu, Chun Chieh; Lin, Kung Tin; Peng, Hui Chin; Huang, Tur Fu

    2017-01-01

    VEGF and VEGFR antibodies have been used as a therapeutic strategy to inhibit angiogenesis in many diseases; however, frequent and repeated administration of these antibodies to patients induces immunogenicity. In previous studies, we demonstrated that aggretin, a heterodimeric snake venom C-type lectin, exhibits pro-angiogenic activities via integrin α2β1 ligation. We hypothesised that small-mass aggretin fragments may bind integrin α2β1 and act as antagonists of angiogenesis. In this study, the anti-angiogenic efficacy of a synthesised aggretin α-chain C-terminus (AACT, residue 106–136) was evaluated in both in vitro and in vivo angiogenesis models. The AACT demonstrated inhibitory effects on collagen-induced platelet aggregation and HUVEC adhesion to immobilised collagen. These results indicated that AACT may block integrin α2β1−collagen interaction. AACT also inhibited HUVEC migration and tube formation. Aortic ring sprouting and Matrigel implant models demonstrated that AACT markedly inhibited VEGF-induced neovascularisation. In addition, induction of FAK/PI3K/ERK1/2 tyrosine phosphorylation and talin 1/2 associated with integrin β1 which are induced by VEGF were blocked by AACT. Similarly, tyrosine phosphorylation of VEFGR2 and ERK1/2 induced by VEGF was diminished in integrin α2-silenced endothelial cells. Our results demonstrate that AACT is a potential therapeutic candidate for angiogenesis related-diseases via integrin α2β1 blockade. PMID:28252668

  12. Quantitative positron emission tomography imaging of angiogenesis in rats with forelimb ischemia using (68)Ga-NOTA-c(RGDyK).

    PubMed

    Kim, Joong Hyun; Kim, Young-Hwa; Kim, Young Joo; Yang, Bo Yeun; Jeong, Jae Min; Youn, Hyewon; Lee, Dong Soo; Lee, Jae Sung

    2013-10-01

    Gallium-68-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-cyclic Arg-Gly-Asp-D-Tyr-Lys (c(RGDyK)) was developed for αvβ3 targeting, and is a promising agent for imaging of cancer and disorders related to angiogenesis. In this study, we performed kinetic analysis of (68)Ga-NOTA-c(RGDyK) in rats with surgically induced forelimb ischemia, and immunohistochemical analysis was also performed to assess αvβ3 immuno-staining level. Animal models were created by excision of the left brachial vessels, and a sham operation was performed on the right brachial region under 2 % isoflurane anesthesia. Using an animal positron emission tomography/computed tomography (PET/CT) scanner, a list mode PET scan (120 min) was started with the injection of (68)Ga-NOTA-c(RGDyK) via the tail vein at 3, 5 and 7 days after ischemic surgery. Volumes of interest were drawn on the left ventricle, sham operation, control, and ischemic regions. Compartmental and two graphical analyses (Logan and RE plots) were performed for kinetic parameter estimation. The immunohistochemical analysis was also performed after the last PET scan, and cell components were scored on a six point scale for quantification of immuno-staining level (0-negative to 5-very high). A 3-compartment model with reversible binding best described the tissue time-activity curves. The distribution volume of the ischemic region was significantly higher than that of the sham operation (P < 10(-6)) and control region (P < 10(-9)). Both the Logan and RE plots showed high correlation with compartmental analysis (R(2) = 0.96 and 0.95 for Logan and RE, respectively). The temporal changes in distribution volume and binding potential were not significant. The immuno-staining level of the ischemic region was significantly higher than that of sham operation (P < 10(-4)) and control region (P < 10(-8)). Kinetic modeling studies with dynamic (68)Ga-NOTA-c(RGDyK) PET scan are feasible based on an image-derived input function in a

  13. Angiogenesis: a curse or cure?

    PubMed

    Gupta, K; Zhang, J

    2005-04-01

    Angiogenesis, the growth of new blood vessels is essential during fetal development, female reproductive cycle, and tissue repair. In contrast, uncontrolled angiogenesis promotes the neoplastic disease and retinopathies, while inadequate angiogenesis can lead to coronary artery disease. A balance between pro-angiogenic and antiangiogenic growth factors and cytokines tightly controls angiogenesis. Considerable progress has been made in identifying these molecular components to develop angiogenesis based treatments. One of the most specific and critical regulators of angiogenesis is vascular endothelial growth factor (VEGF), which regulates endothelial proliferation, permeability, and survival. Several VEGF based treatments including anti-VEGF and anti-VEGF receptor antibodies/agents are in clinical trials along with several other antiangiogenic treatments. While bevacizumab (anti-VEGF antibody) has been approved for clinical use in colorectal cancer, the side effects of antiangiogenic treatment still remain a challenge. The pros and cons of angiogenesis based treatment are discussed.

  14. Quantitative assessment of tumor angiogenesis using real-time motion-compensated contrast-enhanced ultrasound imaging

    PubMed Central

    Pysz, Marybeth A.; Guracar, Ismayil; Foygel, Kira; Tian, Lu; Willmann, Jürgen K.

    2015-01-01

    Purpose To develop and test a real-time motion compensation algorithm for contrast-enhanced ultrasound imaging of tumor angiogenesis on a clinical ultrasound system. Materials and methods The Administrative Institutional Panel on Laboratory Animal Care approved all experiments. A new motion correction algorithm measuring the sum of absolute differences in pixel displacements within a designated tracking box was implemented in a clinical ultrasound machine. In vivo angiogenesis measurements (expressed as percent contrast area) with and without motion compensated maximum intensity persistence (MIP) ultrasound imaging were analyzed in human colon cancer xenografts (n = 64) in mice. Differences in MIP ultrasound imaging signal with and without motion compensation were compared and correlated with displacements in x- and y-directions. The algorithm was tested in an additional twelve colon cancer xenograft-bearing mice with (n = 6) and without (n = 6) anti-vascular therapy (ASA-404). In vivo MIP percent contrast area measurements were quantitatively correlated with ex vivo microvessel density (MVD) analysis. Results MIP percent contrast area was significantly different (P < 0.001) with and without motion compensation. Differences in percent contrast area correlated significantly (P < 0.001) with x- and y-displacements. MIP percent contrast area measurements were more reproducible with motion compensation (ICC = 0.69) than without (ICC = 0.51) on two consecutive ultrasound scans. Following anti-vascular therapy, motion-compensated MIP percent contrast area significantly (P = 0.03) decreased by 39.4 ± 14.6 % compared to non-treated mice and correlated well with ex vivo MVD analysis (Rho = 0.70; P = 0.05). Conclusion Real-time motion-compensated MIP ultrasound imaging allows reliable and accurate quantification and monitoring of angiogenesis in tumors exposed to breathing-induced motion artifacts. PMID:22535383

  15. A phospholipid-PEG2000 conjugate of a vascular endothelial growth factor receptor 2 (VEGFR2)-targeting heterodimer peptide for contrast-enhanced ultrasound imaging of angiogenesis.

    PubMed

    Pillai, R; Marinelli, E R; Fan, H; Nanjappan, P; Song, B; von Wronski, M A; Cherkaoui, S; Tardy, I; Pochon, S; Schneider, M; Nunn, A D; Swenson, R E

    2010-03-17

    The transition of a targeted ultrasound contrast agent from animal imaging to testing in clinical studies requires considerable chemical development. The nature of the construct changes from an agent that is chemically attached to microbubbles to one where the targeting group is coupled to a phospholipid, for direct incorporation to the bubble surface. We provide an efficient method to attach a heterodimeric peptide to a pegylated phospholipid and show that the resulting construct retains nanomolar affinity for its target, vascular endothelial growth factor receptor 2 (VEGFR2), for both the human (kinase insert domain-containing receptor - KDR) and the mouse (fetal liver kinase 1 - Flk-1) receptors. The purified phospholipid-PEG-peptide isolated from TFA-based eluents is not stable with respect to hydrolysis of the fatty ester moieties. This leads to the time-dependent formation of the lysophospholipid and the phosphoglycerylamide derived from the degradation of the product. Purification of the product using neutral eluent systems provides a stable product. Methods to prepare the lysophospholipid (hydrolysis product) are also included. Biacore binding data demonstrated the retention of binding of the lipopeptide to the KDR receptor. The phospholipid-PEG2000-peptide is smoothly incorporated into gas-filled microbubbles and provides imaging of angiogenesis in a rat tumor model.

  16. Advance of Molecular Imaging Technology and Targeted Imaging Agent in Imaging and Therapy

    PubMed Central

    Chen, Zhi-Yi; Wang, Yi-Xiang; Lin, Yan; Zhang, Jin-Shan; Yang, Feng; Zhou, Qiu-Lan; Liao, Yang-Ying

    2014-01-01

    Molecular imaging is an emerging field that integrates advanced imaging technology with cellular and molecular biology. It can realize noninvasive and real time visualization, measurement of physiological or pathological process in the living organism at the cellular and molecular level, providing an effective method of information acquiring for diagnosis, therapy, and drug development and evaluating treatment of efficacy. Molecular imaging requires high resolution and high sensitive instruments and specific imaging agents that link the imaging signal with molecular event. Recently, the application of new emerging chemical technology and nanotechnology has stimulated the development of imaging agents. Nanoparticles modified with small molecule, peptide, antibody, and aptamer have been extensively applied for preclinical studies. Therapeutic drug or gene is incorporated into nanoparticles to construct multifunctional imaging agents which allow for theranostic applications. In this review, we will discuss the characteristics of molecular imaging, the novel imaging agent including targeted imaging agent and multifunctional imaging agent, as well as cite some examples of their application in molecular imaging and therapy. PMID:24689058

  17. Double agents and secret agents: the emerging fields of exogenous chemical exchange saturation transfer and T2-exchange magnetic resonance imaging contrast agents for molecular imaging.

    PubMed

    Daryaei, Iman; Pagel, Mark D

    2015-01-01

    Two relatively new types of exogenous magnetic resonance imaging contrast agents may provide greater impact for molecular imaging by providing greater specificity for detecting molecular imaging biomarkers. Exogenous chemical exchange saturation transfer (CEST) agents rely on the selective saturation of the magnetization of a proton on an agent, followed by chemical exchange of a proton from the agent to water. The selective detection of a biomarker-responsive CEST signal and an unresponsive CEST signal, followed by the ratiometric comparison of these signals, can improve biomarker specificity. We refer to this improvement as a "double-agent" approach to molecular imaging. Exogenous T2-exchange agents also rely on chemical exchange of protons between the agent and water, especially with an intermediate rate that lies between the slow exchange rates of CEST agents and the fast exchange rates of traditional T1 and T2 agents. Because of this intermediate exchange rate, these agents have been relatively unknown and have acted as "secret agents" in the contrast agent research field. This review exposes these secret agents and describes the merits of double agents through examples of exogenous agents that detect enzyme activity, nucleic acids and gene expression, metabolites, ions, redox state, temperature, and pH. Future directions are also provided for improving both types of contrast agents for improved molecular imaging and clinical translation. Therefore, this review provides an overview of two new types of exogenous contrast agents that are becoming useful tools within the armamentarium of molecular imaging.

  18. The cost of developing imaging agents for routine clinical use.

    PubMed

    Nunn, Adrian D

    2006-03-01

    The objective of this study was to estimate the financial cost of developing new imaging agents for clinical use and to discuss the effects of these costs on the future clinical imaging agent environment. Publicly available financial data from the annual reports of major companies developing and selling imaging agents were examined and the data used to develop cost estimates. These estimates were compared with the in-depth data and analyses available for the development costs of therapeutic drugs. The cost of developing a drug for diagnostic imaging to commercialization is in the 100 dollars to 200 million dollars range, whereas a blockbuster imaging drug has current sales of 200 dollars to 400 million dollars. Most of these blockbuster imaging agents have been on the market for some time. The majority provide morphologic images with general indications in a slowly changing section of the market. Future agents will most likely address smaller markets and be in the rapidly developing molecular imaging field. The costs are high and are a significant brake on the development of imaging agents for commercialization. If new imaging agents are to realize their commercial potential, ways must be found to make the financials more attractive. The prices per dose are currently low so they must either be greatly increased for new imaging agents, with a corresponding increase in the value of the information they provide, or the use of imaging agents must be widened and/or their development made less costly in time and money. Without addressing these issues, the commercialization of new imaging agents will continue to be slow and may get slower. This will impact the progress of imaging agents toward use as validated biomarkers.

  19. Micro-CT Imaging of Tumor Angiogenesis: Quantitative Measures Describing Micromorphology and Vascularization

    PubMed Central

    Ehling, Josef; Theek, Benjamin; Gremse, Felix; Baetke, Sarah; Möckel, Diana; Maynard, Juliana; Ricketts, Sally-Ann; Grüll, Holger; Neeman, Michal; Knuechel, Ruth; Lederle, Wiltrud; Kiessling, Fabian; Lammers, Twan

    2014-01-01

    Angiogenesis is a hallmark of cancer, and its noninvasive visualization and quantification are key factors for facilitating translational anticancer research. Using four tumor models characterized by different degrees of aggressiveness and angiogenesis, we show that the combination of functional in vivo and anatomical ex vivo X-ray micro-computed tomography (μCT) allows highly accurate quantification of relative blood volume (rBV) and highly detailed three-dimensional analysis of the vascular network in tumors. Depending on the tumor model, rBV values determined using in vivo μCT ranged from 2.6% to 6.0%, and corresponds well with the values assessed using IHC. Using ultra-high-resolution ex vivo μCT, blood vessels as small as 3.4 mm and vessel branches up to the seventh order could be visualized, enabling a highly detailed and quantitative analysis of the three-dimensional micromorphology of tumor vessels. Microvascular parameters such as vessel size and vessel branching correlated very well with tumor aggressiveness and angiogenesis. In rapidly growing and highly angiogenic A431 tumors, the majority of vessels were small and branched only once or twice, whereas in slowly growing A549 tumors, the vessels were much larger and branched four to seven times. Thus, we consider that combining highly accurate functional with highly detailed anatomical μCT is a useful tool for facilitating high-throughput, quantitative, and translational (anti-) angiogenesis and antiangiogenesis research. PMID:24262753

  20. Osteosarcoma cells enhance angiogenesis visualized by color-coded imaging in the in vivo Gelfoam® assay.

    PubMed

    Uehara, Fuminari; Tome, Yasunori; Miwa, Shinji; Hiroshima, Yukihiko; Yano, Shuya; Yamamoto, Mako; Mii, Sumiyuki; Maehara, Hiroki; Bouvet, Michael; Kanaya, Fuminori; Hoffman, Robert M

    2014-09-01

    We previously described a color-coded imaging model that can quantify the length of nascent blood vessels using Gelfoam® implanted in nestin-driven green fluorescent protein (ND-GFP) nude mice. In ND-GFP mice, nascent blood vessels are labeled with GFP. We report here that osteosarcoma cells promote angiogenesis in the Gelfoam® angiogenesis assay in ND-GFP mice. Gelfoam® was initially transplanted subcutaneously in the flank of transgenic ND-GFP nude mice. Seven days after transplantation of Gelfoam®, skin flaps were made and human 143B osteosarcoma cells expressing green fluorescent protein (GFP) in the nucleus and red fluorescent protein (RFP) in cytoplasm were injected into the transplanted Gelfoam®. The control-group mice had only implanted Gelfoam®. Skin flaps were made at days 14, 21, and 28 after transplantation of the Gelfoam® to allow imaging of vascularization in the Gelfoam® using a variable-magnification small animal imaging system and confocal fluorescence microscopy. ND-GFP expressing nascent blood vessels penetrated and spread into the Gelfoam® in a time-dependent manner in both control and osteosarcoma-implanted mice. ND-GFP expressing blood vessels in the Gelfoam® of the osteosarcoma-implanted mice were associated with the cancer cells and larger and longer than in the Gelfoam®-only implanted mice (P < 0.01). The results presented in this report demonstrate strong angiogenesis induction by osteosarcoma cells and suggest this process is a potential therapeutic target for this disease. © 2014 Wiley Periodicals, Inc.

  1. Fast microbubble dwell-time based ultrasonic molecular imaging approach for quantification and monitoring of angiogenesis in cancer

    PubMed Central

    Pysz, Marybeth A.; Guracar, Ismayil; Tian, Lu

    2012-01-01

    Purpose To develop and test a fast ultrasonic molecular imaging technique for quantification and monitoring of angiogenesis in cancer. Materials and methods A new software algorithm measuring the dwell time of contrast microbubbles in near real-time (henceforth, fast method) was developed and integrated in a clinical ultrasound system. In vivo quantification and monitoring of tumor angiogenesis during anti-VEGF antibody therapy was performed in human colon cancer xenografts in mice (n=20) using the new fast method following administration of vascular endothelial growth factor receptor 2 (VEGFR2)-targeted contrast microbubbles. Imaging results were compared with a traditional destruction/replenishment approach (henceforth, traditional method) in an intra-animal comparison. Results There was excellent correlation (R2=0.93; P<0.001) between the fast method and the traditional method in terms of VEGFR2-targeted in vivo ultrasonic molecular imaging with significantly higher (P=0.002) imaging signal in colon cancer xenografts using VEGFR2-targeted compared to control non-targeted contrast microbubbles. The new fast method was highly reproducible (ICC=0.87). Following anti-angiogenic therapy, ultrasonic molecular imaging signal decreased by an average of 41±10%, whereas imaging signal increased by an average of 54±8% in non-treated tumors over a 72-hour period. Decreased VEGFR2 expression levels following anti-VEGF therapy were confirmed on ex vivo immunofluorescent staining. Conclusions Fast ultrasonic molecular imaging based on dwell time microbubble signal measurements correlates well with the traditional measurement method, and allows reliable in vivo monitoring of anti-angiogenic therapy in human colon cancer xenografts. The improved work-flow afforded by the new quantification approach may facilitate clinical translation of ultrasonic molecular imaging. PMID:22943043

  2. Blocking heme oxygenase-1 by zinc protoporphyrin reduces tumor hypoxia-mediated VEGF release and inhibits tumor angiogenesis as a potential therapeutic agent against colorectal cancer.

    PubMed

    Cheng, Chun-Chia; Guan, Siao-Syun; Yang, Hao-Jhih; Chang, Chun-Chao; Luo, Tsai-Yueh; Chang, Jungshan; Ho, Ai-Sheng

    2016-01-28

    Hypoxia in tumor niche is one of important factors to start regeneration of blood vessels, leading to increase survival, proliferation, and invasion in cancer cells. Under hypoxia microenvironment, furthermore, steadily increased hypoxia-inducible factor -1α (HIF-1α) is observed, and can increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis. Zinc protoporphyrin (ZnPP), a heme oxygenase-1 (HO-1) inhibitor, is potential to inhibit tumor proliferation and progression. However, the mechanism of ZnPP in inhibition of tumor is not completely clear. We hypothesize that ZnPP may modulate HIF-1α through inhibiting HO-1, and then inhibit angiogenesis and tumor progression. This study aimed to dissect the mechanism of ZnPP in tumor suppression. We observed the amount of VEGF was increased in the sera of the colorectal cancer (CRC) patients (n = 34, p < 0.05). Furthermore, increased VEGF expression was also measured in colorectal cancer cells, HCT-15, culturing under mimicking hypoxic condition. It suggested that hypoxia induced VEGF production from cancer cells. VEGF production was significantly reduced from HCT-15 cells after exposure to HIF-1α inhibitor KC7F2, suggesting that HIF-1α regulated VEGF production. Moreover, we observed that the HO-1 inhibitor ZnPP inhibited the expressions of HIF-1α and VEGF coupled with cell proliferations of HCT-15 cells, suggesting that ZnPP blocked HIF-1α expression, and then inhibited the consequent VEGF production. In the xenograft model, we also observed that the animals exposed to ZnPP displayed much smaller tumor nodules and less degree of angiogenesis with decreased expression of the angiogenesis marker, αvβ3 integrin, compared to that in normal control. This study demonstrated that VEGF level in serum was elevated in the patients with CRC. The HO-1 inhibitor, ZnPP, possessed the properties of anti-tumor agent by decreasing HIF-1α levels, blocking VEGF production, impairing tumor

  3. Targeted contrast-enhanced ultrasound imaging of angiogenesis in an orthotopic mouse tumor model of renal carcinoma.

    PubMed

    Wei, Shuping; Fu, Ninghua; Sun, Yu; Yang, Zhijian; Lei, Li; Huang, Pengfei; Yang, Bin

    2014-06-01

    Previous studies have reported that microbubbles bearing targeting ligands to molecular markers of angiogenesis can be successfully detected by ultrasound imaging in various animal models of solid cancer. In the present study, we sought to investigate the activity of microbubbles targeted to vascular endothelial growth factor receptor 2 (VEGFR2) in an orthotopic model of renal cell carcinoma (RCC). Microbubbles conjugated to an anti-VEGFR2 antibody (MBV) were compared with microbubbles conjugated to an isotype control antibody (MBC) or naked microbubbles (MBN). An orthotopic mouse model of human RCC was established by surgically implanting an established tumor within the renal capsule in mice. Tumor growth and blood flow were verified by B-mode and color Doppler ultrasound imaging. VEGFR2 expression within the tumor and renal parenchyma was detected by immunohistochemistry. The duration of contrast enhancement of MBV was much longer than those of MBN and MBC when assessed over 10 min. The baseline-subtracted contrast intensity within the tumor was higher for MBV than for MBC and MBN (p < 0.01). Additionally, the contrast intensity for MBV was significantly higher in the tumor region than in normal parenchyma (p < 0.01). Microbubbles targeting VEGFR2 exhibit suitable properties for imaging angiogenesis in orthotopic models of renal cell carcinoma, with potential applications in life science research and clinical medicine. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

  4. Double agents and secret agents: the emerging fields of exogenous chemical exchange saturation transfer and T2-exchange magnetic resonance imaging contrast agents for molecular imaging

    PubMed Central

    Daryaei, Iman; Pagel, Mark D

    2016-01-01

    Two relatively new types of exogenous magnetic resonance imaging contrast agents may provide greater impact for molecular imaging by providing greater specificity for detecting molecular imaging biomarkers. Exogenous chemical exchange saturation transfer (CEST) agents rely on the selective saturation of the magnetization of a proton on an agent, followed by chemical exchange of a proton from the agent to water. The selective detection of a biomarker-responsive CEST signal and an unresponsive CEST signal, followed by the ratiometric comparison of these signals, can improve biomarker specificity. We refer to this improvement as a “double-agent” approach to molecular imaging. Exogenous T2-exchange agents also rely on chemical exchange of protons between the agent and water, especially with an intermediate rate that lies between the slow exchange rates of CEST agents and the fast exchange rates of traditional T1 and T2 agents. Because of this intermediate exchange rate, these agents have been relatively unknown and have acted as “secret agents” in the contrast agent research field. This review exposes these secret agents and describes the merits of double agents through examples of exogenous agents that detect enzyme activity, nucleic acids and gene expression, metabolites, ions, redox state, temperature, and pH. Future directions are also provided for improving both types of contrast agents for improved molecular imaging and clinical translation. Therefore, this review provides an overview of two new types of exogenous contrast agents that are becoming useful tools within the armamentarium of molecular imaging. PMID:27747191

  5. Correlated magnetic resonance imaging and ultramicroscopy (MR-UM) is a tool kit to assess the dynamics of glioma angiogenesis.

    PubMed

    Breckwoldt, Michael O; Bode, Julia; Kurz, Felix T; Hoffmann, Angelika; Ochs, Katharina; Ott, Martina; Deumelandt, Katrin; Krüwel, Thomas; Schwarz, Daniel; Fischer, Manuel; Helluy, Xavier; Milford, David; Kirschbaum, Klara; Solecki, Gergely; Chiblak, Sara; Abdollahi, Amir; Winkler, Frank; Wick, Wolfgang; Platten, Michael; Heiland, Sabine; Bendszus, Martin; Tews, Björn

    2016-02-02

    Neoangiogenesis is a pivotal therapeutic target in glioblastoma. Tumor monitoring requires imaging methods to assess treatment effects and disease progression. Until now mapping of the tumor vasculature has been difficult. We have developed a combined magnetic resonance and optical toolkit to study neoangiogenesis in glioma models. We use in vivo magnetic resonance imaging (MRI) and correlative ultramicroscopy (UM) of ex vivo cleared whole brains to track neovascularization. T2* imaging allows the identification of single vessels in glioma development and the quantification of neovessels over time. Pharmacological VEGF inhibition leads to partial vascular normalization with decreased vessel caliber, density, and permeability. To further resolve the tumor microvasculature, we performed correlated UM of fluorescently labeled microvessels in cleared brains. UM resolved typical features of neoangiogenesis and tumor cell invasion with a spatial resolution of ~5 µm. MR-UM can be used as a platform for three-dimensional mapping and high-resolution quantification of tumor angiogenesis.

  6. A Novel 99mTc-Labeled Molecular Probe for Tumor Angiogenesis Imaging in Hepatoma Xenografts Model: A Pilot Study

    PubMed Central

    Zhao, Qian; Yan, Ping; Wang, Rong Fu; Zhang, Chun Li; Li, Ling; Yin, Lei

    2013-01-01

    Introduction Visualization of tumor angiogenesis using radionuclide targeting provides important diagnostic information. In previous study, we proved that an arginine-arginine-leucine (RRL) peptide should be a tumor endothelial cell specific binding sequence. The overall aim of this study was to evaluate whether 99mTc-radiolabeled RRL could be noninvasively used for imaging of malignant tumors in vivo, and act as a new molecular probe targeting tumor angiogenesis. Methods The RRL peptide was designed and radiosynthesized with 99mTc by a one-step method. The radiolabeling efficiency and radiochemical purity were then characterized in vitro. 99mTc-RRL was injected intravenously in HepG2 xenograft-bearing BALB/c nude mice. Biodistribution and in vivo imaging were performed periodically. The relationship between tumor size and %ID uptake of 99mTc-RRL was also explored. Results The labeling efficiencies of 99mTc-RRL reached 76.9%±4.5% (n = 6) within 30–60 min at room temperature, and the radiochemical purity exceeded 96% after purification. In vitro stability experiment revealed the radiolabeled peptide was stable. Biodistribution data showed that 99mTc-RRL rapidly cleared from the blood and predominantly accumulated in the kidneys and tumor. The specific uptake of 99mTc-RRL in tumor was significantly higher than that of unlabeled RRL blocking and free pertechnetate control test after injection (p<0.05). The ratio of the tumor-to-muscle exceeded 6.5, tumor-to-liver reached 1.98 and tumor-to-blood reached 1.95. In planar gamma imaging study, the tumors were imaged clearly at 2–6 h after injection of 99mTc-RRL, whereas the tumor was not imaged clearly in blocking group. The tumor-to-muscle ratio of images with 99mTc-RRL was comparable with that of 18F-FDG PET images. Immunohistochemical analysis verified the excessive vasculature of tumor. There was a linear relationship between the tumor size and uptake of 99mTc-RRL with R2 = 0.821. Conclusion 99mTc-RRL can

  7. Gold nanorods: contrast agents for photoacoustic imaging?

    NASA Astrophysics Data System (ADS)

    Ungureanu, C.; Gopal, R. Raja; van Leeuwen, T. G.; Manohar, S.

    2007-07-01

    Gold nanorods are seen as possible contrast agents for photoacoustic imaging since they have strong absorption peaks at near-infrared wavelengths. Also they are easy to conjugate with various proteins. If these particles can be conjugated with cancer affinity proteins then these particles can accumulate specifically at a tumor site. By detecting the presence of accumulation of gold nanorods inside the tissue the indirect detection of tumor can be realized. When these particles are irradiated with light pulses of appropriate temporal properties and energy the temperature around these particles can be high enough to induce apoptosis or necrosis in the surrounding cells. In order to use these particles at their full potential we must determine precisely their optical properties. We simulated the optical properties of gold nanorods synthesized by us using the DDSCAT code. The simulated spectra agree qualitatively with the spectra determined using spectrometry and also determined using photoacoustic spectroscopy. Further the values of molar extinction coefficient derived from the simulations were similar to the data measured experimentally by other groups. These results validated qualitatively the model used in the simulations. During simulations we found that the choice of the dielectric function used in simulations plays an important role in the results.

  8. Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension (sildenafil, iloprost, bosentan): is angiogenesis always beneficial?

    PubMed

    Doganci, S; Yildirim, V; Yesildal, F; Erol, G; Kadan, M; Ozkan, G; Avcu, F; Ozgurtas, T

    2015-05-01

    Pulmonary artery hypertension (PAH) is devastating disease that has very serious outcomes. Dysregulated angiogenesis is one of the main responsible courses in pathophysiology of disease. Our experimental research intends to find out and compare the angiogenic effects of medications used sildenafil, iloprost, and bosentan in the treatment of PAH. This study was performed in Department of Biochemistry and Cancer and Stem Cell Research Laboratory of our institutes between August and October 2014. Angiogenic activity of sildenafil, iloprost, and bosentan were examined in vivo in chick chorioallantoic membrane (CAM) model and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). Proliferative activity of these three agents was also determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on HUVECs. In CAM assay, when compared to the control and drug groups, treatment with sildenafil solutions resulted in a significant dose-dependent increase (budding, sprouting, extravasation) on CAM vessel growth. While there was no significant proliferative effect with iloprost and bosentan, presence of sildenafil caused a statistically significant proliferation on HUVECs following 24 and 48 h incubation (p < 0.05) compared to the control group. Comparing the tube length/area ratio values, there was statistically significant increase in sildenafil group with respect to the other 2 groups (p < 0.05). Iloprost and bosentan did not show a significant effect. The results provide evidence that sildenafil but not iloprost and bosentan induces angiogenesis in vitro and in vivo. Dysregulated angiogenesis, as an important pathophysiological part in the progression of PAH, may be triggered by the chronic ingestion of sildenafil in the long treatment period and may cause negative effects.

  9. CT and MR Imaging Diagnosis and Staging of Hepatocellular Carcinoma: Part II. Extracellular Agents, Hepatobiliary Agents, and Ancillary Imaging Features

    PubMed Central

    Choi, Jin-Young; Lee, Jeong-Min

    2014-01-01

    Computed tomography (CT) and magnetic resonance (MR) imaging play critical roles in the diagnosis and staging of hepatocellular carcinoma (HCC). The second article of this two-part review discusses basic concepts of diagnosis and staging, reviews the diagnostic performance of CT and MR imaging with extracellular contrast agents and of MR imaging with hepatobiliary contrast agents, and examines in depth the major and ancillary imaging features used in the diagnosis and characterization of HCC. © RSNA, 2014 PMID:25247563

  10. Radiolabelled spiroperidol: Possible pituitary adenoma imaging agent

    SciTech Connect

    Otto, C.A.; Marshall, J.C.; Lloyd, R.V.; Sherman, P.S.; Wieland, D.M.

    1984-01-01

    Prolactin-secreting pituitary adenomas are the most common type of pituitary tumors. Detection currently depends on physical symptoms, elevated serum prolactin levels and CT scans. An imaging agent which specifically localized in prolactinomas based on some functional characteristic of the tumor would be of considerable clinical value not only for early detection but also for monitoring of therapy. Tritiated spiroperidol (/sup 3/H-Sp) was selected for evaluation based on 1) the presence of D-2 receptors in normal anterior pituitary and adenoma tissue and 2) the high affinity of spiroperidol for D-2 receptors. Recent data have established that implantation of diethylstilbestrol (DES) in Fischer F344 rats induced prolactin-secreting tumors in the pituitary. /sup 3/HSp was evaluated in pituitary tissue of both control and DES-treated rats. /sup 3/HSp concentration in normal female anterior pituitary tissue was found to be about 0.27% kg dose/g from 5 min to 4hrs. This value was about 10 times levels in cortex, cerebellum and striatum. In DES-treated rats the % kg dose/g values remained approximately the same. A 5-fold increase in serum prolactin was associated with a 6-fold increase in both pituitary weight and % dose/organ. The data suggests that although total pituitary weight has increased due to tumor growth (reflected in increased values for % dose/organ), the relative number of receptors per g of tissue has remained constant. This result is in agreement with observations of others on D-2 receptor concentration in prolactinomas.

  11. Intelligent Design of Nano-Scale Molecular Imaging Agents

    PubMed Central

    Kim, Sung Bae; Hattori, Mitsuru; Ozawa, Takeaki

    2012-01-01

    Visual representation and quantification of biological processes at the cellular and subcellular levels within living subjects are gaining great interest in life science to address frontier issues in pathology and physiology. As intact living subjects do not emit any optical signature, visual representation usually exploits nano-scale imaging agents as the source of image contrast. Many imaging agents have been developed for this purpose, some of which exert nonspecific, passive, and physical interaction with a target. Current research interest in molecular imaging has mainly shifted to fabrication of smartly integrated, specific, and versatile agents that emit fluorescence or luminescence as an optical readout. These agents include luminescent quantum dots (QDs), biofunctional antibodies, and multifunctional nanoparticles. Furthermore, genetically encoded nano-imaging agents embedding fluorescent proteins or luciferases are now gaining popularity. These agents are generated by integrative design of the components, such as luciferase, flexible linker, and receptor to exert a specific on–off switching in the complex context of living subjects. In the present review, we provide an overview of the basic concepts, smart design, and practical contribution of recent nano-scale imaging agents, especially with respect to genetically encoded imaging agents. PMID:23235326

  12. Intelligent design of nano-scale molecular imaging agents.

    PubMed

    Kim, Sung Bae; Hattori, Mitsuru; Ozawa, Takeaki

    2012-12-12

    Visual representation and quantification of biological processes at the cellular and subcellular levels within living subjects are gaining great interest in life science to address frontier issues in pathology and physiology. As intact living subjects do not emit any optical signature, visual representation usually exploits nano-scale imaging agents as the source of image contrast. Many imaging agents have been developed for this purpose, some of which exert nonspecific, passive, and physical interaction with a target. Current research interest in molecular imaging has mainly shifted to fabrication of smartly integrated, specific, and versatile agents that emit fluorescence or luminescence as an optical readout. These agents include luminescent quantum dots (QDs), biofunctional antibodies, and multifunctional nanoparticles. Furthermore, genetically encoded nano-imaging agents embedding fluorescent proteins or luciferases are now gaining popularity. These agents are generated by integrative design of the components, such as luciferase, flexible linker, and receptor to exert a specific on-off switching in the complex context of living subjects. In the present review, we provide an overview of the basic concepts, smart design, and practical contribution of recent nano-scale imaging agents, especially with respect to genetically encoded imaging agents.

  13. PET imaging of tumor angiogenesis in mice with VEGF-A targeted 86Y-CHX-A″-DTPA-bevacizumab

    PubMed Central

    Nayak, Tapan K.; Garmestani, Kayhan; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.

    2010-01-01

    Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted VEGF-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the United States FDA for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, 86Y-CHX-A″-DTPA-bevacizumab, for potential use in PET imaging of VEGF-A tumor angiogenesis and as a surrogate marker for 90Y based radioimmunotherapy. Bevacizumab was conjugated to CHX-A″-DTPA and radiolabeled with 86Y. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated high specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A secreting LS-174T, SKOV-3 and VEGF-A negative MSTO-211H tumors, the tumor uptake at 3 d post-injection (p.i) was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively. The corresponding tumor uptake in mice co-injected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8–2.0 MBq 86Y-CHX-A″-DTPA-bevacizumab. Organ uptake quantified by PET closely correlated (r2=0.87, p=0.64, n=18) to values determined by biodistribution studies. This preclinical study demonstrates the potential of the radioimmunoconjugate, 86Y-CHX-A″-DTPA-bevacizumab, for non-invasive assessment of the VEGF-A tumor angiogenesis status and as a surrogate marker for 90Y-CHX-A″-DTPA-bevacizumab radioimmunotherapy. PMID:20473899

  14. PET imaging of tumor angiogenesis in mice with VEGF-A-targeted (86)Y-CHX-A″-DTPA-bevacizumab.

    PubMed

    Nayak, Tapan K; Garmestani, Kayhan; Baidoo, Kwamena E; Milenic, Diane E; Brechbiel, Martin W

    2011-02-15

    Bevacizumab is a humanized monoclonal antibody that binds to tumor-secreted vascular endothelial growth factor (VEGF)-A and inhibits tumor angiogenesis. In 2004, the antibody was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal carcinoma in combination with chemotherapy. This report describes the preclinical evaluation of a radioimmunoconjugate, (86)Y-CHX-A″-DTPA-bevacizumab, for potential use in Positron Emission Tomography (PET) imaging of VEGF-A tumor angiogenesis and as a surrogate marker for (90)Y-based radioimmunotherapy. Bevacizumab was conjugated to CHX-A″-DTPA and radiolabeled with (86)Y. In vivo biodistribution and PET imaging studies were performed on mice bearing VEGF-A-secreting human colorectal (LS-174T), human ovarian (SKOV-3) and VEGF-A-negative human mesothelioma (MSTO-211H) xenografts. Biodistribution and PET imaging studies demonstrated highly specific tumor uptake of the radioimmunoconjugate. In mice bearing VEGF-A-secreting LS-174T, SKOV-3 and VEGF-A-negative MSTO-211H tumors, the tumor uptake at 3 days postinjection was 13.6 ± 1.5, 17.4 ± 1.7 and 6.8 ± 0.7 % ID/g, respectively. The corresponding tumor uptake in mice coinjected with 0.05 mg cold bevacizumab were 5.8 ± 1.3, 8.9 ± 1.9 and 7.4 ± 1.0 % ID/g, respectively at the same time point, demonstrating specific blockage of the target in VEGF-A-secreting tumors. The LS-174T and SKOV3 tumors were clearly visualized by PET imaging after injecting 1.8-2.0 MBq (86)Y-CHX-A″-DTPA-bevacizumab. Organ uptake quantified by PET closely correlated (r(2) = 0.87, p = 0.64, n = 18) to values determined by biodistribution studies. This preclinical study demonstrates the potential of the radioimmunoconjugate, (86)Y-CHX-A″-DTPA-bevacizumab, for noninvasive assessment of the VEGF-A tumor angiogenesis status and as a surrogate marker for (90)Y-CHX-A″-DTPA-bevacizumab radioimmunotherapy. Copyright © 2010 UICC.

  15. Molecular imaging of angiogenesis in nascent Vx-2 rabbit tumors using a novel alpha(nu)beta3-targeted nanoparticle and 1.5 tesla magnetic resonance imaging.

    PubMed

    Winter, Patrick M; Caruthers, Shelton D; Kassner, Andrea; Harris, Thomas D; Chinen, Lori K; Allen, John S; Lacy, Elizabeth K; Zhang, Huiying; Robertson, J David; Wickline, Samuel A; Lanza, Gregory M

    2003-09-15

    leaky tumor neovasculature but did not appreciably migrate into the interstitium, leading to a 56% increase in MR signal at 2 h. Pretargeting of the alpha(nu)beta(3)-integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of alpha(nu)beta(3)-targeted paramagnetic nanoparticles, decreasing the MR signal enhancement (50%) to a level attributable to local extravasation. The MR signal of adjacent hindlimb muscle or contralateral control tissues was unchanged by either the alpha(nu)beta(3)-targeted or control paramagnetic agents. Immunohistochemistry of alpha(nu)beta(3)-integrin corroborated the extent and asymmetric distribution of neovascularity observed by MRI. These studies demonstrate the potential of this targeted molecular imaging agent to detect and characterize (both biochemically and morphologically) early angiogenesis induced by minute solid tumors with a clinical 1.5 Tesla MRI scanner, facilitating the localization of nascent cancers or metastases, as well as providing tools to phenotypically categorize and segment patient populations for therapy and to longitudinally follow the effectiveness of antitumor treatment regimens.

  16. A Perspective on Vascular Disrupting Agents that Interact with Tubulin: Preclinical Tumor Imaging and Biological Assessment#

    PubMed Central

    Mason, Ralph P.; Zhao, Dawen; Liu, Li; Trawick, Mary Lynn; Pinney, Kevin G.

    2011-01-01

    The tumor microenvironment provides a rich source of potential targets for selective therapeutic intervention with properly designed anticancer agents. Significant physiological differences exist between the microvessels that nourish tumors and those that supply healthy tissue. Selective drug-mediated damage of these tortuous and chaotic microvessels starves a tumor of necessary nutrients and oxygen and eventually leads to massive tumor necrosis. Vascular targeting strategies in oncology are divided into two separate groups: angiogenesis inhibiting agents (AIAs) and vascular disrupting agents (VDAs). The mechanisms of action between these two classes of compounds are profoundly distinct. The AIAs inhibit the actual formation of new vessels, while the VDAs damage and/or destroy existing tumor vasculature. One subset of small-molecule VDAs functions by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature, triggered by a cascade of cell signaling events. Ultimately this results in catastrophic damage to the vessels feeding the tumor. The rapid emergence and subsequent development of the VDA field over the past decade has led to the establishment of a synergistic combination of preclinical state-of-the-art tumor imaging and biological evaluation strategies that are often indicative of future clinical efficacy for a given VDA. This review focuses on an integration of the appropriate biochemical and biological tools necessary to assess (preclinically) new small-molecule, tubulin active VDAs for their potential to be clinically effective anticancer agents. PMID:21321746

  17. In Vivo Magnetic Resonance and Fluorescence Dual-Modality Imaging of Tumor Angiogenesis in Rats Using GEBP11 Peptide Targeted Magnetic Nanoparticles.

    PubMed

    Su, Tao; Wang, Yabin; Wang, Jiinda; Han, Dong; Ma, Sai; Cao, Jianbo; Li, Xiujuan; Zhang, Ran; Qiao, Hongyu; Liang, Jimin; Liu, Gang; Yang, Bo; Liang, Shuhui; Nie, Yongzhan; Wu, Kaichun; Li, Jiayi; Cao, Feng

    2016-05-01

    Angiogenesis is an essential process for tumor progression. Tumor vasculature-targeting peptides have shown great potential for use in cancer imaging and therapy. Our previous studies have shown that GEBP11, a novel vasculature-specific binding peptide that exhibits high affinity and specificity to tumor angiogenesis, is a promising candidate for the diagnosis and targeted radiotherapy of gastric cancer. In the present study, we developed a novel magnetic resonance and fluorescence (MR/Fluo) dual-modality imaging probe by covalently coupling 2,3-dimercaptosuccinnic acid-coated paramagnetic nanoparticles (DMSA-MNPs) and Cy5.5 to the GEBP11 peptide. The probe Cy5.5-GEBP11-DMSA-MNPs (CGD-MNPs), with a hydrodynamic diameter of 82.8 ± 6.5 nm, exhibited good imaging properties, high stability and little cytotoxicity. In vivo MR/Fluo imaging revealed that CGD-MNPs were successfully applied to visualize tumor angiogenesis in SGC-7901 xenograft mouse models. Prussian blue and CD31 immunohistochemical staining confirmed that CGD-MNPs co-localized with tumor blood vessels. In conclusion, CGD-MNPs are promising candidates for use as MR and fluorescence imaging probes for visualizing gastric cancer angiogenesis in vivo.

  18. Imaging angiogenesis using (68)Ga-NOTA-PRGD2 positron emission tomography/computed tomography in patients with severe intracranial atherosclerotic disease.

    PubMed

    Shu, Shi; Zhang, Li; Zhu, Yi Cheng; Li, Fang; Cui, Li Ying; Wang, Hao; Sun, Yi; Wu, Pei Lin; Zhu, Zhao Hui; Peng, Bin

    2017-10-01

    Angiogenesis is a critical compensation route, which has been demonstrated in the brain following ischemic stroke; however, few studies have investigated angiogenesis in chronic intracranial atherosclerosis disease (ICAD). We used (68)Ga-NOTA-PRGD2 positron emission tomography/computed tomography based imaging to detect angiogenesis in chronic ICAD and to explore the factors that may have affected it. A total of 21 participants with unilateral severe chronic ICAD were included in the study. Of the 21 participants, 19 were men; the mean (SD) age was 52 (15) years. In 18 participants, we observed elevated (68)Ga-NOTA-PRGD2 uptake in the peri-infarct, subcortical, and periventricular regions of the lesioned side, with a higher (68)Ga-NOTA-PRGD2 SUVmax compared to that in the contralateral hemisphere (0.15 vs. 0.06, p=0.001). The (18)F-FDG PET SUVmax was significantly lower on the lesioned side (11.28 vs. 13.92, p=0.001). Subgroup analyses revealed that the recent group (<6 months) had a higher lesion-to-contralateral region ratio SUVmax than the remote group (>6 months) (6.73 vs. 2.36, p<0.05). Our results provide molecular imaging evidence of angiogenesis in patients with severe chronic ICAD. Furthermore, the extent of angiogenesis in chronic ICAD may be affected by the post-qualified event time interval, and not by infarction itself or the severity of the arterial lesion.

  19. Utility of a prototype liposomal contrast agent for x-ray imaging of breast cancer: a proof of concept using micro-CT in small animals

    NASA Astrophysics Data System (ADS)

    Badea, C. T.; Samei, E.; Ghaghada, K.; Saunders, R.; Yuan, H.; Qi, Y.; Hedlund, L. W.; Mukundan, S.

    2008-03-01

    Imaging tumor angiogenesis in small animals is extremely challenging due to the size of the tumor vessels. Consequently, both dedicated small animal imaging systems and specialized intravascular contrast agents are required. The goal of this study was to investigate the use of a liposomal contrast agent for high-resolution micro-CT imaging of breast tumors in small animals. A liposomal blood pool agent encapsulating iodine with a concentration of 65.5 mg/ml was used with a Duke Center for In Vivo Microscopy (CIVM) prototype micro-computed tomography (micro-CT) system to image the R3230AC mammary carcinoma implanted in rats. The animals were injected with equivalent volume doses (0.02 ml/kg) of contrast agent. Micro-CT with the liposomal blood pool contrast agent ensured a signal difference between the blood and the muscle higher than 450 HU allowing the visualization of the tumors 3D vascular architecture in exquisite detail at 100-micron resolution. The micro-CT data correlated well with the histological examination of tumor tissue. We also studied the ability to detect vascular enhancement with limited angle based reconstruction, i.e. tomosynthesis. Tumor volumes and their regional vascular percentage were estimated. This imaging approach could be used to better understand tumor angiogenesis and be the basis for evaluating anti-angiogenic therapies.

  20. MMP-2/9-Specific Activatable Lifetime Imaging Agent

    PubMed Central

    Rood, Marcus T.M.; Raspe, Marcel; ten Hove, Jan Bart; Jalink, Kees; Velders, Aldrik H.; van Leeuwen, Fijs W.B.

    2015-01-01

    Optical (molecular) imaging can benefit from a combination of the high signal-to-background ratio of activatable fluorescence imaging with the high specificity of luminescence lifetime imaging. To allow for this combination, both imaging techniques were integrated in a single imaging agent, a so-called activatable lifetime imaging agent. Important in the design of this imaging agent is the use of two luminophores that are tethered by a specific peptide with a hairpin-motive that ensured close proximity of the two while also having a specific amino acid sequence available for enzymatic cleavage by tumor-related MMP-2/9. Ir(ppy)3 and Cy5 were used because in close proximity the emission intensities of both luminophores were quenched and the influence of Cy5 shortens the Ir(ppy)3 luminescence lifetime from 98 ns to 30 ns. Upon cleavage in vitro, both effects are undone, yielding an increase in Ir(ppy)3 and Cy5 luminescence and a restoration of Ir(ppy)3 luminescence lifetime to 94 ns. As a reference for the luminescence activation, a similar imaging agent with the more common Cy3-Cy5 fluorophore pair was used. Our findings underline that the combination of enzymatic signal activation with lifetime imaging is possible and that it provides a promising method in the design of future disease specific imaging agents. PMID:25985157

  1. MMP-2/9-Specific Activatable Lifetime Imaging Agent.

    PubMed

    Rood, Marcus T M; Raspe, Marcel; ten Hove, Jan Bart; Jalink, Kees; Velders, Aldrik H; van Leeuwen, Fijs W B

    2015-05-12

    Optical (molecular) imaging can benefit from a combination of the high signal-to-background ratio of activatable fluorescence imaging with the high specificity of luminescence lifetime imaging. To allow for this combination, both imaging techniques were integrated in a single imaging agent, a so-called activatable lifetime imaging agent. Important in the design of this imaging agent is the use of two luminophores that are tethered by a specific peptide with a hairpin-motive that ensured close proximity of the two while also having a specific amino acid sequence available for enzymatic cleavage by tumor-related MMP-2/9. Ir(ppy)3 and Cy5 were used because in close proximity the emission intensities of both luminophores were quenched and the influence of Cy5 shortens the Ir(ppy)3 luminescence lifetime from 98 ns to 30 ns. Upon cleavage in vitro, both effects are undone, yielding an increase in Ir(ppy)3 and Cy5 luminescence and a restoration of Ir(ppy)3 luminescence lifetime to 94 ns. As a reference for the luminescence activation, a similar imaging agent with the more common Cy3-Cy5 fluorophore pair was used. Our findings underline that the combination of enzymatic signal activation with lifetime imaging is possible and that it provides a promising method in the design of future disease specific imaging agents.

  2. Semiautomatic quantification of angiogenesis.

    PubMed

    Boettcher, Markus; Gloe, Torsten; de Wit, Cor

    2010-07-01

    Angiogenesis is of major interest in developmental biology and cancer research. Different experimental approaches are available to study angiogenesis that have in common the need for microscopy, image acquisition, and analysis. Problems that are encountered hereby are the size of the structures, which requires generation of composite images and difficulties in quantifying angiogenic activity reliably and rapidly. Most graphic software packages lack some of the required functions for easy, semiautomatic quantification of angiogenesis and, consequently, multiple software packages or expensive programs have to be used to cover all necessary functions. A software package (AQuaL) to analyze angiogenic activity was developed using Java, which can be used platform-independently. It includes image acquisition relying on the Java Media Framework and an easy to use image alignment tool. Multiple overlapping images can be aligned and saved without limitations and loss of resolution into a composite image, which requires only the selection of a single point representing a characteristic structure in adjacent images. Angiogenic activity can be quantified in composite images semiautomatically by the assessment of the area overgrown by cells after filtering and image binarization. In addition, tagging of capillary-like structures allows quantification of their length and branching pattern. Both developed methods deliver reliable and correlating data as exemplified in the aortic ring angiogenesis assay. The developed software provides modular functions specifically targeted to quantify angiogenesis. Whereas the area measurement is time saving, length measurement provides additional information about the branching patterns, which is required for a qualitative differentiation of capillary growth. (c) 2010 Elsevier Inc. All rights reserved.

  3. Mixed lanthanide oxide nanoparticles as dual imaging agent in biomedicine

    PubMed Central

    Xu, Wenlong; Bony, Badrul Alam; Kim, Cho Rong; Baeck, Jong Su; Chang, Yongmin; Bae, Ji Eun; Chae, Kwon Seok; Kim, Tae Jeong; Lee, Gang Ho

    2013-01-01

    There is no doubt that the molecular imaging is an extremely important technique in diagnosing diseases. Dual imaging is emerging as a step forward in molecular imaging technique because it can provide us with more information useful for diagnosing diseases than single imaging. Therefore, diverse dual imaging modalities should be developed. Molecular imaging generally relies on imaging agents. Mixed lanthanide oxide nanoparticles could be valuable materials for dual magnetic resonance imaging (MRI)-fluorescent imaging (FI) because they have both excellent and diverse magnetic and fluorescent properties useful for dual MRI-FI, depending on lanthanide ions used. Since they are mixed nanoparticles, they are compact, robust, and stable, which is extremely useful for biomedical applications. They can be also easily synthesized with facile composition control. In this study, we explored three systems of ultrasmall mixed lanthanide (Dy/Eu, Ho/Eu, and Ho/Tb) oxide nanoparticles to demonstrate their usefulness as dual T2 MRI–FI agents. PMID:24220641

  4. Mixed lanthanide oxide nanoparticles as dual imaging agent in biomedicine

    NASA Astrophysics Data System (ADS)

    Xu, Wenlong; Bony, Badrul Alam; Kim, Cho Rong; Baeck, Jong Su; Chang, Yongmin; Bae, Ji Eun; Chae, Kwon Seok; Kim, Tae Jeong; Lee, Gang Ho

    2013-11-01

    There is no doubt that the molecular imaging is an extremely important technique in diagnosing diseases. Dual imaging is emerging as a step forward in molecular imaging technique because it can provide us with more information useful for diagnosing diseases than single imaging. Therefore, diverse dual imaging modalities should be developed. Molecular imaging generally relies on imaging agents. Mixed lanthanide oxide nanoparticles could be valuable materials for dual magnetic resonance imaging (MRI)-fluorescent imaging (FI) because they have both excellent and diverse magnetic and fluorescent properties useful for dual MRI-FI, depending on lanthanide ions used. Since they are mixed nanoparticles, they are compact, robust, and stable, which is extremely useful for biomedical applications. They can be also easily synthesized with facile composition control. In this study, we explored three systems of ultrasmall mixed lanthanide (Dy/Eu, Ho/Eu, and Ho/Tb) oxide nanoparticles to demonstrate their usefulness as dual T2 MRI-FI agents.

  5. Gadolinium oxide nanoparticles as potential multimodal imaging and therapeutic agents.

    PubMed

    Kim, Tae Jeong; Chae, Kwon Seok; Chang, Yongmin; Lee, Gang Ho

    2013-01-01

    Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron ((10)B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis).

  6. In vivo monitoring of angiogenesis inhibition via down-regulation of mir-21 in a VEGFR2-luc murine breast cancer model using bioluminescent imaging.

    PubMed

    Zhao, Dongliang; Tu, Yingfeng; Wan, Lin; Bu, Lihong; Huang, Tao; Sun, Xilin; Wang, Kai; Shen, Baozhong

    2013-01-01

    MicroRNA-21 (miR-21) is overexpressed in a wide range of cancers and involved in tumor proliferation and metastasis. However, the potential function of miR-21 in regulating tumor angiogenesis has been little disclosed. In this study, we treated the cultured 4T1 murine breast cancer cells and human umbilical vein endothelial cells (HUVECs) with miR-21 mimic, antagomir-21 or negative control (scramble), which were subjected to MTT, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), quantitative Reverse Transcriptase PCR (qRT-PCR) and immunoblotting analysis. In addition, 4T1 cells were implanted beneath the right breast fat pad of the VEGFR2-luc transgenic mice, which were randomly divided into three groups and received saline, antagomir-21 or scramble treatment once respectively after tumor model establishment. Bioluminescent imaging was used to monitor tumor growth and angiogenesis in vivo at 0d, 3d, 5d, 7d, 10d, and 14d after treatment. Mice were killed at the end of study and tumor tissues were collected for use. The results showed that knockdown of miR-21 by antagomir-21 decreased cell proliferation and induced apoptosis via targeting PTEN both in 4T1 cells and HUVECs. We also found the anti-angiogenesis and anti-tumor effects of antagomir-21 in the VEGFR2-luc transgenic mouse model using bioluminescent imaging. Moreover, the Western blotting data revealed that antagomir-21 inhibited tumor angiogenesis through suppressing HIF-1α/VEGF/VEGFR2-associated signaling pathway. In conclusion, the results from current study demonstrate that antagomir-21 can effectively suppress tumor growth and angiogenesis in VEGFR2-luc mouse breast tumor model and bioluminescent imaging can be used as a tool for noninvasively and continuously monitoring tumor angiogenesis in vivo.

  7. Molecular Imaging and Contrast Agent Database (MICAD): Evolution and Progress

    PubMed Central

    Chopra, Arvind; Shan, Liang; Eckelman, W. C.; Leung, Kam; Latterner, Martin; Bryant, Stephen H.; Menkens, Anne

    2011-01-01

    The purpose of writing this review is to showcase the Molecular Imaging and Contrast Agent Database (MICAD; www.micad.nlm.nih.gov) to students, researchers and clinical investigators interested in the different aspects of molecular imaging. This database provides freely accessible, current, online scientific information regarding molecular imaging (MI) probes and contrast agents (CA) used for positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging, x-ray/computed tomography, optical imaging and ultrasound imaging. Detailed information on >1000 agents in MICAD is provided in a chapter format and can be accessed through PubMed. Lists containing >4250 unique MI probes and CAs published in peer-reviewed journals and agents approved by the United States Food and Drug Administration (FDA) as well as a CSV file summarizing all chapters in the database can be downloaded from the MICAD homepage. Users can search for agents in MICAD on the basis of imaging modality, source of signal/contrast, agent or target category, preclinical or clinical studies, and text words. Chapters in MICAD describe the chemical characteristics (structures linked to PubChem), the in vitro and in vivo activities and other relevant information regarding an imaging agent. All references in the chapters have links to PubMed. A Supplemental Information Section in each chapter is available to share unpublished information regarding an agent. A Guest Author Program is available to facilitate rapid expansion of the database. Members of the imaging community registered with MICAD periodically receive an e-mail announcement (eAnnouncement) that lists new chapters uploaded to the database. Users of MICAD are encouraged to provide feedback, comments or suggestions for further improvement of the database by writing to the editors at: micad@nlm.nih.gov PMID:21989943

  8. Molecular Imaging and Contrast Agent Database (MICAD): evolution and progress.

    PubMed

    Chopra, Arvind; Shan, Liang; Eckelman, W C; Leung, Kam; Latterner, Martin; Bryant, Stephen H; Menkens, Anne

    2012-02-01

    The purpose of writing this review is to showcase the Molecular Imaging and Contrast Agent Database (MICAD; www.micad.nlm.nih.gov ) to students, researchers, and clinical investigators interested in the different aspects of molecular imaging. This database provides freely accessible, current, online scientific information regarding molecular imaging (MI) probes and contrast agents (CA) used for positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging, X-ray/computed tomography, optical imaging and ultrasound imaging. Detailed information on >1,000 agents in MICAD is provided in a chapter format and can be accessed through PubMed. Lists containing >4,250 unique MI probes and CAs published in peer-reviewed journals and agents approved by the United States Food and Drug Administration as well as a comma separated values file summarizing all chapters in the database can be downloaded from the MICAD homepage. Users can search for agents in MICAD on the basis of imaging modality, source of signal/contrast, agent or target category, pre-clinical or clinical studies, and text words. Chapters in MICAD describe the chemical characteristics (structures linked to PubChem), the in vitro and in vivo activities, and other relevant information regarding an imaging agent. All references in the chapters have links to PubMed. A Supplemental Information Section in each chapter is available to share unpublished information regarding an agent. A Guest Author Program is available to facilitate rapid expansion of the database. Members of the imaging community registered with MICAD periodically receive an e-mail announcement (eAnnouncement) that lists new chapters uploaded to the database. Users of MICAD are encouraged to provide feedback, comments, or suggestions for further improvement of the database by writing to the editors at micad@nlm.nih.gov.

  9. Gadolinium-Based Contrast Agents for MR Cancer Imaging

    PubMed Central

    Zhou, Zhuxian; Lu, Zheng-Rong

    2013-01-01

    Magnetic resonance imaging (MRI) is a clinical imaging modality effective for anatomical and functional imaging of diseased soft tissues, including solid tumors. MRI contrast agents have been routinely used for detecting tumor at an early stage. Gadolinium based contrast agents are the most commonly used contrast agents in clinical MRI. There have been significant efforts to design and develop novel Gd(III) contrast agents with high relaxivity, low toxicity and specific tumor binding. The relaxivity of the Gd(III) contrast agents can be increased by proper chemical modification. The toxicity of Gd(III) contrast agents can be reduced by increasing the agents’ thermodynamic and kinetic stability, as well as optimizing their pharmacokinetic properties. The increasing knowledge in the field of cancer genomics and biology provides an opportunity for designing tumor-specific contrast agents. Various new Gd(III) chelates have been designed and evaluated in animal models for more effective cancer MRI. This review outlines the design and development, physicochemical properties, and in vivo properties of several classes of Gd(III)-based MR contrast agents for tumor imaging. PMID:23047730

  10. Contrast agents for photoacoustic and thermoacoustic imaging: a review.

    PubMed

    Wu, Dan; Huang, Lin; Jiang, Max S; Jiang, Huabei

    2014-12-18

    Photoacoustic imaging (PAI) and thermoacoustic imaging (TAI) are two emerging biomedical imaging techniques that both utilize ultrasonic signals as an information carrier. Unique advantages of PAI and TAI are their abilities to provide high resolution functional information such as hemoglobin and blood oxygenation and tissue dielectric properties relevant to physiology and pathology. These two methods, however, may have a limited detection depth and lack of endogenous contrast. An exogenous contrast agent is often needed to effectively resolve these problems. Such agents are able to greatly enhance the imaging contrast and potentially break through the imaging depth limit. Furthermore, a receptor-targeted contrast agent could trace the molecular and cellular biological processes in tissues. Thus, photoacoustic and thermoacoustic molecular imaging can be outstanding tools for early diagnosis, precise lesion localization, and molecular typing of various diseases. The agents also could be used for therapy in conjugation with drugs or in photothermal therapy, where it functions as an enhancer for the integration of diagnosis and therapy. In this article, we present a detailed review about various exogenous contrast agents for photoacoustic and thermoacoustic molecular imaging. In addition, challenges and future directions of photoacoustic and thermoacoustic molecular imaging in the field of translational medicine are also discussed.

  11. Contrast Agents for Photoacoustic and Thermoacoustic Imaging: A Review

    PubMed Central

    Wu, Dan; Huang, Lin; Jiang, Max S.; Jiang, Huabei

    2014-01-01

    Photoacoustic imaging (PAI) and thermoacoustic imaging (TAI) are two emerging biomedical imaging techniques that both utilize ultrasonic signals as an information carrier. Unique advantages of PAI and TAI are their abilities to provide high resolution functional information such as hemoglobin and blood oxygenation and tissue dielectric properties relevant to physiology and pathology. These two methods, however, may have a limited detection depth and lack of endogenous contrast. An exogenous contrast agent is often needed to effectively resolve these problems. Such agents are able to greatly enhance the imaging contrast and potentially break through the imaging depth limit. Furthermore, a receptor-targeted contrast agent could trace the molecular and cellular biological processes in tissues. Thus, photoacoustic and thermoacoustic molecular imaging can be outstanding tools for early diagnosis, precise lesion localization, and molecular typing of various diseases. The agents also could be used for therapy in conjugation with drugs or in photothermal therapy, where it functions as an enhancer for the integration of diagnosis and therapy. In this article, we present a detailed review about various exogenous contrast agents for photoacoustic and thermoacoustic molecular imaging. In addition, challenges and future directions of photoacoustic and thermoacoustic molecular imaging in the field of translational medicine are also discussed. PMID:25530615

  12. Neo-angiogenesis metabolic biomarker of tumor-genesis tracking by infrared joystick contact imaging in personalized homecare system

    NASA Astrophysics Data System (ADS)

    Szu, Harold; Hoekstra, Philip; Landa, Joseph; Vydelingum, Nadarajen A.

    2014-05-01

    We describe an affordable, harmless, and administrative (AHA) metabolic biomarker (MBM) for homecare cancer screening. It may save hundreds of thousands of women's and thousands of men's lives every year from breast cancer and melanoma. The goal is to increase the specificity of infrared (IR) imagery to reduce the false alarm rate (FAR). The patient's hands are immersed in icy cold water, about 11oC, for 30 seconds. We then compare two IR images, taken before and after the cold stimulus, and the difference reveals an enhanced signal and noise ratio (SNR) at tumorigenesis sites since the contraction of capillaries under cold challenge is natural to healthy capillaries, except those newly built capillaries during angiogenesis (Folkman, Nature 1995). Concomitant with the genome and the phenome (molecular signaling by phosphor-mediate protein causing inflammation by platelet activating factor (PAF) that transform cells from benign to malignant is the amplification of nitric oxide (NO) syntheses, a short-lived reactive oxygen species (ROS) that dilates regional blood vessels; superseding normal autonomic nervous system regulation. A rapidly growing tumor site might implicate accumulation of ROS, for which NO can rapidly stretch the capillary bed system usually having thinning muscular lining known as Neo-Angiogenesis (NA) that could behave like Leaky In-situ Faucet Effect (LIFE) in response to cold challenge. To emphasize the state of art knowledge of NA, we mentioned in passing the first generation of an anticapillary growth drug, Avastin by Genetech; it is an antibody protein that is injected for metastasis, while the second generation drug; Sorafenib by Bayers (2001) and Sutent by Pfizer (2000) both target molecular signaling loci to block receptor

  13. Small-animal microangiography using phase-contrast X-ray imaging and gas as contrast agent

    NASA Astrophysics Data System (ADS)

    Lundström, Ulf; Larsson, Daniel H.; Westermark, Ulrica K.; Burvall, Anna; Hertz, Hans M.

    2014-03-01

    We use propagation-based phase-contrast X-ray imaging with gas as contrast agent to visualize the microvasculature in small animals like mice and rats. The radiation dose required for absorption X-ray imaging is proportional to the minus fourth power of the structure size to be detected. This makes small vessels impossible to image at reasonable radiation doses using the absorption of conventional iodinated contrast agents. Propagation-based phase contrast gives enhanced contrast for high spatial frequencies by moving the detector away from the sample to let phase variations in the transmitted X-rays develop into intensity variations at the detector. Blood vessels are normally difficult to observe in phase contrast even with iodinated contrast agents as the density difference between blood and most tissues is relatively small. By injecting gas into the blood stream this density difference can be greatly enhanced giving strong phase contrast. One possible gas to use is carbon dioxide, which is a clinically accepted X-ray contrast agent. The gas is injected into the blood stream of patients to temporarily displace the blood in a region and thereby reduce the X-ray absorption in the blood vessels. We have shown that this method can be used to image blood vessels down to 8 μm in diameter in mouse ears. The low dose requirements of this method indicate a potential for live small-animal imaging and longitudinal studies of angiogenesis.

  14. In vivo spectral and fluorescence imaging microscopy of tumor microvessel blood supply and oxygenation changes following vascular targeting agent treatment

    NASA Astrophysics Data System (ADS)

    Lee, Jennifer; Kozikowski, Raymond; Molnar, Nikolett; Siemann, Dietmar W.; Sorg, Brian S.

    2012-03-01

    The formation of new microvasculature is essential for a tumor mass to grow. Vascular targeting agents (VTAs), including anti-angiogenic drugs and vascular disrupting agents, aim to either inhibit new vasculature growth or destroy existing vasculature, respectively. Because the mechanisms for anti-angiogenic drugs and vascular disrupting agents are complementary, analysis of these drugs used together is under investigation for the enhanced treatment of tumors in comparison to each treatment alone. The preclinical evaluation of the effects of VTAs on tumor growth in small animal models is vital for the development of effective drugs for clinical use. In vivo hyperspectral imaging microscopy of hemoglobin saturation has been used previously to investigate the efficacy of VTAs through analysis of tumor microvessel oxygenation after drug administration. Combining this imaging modality with first-pass fluorescence angiographic imaging can give additional important information about the vessel morphology and blood flow changes that occur after VTA treatment, thus elucidating the relationship between microvessel structure changes and oxygenation. In this study, we report the combined use of hyperspectral and first pass fluorescence angiographic imaging to examine the relationship between vessel morphology and oxygenation of human prostate cancer tumors in mice following treatment with vascular disrupting agents, OXi4503, and anti-VEGF angiogenesis inhibitor, cediranib. Imaging of the tumors is completed before treatment as well as in the days following treatment.

  15. Carbamoylating Activity Associated with the Activation of the Antitumor Agent Laromustine Inhibits Angiogenesis by Inducing ASK1-Dependent Endothelial Cell Death

    PubMed Central

    Praggastis, Alexandra; Li, Yonghao; Zhou, Huanjiao Jenny; He, Yun; Ghazvinian, Roxanne; Cincotta, Dylan J.; Rice, Kevin P.; Min, Wang

    2014-01-01

    The anticancer agent 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine), upon decomposition in situ, yields methyl isocyanate and the chloroethylating species 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine (90CE). 90CE has been shown to kill tumor cells via a proposed mechanism that involves interstrand DNA cross-linking. However, the role of methyl isocyanate in the antineoplastic function of laromustine has not been delineated. Herein, we show that 1,2-bis(methylsulfonyl)-1-[(methylamino)carbonyl]hydrazine (101MDCE), an analog of laromustine that generates only methyl isocyanate, activates ASK1-JNK/p38 signaling in endothelial cells (EC). We have previously shown that ASK1 forms a complex with reduced thioredoxin (Trx1) in resting EC, and that the Cys residues in ASK1 and Trx1 are critical for their interaction. 101MDCE dissociated ASK1 from Trx1, but not from the phosphoserine-binding inhibitor 14-3-3, in whole cells and in cell lysates, consistent with the known ability of methyl isocyanate to carbamoylate free thiol groups of proteins. 101MDCE had no effect on the kinase activity of purified ASK1, JNK, or the catalytic activity of Trx1. However, 101MDCE, but not 90CE, significantly decreased the activity of Trx reductase-1 (TrxR1). We conclude that methyl isocyanate induces dissociation of ASK1 from Trx1 either directly by carbamoylating the critical Cys groups in the ASK1-Trx1 complex or indirectly by inhibiting TrxR1. Furthermore, 101MDCE (but not 90CE) induced EC death through a non-apoptotic (necroptotic) pathway leading to inhibition of angiogenesis in vitro. Our study has identified methyl isocyanates may contribute to the anticancer activity in part by interfering with tumor angiogenesis. PMID:25068797

  16. Multifunctional ultrasound contrast agents for imaging guided photothermal therapy.

    PubMed

    Guo, Caixin; Jin, Yushen; Dai, Zhifei

    2014-05-21

    Among all the imaging techniques, ultrasound imaging has a unique advantage due to its features of real-time, low cost, high safety, and portability. Ultrasound contrast agents (UCAs) have been widely used to enhance ultrasonic signals. One of the most exciting features of UCAs for use in biomedicine is the possibility of easily putting new combinations of functional molecules into microbubbles (MBs), which are the most routinely used UCAs. Various therapeutic agents and medical nanoparticles (quantum dots, gold, Fe3O4, etc.) can be loaded into ultrasound-responsive MBs. Hence, UCAs can be developed as multifunctional agents that integrate capabilities for early detection and diagnosis and for imaging guided therapy of various diseases. The current review will focus on such state-of-the-art UCA platforms that have been exploited for multimodal imaging and for imaging guided photothermal therapy.

  17. Optimal flushing agents for integrated optical and acoustic imaging systems

    NASA Astrophysics Data System (ADS)

    Li, Jiawen; Minami, Hataka; Steward, Earl; Ma, Teng; Mohar, Dilbahar; Robertson, Claire; Shung, Kirk; Zhou, Qifa; Patel, Pranav; Chen, Zhongping

    2015-05-01

    An increasing number of integrated optical and acoustic intravascular imaging systems have been developed and hold great promise for accurately diagnosing vulnerable plaques and guiding atherosclerosis treatment. However, in any intravascular environment, the vascular lumen is filled with blood, a high-scattering source for optical and high-frequency ultrasound signals. Blood must be flushed away to provide clearer images. To our knowledge, no research has been performed to find the ideal flushing agent for combined optical and acoustic imaging techniques. We selected three solutions as potential flushing agents for their image-enhancing effects: mannitol, dextran, and iohexol. Testing of these flushing agents was performed in a closed-loop circulation model and in vivo on rabbits. We found that a high concentration of dextran was the most useful for simultaneous intravascular ultrasound and optical coherence tomography imaging.

  18. PET/SPECT imaging agents for neurodegenerative diseases

    PubMed Central

    Zhu, Lin; Ploessl, Karl; Kung, Hank F.

    2014-01-01

    Single photon emission computed tomography (SPECT) or positron emission computed tomography (PET) imaging agents for neurodegenerative disease have a significant impact on clinical diagnosis and patient care. The examples of Parkinson’s Disease (PD) and Alzheimer’s Disease (AD) imaging agents described in this paper provide a general view on how imaging agents, ie radioactive drugs, are selected, chemically prepared and applied in humans. Imaging the living human brain can provide unique information on the pathology and progression of neurodegenerative diseases, such as AD and PD. The imaging method will also facilitate preclinical and clinical trials of new drugs offering specific information related to drug binding sites in the brain. In the future, chemists will continue to play important roles in identifying specific targets, synthesizing target-specific probes for screening and ultimately testing them by in vitro and in vivo assays. PMID:24676152

  19. Optimal flushing agents for integrated optical and acoustic imaging systems.

    PubMed

    Li, Jiawen; Minami, Hataka; Steward, Earl; Ma, Teng; Mohar, Dilbahar; Robertson, Claire; Shung, Kirk; Zhou, Qifa; Patel, Pranav; Chen, Zhongping

    2015-05-01

    An increasing number of integrated optical and acoustic intravascular imaging systems have been developed and hold great promise for accurately diagnosing vulnerable plaques and guiding atherosclerosis treatment. However, in any intravascular environment, the vascular lumen is filled with blood, a high-scattering source for optical and high-frequency ultrasound signals. Blood must be flushed away to provide clearer images. To our knowledge, no research has been performed to find the ideal flushing agent for combined optical and acoustic imaging techniques. We selected three solutions as potential flushing agents for their image-enhancing effects: mannitol, dextran, and iohexol. Testing of these flushing agents was performed in a closed-loop circulation model and in vivo on rabbits. We found that a high concentration of dextran was the most useful for simultaneous intravascular ultrasound and optical coherence tomography imaging.

  20. Optimal flushing agents for integrated optical and acoustic imaging systems

    PubMed Central

    Li, Jiawen; Minami, Hataka; Steward, Earl; Ma, Teng; Mohar, Dilbahar; Robertson, Claire; Shung, Kirk; Zhou, Qifa; Patel, Pranav; Chen, Zhongping

    2015-01-01

    Abstract. An increasing number of integrated optical and acoustic intravascular imaging systems have been developed and hold great promise for accurately diagnosing vulnerable plaques and guiding atherosclerosis treatment. However, in any intravascular environment, the vascular lumen is filled with blood, a high-scattering source for optical and high-frequency ultrasound signals. Blood must be flushed away to provide clearer images. To our knowledge, no research has been performed to find the ideal flushing agent for combined optical and acoustic imaging techniques. We selected three solutions as potential flushing agents for their image-enhancing effects: mannitol, dextran, and iohexol. Testing of these flushing agents was performed in a closed-loop circulation model and in vivo on rabbits. We found that a high concentration of dextran was the most useful for simultaneous intravascular ultrasound and optical coherence tomography imaging. PMID:25985096

  1. Intravascular contrast agents suitable for magnetic resonance imaging. [Dogs

    SciTech Connect

    Runge, V.M.; Clanton, J.A.; Herzer, W.A.; Gibbs, S.J.; Price, A.C.; Partain, C.L.; James, A.E. Jr.

    1984-10-01

    Two paramagnetic chelates, chromium EDTA and gadolinium DTPA, were evaluated as potential intravenous contrast agents for magnetic resonance imaging. After evaluating both agents in vitro, in vivo studies were conducted in dogs to document changes in renal appearance produced by contrast injection. Acute splenic and renal infarction were diagnosed with contrast-enhanced MR and confirmed by gamma camera imaging following administration of Tc-99m-labeled DMSA and sulfur colloid. The authors conclude that intravenous paramagnetic contrast agents presently offer the best mechanism for assessment of tissue function and changes in perfusion with MR.

  2. [Contrast agents in magnetic resonance imaging: development and problems].

    PubMed

    Xu, Yi-kai

    2002-09-01

    In spite of the inherent versatility of magnetic resonance imaging (MRI), researchers and clinicians from both home and aboard have made great achievements in developing safe and effective contrast agents. Many new agents are expected to be available for clinical use in the near future. It is of clinical importance that the agents should expand the diagnostic utility of MRI, improve the detection of tiny lesions and help evaluate specific tissue or organ functions. This article aims to examine current status of contrast agents for MRI and the problems waiting for solutions.

  3. Correlated magnetic resonance imaging and ultramicroscopy (MR-UM) is a tool kit to assess the dynamics of glioma angiogenesis

    PubMed Central

    Breckwoldt, Michael O; Bode, Julia; Kurz, Felix T; Hoffmann, Angelika; Ochs, Katharina; Ott, Martina; Deumelandt, Katrin; Krüwel, Thomas; Schwarz, Daniel; Fischer, Manuel; Helluy, Xavier; Milford, David; Kirschbaum, Klara; Solecki, Gergely; Chiblak, Sara; Abdollahi, Amir; Winkler, Frank; Wick, Wolfgang; Platten, Michael; Heiland, Sabine; Bendszus, Martin; Tews, Björn

    2016-01-01

    Neoangiogenesis is a pivotal therapeutic target in glioblastoma. Tumor monitoring requires imaging methods to assess treatment effects and disease progression. Until now mapping of the tumor vasculature has been difficult. We have developed a combined magnetic resonance and optical toolkit to study neoangiogenesis in glioma models. We use in vivo magnetic resonance imaging (MRI) and correlative ultramicroscopy (UM) of ex vivo cleared whole brains to track neovascularization. T2* imaging allows the identification of single vessels in glioma development and the quantification of neovessels over time. Pharmacological VEGF inhibition leads to partial vascular normalization with decreased vessel caliber, density, and permeability. To further resolve the tumor microvasculature, we performed correlated UM of fluorescently labeled microvessels in cleared brains. UM resolved typical features of neoangiogenesis and tumor cell invasion with a spatial resolution of ~5 µm. MR-UM can be used as a platform for three-dimensional mapping and high-resolution quantification of tumor angiogenesis. DOI: http://dx.doi.org/10.7554/eLife.11712.001 PMID:26830460

  4. Inorganic nanoparticle-based contrast agents for molecular imaging

    PubMed Central

    Cho, Eun Chul; Glaus, Charles; Chen, Jingyi; Welch, Michael J.; Xia, Younan

    2010-01-01

    Inorganic nanoparticles including semiconductor quantum dots, iron oxide nanoparticles, and gold nanoparticles have been developed as contrast agents for diagnostics by molecular imaging. Compared to traditional contrast agents, nanoparticles offer several advantages: their optical and magnetic properties can be tailored by engineering the composition, structure, size, and shape; their surfaces can be modified with ligands to target specific biomarkers of disease; the contrast enhancement provided can be equivalent to millions of molecular counterparts; and they can be integrated with a combination of different functions for multi-modal imaging. Here, we review recent advances in the development of contrast agents based on inorganic nanoparticles for molecular imaging, with a touch on contrast enhancement, surface modification, tissue targeting, clearance, and toxicity. As research efforts intensify, contrast agents based on inorganic nanoparticles that are highly sensitive, target-specific, and safe to use are expected to enter clinical applications in the near future. PMID:21074494

  5. Nanogels as imaging agents for modalities spanning the electromagnetic spectrum.

    PubMed

    Chan, Minnie; Almutairi, Adah

    2016-01-21

    In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents.

  6. Nanogels as imaging agents for modalities spanning the electromagnetic spectrum

    PubMed Central

    Chan, Minnie

    2016-01-01

    In the past few decades, advances in imaging equipment and protocols have expanded the role of imaging in in vivo diagnosis and disease management, especially in cancer. Traditional imaging agents have rapid clearance and low specificity for disease detection. To improve accuracy in disease identification, localization and assessment, novel nanomaterials are frequently explored as imaging agents to achieve high detection specificity and sensitivity. A promising material for this purpose are hydrogel nanoparticles, whose high hydrophilicity, biocompatibility, and tunable size in the nanometer range make them ideal for imaging. These nanogels (10 to 200 nm) can circumvent uptake by the reticuloendothelial system, allowing longer circulation times than small molecules. In addition, their size/surface properties can be further tailored to optimize their pharmacokinetics for imaging of a particular disease. Herein, we provide a comprehensive review of nanogels as imaging agents in various modalities with sources of signal spanning the electromagnetic spectrum, including MRI, NIR, UV-vis, and PET. Many materials and formulation methods will be reviewed to highlight the versatility of nanogels as imaging agents. PMID:27398218

  7. Ideal flushing agents for integrated optical acoustic imaging systems

    NASA Astrophysics Data System (ADS)

    Li, Jiawen; Minami, Hataka; Steward, Earl; Ma, Teng; Mohar, Dilbahar; Robertson, Claire; Shung, K. Kirk; Zhou, Qifa; Patel, Pranav M.; Chen, Zhongping

    2015-02-01

    An increased number of integrated optical acoustic intravascular imaging systems have been researched and hold great hope for accurate diagnosing of vulnerable plaques and for guiding atherosclerosis treatment. However, in any intravascular environment, vascular lumen is filled with blood, which is a high-scattering source for optical and high frequency ultrasound signals. Blood must be flushed away to make images clear. To our knowledge, no research has been performed to find the ideal flushing agent that works for both optical and acoustic imaging techniques. We selected three solutions, mannitol, dextran and iohexol, as flushing agents because of their image-enhancing effects and low toxicities. Quantitative testing of these flushing agents was performed in a closed loop circulation model and in vivo on rabbits.

  8. Multifunctional photosensitizer-based contrast agents for photoacoustic imaging.

    PubMed

    Ho, Chris Jun Hui; Balasundaram, Ghayathri; Driessen, Wouter; McLaren, Ross; Wong, Chi Lok; Dinish, U S; Attia, Amalina Binte Ebrahim; Ntziachristos, Vasilis; Olivo, Malini

    2014-06-18

    Photoacoustic imaging is a novel hybrid imaging modality combining the high spatial resolution of optical imaging with the high penetration depth of ultrasound imaging. Here, for the first time, we evaluate the efficacy of various photosensitizers that are widely used as photodynamic therapeutic (PDT) agents as photoacoustic contrast agents. Photoacoustic imaging of photosensitizers exhibits advantages over fluorescence imaging, which is prone to photobleaching and autofluorescence interference. In this work, we examined the photoacoustic activity of 5 photosensitizers: zinc phthalocyanine, protoporphyrin IX, 2,4-bis [4-(N,N-dibenzylamino)-2,6-dihydroxyphenyl] squaraine, chlorin e6 and methylene blue in phantoms, among which zinc phthalocyanine showed the highest photoacoustic activity. Subsequently, we evaluated its tumor localization efficiency and biodistribution at multiple time points in a murine model using photoacoustic imaging. We observed that the probe localized at the tumor within 10 minutes post injection, reaching peak accumulation around 1 hour and was cleared within 24 hours, thus, demonstrating the potential of photosensitizers as photoacoustic imaging contrast agents in vivo. This means that the known advantages of photosensitizers such as preferential tumor uptake and PDT efficacy can be combined with photoacoustic imaging capabilities to achieve longitudinal monitoring of cancer progression and therapy in vivo.

  9. Imaging agents for in vivo magnetic resonance and scintigraphic imaging

    DOEpatents

    Engelstad, B.L.; Raymond, K.N.; Huberty, J.P.; White, D.L.

    1991-04-23

    Methods are provided for in vivo magnetic resonance imaging and/or scintigraphic imaging of a subject using chelated transition metal and lanthanide metal complexes. Novel ligands for these complexes are provided. No Drawings

  10. Imaging agents for in vivo magnetic resonance and scintigraphic imaging

    DOEpatents

    Engelstad, Barry L.; Raymond, Kenneth N.; Huberty, John P.; White, David L.

    1991-01-01

    Methods are provided for in vivo magnetic resonance imaging and/or scintigraphic imaging of a subject using chelated transition metal and lanthanide metal complexes. Novel ligands for these complexes are provided.

  11. Silicon Nanoparticles as Hyperpolarized Magnetic Resonance Imaging Agents

    PubMed Central

    Aptekar, Jacob W.; Cassidy, Maja C.; Johnson, Alexander C.; Barton, Robert A.; Lee, Menyoung; Ogier, Alexander C.; Vo, Chinh; Anahtar, Melis N.; Ren, Yin; Bhatia, Sangeeta N.; Ramanathan, Chandrasekhar; Cory, David G.; Hill, Alison L.; Mair, Ross W.; Rosen, Matthew S.; Walsworth, Ronald L.

    2014-01-01

    Magnetic resonance imaging of hyperpolarized nuclei provides high image contrast with little or no background signal. To date, in-vivo applications of pre-hyperpolarized materials have been limited by relatively short nuclear spin relaxation times. Here, we investigate silicon nanoparticles as a new type of hyperpolarized magnetic resonance imaging agent. Nuclear spin relaxation times for a variety of Si nanoparticles are found to be remarkably long, ranging from many minutes to hours at room temperature, allowing hyperpolarized nanoparticles to be transported, administered, and imaged on practical time scales. Additionally, we demonstrate that Si nanoparticles can be surface functionalized using techniques common to other biologically targeted nanoparticle systems. These results suggest that Si nanoparticles can be used as a targetable, hyperpolarized magnetic resonance imaging agent with a large range of potential applications. PMID:19950973

  12. Recent Advances in Higher-Order, Multimodal, Biomedical Imaging Agents.

    PubMed

    Rieffel, James; Chitgupi, Upendra; Lovell, Jonathan F

    2015-09-16

    Advances in biomedical imaging have spurred the development of integrated multimodal scanners, usually capable of two simultaneous imaging modes. The long-term vision of higher-order multimodality is to improve diagnostics or guidance through the analysis of complementary, data-rich, co-registered images. Synergies achieved through combined modalities could enable researchers to better track diverse physiological and structural events, analyze biodistribution and treatment efficacy, and compare established and emerging modalities. Higher-order multimodal approaches stand to benefit from molecular imaging probes and, in recent years, contrast agents that have hypermodal characteristics have increasingly been reported in preclinical studies. Given the chemical requirements for contrast agents representing various modalities to be integrated into a single entity, the higher-order multimodal agents reported so far tend to be of nanoparticulate form. To date, the majority of reported nanoparticles have included components that are active for magnetic resonance. Herein, recent progress in higher-order multimodal imaging agents is reviewed, spanning a range of material and structural classes, and demonstrating utility in three (or more) imaging modalities.

  13. Perfusion Imaging with a Freely Diffusible Hyperpolarized Contrast Agent

    PubMed Central

    Grant, Aaron K.; Vinogradov, Elena; Wang, Xiaoen; Lenkinski, Robert E.; Alsop, David C.

    2011-01-01

    Contrast agents that can diffuse freely into or within tissue have numerous attractive features for perfusion imaging. Here we present preliminary data illustrating the suitability of hyperpolarized 13C labeled 2-methylpropan-2-ol (also known as dimethylethanol, tertiary butyl alcohol and tert-butanol) as a freely diffusible contrast agent for magnetic resonance perfusion imaging. Dynamic 13C images acquired in rat brain with a balanced steady-state free precession (bSSFP) sequence following administration of hyperpolarized 2-methylpropan-2-ol show that this agent can be imaged with 2–4s temporal resolution, 2mm slice thickness, and 700 micron in-plane resolution while retaining adequate signal-to-noise ratio. 13C relaxation measurements on 2-methylpropan-2-ol in blood at 9.4T yield T1=46±4s and T2=0.55±0.03s. In the rat brain at 4.7T, analysis of the temporal dynamics of the bSSFP image intensity in tissue and venous blood indicate that 2-methylpropan-2-ol has a T2 of roughly 2–4s and a T1 of 43±24s. In addition, the images indicate that 2-methylpropan-2-ol is freely diffusible in brain and hence has a long residence time in tissue; this in turn makes it possible to image the agent continuously for tens of seconds. These characteristics show that 2-methylpropan-2-ol is a promising agent for robust and quantitative perfusion imaging in the brain and body. PMID:21432901

  14. Tumour angiogenesis.

    PubMed Central

    Arnold, F.

    1985-01-01

    Tumours induce the growth of host blood vessels to support their proliferation. This process of angiogenesis is evoked by specific chemical signals. Recognition of these angiogenic factors has led to experimental methods for cancer diagnosis and for inhibiting malignant growth by specifically blocking neovascularisation. The clinical potential of these techniques is discussed. PMID:2413796

  15. Blood pool contrast agents for venous magnetic resonance imaging

    PubMed Central

    Oliveira, Irai S.; Li, Weier; Ganguli, Suvranu; Prabhakar, Anand M.

    2016-01-01

    Imaging of the venous system plays a vital role in the diagnosis and management of a wide range of clinically significant disorders. There have been great advances in venous imaging techniques, culminating in the use of magnetic resonance venography (MRV). Although MRV has distinct advantages in anatomic and quantitative cross sectional imaging without ionizing radiation, there are well-known challenges in acquisition timing and contrast administration in patients with renal impairment. The latest advancement involves the addition of new contrast media agents, which have emerged as valuable alternatives in these difficult scenarios. In this review, we will focus on a group of specific contrast agents called blood pool agents and discuss their salient features and clinical applications. PMID:28123972

  16. Angiogenesis imaging in myocardial infarction using 68Ga-NOTA-RGD PET: characterization and application to therapeutic efficacy monitoring in rats.

    PubMed

    Eo, Jae Seon; Paeng, Jin Chul; Lee, Song; Lee, Yun-Sang; Jeong, Jae Min; Kang, Keon Wook; Chung, June-Key; Lee, Dong Soo

    2013-06-01

    Ga-NOTA-RGD PET is a newly developed molecular imaging for angiogenesis. In this study, Ga-NOTA-RGD PET was used to investigate imaging characteristics in a rat myocardial infarction (MI) model and to monitor the efficacy of an angiogenesis induction therapy. Ga-NOTA-RGD PET was performed serially in rats with MI or sham operation, and myocardial uptake was analyzed with respect to time duration and tissue characteristics. Subsequently, Ga-NOTA-RGD PET was serially performed for therapeutic efficacy monitoring in MI-induced rats, which were treated with basic fibroblast growth factor (bFGF) injection or saline injection. Image findings were compared with the final change in MI lesion. Ga-NOTA-RGD uptake was significantly increased in MI lesion and gradually decreased over time. Ga-NOTA-RGD uptake in the infarcted tissue corresponded with vascular endothelial growth factor expression and macrophage accumulation. In monitoring of therapeutic efficacy, the lesion uptake in the bFGF-injected group was significantly higher than that of the saline-injected and sham-operated groups on the first day. However, no significant differences were observed between bFGF and saline-injected groups at subsequent time points, corresponding to the final infarct size change. Ga-NOTA-RGD PET would be a useful angiogenesis imaging modality in MI for assessment of pathophysiology or monitoring of therapeutic efficacy.

  17. Iron Oxide Nanoparticle Based Contrast Agents for Magnetic Resonance Imaging.

    PubMed

    Shen, Zheyu; Wu, Aiguo; Chen, Xiaoyuan

    2017-05-01

    Magnetic iron oxide nanoparticles (MIONs) have attracted enormous attention due to their wide applications, including for magnetic separation, for magnetic hyperthermia, and as contrast agents for magnetic resonance imaging (MRI). This review article introduces the methods of synthesizing MIONs, and their application as MRI contrast agents. Currently, many methods have been reported for the synthesis of MIONs. Herein, we only focus on the liquid-based synthesis methods including aqueous phase methods and organic phase methods. In addition, the MIONs larger than 10 nm can be used as negative contrast agents and the recently emerged extremely small MIONs (ES-MIONs) smaller than 5 nm are potential positive contrast agents. In this review, we focus on the ES-MIONs because ES-MIONs avoid the disadvantages of MION-based T2- and gadolinium chelate-based T1-weighted contrast agents.

  18. Radioiodinated agents for imaging multidrug resistant tumors.

    PubMed

    Kortylewicz, Zbigniew P; Augustine, Ann M; Nearman, Jessica; McGarry, Jonathon; Baranowska-Kortylewicz, Janina

    2009-03-01

    Diagnostic agents enabling characterization of multidrug resistance (MDR) in tumors can aid in the selection of chemotherapy regimens. We report here synthesis and evaluation of radiopharmaceuticals based on the second-generation MDR-reversing drug MS-209. 5-[3-{4-(2-Phenyl-2-(4'-[(125)I]iodo-phenyl)acetyl)piperazin-1-yl}-2-hydroxypropoxy]quino-line (17) was prepared from the 4'-tributylstannyl precursor (16) in >95% radiochemical yield. (16) was synthesized in a six-step process with the overall yield of 25%. In vitro studies were conducted in MES-SA (drug-sensitive) and MES-SA/Dx5 (MDR) human uterine sarcoma cell lines. In vivo studies were performed in athymic mice bearing MES-SA and MES-SA/Dx5 xenografts. The uptake of (17) is higher in MES-SA than MES-SA/Dx5 cells. The uptake and efflux of (17) depend on temperature and concentration, and indicate active transport mechanism(s). Incubation of drug sensitive MES-SA cells with verapamil or (15), a nonradioactive analog of (17), alters the cellular retention of radioactivity only marginally. However, MES-SA/Dx5 cells retain approximately 12% more of (17) when incubated with 10 muM verapamil. The addition of (15) or high concentrations of (17) also increase the uptake of (17) in MES-SA/Dx5 up to 200%, depending on the concentration and temperature. The dependence of (17) uptake on the MDR status is also evident in the ex vivo binding studies. In vivo tests in mice xenografted simultaneously with both tumor cell lines indicate distinct pharmacokinetics for each tumor. The absorption half-life in MES-SA/Dx5 xenograft is approximately 10x shorter and the mean residence time approximately 50% shorter compared to MES-SA xenograft in the same mouse. Radioiodinated derivatives of MS-209 appear to be good indicators of multidrug resistance.

  19. VEGF-Iron Oxide Conjugate for Dual MR and PET Imaging of Breast Cancer Angiogenesis

    DTIC Science & Technology

    2007-09-01

    iron oxide nanoparticles conjugated with macrocyclic chelating agent DOTA for 64Cu-labeling and cyclic RGD peptide for integrin alpha (v)beta(3...Nanoparticles We have developed two types of novel superparamagentic iron oxide nanoparticles (USPIO), namely, PVP -IO and PASP-IO...Polyvinylpyrrolidone ( PVP )-coated iron oxide ( PVP -IO) nanoparticles were synthesized by a one-step thermal decomposition method (Fig. 3). The overall size of the

  20. 4-haloethenylphenyl tropane:serotonin transporter imaging agents

    DOEpatents

    Goodman, Mark M.; Martarello, Laurent

    2005-01-18

    A series of compounds in the 4-fluoroalkyl-3-halophenyl nortropanes and 4-haloethenylphenyl tropane families are described as diagnostic and therapeutic agents for diseases associated with serotonin transporter dysfunction. These compounds bind to serotonin transporter protein with high affinity and selectivity. The invention provides methods of synthesis which incorporate radioisotopic halogens at a last step which permit high radiochemical yield and maximum usable product life. The radiolabeled compounds of the invention are useful as imaging agents for visualizing the location and density of serotonin transporter by PET and SPECT imaging.

  1. Chemical agent detection and quantification with imaging spectrometry

    NASA Astrophysics Data System (ADS)

    Ifarraguerri, Augustin I.

    1999-10-01

    Passive standoff detection of chemical warfare (CW) agents is currently achieved by remote sensing infrared spectrometry in the 8 - 12 micrometer atmospheric window with the aid of automatic spectral analysis algorithms. Introducing an imaging capability would allow for rapid wide-area reconnaissance and mapping of vapor clouds, as well as reduce false alarms by exploiting the added spatial information. This paper contains an overview of the CW agent standoff detection problem and the challenges associated with developing imaging LWIR hyperspectral sensors for the detection and quantification of vapor clouds, as well as a discussion of spectral processing techniques which can be used to exploit the added data dimensionality.

  2. Dendrimer-entrapped metal colloids as imaging agents.

    PubMed

    Li, Du; Wen, Shihui; Shi, Xiangyang

    2015-01-01

    This review reports the recent advances in dendrimer-entrapped metal colloids as contrast agents for biomedical imaging applications. The versatile dendrimer scaffolds with 3-dimensional spherical shape, highly branched internal cavity, tunable surface conjugation chemistry, and excellent biocompatibility and nonimmunogenicity afford their uses as templates to create multifunctional dendrimer-entrapped metal colloids for mono- or multi- mode molecular imaging applications. In particular, multifunctional dendrimer-entrapped gold nanoparticles with different surface modifications have been used for fluorescence imaging, targeted tumor computed tomography (CT) imaging, enhanced blood pool CT imaging, dual mode CT/MR imaging, and tumor theranostics (combined CT imaging and chemotherapy) will be introduced and discussed in detail. © 2015 Wiley Periodicals, Inc.

  3. Peptide-based imaging agents for cancer detection☆

    PubMed Central

    Sun, Xiaolian; Li, Yesen; Liu, Ting; Li, Zijing; Zhang, Xianzhong; Chen, Xiaoyuan

    2017-01-01

    Selective receptor-targeting peptide based agents have attracted considerable attention in molecular imaging of tumor cells that overexpress corresponding peptide receptors due to their unique properties such as rapid clearance from circulation as well as high affinities and specificities for their targets. The rapid growth of chemistry modification techniques has enabled the design and development of various peptide-based imaging agents with enhanced metabolic stability, favorable pharmacokinetics, improved binding affinity and selectivity, better imaging ability as well as biosafety. Among them, many radiolabeled peptides have already been translated into the clinic with impressive diagnostic accuracy and sensitivity. This review summarizes the current status in the development of peptide-based imaging agents with an emphasis on the consideration of probe design including the identification of suitable peptides, the chemical modification of probes and the criteria for clinical translation. Specific examples in clinical trials have been provided as well with respect to their diagnostic capability compared with other FDA approved imaging agents. PMID:27327937

  4. Imaging considerations for a technetium-99m myocardial perfusion agent

    SciTech Connect

    English, R.J.; Jones, A.G.; Davison, A.; Lister-James, J.; Campbell, S.; Holman, B.L.

    1986-03-01

    Myocardial perfusion imaging with /sup 201/Tl chloride suffers from a number of physical, geometric, and dosimetric constraints that could be diminished if an agent labeled with /sup 99m/Tc were available. The cationic complex /sup 99m/Tc hexakis-(t-butylisonitrile)technetium(I) ((/sup 99m/Tc)TBI) has been shown to concentrate in the myocardial tissue of both animals and humans, with preliminary clinical studies demonstrating a number of technical attributes not possible with /sup 201/Tl. Technetium-99m-TBI is a promising myocardial imaging agent that may permit high quality planar, gated, and tomographic imaging of both myocardial ischemia and infarction with reduced imaging times and improved resolution.

  5. IDH mutation status is associated with a distinct hypoxia/angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging in human glioma.

    PubMed

    Kickingereder, Philipp; Sahm, Felix; Radbruch, Alexander; Wick, Wolfgang; Heiland, Sabine; Deimling, Andreas von; Bendszus, Martin; Wiestler, Benedikt

    2015-11-05

    The recent identification of IDH mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we analyzed mRNA expression profiles of 288 glioma patients and show decreased expression of HIF1A targets on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH mutant tumors. Genotype/imaging phenotype correlation analysis with relative cerebral blood volume (rCBV) MRI - a robust and non-invasive estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas showed that a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH mutation and correctly predicted IDH mutation status in 88% of patients. Together, these findings (1) show that IDH mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV imaging and (2) highlight the potential future of radiogenomics (i.e. the correlation between cancer imaging and genomic features) towards a more accurate diagnostic workup of brain tumors.

  6. A Brief Account of Nanoparticle Contrast Agents for Photoacoustic Imaging

    PubMed Central

    Pan, Dipanjan; Kim, Benjamin; Wang, Lihong V.; Lanza, Gregory M

    2014-01-01

    Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser-generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle-based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds. PMID:23983210

  7. [Gadolinium-based contrast agents for magnetic resonance imaging].

    PubMed

    Carrasco Muñoz, S; Calles Blanco, C; Marcin, Javier; Fernández Álvarez, C; Lafuente Martínez, J

    2014-06-01

    Gadolinium-based contrast agents are increasingly being used in magnetic resonance imaging. These agents can improve the contrast in images and provide information about function and metabolism, increasing both sensitivity and specificity. We describe the gadolinium-based contrast agents that have been approved for clinical use, detailing their main characteristics based on their chemical structure, stability, and safety. In general terms, these compounds are safe. Nevertheless, adverse reactions, the possibility of nephrotoxicity from these compounds, and the possibility of developing nephrogenic systemic fibrosis will be covered in this article. Lastly, the article will discuss the current guidelines, recommendations, and contraindications for their clinical use, including the management of pregnant and breast-feeding patients.

  8. Theranostic agents for intracellular gene delivery with spatiotemporal imaging

    PubMed Central

    Knipe, Jennifer M.; Peters, Jonathan T.; Peppas, Nicholas A.

    2013-01-01

    Gene therapy is the modification of gene expression to treat a disease. However, efficient intracellular delivery and monitoring of gene therapeutic agents is an ongoing challenge. Use of theranostic agents with suitable targeted, controlled delivery and imaging modalities has the potential to greatly advance gene therapy. Inorganic nanoparticles including magnetic nanoparticles, gold nanoparticles, and quantum dots have been shown to be effective theranostic agents for the delivery and spatiotemporal tracking of oligonucleotides in vitro and even a few cases in vivo. Major concerns remain to be addressed including cytotoxicity, particularly of quantum dots; effective dosage of nanoparticles for optimal theranostic effect; development of real-time in vivo imaging; and further improvement of gene therapy efficacy. PMID:23606894

  9. A brief account of nanoparticle contrast agents for photoacoustic imaging.

    PubMed

    Pan, Dipanjan; Kim, Benjamin; Wang, Lihong V; Lanza, Gregory M

    2013-01-01

    Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser-generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle-based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds.

  10. Ultrasound imaging beyond the vasculature with new generation contrast agents.

    PubMed

    Perera, Reshani H; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan; Exner, Agata A

    2015-01-01

    Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 µm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. © 2015 Wiley Periodicals, Inc.

  11. Ultrasound Imaging Beyond the Vasculature with New Generation Contrast Agents

    PubMed Central

    Perera, Reshani H.; Hernandez, Christopher; Zhou, Haoyan; Kota, Pavan; Burke, Alan

    2015-01-01

    Current commercially available ultrasound contrast agents are gas-filled, lipid- or protein-stabilized microbubbles larger than 1 μm in diameter. Because the signal generated by these agents is highly dependent on their size, small yet highly echogenic particles have been historically difficult to produce. This has limited the molecular imaging applications of ultrasound to the blood pool. In the area of cancer imaging, microbubble applications have been constrained to imaging molecular signatures of tumor vasculature and drug delivery enabled by ultrasound-modulated bubble destruction. Recently, with the rise of sophisticated advancements in nanomedicine, ultrasound contrast agents, which are an order of magnitude smaller (100-500 nm) than their currently utilized counterparts, have been undergoing rapid development. These agents are poised to greatly expand the capabilities of ultrasound in the field of targeted cancer detection and therapy by taking advantage of the enhanced permeability and retention phenomenon of many tumors and can extravasate beyond the leaky tumor vasculature. Agent extravasation facilitates highly sensitive detection of cell surface or microenvironment biomarkers, which could advance early cancer detection. Likewise, when combined with appropriate therapeutic agents and ultrasound-mediated deployment on demand, directly at the tumor site, these nanoparticles have been shown to contribute to improved therapeutic outcomes. Ultrasound's safety profile, broad accessibility and relatively low cost make it an ideal modality for the changing face of healthcare today. Aided by the multifaceted nano-sized contrast agents and targeted theranostic moieties described herein, ultrasound can considerably broaden its reach in future applications focused on the diagnosis and staging of cancer. PMID:25580914

  12. Recent advances in the development of amyloid imaging agents.

    PubMed

    Furumoto, Shozo; Okamura, Nobuyuki; Iwata, Ren; Yanai, Kazuhiko; Arai, Hiroyuki; Kudo, Yukitsuka

    2007-01-01

    Excessive amyloid-beta (Abeta) deposition in the brain is one of the most crucial events in the early pathological stage of Alzheimer's disease (AD). Therefore, Abeta deposits have enough potential to become a useful biomarker for not only an early diagnosis of AD, but also for the assessment of the clinical efficacy of anti-Abeta therapies, if they can be measured non-invasively and reliably in living patients. As a potent candidate technique to measure this biomarker, PET amyloid imaging using a radioligand for Abeta deposits has received much attention. A large number of Abeta ligands have been synthesized and evaluated as candidates for amyloid imaging agents. These can be classified into six categories of derivatives: Congo-red, Thioflavine T, stilbene, vinylbenzoxazole, DDNP, and miscellaneous. Many of these derivatives exhibit high binding affinities to Abeta fibrils (below 20 nM) and some of them also show excellent brain pharmacokinetic profiles. The concept of amyloid imaging is currently being tested in human PET studies using optimized amyloid imaging agents. Despite the small number of subjects, these studies have demonstrated sufficiently promising results. This review article provides an overview of recent advances in the development of amyloid imaging agents, and includes: a summary of the fundamental basis and clinical significance of amyloid imaging; lists of binding affinity data for 135 compounds classified into 12 molecular frameworks; a comprehensive discussion of the in vitro and in vivo features of representative Abeta ligands; and a discussion of the current state of clinical evaluation of these amyloid imaging agents (PIB, SB-13, BF-227, and FDDNP).

  13. Angiogenesis Assays.

    PubMed

    Nambiar, Dhanya K; Kujur, Praveen K; Singh, Rana P

    2016-01-01

    Neoangiogenesis constitutes one of the first steps of tumor progression beyond a critical size of tumor growth, which supplies a dormant mass of cancerous cells with the required nutrient supply and gaseous exchange through blood vessels essentially needed for their sustained and aggressive growth. In order to understand any biological process, it becomes imperative that we use models, which could mimic the actual biological system as closely as possible. Hence, finding the most appropriate model is always a vital part of any experimental design. Angiogenesis research has also been much affected due to lack of simple, reliable, and relevant models which could be easily quantitated. The angiogenesis models have been used extensively for studying the action of various molecules for agonist or antagonistic behaviour and associated mechanisms. Here, we have described two protocols or models which have been popularly utilized for studying angiogenic parameters. Rat aortic ring assay tends to bridge the gap between in vitro and in vivo models. The chorioallantoic membrane (CAM) assay is one of the most utilized in vivo model system for angiogenesis-related studies. The CAM is highly vascularized tissue of the avian embryo and serves as a good model to study the effects of various test compounds on neoangiogenesis.

  14. Developments Toward Diagnostic Breast Cancer Imaging Using Near-Infrared Optical Measurements and Fluorescent Contrast Agents1

    PubMed Central

    Hawrysz, Daniel J; Sevick-Muraca, Eva M

    2000-01-01

    Abstract The use of near-infrared (NIR) light to interrogate deep tissues has enormous potential for molecular-based imaging when coupled with NIR excitable dyes. More than a decade has now passed since the initial proposals for NIR optical tomography for breast cancer screening using time-dependent measurements of light propagation in the breast. Much accomplishment in the development of optical mammography has been demonstrated, most recently in the application of time-domain, frequency-domain, and continuous-wave measurements that depend on endogenous contrast owing to angiogenesis and increased hemoglobin absorbance for contrast. Although exciting and promising, the necessity of angiogenesis-mediated absorption contrast for diagnostic optical mammography minimizes the potential for using NIR techniques to assess sentinel lymph node staging, metastatic spread, and multifocality of breast disease, among other applications. In this review, we summarize the progress made in the development of optical mammography, and focus on the emerging work underway in the use of diagnostic contrast agents for the molecular-based, diagnostic imaging of breast. PMID:11191107

  15. Angiogenesis assays in the chick CAM.

    PubMed

    Storgard, Chris; Mikolon, David; Stupack, Dwayne G

    2005-01-01

    The growth of new blood vessels from pre-existing vascular elements, or angiogenesis, involves coordinated signals to the adhesion, migration, and survival machinery within the target endothelial cell. Agents that interfere with any of these processes may therefore influence angiogenesis. Here, we describe the angiogenesis assay in the chick chorioallantoic membrane (CAM). The CAM is a useful tool to studying angiogenesis because 1) it is amenable to both intravascular and topical administration of study agents, 2) it is a relatively rapid assay, and 3) it can be adapted very easily to study angiogenesis-dependent processes, such as tumor growth. Importantly, the CAM provides a physiological setting that permits investigation of pro- and anti-angiogenic agent interactions in vivo.

  16. Spectral imaging of microvascular function in a renal cell carcinoma after treatment with a vascular disrupting agent

    NASA Astrophysics Data System (ADS)

    Wankhede, Mamta; deDeugd, Casey; Siemann, Dietmar W.; Sorg, Brian S.

    2009-02-01

    Tumors are highly metabolically active and thus require ample oxygen and nutrients to proliferate. Neovasculature generated by angiogenesis is required for tumors to grow beyond a size of about 1-2mm. Functional tumor vasculature also provides an access point for development of distant metastases. Due to the importance of the microvasculature for tumor growth, proliferation, and metastasis, the microvasculature has emerged as a therapeutic target for treatment of solid tumors. We employed spectral imaging in a rodent window chamber model to observe and measure the oxygen transport function of tumor microvasculature in a human renal cell carcinoma after treatment with a fast acting vascular disrupting agent. Human Caki-1 cells were grown in a dorsal skin-fold window chamber in athymic nude mice. Spectral imaging was used to measure hemoglobin saturation immediately before, immediately after and also at 2, 4, 6, 8, 24 and 48 hours after administration of the tubulin binding agent OXi4503. Up to 4 hours after treatment, tumor microvasculature was disrupted from the tumor core towards the periphery as seen in deoxygenation as well as structural changes of the vasculature. Reoxygenation and neovascularization commenced from the periphery towards the core from 6 - 48 hours after treatment. The timing of the effects of vascular disrupting agents can influence scheduling of repeat treatments and combinatorial treatments such as chemotherapy and radiation therapy. Spectral imaging can potentially provide this information in certain laboratory models from endogenous signals with microvessel resolution.

  17. Nanoengineered multimodal contrast agent for medical image guidance

    NASA Astrophysics Data System (ADS)

    Perkins, Gregory J.; Zheng, Jinzi; Brock, Kristy; Allen, Christine; Jaffray, David A.

    2005-04-01

    Multimodality imaging has gained momentum in radiation therapy planning and image-guided treatment delivery. Specifically, computed tomography (CT) and magnetic resonance (MR) imaging are two complementary imaging modalities often utilized in radiation therapy for visualization of anatomical structures for tumour delineation and accurate registration of image data sets for volumetric dose calculation. The development of a multimodal contrast agent for CT and MR with prolonged in vivo residence time would provide long-lasting spatial and temporal correspondence of the anatomical features of interest, and therefore facilitate multimodal image registration, treatment planning and delivery. The multimodal contrast agent investigated consists of nano-sized stealth liposomes encapsulating conventional iodine and gadolinium-based contrast agents. The average loading achieved was 33.5 +/- 7.1 mg/mL of iodine for iohexol and 9.8 +/- 2.0 mg/mL of gadolinium for gadoteridol. The average liposome diameter was 46.2 +/- 13.5 nm. The system was found to be stable in physiological buffer over a 15-day period, releasing 11.9 +/- 1.1% and 11.2 +/- 0.9% of the total amounts of iohexol and gadoteridol loaded, respectively. 200 minutes following in vivo administration, the contrast agent maintained a relative contrast enhancement of 81.4 +/- 13.05 differential Hounsfield units (ΔHU) in CT (40% decrease from the peak signal value achieved 3 minutes post-injection) and 731.9 +/- 144.2 differential signal intensity (ΔSI) in MR (46% decrease from the peak signal value achieved 3 minutes post-injection) in the blood (aorta), a relative contrast enhancement of 38.0 +/- 5.1 ΔHU (42% decrease from the peak signal value achieved 3 minutes post-injection) and 178.6 +/- 41.4 ΔSI (62% decrease from the peak signal value achieved 3 minutes post-injection) in the liver (parenchyma), a relative contrast enhancement of 9.1 +/- 1.7 ΔHU (94% decrease from the peak signal value achieved 3 minutes

  18. Cellular image segmentation using n-agent cooperative game theory

    NASA Astrophysics Data System (ADS)

    Dimock, Ian B.; Wan, Justin W. L.

    2016-03-01

    Image segmentation is an important problem in computer vision and has significant applications in the segmentation of cellular images. Many different imaging techniques exist and produce a variety of image properties which pose difficulties to image segmentation routines. Bright-field images are particularly challenging because of the non-uniform shape of the cells, the low contrast between cells and background, and imaging artifacts such as halos and broken edges. Classical segmentation techniques often produce poor results on these challenging images. Previous attempts at bright-field imaging are often limited in scope to the images that they segment. In this paper, we introduce a new algorithm for automatically segmenting cellular images. The algorithm incorporates two game theoretic models which allow each pixel to act as an independent agent with the goal of selecting their best labelling strategy. In the non-cooperative model, the pixels choose strategies greedily based only on local information. In the cooperative model, the pixels can form coalitions, which select labelling strategies that benefit the entire group. Combining these two models produces a method which allows the pixels to balance both local and global information when selecting their label. With the addition of k-means and active contour techniques for initialization and post-processing purposes, we achieve a robust segmentation routine. The algorithm is applied to several cell image datasets including bright-field images, fluorescent images and simulated images. Experiments show that the algorithm produces good segmentation results across the variety of datasets which differ in cell density, cell shape, contrast, and noise levels.

  19. Functional Imaging of the Lungs with Gas Agents

    PubMed Central

    Kruger, Stanley J.; Nagle, Scott K.; Couch, Marcus J.; Ohno, Yoshiharu; Albert, Mitchell; Fain, Sean B.

    2015-01-01

    This review focuses on the state-of-the-art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI) – hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas – and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multi-detector computed tomography (CT). However, MRI also offers capabilities for fast multi-spectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultra-short echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. Relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis (CF) in both adults and children. PMID:26218920

  20. Functional imaging of the lungs with gas agents.

    PubMed

    Kruger, Stanley J; Nagle, Scott K; Couch, Marcus J; Ohno, Yoshiharu; Albert, Mitchell; Fain, Sean B

    2016-02-01

    This review focuses on the state-of-the-art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI)-hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas--and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multidetector computed tomography (CT). However, MRI also offers capabilities for fast multispectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultrashort echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. The relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis in both adults and children.

  1. WE-E-17A-01: Characterization of An Imaging-Based Model of Tumor Angiogenesis

    SciTech Connect

    Adhikarla, V; Jeraj, R

    2014-06-15

    Purpose: Understanding the transient dynamics of tumor oxygenation is important when evaluating tumor-vasculature response to anti-angiogenic therapies. An imaging-based tumor-vasculature model was used to elucidate factors that affect these dynamics. Methods: Tumor growth depends on its doubling time (Td). Hypoxia increases pro-angiogenic factor (VEGF) concentration which is modeled to reduce vessel perfusion, attributing to its effect of increasing vascular permeability. Perfused vessel recruitment depends on the existing perfused vasculature, VEGF concentration and maximum VEGF concentration (VEGFmax) for vessel dysfunction. A convolution-based algorithm couples the tumor to the normal tissue vessel density (VD-nt). The parameters are benchmarked to published pre-clinical data and a sensitivity study evaluating the changes in the peak and time to peak tumor oxygenation characterizes them. The model is used to simulate changes in hypoxia and proliferation PET imaging data obtained using [Cu- 61]Cu-ATSM and [F-18]FLT respectively. Results: Td and VD-nt were found to be the most influential on peak tumor pO2 while VEGFmax was marginally influential. A +20 % change in Td, VD-nt and VEGFmax resulted in +50%, +25% and +5% increase in peak pO2. In contrast, Td was the most influential on the time to peak oxygenation with VD-nt and VEGFmax playing marginal roles. A +20% change in Td, VD-nt and VEGFmax increased the time to peak pO2 by +50%, +5% and +0%. A −20% change in the above parameters resulted in comparable decreases in the peak and time to peak pO2. Model application to the PET data was able to demonstrate the voxel-specific changes in hypoxia of the imaged tumor. Conclusion: Tumor-specific doubling time and vessel density are important parameters to be considered when evaluating hypoxia transients. While the current model simulates the oxygen dynamics of an untreated tumor, incorporation of therapeutic effects can make the model a potent tool for analyzing

  2. Screening CEST contrast agents using ultrafast CEST imaging

    NASA Astrophysics Data System (ADS)

    Xu, Xiang; Yadav, Nirbhay N.; Song, Xiaolei; McMahon, Michael T.; Jerschow, Alexej; van Zijl, Peter C. M.; Xu, Jiadi

    2016-04-01

    A chemical exchange saturation transfer (CEST) experiment can be performed in an ultrafast fashion if a gradient field is applied simultaneously with the saturation pulse. This approach has been demonstrated for studying dia- and para-magnetic CEST agents, hyperpolarized Xe gas and in vivo spectroscopy. In this study we present a simple method for the simultaneous screening of multiple samples. Furthermore, by interleaving a number of saturation and readout periods within the TR, a series of images with different saturation times can be acquired, allowing for the quantification of exchange rates using the variable saturation time (QUEST) approach in a much accelerated fashion, thus enabling high throughput screening of CEST contrast agents.

  3. Investigating in vitro angiogenesis by computer-assisted image analysis and computational simulation.

    PubMed

    Guidolin, Diego; Fede, Caterina; Albertin, Giovanna; De Caro, Raffaele

    2015-01-01

    In vitro assays that stimulate the formation of capillary-like structures by EC have become increasingly popular, because they allow the study of the EC's intrinsic ability to self-organize to form vascular-like patterns. Here we describe a widely applied protocol involving the use of basement membrane matrix (Matrigel) as a suitable environment to induce an angiogenic phenotype in cultured EC. EC differentiation on basement membrane matrix is a highly specific process, which recapitulates many steps in blood vessel formation and for this reason it is presently considered as a reliable in vitro tool to identify factors with potential antiangiogenic or pro-angiogenic properties. The morphological features of the obtained cell patterns can also be accurately quantified by computer-assisted image analysis and the main steps of such a procedure will be here outlined and discussed. The dynamics of in vitro EC self-organization is a complex biological process, involving a network of interactions between a high number of cells. For this reason, the combined use of in vitro experiments and computational modeling can represent a key approach to unravel how mechanical and chemical signaling by EC coordinates their organization into capillary-like tubes. Thus, a particularly helpful approach to modeling is also briefly described together with examples of its application.

  4. Role of angiogenesis in chronic lymphocytic leukemia.

    PubMed

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  5. Development of [F-18]-Labeled Amyloid Imaging Agents for PET

    SciTech Connect

    Mathis, CA

    2007-05-09

    The applicant proposes to design and synthesize a series of fluorine-18-labeled radiopharmaceuticals to be used as amyloid imaging agents for positron emission tomography (PET). The investigators will conduct comprehensive iterative in vitro and in vivo studies based upon well defined acceptance criteria in order to identify lead agents suitable for human studies. The long term goals are to apply the selected radiotracers as potential diagnostic agents of Alzheimer's disease (AD), as surrogate markers of amyloid in the brain to determine the efficacy of anti-amyloid therapeutic drugs, and as tools to help address basic scientific questions regarding the progression of the neuropathology of AD, such as testing the "amyloid cascade hypothesis" which holds that amyloid accumulation is the primary cause of AD.

  6. Tumor resistance to vascular disrupting agents: mechanisms, imaging, and solutions

    PubMed Central

    Liang, Wenjie; Ni, Yicheng; Chen, Feng

    2016-01-01

    The emergence of vascular disrupting agents (VDAs) is a significant advance in the treatment of solid tumors. VDAs induce rapid and selective shutdown of tumor blood flow resulting in massive necrosis. However, a viable marginal tumor rim always remains after VDA treatment and is a major cause of recurrence. In this review, we discuss the mechanisms involved in the resistance of solid tumors to VDAs. Hypoxia, tumor-associated macrophages, and bone marrow-derived circulating endothelial progenitor cells all may contribute to resistance. Resistance can be monitored using magnetic resonance imaging markers. The various solutions proposed to manage tumor resistance to VDAs emphasize combining these agents with other approaches including antiangiogenic agents, chemotherapy, radiotherapy, radioimmunotherapy, and sequential dual-targeting internal radiotherapy. PMID:26812886

  7. Platelets actively sequester angiogenesis regulators

    PubMed Central

    Yip, Tai-Tung; Cassiola, Flavia; Kikuchi, Lena; Cervi, David; Podust, Vladimir; Italiano, Joseph E.; Wheatley, Erin; Abou-Slaybi, Abdo; Bender, Elise; Almog, Nava; Kieran, Mark W.; Folkman, Judah

    2009-01-01

    Clinical trials with antiangiogenic agents have not been able to validate plasma or serum levels of angiogenesis regulators as reliable markers of cancer presence or therapeutic response. We recently reported that platelets contain numerous proteins that regulate angiogenesis. We now show that accumulation of angiogenesis regulators in platelets of animals bearing malignant tumors exceeds significantly their concentration in plasma or serum, as well as their levels in platelets from non–tumor-bearing animals. This process is selective, as platelets do not take up a proportional amount of other plasma proteins (eg, albumin), even though these may be present at higher concentrations. We also find that VEGF-enriched Matrigel pellets implanted subcutaneously into mice or the minute quantities of VEGF secreted by microscopic subcutaneous tumors (0.5-1 mm3) result in an elevation of VEGF levels in platelets, without any changes in its plasma levels. The profile of other angiogenesis regulatory proteins (eg, platelet-derived growth factor, basic fibroblast growth factor) sequestered by platelets also reflects the presence of tumors in vivo before they can be macroscopically evident. The ability of platelets to selectively take up angiogenesis regulators in cancer-bearing hosts may have implications for the diagnosis and management of many angiogenesis-related diseases and provide a guide for antiangiogenic therapies. PMID:19036702

  8. Contrast agents for preclinical targeted X-ray imaging.

    PubMed

    Li, Xiang; Anton, Nicolas; Zuber, Guy; Vandamme, Thierry

    2014-09-30

    Micro-computed tomography (micro-CT) is an X-ray based instrument that it is specifically designed for biomedical research at a preclinical stage for live imaging of small animals. This imaging modality is cost-effective, fast, and produces remarkable high-resolution images of X-ray opaque skeleton. Administration of biocompatible X-ray opaque contrast agent allows delineation of the blood vessels, and internal organs and even detection of tumor metastases as small as 300 μm. However, the main limitation of micro-CT lies in the poor efficacy or toxicity of the contrast agents. Moreover, contrast agents for micro-CT have to be stealth nanoparticulate systems, i.e. preventing their rapid renal clearance. The chemical composition and physicochemical properties will condition their uptake and elimination pathways, and therefore all the biological fluids, organs, and tissues trough this elimination route of the nanoparticles will be contrasted. Furthermore, several technologies playing on the nanoparticle properties, aim to influence these biological pathways in order to induce their accumulation onto given targeted sites, organs of tumors. In function of the methodologies carried out, taking benefit or not of the action of immune system, of the natural response of the organism like hepatocyte uptake or enhanced permeation and retention effect, or even accumulation due to ligand/receptor interactions, the technologies are called passive or active targeted imaging. The present review presents the most recent advances in the development of specific contrast agents for targeted X-ray imaging micro-CT, discussing the recent advance of in vivo targeting of nanoparticulate contrast agents, and the influence of the formulations, nature of the nanocarrier, nature and concentration of the X-ray contrasting materials, effect of the surface properties, functionalization and bioconjugation. The pharmacokinetic and versatility of nanometric systems appear particularly advantageous

  9. Silver Nanoplate Contrast Agents for In Vivo Molecular Photoacoustic Imaging

    PubMed Central

    Homan, Kimberly A.; Souza, Michael; Truby, Ryan; Luke, Geoffrey P.; Green, Christopher; Vreeland, Erika; Emelianov, Stanislav

    2012-01-01

    Silver nanoplates are introduced as a new photoacoustic contrast agent that can be easily functionalized for molecular photoacoustic imaging in vivo. Methods are described for synthesis, functionalization, and stabilization of silver nanoplates using biocompatible (“green”) reagents. Directional antibody conjugation to the nanoplate surface is presented along with proof of molecular sensitivity in vitro with pancreatic cancer cells. Cell viability tests show the antibody-conjugated silver nanoplates to be nontoxic at concentrations up to 1 mg/ml. Furthermore, the silver nanoplates' potential for in vivo application as a molecularly sensitive photoacoustic contrast agent is demonstrated using an orthotopic mouse model of pancreatic cancer. Results of these studies suggest that the synthesized silver nanoplates are well suited for a host of biomedical imaging and sensing applications. PMID:22188516

  10. Proflavine derivatives as fluorescent imaging agents of amyloid deposits.

    PubMed

    Garin, Dominique; Oukhatar, Fatima; Mahon, Andrew B; Try, Andrew C; Dubois-Dauphin, Michel; Laferla, Frank M; Demeunynck, Martine; Sallanon, Marcelle Moulin; Chierici, Sabine

    2011-04-15

    A series of proflavine derivatives for use to further image Aβ amyloid deposits were synthesized and characterized. Aged 3xTg-AD (23 months old) mice hippocampus sections incubated with these derivatives revealed preferential labeling of amyloid plaques. Furthermore an in vitro binding study showed an inhibitory effect, although moderate, of these compounds on Aβ(40) fibril formation. This study highlights the potential of proflavine as a molecular scaffold for designing new Aβ imaging agents, its native fluorescence allowing in vitro neuropathological staining in AD damaged brain sections.

  11. Perfluorocarbon Nanoparticles: Evolution of a Multimodality and Multifunctional Imaging Agent

    PubMed Central

    Winter, Patrick M.

    2014-01-01

    Perfluorocarbon nanoparticles offer a biologically inert, highly stable, and nontoxic platform that can be specifically designed to accomplish a range of molecular imaging and drug delivery functions in vivo. The particle surface can be decorated with targeting ligands to direct the agent to a variety of biomarkers that are associated with diseases such as cancer, cardiovascular disease, obesity, and thrombosis. The surface can also carry a high payload of imaging agents, ranging from paramagnetic metals for MRI, radionuclides for nuclear imaging, iodine for CT, and florescent tags for histology, allowing high sensitivity mapping of cellular receptors that may be expressed at very low levels in the body. In addition to these diagnostic imaging applications, the particles can be engineered to carry highly potent drugs and specifically deposit them into cell populations that display biosignatures of a variety of diseases. The highly flexible and robust nature of this combined molecular imaging and drug delivery vehicle has been exploited in a variety of animal models to demonstrate its potential impact on the care and treatment of patients suffering from some of the most debilitating diseases. PMID:25024867

  12. Perfluorocarbon nanoparticles: evolution of a multimodality and multifunctional imaging agent.

    PubMed

    Winter, Patrick M

    2014-01-01

    Perfluorocarbon nanoparticles offer a biologically inert, highly stable, and nontoxic platform that can be specifically designed to accomplish a range of molecular imaging and drug delivery functions in vivo. The particle surface can be decorated with targeting ligands to direct the agent to a variety of biomarkers that are associated with diseases such as cancer, cardiovascular disease, obesity, and thrombosis. The surface can also carry a high payload of imaging agents, ranging from paramagnetic metals for MRI, radionuclides for nuclear imaging, iodine for CT, and florescent tags for histology, allowing high sensitivity mapping of cellular receptors that may be expressed at very low levels in the body. In addition to these diagnostic imaging applications, the particles can be engineered to carry highly potent drugs and specifically deposit them into cell populations that display biosignatures of a variety of diseases. The highly flexible and robust nature of this combined molecular imaging and drug delivery vehicle has been exploited in a variety of animal models to demonstrate its potential impact on the care and treatment of patients suffering from some of the most debilitating diseases.

  13. Development of a Multifaceted Ovarian Cancer Imaging Agent

    DTIC Science & Technology

    2010-04-01

    method for a recombinant disintegrin vicrostatin (VN), whose structure is based on the snake venom disintegrin contortrostatin (CN), and the use of the...an innovative imaging and diagnostic agent for ovarian cancer (OC). Vicrostatin (VN) is a recombinant protein based on the venom disintegrin...form of the venom derived disintegrin contortrostatin, was compared to a cyclic peptide, cyclo(-RGDfV-), similar to Cilengitide, which is currently in

  14. Radiolabelled D2 agonists as prolactinoma imaging agents

    SciTech Connect

    Otto, C.A.

    1991-12-31

    Research conducted in this terminal year of support centered on three distinct areas: mAChR ligand localization in pancreas and the effect of Ca{sup +2} on localization, continuation of assessment of quaternized and neutral mAChR ligands for possible use as PET myocardial imaging agents, and initiation of a study to determine the relationship of the nAChR receptor to the cellular receptor for measles virus. Several tables and figures illustrating the results are included.

  15. Phosphoramidate-based Peptidomimetic Prostate Cancer PET Imaging Agents

    DTIC Science & Technology

    2013-07-01

    develop a PET imaging agent based on modifying the peptidomimetic PSMA inhibitor which will result in improved tumor uptake and clearance mechanism...Different fluorination approaches were attempted with PSMA module compounds such as direct labeling, cupper free chemistry and the use of...labeling approaches are established, and then the labeling of the modified PSMA inhibitor analogues will be investigated in vitro as well as in vivo. 15

  16. Phosphoramidate-based Peptidomimetic Prostate Cancer PET Imaging Agents

    DTIC Science & Technology

    2013-11-01

    goal is to develop a PET imaging agent based on modifying the peptidomimetic PSMA inhibitor which will result in improved tumor uptake and clearance...mechanism. Different fluorination approaches were attempted with PSMA module compounds such as direct labeling, cupper free chemistry and the use of...the labeling approaches are established, and then the labeling of the modified PSMA inhibitor analogues will be investigated in vitro as well as in

  17. Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging.

    PubMed

    Yano, Shuya; Takehara, Kiyoto; Tazawa, Hiroshi; Kishimoto, Hiroyuki; Urata, Yasuo; Kagawa, Shunsuke; Fujiwara, Toshiyoshi; Hoffman, Robert M

    2017-03-04

    We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G2 phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

  18. Contrast agent stability: a continuous B-mode imaging approach.

    PubMed

    Sboros, V; Moran, C M; Pye, S D; McDicken, W N

    2001-10-01

    The stability of contrast agents in suspensions with various dissolved gas levels has not been reported in the literature. An in vitro investigation has been carried out that studied the combined effect of varying the acoustic pressure along with degassing the suspension environment. In this study, the contrast agents were introduced into suspensions with different oxygen concentration levels, and their relative performance was assessed in terms of decay rate of their backscatter echoes. The partial pressures of oxygen in those solutions ranged between 1.5 and 26 kPa. Two IV and one arterial contrast agents were used: Definity, Quantison, and Myomap. It was found that Quantison and Myomap released free bubbles at high acoustic pressure that also dissolved faster in degassed suspensions. The backscatter decay for Definity did not depend on the air content of the suspensions. The destruction of bubbles was dependent on acoustic pressure. Different backscatter performance was observed by different populations of bubbles of the last two agents. The physical quantity of "overall backscatter" (OB) was defined as the integral of the decay rate over time of the backscatter of the contrast suspensions, and improved significantly the understanding of the behaviour of the agents. A quantitative analysis of the backscatter properties of contrast agents using a continuous imaging approach was difficult to achieve. This is due to the fact that the backscatter in the field of view is representative of a bubble population affected by the ultrasound (US) field, but this bubble population is not representative of the contrast suspension in the whole tank. Single frame insonation is suggested to avoid the effects of decay due to the ultrasonic field, and to measure a tank-representative backscatter. The definition of OB was useful, however, in understanding the behaviour of the agents.

  19. Magnetic resonance imaging with hyperpolarized agents: methods and applications

    NASA Astrophysics Data System (ADS)

    Adamson, Erin B.; Ludwig, Kai D.; Mummy, David G.; Fain, Sean B.

    2017-07-01

    In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium (3He) and xenon (129Xe) gases have reached the stage where they are under study in clinical research. HP 129Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of 129Xe gas exchange into lung tissue and blood, HP 129Xe MRI is attracting new attention. In parallel, HP 13C and 15N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-13C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP 13C and 15N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways in cancer and cardiac

  20. Magnetic resonance imaging with hyperpolarized agents: methods and applications.

    PubMed

    Adamson, Erin B; Ludwig, Kai D; Mummy, David G; Fain, Sean B

    2017-07-07

    In the past decade, hyperpolarized (HP) contrast agents have been under active development for MRI applications to address the twin challenges of functional and quantitative imaging. Both HP helium ((3)He) and xenon ((129)Xe) gases have reached the stage where they are under study in clinical research. HP (129)Xe, in particular, is poised for larger scale clinical research to investigate asthma, chronic obstructive pulmonary disease, and fibrotic lung diseases. With advances in polarizer technology and unique capabilities for imaging of (129)Xe gas exchange into lung tissue and blood, HP (129)Xe MRI is attracting new attention. In parallel, HP (13)C and (15)N MRI methods have steadily advanced in a wide range of pre-clinical research applications for imaging metabolism in various cancers and cardiac disease. The HP [1-(13)C] pyruvate MRI technique, in particular, has undergone phase I trials in prostate cancer and is poised for investigational new drug trials at multiple institutions in cancer and cardiac applications. This review treats the methodology behind both HP gases and HP (13)C and (15)N liquid state agents. Gas and liquid phase HP agents share similar technologies for achieving non-equilibrium polarization outside the field of the MRI scanner, strategies for image data acquisition, and translational challenges in moving from pre-clinical to clinical research. To cover the wide array of methods and applications, this review is organized by numerical section into (1) a brief introduction, (2) the physical and biological properties of the most common polarized agents with a brief summary of applications and methods of polarization, (3) methods for image acquisition and reconstruction specific to improving data acquisition efficiency for HP MRI, (4) the main physical properties that enable unique measures of physiology or metabolic pathways, followed by a more detailed review of the literature describing the use of HP agents to study: (5) metabolic pathways

  1. Construction of specific magnetic resonance imaging/optical dual-modality molecular probe used for imaging angiogenesis of gastric cancer.

    PubMed

    Yan, Xuejie; Song, Xiaoyan; Wang, Zhenbo

    2017-05-01

    The purpose of the study was to construct specific magnetic resonance imaging (MRI)/optical dual-modality molecular probe. Tumor-bearing animal models were established. MRI/optical dual-modality molecular probe was construed by coupling polyethylene glycol (PEG)-modified nano-Fe3O4 with specific targeted cyclopeptide GX1 and near-infrared fluorescent dyes Cy5.5. MRI/optical imaging effects of the probe were observed and the feasibility of in vivo double-modality imaging was discussed. It was found that, the double-modality probe was of high stability; tumor signal of the experimental group tended to be weak after injection of the probe, but rose to a level which was close to the previous level after 18 h (p > 0.05). We successively completed the construction of an ideal MRI/optical dual-modality molecular probe. MRI/optical dual-modality molecular probe which can selectively gather in gastric cancer is expected to be a novel probe used for diagnosing gastric cancer in the early stage.

  2. [Anti-angiogenesis and molecular targeted therapies].

    PubMed

    Miyanaga, Akihiko; Gemma, Akihiko

    2015-08-01

    Tumor angiogenesis contributes to the development of tumor progression. Several vascular endothelial growth factor(VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. In particular, bevacizumab is a humanized monoclonal antibody that specifically targets VEGF, inhibiting angiogenesis, thereby impeding tumor growth and survival. It is also possible that combined VEGF and the epidermal growth factor (EGFR) pathway blockade could further enhance antitumor efficacy and help prevent resistance to therapy. Preclinical and clinical studies have shown new various molecular targets and the functional characteristics of tumor angiogenesis, which may provide strategies for improving the therapeutic benefit.

  3. Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging

    NASA Astrophysics Data System (ADS)

    Wang, Taejun; Jang, Won Hyuk; Lee, Seunghun; Yoon, Calvin J.; Lee, Jun Ho; Kim, Bumju; Hwang, Sekyu; Hong, Chun-Pyo; Yoon, Yeoreum; Lee, Gilgu; Le, Viet-Hoan; Bok, Seoyeon; Ahn, G.-One; Lee, Jaewook; Gho, Yong Song; Chung, Euiheon; Kim, Sungjee; Jang, Myoung Ho; Myung, Seung-Jae; Kim, Myoung Joon; So, Peter T. C.; Kim, Ki Hean

    2016-06-01

    Multiphoton microscopy (MPM) is a nonlinear fluorescence microscopic technique widely used for cellular imaging of thick tissues and live animals in biological studies. However, MPM application to human tissues is limited by weak endogenous fluorescence in tissue and cytotoxicity of exogenous probes. Herein, we describe the applications of moxifloxacin, an FDA-approved antibiotic, as a cell-labeling agent for MPM. Moxifloxacin has bright intrinsic multiphoton fluorescence, good tissue penetration and high intracellular concentration. MPM with moxifloxacin was demonstrated in various cell lines, and animal tissues of cornea, skin, small intestine and bladder. Clinical application is promising since imaging based on moxifloxacin labeling could be 10 times faster than imaging based on endogenous fluorescence.

  4. Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging

    PubMed Central

    Wang, Taejun; Jang, Won Hyuk; Lee, Seunghun; Yoon, Calvin J.; Lee, Jun Ho; Kim, Bumju; Hwang, Sekyu; Hong, Chun-Pyo; Yoon, Yeoreum; Lee, Gilgu; Le, Viet-Hoan; Bok, Seoyeon; Ahn, G-One; Lee, Jaewook; Gho, Yong Song; Chung, Euiheon; Kim, Sungjee; Jang, Myoung Ho; Myung, Seung-Jae; Kim, Myoung Joon; So, Peter T. C.; Kim, Ki Hean

    2016-01-01

    Multiphoton microscopy (MPM) is a nonlinear fluorescence microscopic technique widely used for cellular imaging of thick tissues and live animals in biological studies. However, MPM application to human tissues is limited by weak endogenous fluorescence in tissue and cytotoxicity of exogenous probes. Herein, we describe the applications of moxifloxacin, an FDA-approved antibiotic, as a cell-labeling agent for MPM. Moxifloxacin has bright intrinsic multiphoton fluorescence, good tissue penetration and high intracellular concentration. MPM with moxifloxacin was demonstrated in various cell lines, and animal tissues of cornea, skin, small intestine and bladder. Clinical application is promising since imaging based on moxifloxacin labeling could be 10 times faster than imaging based on endogenous fluorescence. PMID:27283889

  5. A paramagnetic CEST agent for imaging glucose by MRI.

    PubMed

    Zhang, Shanrong; Trokowski, Robert; Sherry, A Dean

    2003-12-17

    The europium(III) complex of a DOTA-tetraamide ligand (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' ''-tetraacetic acids) containing two phenyl boronate pendent arms binds glucose reversibly with an association constant of 383 M-1 at pH 7. Glucose binding results in slowing of water exchange between a single Eu(III)-bound water molecule and bulk water, and this can be imaged by MRI using chemical exchange saturation transfer (CEST) imaging sequence. This metabolite-responsive paramagnetic CEST agent responds to changes in glucose over the physiologically important range (0-20 mM), and thus it offers the possibility of high-sensitivity MR imaging glucose in tissues using bulk water protons as antenna.

  6. The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis.

    PubMed

    Kenny, Laura

    2016-02-01

    The balance between proliferation and cell death is pivotal to breast tumor growth. Because of a combination of environmental and genetic factors leading to activation of oncogenes or inactivation of tumor suppressor genes, these processes become deregulated in cancer. PET imaging of proliferation, angiogenesis, and DNA damage and repair offers the opportunity to monitor therapeutic efficacy to detect changes in tumor biology that may precede physical size reduction and simultaneously allows the study of intratumoral and intertumoral heterogeneity.This review examines recent developments in breast cancer imaging using novel probes. The probes discussed here are not licensed for routine use and are at various stages of development ranging from preclinical development (e.g., the DNA repair marker γH2AX) to clinical validation in larger studies (such as the proliferation probe 3'-deoxy-3'-(18)F-fluorothymidine [(18)F-FLT]). In breast cancer, most studies have focused on proliferation imaging mainly based on (18)F-labeled thymidine analogs. Initial studies have been promising; however, the results of larger validation studies are necessary before being incorporated into routine clinical use. Although there are distinct advantages in using process-specific probes, properties such as metabolism need careful consideration, because high background uptake in the liver due to glucuronidation in the case of (18)F-FLT may limit utility for imaging of liver metastases.Targeting angiogenesis has had some success in tumors such as renal cell carcinoma; however, angiogenesis inhibitors have not been particularly successful in the clinical treatment of breast cancer. This could be potentially attributed to patient selection due to the lack of validated predictive and responsive biomarkers; the quest for a successful noninvasive biomarker for angiogenesis could solve this challenge. Finally, we look at cell death including apoptosis and DNA damage and repair probes, the most well

  7. One-step radiosynthesis of ¹⁸F-AlF-NOTA-RGD₂ for tumor angiogenesis PET imaging.

    PubMed

    Liu, Shuanglong; Liu, Hongguang; Jiang, Han; Xu, Yingding; Zhang, Hong; Cheng, Zhen

    2011-09-01

    One of the major obstacles of the clinical translation of (18)F-labeled arginine-glycine-aspartic acid (RGD) peptides has been the laborious multistep radiosynthesis. In order to facilitate the application of RGD-based positron emission tomography (PET) probes in the clinical setting we investigated in this study the feasibility of using the chelation reaction between Al(18)F and a macrocyclic chelator-conjugated dimeric RGD peptide as a simple one-step (18)F labeling strategy for development of a PET probe for tumor angiogenesis imaging. Dimeric cyclic peptide E[c(RGDyK)](2) (RGD(2)) was first conjugated with a macrocyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the resulting bioconjugate NOTA-RGD(2) was then radiofluorinated via Al(18)F intermediate to synthesize (18)F-AlF-NOTA-RGD(2). Integrin binding affinities of the peptides were assessed by a U87MG cell-based receptor binding assay using (125)I-echistatin as the radioligand. The tumor targeting efficacy and in vivo profile of (18)F-AlF-NOTA-RGD(2) were further evaluated in a subcutaneous U87MG glioblastoma xenograft model by microPET and biodistribution. NOTA-RGD(2) was successfully (18)F-fluorinated with good yield within 40 min using the Al(18)F intermediate. The IC(50) of (19)F-AlF-NOTA-RGD(2) was determined to be 46 ± 4.4 nM. Quantitative microPET studies demonstrated that (18)F-AlF-NOTA-RGD(2) showed high tumor uptake, fast clearance from the body, and good tumor to normal organ ratios. NOTA-RGD(2) bioconjugate has been successfully prepared and labeled with Al(18)F in one single step of radiosynthesis. The favorable in vivo performance and the short radiosynthetic route of (18)F-AlF-NOTA-RGD(2) warrant further optimization of the probe and the radiofluorination strategy to accelerate the clinical translation of (18)F-labeled RGD peptides.

  8. One-step radiosynthesis of 18F-AlF-NOTA-RGD2 for tumor angiogenesis PET imaging

    PubMed Central

    Liu, Shuanglong; Liu, Hongguang; Jiang, Han; Xu, Yingding; Zhang, Hong

    2014-01-01

    Purpose One of the major obstacles of the clinical translation of 18F-labeled arginine-glycine-aspartic acid (RGD) peptides has been the laborious multistep radiosynthesis. In order to facilitate the application of RGD-based positron emission tomography (PET) probes in the clinical setting we investigated in this study the feasibility of using the chelation reaction between Al18F and a macrocyclic chelator-conjugated dimeric RGD peptide as a simple one-step 18F labeling strategy for development of a PET probe for tumor angiogenesis imaging. Methods Dimeric cyclic peptide E[c(RGDyK)]2 (RGD2) was first conjugated with a macrocyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the resulting bioconjugate NOTA-RGD2 was then radiofluorinated via Al18F intermediate to synthesize 18F-AlF-NOTA-RGD2. Integrin binding affinities of the peptides were assessed by a U87MG cell-based receptor binding assay using 125I-echistatin as the radioligand. The tumor targeting efficacy and in vivo profile of 18F-AlF-NOTA-RGD2 were further evaluated in a subcutaneous U87MG glioblastoma xenograft model by microPET and biodistribution. Results NOTA-RGD2 was successfully 18F-fluorinated with good yield within 40 min using the Al18F intermediate. The IC50 of 19F-AlF-NOTA-RGD2 was determined to be 46±4.4 nM. Quantitative microPET studies demonstrated that 18F-AlF-NOTA-RGD2 showed high tumor uptake, fast clearance from the body, and good tumor to normal organ ratios. Conclusion NOTA-RGD2 bioconjugate has been successfully prepared and labeled with Al18F in one single step of radiosynthesis. The favorable in vivo performance and the short radiosynthetic route of 18F-AlF-NOTA-RGD2 warrant further optimization of the probe and the radiofluorination strategy to accelerate the clinical translation of 18F-labeled RGD peptides. PMID:21617974

  9. PET imaging of angiogenesis after myocardial infarction/reperfusion using a one-step labeled integrin-targeted tracer 18F-AlF-NOTA-PRGD2.

    PubMed

    Gao, Haokao; Lang, Lixin; Guo, Ning; Cao, Feng; Quan, Qimeng; Hu, Shuo; Kiesewetter, Dale O; Niu, Gang; Chen, Xiaoyuan

    2012-04-01

    The α(v)β(3) integrin represents a potential target for noninvasive imaging of angiogenesis. The purpose of this study was to evaluate a novel one-step labeled integrin α(v)β(3)-targeting positron emission tomography (PET) probe, (18)F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infarction/reperfusion (MI/R) animal model. Male Sprague-Dawley rats underwent 45-min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, (18)F-fluorodeoxyglucose (FDG) imaging, and cardiac ultrasound. In vivo PET imaging was used to determine myocardial uptake of (18)F-AlF-NOTA-PRGD2 at different time points following reperfusion. The control peptide RAD was labeled with a similar procedure and used to confirm the specificity. Ex vivo autoradiographic analysis and CD31/CD61 double immunofluorescence staining were performed to validate the PET results. Myocardial origin of the (18)F-AlF-NOTA-PRGD2 accumulation was confirmed by (18)F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of (18)F-AlF-NOTA-PRGD2 in the infarcted area which started at day 3 (0.28 ± 0.03%ID/g, p < 0.05) and peaked between 1 and 3 weeks (0.59 ± 0.16 and 0.55 ± 0.13%ID/g, respectively). The focal accumulation decreased but still kept at a higher level than the sham group after 4 months of reperfusion (0.31 ± 0.01%ID/g, p < 0.05). Pretreatment with unlabeled arginine-glycine-aspartic acid (RGD) peptide significantly decreased tracer uptake, indicating integrin specificity of this tracer. At 1 week after MI/R, uptake of the control tracer (18)F-AlF-NOTA-RAD that does not bind to integrin, in the infarcted area, was only 0.21 ± 0.01%ID/g. Autoradiographic imaging showed the same trend of uptake in the myocardial infarction area. The time course of focal tracer uptake was consistent with the pattern of vascular density and integrin β(3) expression as measured by CD31 and CD61 immunostaining analysis. PET

  10. PET Imaging of Angiogenesis after Myocardial Infarction/Reperfusion using a One-Step Labeled Integrin Targeted Tracer 18F-AlF-NOTA-PRGD2

    PubMed Central

    Gao, Haokao; Lang, Lixin; Guo, Ning; Cao, Feng; Quan, Qimeng; Hu, Shuo; Kiesewetter, Dale O.; Niu, Gang; Chen, Xiaoyuan

    2012-01-01

    Objective The αvβ3 integrin represents a potential target for noninvasive imaging of angiogenesis. The purpose of this study was to evaluate a novel one-step labeled integrin αvβ3 targeting PET probe, 18F-AlF-NOTA-PRGD2, for angiogenesis imaging in a myocardial infract/reperfusion (MI/R) animal model. Methods Male SD rats underwent 45 min transient left coronary artery occlusion followed by reperfusion. The myocardial infarction was confirmed by ECG, 18F-FDG imaging and cardiac ultrasound. In vivo PET imaging were used to determine myocardial uptake of 18F-AlF-NOTA-PRGD2 at different time points following reperfusion. The control peptide RAD was labeled with a similar procedure and used to confirm the specificity. Ex vivo autoradiographic analysis and CD31/CD61 double immunofluoresence staining were performed to validate the PET results. Results Myocardial origin of the 18F-AlF-NOTA-PRGD2 accumulation was confirmed by 18F-FDG and autoradiography. PET imaging demonstrated increased focal accumulation of 18F-AlF-NOTA-PRGD2 in the infarcted area started at day 3 (0.28 ± 0.03 %ID/g, p < 0.05), peaked between 1 and 3 weeks (0.59 ± 0.16 and 0.55 ± 0.13 %ID/g, respectively). The focal accumulation decreased but still kept at a higher level than the sham group after 4 months of reperfusion (0.31 ± 0.01 %ID/g, p < 0.05). Pretreatment with unlabeled RGD peptide significantly decreased tracer uptake, indicating integrin specificity of this tracer. At 1 week after MI/R, uptake of the control tracer 18F-AlF-NOTA-RAD that does not bind to integrin, in the infarcted area, was only 0.21 ± 0.01 %ID/g. Autoradiographic imaging showed the same trend of uptake in myocardial infarction area. The time course of focal tracer uptake was consistent with the pattern of vascular density and integrin β3 expression as measured by CD31 and CD61 immunostaining analysis. Conclusion PET imaging using one-step labeled 18F-AlF-NOTA-PRGD2 allows noninvasive visualization of ischemia

  11. The use of contrast agent for imaging biological samples

    NASA Astrophysics Data System (ADS)

    Dammer, J.; Weyda, F.; Sopko, V.; Jakubek, J.

    2011-01-01

    The technique of X-ray transmission imaging has been available for over a century and is still among the fastest and easiest approaches to the studies of internal structure of biological samples. Recent advances in semiconductor technology have led to the development of new types of X-ray detectors with direct conversion of interacting X-ray photon to an electric signal. Semiconductor pixel detectors seem to be specially promising; compared to the film technique, they provide single-quantum and real-time digital information about the objects being studied. We describe the recently developed radiographic apparatus, equipped with Medipix2 semiconductor pixel detector. The detector is used as an imager that counts individual photons of ionizing radiation, emitted by an X-ray tube (micro- or nano-focus FeinFocus). Thanks to the wide dynamic range of the Medipix2 detector and its high spatial resolution better than 1μm, the setup is particularly suitable for radiographic imaging of small biological samples, including in-vivo observations with contrast agent (Optiray). Along with the description of the apparatus we provide examples of the use iodine contrast agent as a tracer in various insects as model organisms. The motivation of our work is to develop our imaging techniques as non-destructive and non-invasive. Microradiographic imaging helps detect organisms living in a not visible environment, visualize the internal biological processes and also to resolve the details of their body (morphology). Tiny live insects are an ideal object for our studies.

  12. Angiogenesis and Endometriosis

    PubMed Central

    Rocha, Ana Luiza L.; Reis, Fernando M.; Taylor, Robert N.

    2013-01-01

    A comprehensive review was performed to survey the role of angiogenesis in the pathogenesis of endometriosis. This is a multifactorial disease in which the development and maintenance of endometriotic implants depend on their invasive capacity and angiogenic potential. The peritoneal fluid of patients with endometriosis is a complex suspension carrying inflammatory cytokines, growth factors, steroid hormones, proangiogenic factors, macrophages, and endometrial and red blood cells. These cells and their signaling products concur to promote the spreading of new blood vessels at the endometriotic lesions and surroundings, which contributes to the endometriotic implant survival. Experimental studies of several antiangiogenic agents demonstrated the regression of endometriotic lesions by reducing their blood supply. Further studies are necessary before these novel agents can be introduced into clinical practice, in particular the establishment of the safety of anti-angiogenic medications in women who are seeking to become pregnant. PMID:23766765

  13. 99mTc-Labeled Iron Oxide Nanoparticles for Dual-Contrast (T1/T2) Magnetic Resonance and Dual-Modality Imaging of Tumor Angiogenesis.

    PubMed

    Xue, Sihan; Zhang, Chunfu; Yang, Yi; Zhang, Lu; Cheng, Dengfeng; Zhang, Jianping; Shi, Hongcheng; Zhang, Yingjian

    2015-06-01

    Multi functional probes possessing magnetic resonance imaging and single-photon emission computed tomography properties are favorable for the molecular imaging of cancers. In this study, ultra small super paramagnetic iron oxide nanoparticles, about 3.5 nm in size, were synthesized by the polyol method. The particles were functionalized using c(RGDyC) peptides and labeled with 99mTc to prepare molecular imaging probes for detecting tumor angiogenesis. The probes demonstrated good T1 (r1 = 8.2 s(-1) mM(-1)) and reasonable T2 contrast effects (r2 = 20.1 s(-1) mM(-1)) and could specifically target avβ3-positive cells, inducing more cell ingestion, unlike that in case of the control probes [functionalized with scrambled c(RADyC) peptides]. After the probes were injected into the mice bearing H1299 lung tumors, T1/T2-weighted magnetic resonance imaging and single-photon emission computed tomography revealed that they addressed tumor angiogenic vessels, which were distributed mainly in the peripheral region of tumors. Biodistribution studies indicated that tumor accumulation of the probes was significant [13.8 ± 9.6%ID/g (p < 0.01), which is more than that of the control probes, 4.5 ± 1.9%ID/g], and could be inhibited by free RGD peptides (6.0 ± 2.8%ID/g, p < 0.01). Our study demonstrated that the dual-contrast (T1/T2) magnetic resonance and dual-modal imaging probe based on ultra small superparamagnetic iron oxide nanoparticles is very promising for the molecular imaging of tumor angiogenesis.

  14. Molecular imaging agents: impact on diagnosis and therapeutics in oncology

    PubMed Central

    Seaman, Marc E.; Contino, Gianmarco; Bardeesy, Nabeel; Kelly, Kimberly A.

    2011-01-01

    Imaging has become a crucial tool in oncology throughout the course of disease detection and management and is an integral part of clinical trials. Anatomic and functional imaging led the way, providing valuable information used in the diagnosis of disease, including data regarding the size and location of the tumor and on physiologic processes such as blood flow and perfusion. As understanding of cancer pathogenesis has advanced through the identification of genetic, biochemical, and cellular alterations in evolving tumors, emphasis has been made on developing methods to detect and serially monitor such alterations. This class of approaches is referred to as molecular imaging. Molecular imaging offers the potential for increasingly sensitive and specific visualization and quantification of biological processes at the cellular and molecular level. These approaches have become established as essential tools for cancer research, early cancer detection and staging and monitoring and predicting response to targeted therapies. Here, we will discuss recent advances in the development of molecular imaging agents and their implementation in basic cancer research as well as in more rationalized approaches to cancer care. PMID:20633310

  15. In Vivo Imaging of GLP-1R with a Targeted Bimodal PET/Fluorescence Imaging Agent

    PubMed Central

    2015-01-01

    Accurate visualization and quantification of β-cell mass is critical for the improved understanding, diagnosis, and treatment of both type 1 diabetes (T1D) and insulinoma. Here, we describe the synthesis of a bimodal imaging probe (PET/fluorescence) for imaging GLP-1R expression in the pancreas and in pancreatic islet cell tumors. The conjugation of a bimodal imaging tag containing a near-infrared fluorescent dye, and the copper chelator sarcophagine to the GLP-1R targeting peptide exendin-4 provided the basis for the bimodal imaging probe. Conjugation was performed via a novel sequential one-pot synthetic procedure including 64Cu radiolabeling and copper-catalyzed click-conjugation. The bimodal imaging agent 64Cu-E4-Fl was synthesized in good radiochemical yield and specific activity (RCY = 36%, specific activity: 141 μCi/μg, >98% radiochemical purity). The agent showed good performance in vivo and ex vivo, visualizing small xenografts (<2 mm) with PET and pancreatic β-cell mass by phosphor autoradiography. Using the fluorescent properties of the probe, we were able to detect individual pancreatic islets, confirming specific binding to GLP-1R and surpassing the sensitivity of the radioactive label. The use of bimodal PET/fluorescent imaging probes is promising for preoperative imaging and fluorescence-assisted analysis of patient tissues. We believe that our procedure could become relevant as a protocol for the development of bimodal imaging agents. PMID:24856928

  16. In Vivo Time-Course Imaging of Tumor Angiogenesis in Colorectal Liver Metastases in the Same Living Mice Using Two-Photon Laser Scanning Microscopy

    PubMed Central

    Tanaka, Koji; Morimoto, Yuhki; Toiyama, Yuji; Matsushita, Kohei; Kawamura, Mikio; Koike, Yuhki; Okugawa, Yoshinaga; Inoue, Yasuhiro; Uchida, Keiichi; Araki, Toshimitsu; Mizoguchi, Akira; Kusunoki, Masato

    2012-01-01

    In vivo real-time visualization of the process of angiogenesis in secondary tumors in the same living animals presents a major challenge in metastasis research. We developed a technique for intravital imaging of colorectal liver metastasis development in live mice using two-photon laser scanning microscopy (TPLSM). We also developed time-series TPLSM in which intravital TPLSM procedures were performed several times over periods of days to months. Red fluorescent protein-expressing colorectal cancer cells were inoculated into the spleens of green fluorescent protein-expressing mice. First- and second-round intravital TPLSM allowed visualization of viable cancer cells (red) in hepatic sinusoids or the space of Disse. Third-round intravital TPLSM demonstrated liver metastatic colonies consisting of viable cancer cells and surrounding stroma with tumor vessels (green). In vivo time-course imaging of tumor angiogenesis in the same living mice using time-series TPLSM could be an ideal tool for antiangiogenic drug evaluation, reducing the effects of interindividual variation. PMID:22131993

  17. Multi-agent system for line detection on images

    NASA Astrophysics Data System (ADS)

    Alpatov, Boris A.; Babayan, Pavel V.; Shubin, Nikita Yu.

    2016-10-01

    Lines are one of the most informative structure elements on any images. For this reason, objects detection and recognition problems are often reduced to edge detection task. One of the most popular approaches to detect lines is based on the Hough transform or Radon transform. However, using both of transforms allows estimating the infinite lines parameters only. It is necessary to use additional approaches to estimate the ends of the detected lines. Moreover, Radon transform does not allow detecting non-straight curve shapes at all. This work is oriented to solve line detection problem using Radon transform and multi-agent approach. The results of the experimental researches that confirm the effectiveness of the proposed approach are given. The real full HD image sequences are used. The direction of further improvements is proposed.

  18. DNA as sensors and imaging agents for metal ions.

    PubMed

    Xiang, Yu; Lu, Yi

    2014-02-17

    Increasing interest in detecting metal ions in many chemical and biomedical fields has created demands for developing sensors and imaging agents for metal ions with high sensitivity and selectivity. This review covers recent progress in DNA-based sensors and imaging agents for metal ions. Through both combinatorial selection and rational design, a number of metal-ion-dependent DNAzymes and metal-ion-binding DNA structures that can selectively recognize specific metal ions have been obtained. By attachment of these DNA molecules with signal reporters such as fluorophores, chromophores, electrochemical tags, and Raman tags, a number of DNA-based sensors for both diamagnetic and paramagnetic metal ions have been developed for fluorescent, colorimetric, electrochemical, and surface Raman detection. These sensors are highly sensitive (with a detection limit down to 11 ppt) and selective (with selectivity up to millions-fold) toward specific metal ions. In addition, through further development to simplify the operation, such as the use of "dipstick tests", portable fluorometers, computer-readable disks, and widely available glucose meters, these sensors have been applied for on-site and real-time environmental monitoring and point-of-care medical diagnostics. The use of these sensors for in situ cellular imaging has also been reported. The generality of the combinatorial selection to obtain DNAzymes for almost any metal ion in any oxidation state and the ease of modification of the DNA with different signal reporters make DNA an emerging and promising class of molecules for metal-ion sensing and imaging in many fields of applications.

  19. DNA as Sensors and Imaging Agents for Metal Ions

    PubMed Central

    Xiang, Yu

    2014-01-01

    Increasing interests in detecting metal ions in many chemical and biomedical fields have created demands for developing sensors and imaging agents for metal ions with high sensitivity and selectivity. This review covers recent progress in DNA-based sensors and imaging agents for metal ions. Through both combinatorial selection and rational design, a number of metal ion-dependent DNAzymes and metal ion-binding DNA structures that can selectively recognize specific metal ions have been obtained. By attaching these DNA molecules with signal reporters such as fluorophores, chromophores, electrochemical tags, and Raman tags, a number of DNA-based sensors for both diamagnetic and paramagnetic metal ions have been developed for fluorescent, colorimetric, electrochemical, and surface Raman detections. These sensors are highly sensitive (with detection limit down to 11 ppt) and selective (with selectivity up to millions-fold) toward specific metal ions. In addition, through further development to simplify the operation, such as the use of “dipstick tests”, portable fluorometers, computer-readable discs, and widely available glucose meters, these sensors have been applied for on-site and real-time environmental monitoring and point-of-care medical diagnostics. The use of these sensors for in situ cellular imaging has also been reported. The generality of the combinatorial selection to obtain DNAzymes for almost any metal ion in any oxidation state, and the ease of modification of the DNA with different signal reporters make DNA an emerging and promising class of molecules for metal ion sensing and imaging in many fields of applications. PMID:24359450

  20. Anti-αvβ3 antibody guided three-step pretargeting approach using magnetoliposomes for molecular magnetic resonance imaging of breast cancer angiogenesis.

    PubMed

    Yan, Chenggong; Wu, Yuankui; Feng, Jie; Chen, Wufan; Liu, Xiang; Hao, Peng; Yang, Ruimeng; Zhang, Juan; Lin, Bingquan; Xu, Yikai; Liu, Ruiyuan

    2013-01-01

    Pretargeting of biomarkers with nanoparticles in molecular imaging is promising to improve diagnostic specificity and realize signal amplification, but data regarding its targeting potential in magnetic resonance (MR) imaging are limited. The purpose of this study was to evaluate the tumor angiogenesis targeting efficacy of the anti-αvβ3 antibody guided three-step pretargeting approach with magnetoliposomes. Polyethylene glycol-modified and superparamagnetic iron oxide-encapsulated magnetoliposomes with and without biotin were synthesized and characterized. The cytotoxicity of both probes was evaluated using the methyl thiazdyl tetrazolium assay, and their cellular uptake by mouse macrophage was visualized using Prussian blue staining. Three-step pretargeting MR imaging was performed on MDA-MB-435S breast cancer-bearing mice by intravenous administration of biotinylated anti-αvβ3 monoclonal antibodies (first step), followed by avidin and streptavidin (second step), and by biotinylated magnetoliposomes or magnetoliposomes in the targeted or nontargeted group, respectively (third step). The specificity of αvβ3 targeting was assessed by histologic examinations. The developed magnetoliposomes were superparamagnetic and biocompatible as confirmed by cell toxicity assay. The liposomal bilayer and polyethylene glycol modification protected Fe(3)O(4) cores from uptake by macrophage cells. MR imaging by three-step pretargeting resulted in a greater signal enhancement along the tumor periphery, occupying 7.0% of the tumor area, compared with 2.0% enhancement of the nontargeted group (P < 0.05). Histologic analysis demonstrated the targeted magnetoliposomes colocalized with neovasculature, which was responsible for the MR signal decrease. These results indicate that our strategy for MR imaging of αvβ3-integrin is an effective means for sensitive detection of tumor angiogenesis, and may provide a targetable nanodelivery system for anticancer drugs.

  1. Vascular flow and perfusion imaging with ultrasound contrast agents.

    PubMed

    Bruce, Matthew; Averkiou, Mike; Tiemann, Klaus; Lohmaier, Stefan; Powers, Jeff; Beach, Kirk

    2004-06-01

    Current techniques for imaging ultrasound (US) contrast agents (UCA) make no distinction between low-velocity microbubbles in the microcirculation and higher-velocity microbubbles in the larger vasculature. A combination of radiofrequency (RF) and Doppler filtering on a low mechanical index (MI) pulse inversion acquisition is presented that differentiates low-velocity microbubbles (on the order of mm/s) associated with perfusion, from the higher-velocity microbubbles (on the order of cm/s) in larger vessels. In vitro experiments demonstrate the ability to separate vascular flow using both harmonic and fundamental Doppler signals. Fundamental and harmonic Doppler signals from microbubbles using a low-MI pulse-inversion acquisition are compared with conventional color Doppler signals in vivo. Due to the lower transmit amplitude and enhanced backscatter from microbubbles, the in vivo signal to clutter ratios for both the fundamental (-11 dB) and harmonic (-4 dB) vascular flow signals were greater than with conventional power Doppler (-51 dB) without contrast agent. The processing investigated here, in parallel with conventional pulse-inversion processing, enables the simultaneous display of both perfusion and vascular flow. In vivo results demonstrating the feasibility and potential utility of the real-time display of both perfusion and vascular flow using US contrast agents are presented and discussed.

  2. Development of Ga-67 Maltolate Complex as an Imaging Agent

    PubMed Central

    Fazaeli, Yousef; Jalilian, Amir Reza; Mohammadpour Amini, Mostafa; Majdabadi, Abbas; Rahiminejad, Ali; Bolourinovin, Fatemeh; Pouladi, Mehraban

    2012-01-01

    Due to the antitumor activity of Gallium MAL complex, as well as recent findings on new targeted biomolecules in malignant cells through this complex, the development of radiolabeled gallium complex for future imaging studies was targeted. Ga-67 labeled 3-hydroxy-2-methyl-4H-pyran-4-onate (Ga-67 MAL) was prepared using freshly prepared Ga-67 chloride and 3-hydroxy-2-methyl-4H-pyran-4-onate in a sodium salt form in 25 min at 40° C. The stability of the complex was checked in final formulation and human serum for 24 h followed by the administration in Swiss mice for biodistribution studies. The complex was prepared in high radiochemical purity (> 97% ITLC, > 98% HPLC) and specific activity of 13-14 GBq/mmol and was stable in the presence of serum for 48 h. The partition coefficient was calculated for the compound (log p = 0.40). A detailed comparative pharmacokinetic study was performed for Ga-67 cation and Ga-67-MAL. The complex is more rapidly washed out from the circulation through kidneys and liver compared to Ga-67 cation and can be an interesting tumor imaging agent due to the fact that the cold compound is undergoing clinical trials as a safe and potential therapeutic agent for cancer. PMID:24250502

  3. Fluorescent rhenium-naphthalimide conjugates as cellular imaging agents.

    PubMed

    Langdon-Jones, Emily E; Symonds, Nadine O; Yates, Sara E; Hayes, Anthony J; Lloyd, David; Williams, Rebecca; Coles, Simon J; Horton, Peter N; Pope, Simon J A

    2014-04-07

    A range of biologically compatible, fluorescent rhenium-naphthalimide conjugates, based upon the rhenium fac-tricarbonyl core, has been synthesized. The fluorescent ligands are based upon a N-functionalized, 4-amino-derived 1,8-naphthalimide core and incorporate a dipicolyl amine binding unit to chelate Re(I); the structural variations accord to the nature of the alkylated imide with ethyl ester glycine (L(1)), 3-propanol (L(2)), diethylene glycol (L(3)), and benzyl alcohol (L(4)) variants. The species are fluorescent in the visible region between 505 and 537 nm through a naphthalimide-localized intramolecular charge transfer, with corresponding fluorescent lifetimes of up to 9.8 ns. The ligands and complexes were investigated for their potential as imaging agents for human osteoarthritic cells and protistan fish parasite Spironucleus vortens using confocal fluorescence microscopy. The results show that the specific nature of the naphthalimide structure serves to control the uptake and intracellular localization of these imaging agents. Significant differences were noted between the free ligands and complexes, with the Re(I) complex of L(2) showing hydrogenosomal localization in S. vortens.

  4. Development of Tc-99m Imaging Agents for Abeta Plaques

    SciTech Connect

    Zhi-Ping, Zhuang; Mei-Ping Kung; Catherihne Hou; Hank F. Kung

    2008-09-26

    Development of SPECT imaging agents based on Tc-99m targeting Aβ plaques is useful for diagnosis of Alzheimer’s disease (AD). A stilbene derivative, [11C]SB-13, showing promise in detecting senile plaques present in AD patients has been reported previously1,2. Based on the 4’-amino-stilbene core structure we have added substituted groups through which a chelating group, N2S2, was conjugated. We report herein a series of Tc-99m labeled stilbene derivative conjugated with a TcO[N2S2] core. The syntheses of stilbenes containing a N2S2 chelating ligand are achieved by a scheme shown. Lipophilic 99mTc stilbene complexes were successfully prepared and purified through HPLC. Preliminary results of in vitro labeling of brain sections from transgenic mice showed very promising plaque labeling. These 99mTc stilbene derivatives are warranted for further evaluations as potential imaging agents targeting amyloid plaques.

  5. Molecular photoacoustic imaging using gold nanoparticles as a contrast agent

    NASA Astrophysics Data System (ADS)

    Kim, Chulhong; Cho, Eun Chul; Chen, Jingyi; Song, Kwang Hyun; Au, Leslie; Favazza, Christopher P.; Zhang, Qiang; Cobley, Claire M.; Xia, Younan; Wang, Lihong V.

    2010-02-01

    Gold nanoparticles have received much attention due to their potential diagnostic and therapeutic applications. Gold nanoparticles are attractive in many biomedical applications because of their biocompatibility, easily modifiable surfaces for targeting, lack of heavy metal toxicity, wide range of sizes (35-100 nm), tunable plasmonic resonance peak, encapsulated site-specific drug delivery, and strong optical absorption in the near-infrared regime. Specifically, due to their strong optical absorption, gold nanoparticles have been used as a contrast agent for molecular photoacoustic (PA) imaging of tumor. The plasmonic resonance peak of the gold nanocages (AuNCs) was tuned to the near-infrared region, and the ratio of the absorption cross-section to the extinction cross-section was approximately ~70%, as measured by PA sensing. We used PEGylated gold nanocages (PEG-AuNCs) as a passive targeting contrast agent on melanomas. After 6-h intravenous injection of PEG-AuNCs, PA amplitude was increased by ~14 %. These results strongly suggest PA imaging paired with AuNCs is a promising diagnostic tool for early cancer detection.

  6. Shape Effects in Nanoparticle-Based Imaging Agents

    NASA Astrophysics Data System (ADS)

    Culver, Kayla Shani Brook

    At the nanoscale, material properties become highly size and shape dependent. These properties can be manipulated and exploited for a variety of biomedical applications, including sensing, drug delivery, diagnostics, and imaging. In particular, nanoparticles of different materials, sizes and shapes have been developed as high-performance contrast agents for optical, electron, and medical imaging. In this thesis, I focus on gold nanoparticles because they are widely used as contrast agents in multiple types of imaging modalities. Additionally, the surface of gold can be readily functionalized with ligands and the structure of the particles can be manipulated to modulate their performance as imaging agents. The properties of nanoparticles can generate contrast directly. For example, the light scattering properties of gold particles can be visualized in optical microscopy, the high electron density of gold produces contrast in electron microscopy, and the x-ray absorption properties of gold can be detected in medical x-ray and computed tomography imaging. Alternatively, the properties of the nanomaterial can be exploited to modulate the signal produced by other molecules that are bound to the particle surface. The light emission of molecular fluorophores can be quenched or dramatically increased by coupling to the optical field enhancements of gold nanoparticles, and the performance of gadolinium (Gd(III))-based magnetic resonance imaging (MRI) contrast agents can be increased by coupling to the rotational motion of nanoparticles. In this dissertation, I focus specifically on how the structure of star-shaped gold particles (nanostars) can be exploited as single-particle optical probes and to dramatically enhance the relaxivity of Gd(III) bound to the surface. Differential interference contrast (DIC) is a type of wide-field diffraction-limited optical microscopy that is commonly used by biologists to image cells without labels. Here, I demonstrate the DIC can be used

  7. Dietary proteins and angiogenesis.

    PubMed

    Medina, Miguel Ángel; Quesada, Ana R

    2014-01-17

    Both defective and persistent angiogenesis are linked to pathological situations in the adult. Compounds able to modulate angiogenesis have a potential value for the treatment of such pathologies. Several small molecules present in the diet have been shown to have modulatory effects on angiogenesis. This review presents the current state of knowledge on the potential modulatory roles of dietary proteins on angiogenesis. There is currently limited available information on the topic. Milk contains at least three proteins for which modulatory effects on angiogenesis have been previously demonstrated. On the other hand, there is some scarce information on the potential of dietary lectins, edible plant proteins and high protein diets to modulate angiogenesis.

  8. Simultaneous Dual-Nuclei Imaging for Motion Corrected Detection and Quantification of 19F Imaging Agents

    PubMed Central

    Keupp, Jochen; Rahmer, Jürgen; Grässlin, Ingmar; Mazurkewitz, Peter C.; Schaeffter, Tobias; Lanza, Gregory M.; Wickline, Samuel A.; Caruthers, Shelton D.

    2011-01-01

    Fluorine MRI offers broad potential for specific detection and quantification of molecularly targeted agents in diagnosis and therapy planning or monitoring. Because non-proton MRI applications lack morphological information, accompanying proton images are needed to elucidate the spatial tissue context. Furthermore, low concentrations typical of targeted molecular imaging agents require long examinations for signal averaging during which physiological motion may lead to blurring, underestimation in signal quantification, and erroneous localization of the agent distribution. Novel methods for truly-simultaneous acquisition of dual-nuclei MR data are presented that offer efficient and precise anatomical localization of fluorine signals using accurate motion correction based on contemporaneous proton signals. The feasibility of simultaneous dual-nuclei MRI motion correction and corresponding dual-resolution reconstruction, providing nuclei-specific spatial resolution to retrospectively optimize the balance between signal-to-noise ratio and resolution, is shown on a clinical 3T MR system. PMID:21394779

  9. Positrons as imaging agents and probes in nanotechnology

    NASA Astrophysics Data System (ADS)

    Smith, Suzanne V.

    2009-09-01

    Positron emission tomography (PET) tracks a positron emitting radiopharmaceutical injected into the body and generates a 3-dimensional image of its location. Introduced in the early 70s, it has now developed into a powerful medical diagnostic tool for routine clinical use as well as in drug development. Unrivalled as a highly sensitive, specific and non-invasive imaging tool, PET unfortunately lacks the resolution of Computer Tomography (CT) and Magnetic Resonance Imaging (MRI). As the resolution of PET depends significantly on the energy of the positron incorporated in the radiopharmaceutical and its interaction with its surrounding tissue, there is growing interest in expanding our understanding of how positrons interact at the atomic and molecular level. A better understanding of these interactions will contribute to improving the resolution of PET and assist in the design of better imaging agents. Positrons are also used in Positron Annihilation Lifetime Spectroscopy (PALS) to determine electron density and or presence and incidence of micro- and mesopores (0.1 to 10 nm) in materials. The control of porosity in engineered materials is crucial for applications such as controlled release or air and water resistant films. Equally important to the design of nano and microtechnologies, is our understanding of the microenvironments within these pores and on surfaces. Hence as radiopharmaceuticals are designed to track disease, nuclear probes (radioactive molecules) are synthesized to investigate the chemical properties within these pores. This article will give a brief overview of the present role of positrons in imaging as well as explore its potential to contribute in the engineering of new materials to the marketplace.

  10. Gadolinium chloride as a contrast agent for imaging wood composite components by magnetic resonance

    Treesearch

    Thomas L. Eberhardt; Chi-Leung So; Andrea Protti; Po-Wah So

    2009-01-01

    Although paramagnetic contrast agents have an established track record in medical uses of magnetic resonance imaging (MRI), only recently has a contrast agent been used for enhancing MRI images of solid wood specimens. Expanding on this concept, wood veneers were treated with a gadolinium-based contrast agent and used in a model system comprising three-ply plywood...

  11. Gold nanoparticles as high-resolution X-ray imaging contrast agents for the analysis of tumor-related micro-vasculature

    SciTech Connect

    Chien C.; Yong C.; Hsiang-Hsin, C.; Sheng-Feng, L.; Kang-Chao W.; Xiaoqing C.; Yeukuang, H.; Petibois, C.; Margaritondo, G.

    2012-03-12

    Angiogenesis is widely investigated in conjunction with cancer development, in particular because of the possibility of early stage detection and of new therapeutic strategies. However, such studies are negatively affected by the limitations of imaging techniques in the detection of microscopic blood vessels (diameter 3-5 {micro}m) grown under angiogenic stress. We report that synchrotron-based X-ray imaging techniques with very high spatial resolution can overcome this obstacle, provided that suitable contrast agents are used. We tested different contrast agents based on gold nanoparticles (AuNPs) for the detection of cancer-related angiogenesis by synchrotron microradiology, microtomography and high resolution X-ray microscopy. Among them only bare-AuNPs in conjunction with heparin injection provided sufficient contrast to allow in vivo detection of small capillary species (the smallest measured lumen diameters were 3-5 {micro}m). The detected vessel density was 3-7 times higher than with other nanoparticles. We also found that bare-AuNPs with heparin allows detecting symptoms of local extravascular nanoparticle diffusion in tumor areas where capillary leakage appeared. Although high-Z AuNPs are natural candidates as radiology contrast agents, their success is not guaranteed, in particular when targeting very small blood vessels in tumor-related angiography. We found that AuNPs injected with heparin produced the contrast level needed to reveal--for the first time by X-ray imaging--tumor microvessels with 3-5 {micro}m diameter as well as extravascular diffusion due to basal membrane defenestration. These results open the interesting possibility of functional imaging of the tumor microvasculature, of its development and organization, as well as of the effects of anti-angiogenic drugs.

  12. Hyperpolarized water as an authentic magnetic resonance imaging contrast agent

    PubMed Central

    McCarney, Evan R.; Armstrong, Brandon D.; Lingwood, Mark D.; Han, Songi

    2007-01-01

    Pure water in a highly 1H spin-polarized state is proposed as a contrast-agent-free contrast agent to visualize its macroscopic evolution in aqueous media by MRI. Remotely enhanced liquids for image contrast (RELIC) utilizes a 1H signal of water that is enhanced outside the sample in continuous-flow mode and immediately delivered to the sample to obtain maximum contrast between entering and bulk fluids. Hyperpolarization suggests an ideal contrast mechanism to highlight the ubiquitous and specific function of water in physiology, biology, and materials because the physiological, chemical, and macroscopic function of water is not altered by the degree of magnetization. We present an approach that is capable of instantaneously enhancing the 1H MRI signal by up to 2 orders of magnitude through the Overhauser effect under ambient conditions at 0.35 tesla by using highly spin-polarized unpaired electrons that are covalently immobilized onto a porous, water-saturated gel matrix. The continuous polarization of radical-free flowing water allowed us to distinctively visualize vortices in model reactors and dispersion patterns through porous media. A 1H signal enhancement of water by a factor of −10 and −100 provides for an observation time of >4 and 7 s, respectively, upon its injection into fluids with a T1 relaxation time of >1.5 s. The implications for chemical engineering or biomedical applications of using hyperpolarized solvents or physiological fluids to visualize mass transport and perfusion with high and authentic MRI contrast originating from water itself, and not from foreign contrast agents, are immediate. PMID:17264210

  13. Hyperpolarized water as an authentic magnetic resonance imaging contrast agent.

    PubMed

    McCarney, Evan R; Armstrong, Brandon D; Lingwood, Mark D; Han, Songi

    2007-02-06

    Pure water in a highly (1)H spin-polarized state is proposed as a contrast-agent-free contrast agent to visualize its macroscopic evolution in aqueous media by MRI. Remotely enhanced liquids for image contrast (RELIC) utilizes a (1)H signal of water that is enhanced outside the sample in continuous-flow mode and immediately delivered to the sample to obtain maximum contrast between entering and bulk fluids. Hyperpolarization suggests an ideal contrast mechanism to highlight the ubiquitous and specific function of water in physiology, biology, and materials because the physiological, chemical, and macroscopic function of water is not altered by the degree of magnetization. We present an approach that is capable of instantaneously enhancing the (1)H MRI signal by up to 2 orders of magnitude through the Overhauser effect under ambient conditions at 0.35 tesla by using highly spin-polarized unpaired electrons that are covalently immobilized onto a porous, water-saturated gel matrix. The continuous polarization of radical-free flowing water allowed us to distinctively visualize vortices in model reactors and dispersion patterns through porous media. A (1)H signal enhancement of water by a factor of -10 and -100 provides for an observation time of >4 and 7 s, respectively, upon its injection into fluids with a T(1) relaxation time of >1.5 s. The implications for chemical engineering or biomedical applications of using hyperpolarized solvents or physiological fluids to visualize mass transport and perfusion with high and authentic MRI contrast originating from water itself, and not from foreign contrast agents, are immediate.

  14. Tailored Near-Infrared Contrast Agents for Image Guided Surgery

    PubMed Central

    Njiojob, Costyl N.; Owens, Eric A.; Narayana, Lakshminarayana; Hyun, Hoon; Choi, Hak Soo; Henary, Maged

    2015-01-01

    The success of near-infrared (NIR) fluorescence to be employed for intraoperative imaging relies on the ability to develop a highly stable, NIR fluorescent, nontoxic, biocompatible, and highly excreted compound that retains a reactive functionality for conjugation to a cancer-recognizing peptide. Herein, systematic modifications to previously detailed fluorophore ZW800-1 are explored. Specific modifications, including the isosteric replacement of the O atom of ZW800-1, include nucleophilic amine and sulfur species attached to the heptamethine core. These novel compounds have shown similar satisfactory results in biodistribution and clearance while also expressing increased stability in serum. Most importantly, all of the synthesized and evaluated compounds display a reactive functionality (either a free amino group or carboxylic acid moiety) for further bioconjugation. The results obtained from the newly prepared derivatives demonstrate that the central substitution with the studied linking agents retains the ultralow background in vivo performance of the fluorophores regardless of the total net charge. PMID:25711712

  15. Uptake of myocardial imaging agents by rejected hearts

    SciTech Connect

    Bergsland, J.; Carr, E.A.; Carroll, M.; Wright, J.W.; Feldman, M.J.; Massucci, J.; Bhayana, J.N.; Gona, J.M.

    1985-09-01

    Technetium 99 m pyrophosphate, Gallium 67 and Thallium 201 uptakes were measured in heterotopically transplanted rat hearts. Five days after transplantation, Technetium 99 m pyrophosphate, and Gallium 67 uptakes were significantly higher in allogeneic grafts than in syngeneic grafts. At an early stage of rejection (three days after transplantation), only Technetium 99 m pyrophosphate uptake in the left ventricle of allogeneic grafts showed a significant difference (p less than 0.04). At five days, Thallium 201 uptake was significantly lower in allo- than syngeneic grafts. There was a positive correlation between radionuclide uptake and histologic degree of rejection for Technetium 99 m pyrophosphate and Gallium 67 while Thallium 201 uptake correlated negatively. Analysis of variance revealed that hearts with no or minimal rejection had statistically different uptakes than hearts with mild to moderate rejection. These results suggest that uptake of imaging agents might be useful in the diagnosis of rejection of the transplanted heart.

  16. Characterization of nanoparticle-based contrast agents for molecular magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Shan, Liang; Chopra, Arvind; Leung, Kam; Eckelman, William C.; Menkens, Anne E.

    2012-09-01

    The development of molecular imaging agents is currently undergoing a dramatic expansion. As of October 2011, 4,800 newly developed agents have been synthesized and characterized in vitro and in animal models of human disease. Despite this rapid progress, the transfer of these agents to clinical practice is rather slow. To address this issue, the National Institutes of Health launched the Molecular Imaging and Contrast Agents Database (MICAD) in 2005 to provide freely accessible online information regarding molecular imaging probes and contrast agents for the imaging community. While compiling information regarding imaging agents published in peer-reviewed journals, the MICAD editors have observed that some important information regarding the characterization of a contrast agent is not consistently reported. This makes it difficult for investigators to evaluate and meta-analyze data generated from different studies of imaging agents, especially for the agents based on nanoparticles. This article is intended to serve as a guideline for new investigators for the characterization of preclinical studies performed with nanoparticle-based MRI contrast agents. The common characterization parameters are summarized into seven categories: contrast agent designation, physicochemical properties, magnetic properties, in vitro studies, animal studies, MRI studies, and toxicity. Although no single set of parameters is suitable to define the properties of the various types of contrast agents, it is essential to ensure that these agents meet certain quality control parameters at the preclinical stage, so that they can be used without delay for clinical studies.

  17. Immune cells and angiogenesis

    PubMed Central

    Ribatti, Domenico; Crivellato, Enrico

    2009-01-01

    Both innate and adaptive immune cells are involved in the mechanisms of endothelial cell proliferation, migration and activation, through the production and release of a large spectrum of pro-angiogenic mediators. These may create the specific microenvironment that favours an increased rate of tissue vascularization. In this review, we will focus on the immune cell component of the angiogenic process in inflammation and tumour growth. As angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators, we will also provide information on some antiangiogenic properties of immune cells that may be utilized for a potential pharmacological use as antiangiogenic agents in inflammation as well as in cancer. PMID:19538473

  18. Immune cells and angiogenesis.

    PubMed

    Ribatti, Domenico; Crivellato, Enrico

    2009-09-01

    Both innate and adaptive immune cells are involved in the mechanisms of endothelial cell proliferation, migration and activation, through the production and release of a large spectrum of pro-angiogenic mediators. These may create the specific microenvironment that favours an increased rate of tissue vascularization. In this review, we will focus on the immune cell component of the angiogenic process in inflammation and tumour growth. As angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators, we will also provide information on some antiangiogenic properties of immune cells that may be utilized for a potential pharmacological use as antiangiogenic agents in inflammation as well as in cancer.

  19. Spectral imaging based in vivo model system for characterization of tumor microvessel response to vascular targeting agents

    NASA Astrophysics Data System (ADS)

    Wankhede, Mamta

    Functional vasculature is vital for tumor growth, proliferation, and metastasis. Many tumor-specific vascular targeting agents (VTAs) aim to destroy this essential tumor vasculature to induce indirect tumor cell death via oxygen and nutrition deprivation. The tumor angiogenesis-inhibiting anti-angiogenics (AIs) and the established tumor vessel targeting vascular disrupting agents (VDAs) are the two major players in the vascular targeting field. Combination of VTAs with conventional therapies or with each other, have been shown to have additive or supra-additive effects on tumor control and treatment. Pathophysiological changes post-VTA treatment in terms of structural and vessel function changes are important parameters to characterize the treatment efficacy. Despite the abundance of information regarding these parameters acquired using various techniques, there remains a need for a quantitative, real-time, and direct observation of these phenomenon in live animals. Through this research we aspired to develop a spectral imaging based mouse tumor system for real-time in vivo microvessel structure and functional measurements for VTA characterization. A model tumor system for window chamber studies was identified, and then combinatorial effects of VDA and AI were characterized in model tumor system. (Full text of this dissertation may be available via the University of Florida Libraries web site. Please check http://www.uflib.ufl.edu/etd.html)

  20. The diversity of (68)Ga-based imaging agents.

    PubMed

    Velikyan, Irina

    2013-01-01

    Development of new radiopharmaceuticals and their availability are crucial factors influencing the expansion of clinical nuclear medicine. The number of new (68)Ga-based imaging agents for positron emission tomography (PET) is increasing greatly. (68)Ga has been used for labeling of a broad range of molecules (small organic molecules, peptides, proteins, and oligonucleotides) as well as particles, thus demonstrating its potential to become a PET analog of the legendary generator-produced gamma-emitting (99m)Tc but with added value of higher sensitivity and resolution as well as quantitation and dynamic scanning. Further, the availability of technology for GMP-compliant automated tracer production can facilitate the introduction of new radiopharmaceuticals and enable standardized, harmonized multicenter studies to be conducted for regulatory approval. This chapter presents some examples of tracers for targeted, pretargeted, and nontargeted imaging with emphasis on the potential of (68)Ga to facilitate clinically practical PET development and to promote the PET technique worldwide for earlier and better diagnostics, and personalized medicine with the ultimate objective of improved therapeutic outcome.

  1. Harmonic chirp imaging method for ultrasound contrast agent.

    PubMed

    Borsboom, Jerome M G; Chin, Chien Ting; Bouakaz, Ayache; Versluis, Michel; de Jong, Nico

    2005-02-01

    Coded excitation is currently used in medical ultrasound to increase signal-to-noise ratio (SNR) and penetration depth. We propose a chirp excitation method for contrast agents using the second harmonic component of the response. This method is based on a compression filter that selectively compresses and extracts the second harmonic component from the received echo signal. Simulations have shown a clear increase in response for chirp excitation over pulse excitation with the same peak amplitude. This was confirmed by two-dimensional (2-D) optical observations of bubble response with a fast framing camera. To evaluate the harmonic compression method, we applied it to simulated bubble echoes, to measured propagation harmonics, and to B-mode scans of a flow phantom and compared it to regular pulse excitation imaging. An increase of approximately 10 dB in SNR was found for chirp excitation. The compression method was found to perform well in terms of resolution. Axial resolution was in all cases within 10% of the axial resolution from pulse excitation. Range side-lobe levels were 30 dB below the main lobe for the simulated bubble echoes and measured propagation harmonics. However, side-lobes were visible in the B-mode contrast images.

  2. Development of a calcium-sensing receptor molecular imaging agent

    PubMed Central

    Yusof, Adlina Mohd; Kothandaraman, Shankaran; Zhang, Xiaoli; Saji, Motoyasu; Ringel, Matthew D.; Tweedle, Michael F.; Phay, John E.

    2015-01-01

    Background Calcium-sensing receptor (CaSR) is expressed by parathyroid cells and thyroid C-cells (from which medullary thyroid carcinoma [MTC] is derived). A molecular imaging agent localizing to the CaSR could improve the detection of parathyroids and MTC preoperatively or intraoperatively. We synthesized a novel compound containing a fluorine residue for potential future labeling and demonstrated that the compound inhibited CaSR function in vitro. Methods We synthesized compound M, a derivative of a known calcilytic compound, Calhex-231. Human embryonic kidney cells transfected with green-fluorescent protein-tagged CaSR or control vector were preincubated with compound M before the addition of calcium. Immunoblotting for total mitogen-activated protein kinase (MAPK: ERK1/2), activated MAPK (phosphorylated ERK1/2), and glyceraldehyde 3-phosphate dehydrogenase was performed. Results Synthesis of compound M was confirmed by mass spectrometry. Inhibition of the MAPK signaling pathway by compound M was demonstrated in a dose-dependent manner by a decrease in phosphorylated ERK1/2 with no change in total ERK1/2 levels. Compound M inhibited MAPK signaling slightly better than the parent compound. Conclusion We have developed a novel molecule which demonstrates functional inhibition of CaSR and has a favorable structure for labeling. This compound appears to be appropriate for further development as a molecular imaging tool to enhance the surgical treatment of parathyroid disease and MTC. PMID:24238055

  3. Multi-modality PET-CT imaging of breast cancer in an animal model using nanoparticle x-ray contrast agent and 18F-FDG

    NASA Astrophysics Data System (ADS)

    Badea, C. T.; Ghaghada, K.; Espinosa, G.; Strong, L.; Annapragada, A.

    2011-03-01

    Multi-modality PET-CT imaging is playing an important role in the field of oncology. While PET imaging facilitates functional interrogation of tumor status, the use of CT imaging is primarily limited to anatomical reference. In an attempt to extract comprehensive information about tumor cells and its microenvironment, we used a nanoparticle xray contrast agent to image tumor vasculature and vessel 'leakiness' and 18F-FDG to investigate the metabolic status of tumor cells. In vivo PET/CT studies were performed in mice implanted with 4T1 mammary breast cancer cells.Early-phase micro-CT imaging enabled visualization 3D vascular architecture of the tumors whereas delayedphase micro-CT demonstrated highly permeable vessels as evident by nanoparticle accumulation within the tumor. Both imaging modalities demonstrated the presence of a necrotic core as indicated by a hypo-enhanced region in the center of the tumor. At early time-points, the CT-derived fractional blood volume did not correlate with 18F-FDG uptake. At delayed time-points, the tumor enhancement in 18F-FDG micro-PET images correlated with the delayed signal enhanced due to nanoparticle extravasation seen in CT images. The proposed hybrid imaging approach could be used to better understand tumor angiogenesis and to be the basis for monitoring and evaluating anti-angiogenic and nano-chemotherapies.

  4. Functional in vivo optical imaging of tumor angiogenesis, growth, and metastasis prevented by administration of anti-human VEGF antibody in xenograft model of human fibrosarcoma HT1080 cells.

    PubMed

    Hanyu, Aki; Kojima, Kiyotsugu; Hatake, Kiyohiko; Nomura, Kimie; Murayama, Hironori; Ishikawa, Yuichi; Miyata, Satoshi; Ushijima, Masaru; Matsuura, Masaaki; Ogata, Etsuro; Miyazawa, Keiji; Imamura, Takeshi

    2009-11-01

    Angiogenesis plays a crucial role in cancer progression and metastasis. Thus, blocking tumor angiogenesis is potentially a universal approach to prevent tumor establishment and metastasis. In this study, we used in vivo and ex vivo fluorescence imaging to show that an antihuman vascular endothelial growth factor (VEGF) antibody represses angiogenesis and the growth of primary tumors of human fibrosarcoma HT1080 cells in implanted nude mice. Interestingly, administering the antihuman VEGF antibody reduced the development of new blood vessels and normalized pre-existing tumor vasculature in HT1080 cell tumors. In addition, antihuman VEGF antibody treatment decreased lung metastasis from the primary tumor, whereas it failed to block lung metastasis in a lung colonization experiment in which tumor cells were injected into the tail vein. These results suggest that VEGF produced by primary HT1080 cell tumors has a crucial effect on lung metastasis. The present study indicates that the in vivo fluorescent microscopy system will be useful to investigate the biology of angiogenesis and test the effectiveness of angiogenesis inhibitors.

  5. (18)F-labelled metomidate analogues as adrenocortical imaging agents.

    PubMed

    Erlandsson, Maria; Karimi, Farhad; Lindhe, Orjan; Långström, Bengt

    2009-05-01

    Two- and one-step syntheses of (18)F-labelled analogues of metomidate, such as 2-[(18)F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[(18)F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[(18)F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[(18)F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented. Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[(18)F]fluoroethyl 4-methylbenzenesulfonate or 3-[(18)F]fluoropropyl 4-methylbenzenesulfonate. These were used as (18)F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3. The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46+/-3% and 79+/-30%, respectively. Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.

  6. Mn Porphyrins as Novel Molecular Magnetic Resonance Imaging Contrast Agents

    PubMed Central

    Mouraviev, Vladimir; Venkatraman, Talaignair N.; Tovmasyan, Artak; Kimura, Masaki; Tsivian, Matvey; Mouravieva, Vladimira; Polascik, Tom J.; Wang, Haichen; Amrhein, Timothy J.; Batinic-Haberle, Ines

    2012-01-01

    Abstract Background and Purpose In this study, we investigated the potential of a new class of therapeutic Mn porphyrins as molecular MRI probes for prostate cancer imaging. Two compounds of different bioavailibility were investigated: Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP5+) and Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP5+). These compounds have previously been shown to have adjunctive antineoplastic activity through their actions as powerful superoxide dismutase mimics, peroxynitrite scavengers, and modulators of cellular redox-based signaling pathways. Strong paramagnetic MRI contrast properties and affinity for cancer cells suggest their potential application as novel diagnostic imaging agents. Materials and Methods MRI experiments were performed at 7.0T on a Bruker Biospec horizontal bore scanner. All in-vivo experiments were performed on 12 C57 black mice implanted with RM-9 prostate cancer cells on the hind limb. Two mg/kg of MnTnHex-2-PyP5+ (n=6) and 8 mg/kg MnTE-2-PyP5+ (n=6) were administered intraperitoneally 90 minutes before imaging. All the images were collected using a volume coil and processed using Paravision 4.0. Results Phantom studies reveal remarkably high T1 relaxivity changes for both metalloporphyrins, which are twofold to threefold higher than commercially available gadolinium chelates. Observable detection limits using conventional T1-weighted MRI are in the low micromolar range for both compounds. In vivo, MR relaxation changes in prostate tumor xenografts were readily observed after a single injection of either MnTE-2-PyP5+or MnTnHex-2-PyP5+, with tumor contrast to background ratio greatest after MnTE-2-PyP5+ administration. Conclusion After a single dose of MnTE-2-PyP5+, contrast changes in prostate tumors are up to sixfold greater than in surrounding, noncancerous tissues, suggesting the potential use of this metalloporphyrin as a novel diagnostic probe for detecting prostate

  7. Mn porphyrins as novel molecular magnetic resonance imaging contrast agents.

    PubMed

    Mouraviev, Vladimir; Venkatraman, Talaignair N; Tovmasyan, Artak; Kimura, Masaki; Tsivian, Matvey; Mouravieva, Vladimira; Polascik, Tom J; Wang, Haichen; Amrhein, Timothy J; Batinic-Haberle, Ines; Lascola, Christopher

    2012-11-01

    In this study, we investigated the potential of a new class of therapeutic Mn porphyrins as molecular MRI probes for prostate cancer imaging. Two compounds of different bioavailibility were investigated: Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP(5+)) and Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin (MnTnHex-2-PyP(5+)). These compounds have previously been shown to have adjunctive antineoplastic activity through their actions as powerful superoxide dismutase mimics, peroxynitrite scavengers, and modulators of cellular redox-based signaling pathways. Strong paramagnetic MRI contrast properties and affinity for cancer cells suggest their potential application as novel diagnostic imaging agents. MRI experiments were performed at 7.0T on a Bruker Biospec horizontal bore scanner. All in-vivo experiments were performed on 12 C57 black mice implanted with RM-9 prostate cancer cells on the hind limb. Two mg/kg of MnTnHex-2-PyP(5+) (n=6) and 8 mg/kg MnTE-2-PyP(5+) (n=6) were administered intraperitoneally 90 minutes before imaging. All the images were collected using a volume coil and processed using Paravision 4.0. Phantom studies reveal remarkably high T1 relaxivity changes for both metalloporphyrins, which are twofold to threefold higher than commercially available gadolinium chelates. Observable detection limits using conventional T1-weighted MRI are in the low micromolar range for both compounds. In vivo, MR relaxation changes in prostate tumor xenografts were readily observed after a single injection of either MnTE-2-PyP(5+)or MnTnHex-2-PyP(5+), with tumor contrast to background ratio greatest after MnTE-2-PyP(5+) administration. After a single dose of MnTE-2-PyP(5+), contrast changes in prostate tumors are up to sixfold greater than in surrounding, noncancerous tissues, suggesting the potential use of this metalloporphyrin as a novel diagnostic probe for detecting prostate malignancy using MRI.

  8. Design Principles of Nanoparticles as Contrast Agents for Magnetic Resonance Imaging

    NASA Astrophysics Data System (ADS)

    Shan, Liang; Gu, Xinbin; Wang, Paul

    2013-09-01

    Molecular imaging is an emerging field that introduces molecular agents into traditional imaging techniques, enabling visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. The promise of molecular imaging lies in its potential for selective potency by targeting biomarkers or molecular targets and the imaging agents serve as reporters for the selectivity of targeting. Development of an efficient molecular imaging agent depends on well-controlled high-quality experiment design involving target selection, agent synthesis, in vitro characterization, and in vivo animal characterization before it is applied in humans. According to the analysis from the Molecular Imaging and Contrast Agent Database (MICAD, ), more than 6000 molecular imaging agents with sufficient preclinical evaluation have been reported to date in the literature and this number increases by 250-300 novel agents each year. The majority of these agents are radionuclides, which are developed for positron emission tomography (PET) and single photon emission computed tomography (SPECT). Contrast agents for magnetic resonance imaging (MRI) account for only a small part. This is largely due to the fact that MRI is currently not a fully quantitative imaging technique and is less sensitive than PET and SPECT. However, because of the superior ability to simultaneously extract molecular and anatomic information, molecular MRI is attracting significant interest and various targeted nanoparticle contrast agents have been synthesized for MRI. The first and one of the most critical steps in developing a targeted nanoparticle contrast agent is target selection, which plays the central role and forms the basis for success of molecular imaging. This chapter discusses the design principles of targeted contrast agents in the emerging frontiers of molecular MRI.

  9. Pravastatin stimulates angiogenesis in a murine hindlimb ischemia model: a positron emission tomography imaging study with (64)Cu-NOTA-TRC105.

    PubMed

    Orbay, Hakan; Hong, Hao; Koch, Jill M; Valdovinos, Hector F; Hacker, Timothy A; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

    2013-01-01

    In this study, (64)Cu-NOTA-TRC105 (TRC105 is an anti-CD105 monoclonal antibody that binds to both human and murine CD105) positron emission tomography (PET) was used to assess the response to pravastatin treatment in a murine model of peripheral artery disease (PAD). Hindlimb ischemia was induced by ligation of the right femoral arteries in BALB/c mice under anesthesia, and the left hindlimb served as an internal control. Mice in the treatment group were given intraperitoneal pravastatin daily until the end of the study, whereas the animals in the control group were injected with 0.9% sodium chloride solution. Laser Doppler imaging showed that blood flow in the ischemic hindlimb plummeted to ~20% of the normal level after surgery, and gradually recovered to near normal level on day 10 in the treatment group and on day 20 in the control group. Angiogenesis was non-invasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 3, 10, 17, and 24. Tracer uptake at 48 h post-injection in the ischemic hindlimb in the treatment group was significantly higher than that of the control group on day 10 (20.5 ± 1.9 %ID/g vs 11.4 ± 1.5 %ID/g), suggesting increased CD105 expression and higher level of angiogenesis upon pravastatin treatment, and gradually decreased to background levels in both groups (4.9 ± 0.8 %ID/g vs 3.4 ± 1.9 %ID/g on day 24). The in vivo PET data correlated well with ex vivo biodistribution studies performed on day 24. Increased CD105 expression on days 3 and 10 following ischemia was further confirmed by immunofluorescence staining. Taken together, our results indicated that (64)Cu-NOTA-TRC105 PET is a suitable and non-invasive method to monitor the angiogenesis and therapeutic response in PAD, which can also be utilized for non-invasive evaluation of other pro-angiogenic/anti-angiogenic drugs in other cardiovascular diseases and cancer.

  10. Radioiodinated carnitine and acylcarnitine analogs as potential myocardial imaging agents

    SciTech Connect

    McConnell, D.S.

    1991-01-01

    R-carnitine is extremely important in mammalian energy metabolism. Gamma-butyrobetaine, the immediate biosynthetic precursor to R-carnitine, is synthesized in many organs. However, only liver can hydroxylate gamma-butyrobetaine to carnitine. Thus the transport of carnitine from its site of synthesis to the site of utilization is of utmost importance. Carnitine is found in highest concentration in cardiac and skeletal muscle, where it is required for the transport of fatty acids into the mitochondria. Before fatty acids are utilized as fuel for the myocyte by beta-oxidation, they are bound to carnitine as an acylcarnitine ester at the 3-hydroxyl, and transported across the micochondrial membranes. R,S-Carnitine has been shown to be taken up by myocytes. The author has begun a study on the use of carnitine derivatives as potential carriers for the site-specific delivery of radioiodine to bidning sites in the myocardium. Such agents labeled with a gamma-emitting nuclide such as iodine-123 would be useful for the noninvasive imaging of these tissues. The aim was to synthesize a variety of radiolabeled analogs of carnitine and acylcarnitine to address questions of transport, binding and availability for myocardial metabolism. These analogs consist of N-alkylated derivatives of carnitine, acylcarnitine esters as well as carnitine amides and ethers. One C-alkylated derivative showed interesting biodistribution, elevated myocardial uptake and competition with carnitine for binding in the myocardium.

  11. Development of Iron Doped Silicon Nanoparticles as Bimodal Imaging Agents

    PubMed Central

    Singh, Mani P.; Atkins, Tonya M.; Muthuswamy, Elayaraja; Kamali, Saeed; Tu, Chuqiao; Louie, Angelique Y.; Kauzlarich, Susan M.

    2012-01-01

    We demonstrate the synthesis of water-soluble allylamine terminated Fe doped Si (SixFe) nanoparticles as bimodal agents for optical and magnetic imaging. The preparation involves the synthesis of a single source iron containing precursor, Na4Si4 with x% Fe (x = 1, 5, 10), and its subsequent reaction with NH4Br to produce hydrogen terminated SixFe nanoparticles. The hydrogen-capped nanoparticles are further terminated with allylamine via thermal hydrosilylation. Transmission electron microscopy (TEM) indicates that the average particle diameter is ~3.0±1.0 nm. The Si5Fe nanoparticles show strong photoluminescence quantum yield in water (~ 10 %) with significant T2 contrast (r2/r1value of 4.31). Electron paramagnetic resonance (EPR) and Mössbauer spectroscopies indicate that iron in the nanoparticles is in the +3 oxidation state. Analysis of cytotoxicity using the resazurin assay on HepG2 liver cells indicates that the particles have minimal toxicity. PMID:22616623

  12. Angiogenesis and liver fibrosis

    PubMed Central

    Elpek, Gülsüm Özlem

    2015-01-01

    Recent data indicate that hepatic angiogenesis, regardless of the etiology, takes place in chronic liver diseases (CLDs) that are characterized by inflammation and progressive fibrosis. Because anti-angiogenic therapy has been found to be efficient in the prevention of fibrosis in experimental models of CLDs, it is suggested that blocking angiogenesis could be a promising therapeutic option in patients with advanced fibrosis. Consequently, efforts are being directed to revealing the mechanisms involved in angiogenesis during the progression of liver fibrosis. Literature evidences indicate that hepatic angiogenesis and fibrosis are closely related in both clinical and experimental conditions. Hypoxia is a major inducer of angiogenesis together with inflammation and hepatic stellate cells. These profibrogenic cells stand at the intersection between inflammation, angiogenesis and fibrosis and play also a pivotal role in angiogenesis. This review mainly focuses to give a clear view on the relevant features that communicate angiogenesis with progression of fibrosis in CLDs towards the-end point of cirrhosis that may be translated into future therapies. The pathogenesis of hepatic angiogenesis associated with portal hypertension, viral hepatitis, non-alcoholic fatty liver disease and alcoholic liver disease are also discussed to emphasize the various mechanisms involved in angiogenesis during liver fibrogenesis. PMID:25848465

  13. Theragnostics for tumor and plaque angiogenesis with perfluorocarbon nanoemulsions

    PubMed Central

    Winter, P. M.; Caruthers, S. D.; Hughes, M. S.; Hu, Grace; Schmieder, A. H.; Wickline, S. A.

    2011-01-01

    Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cell-surface biochemical signatures. Although originally the purview of nuclear medicine, “molecular imaging” is now studied in conjunction with all clinically relevant imaging modalities. Of the myriad of particles that have emerged as prospective candidates for clinical translation, perfluorocarbon nanoparticles offer great potential for combining targeted imaging with drug delivery, much like the “magic bullet” envisioned by Paul Ehrlich 100 years ago. Perfluorocarbon nanoparticles, once studied in Phase III clinical trials as blood substitutes, have found new life for molecular imaging and drug delivery. The particles have been adapted for use with all clinically relevant modalities and for targeted drug delivery. In particular, their intravascular constraint due to particle size provides a distinct advantage for angiogenesis imaging and antiangiogenesis therapy. As perfluorocarbon nanoparticles have recently entered Phase I clinical study, this review provides a timely focus on the development of this platform technology and its application for angiogenesis-related pathologies. PMID:20411320

  14. Liver-specific agents for contrast-enhanced MRI: role in oncological imaging

    PubMed Central

    Thian, Yee Liang; Riddell, Angela M.

    2013-01-01

    Abstract Liver-specific magnetic resonance (MR) contrast agents are increasingly used in evaluation of the liver. They are effective in detection and morphological characterization of lesions, and can be useful for evaluation of biliary tree anatomy and liver function. The typical appearances and imaging pitfalls of various tumours at MR imaging performed with these agents can be understood by the interplay of pharmacokinetics of these contrast agents and transporter expression of the tumour. This review focuses on the applications of these agents in oncological imaging. PMID:24434892

  15. Angiogenesis: a prognostic determinant in pancreatic cancer?

    PubMed

    van der Zee, Jill A; van Eijck, Casper H J; Hop, Wim C J; van Dekken, Herman; Dicheva, Bilyana M; Seynhaeve, Ann L B; Koning, Gerben A; Eggermont, Alexander M M; ten Hagen, Timo L M

    2011-11-01

    Angiogenesis has been associated with disease progression in many solid tumours, however the statement that tumours need angiogenesis to grow, invade and metastasise seems no longer applicable to all tumours or to all tumour subtypes. Prognostic studies in pancreatic cancer are conflicting. In fact, pancreatic cancer has been suggested an example of a tumour in which angiogenesis is less essential for tumour progression. The aim of the present study was therefore to measure angiogenesis in two anatomically closely related however prognostically different types of pancreatic cancer, pancreatic head and periampullary cancer, and investigate its relation with outcome. Vessels were stained by CD31 on original paraffin embedded tissue from 206 patients with microscopic radical resection (R0) of pancreatic head (n=98) or periampullary cancer (n=108). Angiogenesis was quantified by microvessel density (MVD) and measured by computerised image analysis of three randomly selected fields and investigated for associations with recurrence free survival (RFS), cancer specific survival (CSS), overall survival (OS) and conventional prognostic factors. MVD was heterogeneous both between and within tumours. A higher MVD was observed in periampullary cancers compared with pancreatic head cancers (p<.01). Furthermore, MVD was associated with lymph node involvement in pancreatic head (p=.014), but not in periampullary cancer (p=.55). Interestingly, MVD was not associated with RFS, CSS or with OS. In conclusion, angiogenesis is higher in periampullary cancer and although associated with nodal involvement in pancreatic head cancer, pancreatic cancer prognosis seems indeed angiogenesis independent.

  16. Development of New Contrast Agents for Imaging Function and Metabolism by Magnetic Resonance Imaging

    PubMed Central

    Carvalho, Alexandra; Gonçalves, M Clara; Corvo, M Luísa; Martins, M Bárbara F

    2017-01-01

    Liposomes are interesting nanosystems with a wide range of medical application. One particular application is their ability to enhance contrast in magnetic resonance images; when properly loaded with magnetic/superparamagnetic nanoparticles, this means to act as contrast agents. The design of liposomes loaded with magnetic particles, magnetoliposomes, presents a large number of possibilities depending on the application from image function to metabolism. More interesting is its double function application as theranostics (diagnostics and therapy). The synthesis, characterization, and possible medical applications of two types of magnetoliposomes are reviewed. Their performance will be compared, in particular, their efficiency as contrast agents for magnetic resonance imaging, measured by their relaxivities r1 and r2 relating to their particular composition. One of the magnetoliposomes had 1,2-diacyl-sn-glycero-3-phosphocholine (soy) as the main phospholipid component, with and without cholesterol, varying its phospholipid to cholesterol molar ratios. The other formulation is a long-circulating liposome composed of 1,2-diacyl-sn-glycero-3-phosphocholine (egg), cholesterol, and 1,2-distearoyl-sn-glycerol-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Both nanosystems were loaded with superparamagnetic iron oxide nanoparticles with different sizes and coatings. PMID:28804244

  17. Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent “Pimonidazole” in Hypoxia

    PubMed Central

    Yoshioka, Takeshi; Feng, Fei; Zhao, Songji; Higashino, Kenichi; Numata, Yoshito; Kuge, Yuji

    2016-01-01

    Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole-based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group. However, the detailed mechanism of its accumulation remains unknown. In this study, we investigated the accumulation mechanism of pimonidazole in hypoxic tumor tissues in a mouse model by mass spectrometric analyses including imaging mass spectrometry (IMS). Pimonidazole and its reductive metabolites were observed in the tumor tissues. However, their locations in the tumor sections were not similar to the positively stained areas in pimonidazole-immunohistochemistry, an area considered hypoxic. The glutathione conjugate of reduced pimonidazole, a low-molecular-weight metabolite of pimonidazole, was found in tumor tissues by LC-MS analysis, and our IMS study determined that the intratumor localization of the glutathione conjugate was consistent with the area positively immunostained for pimonidazole. We also found complementary localization of the glutathione conjugate and reduced glutathione (GSH), implying that formation of the glutathione conjugate occurred in the tumor tissue. These results suggest that in hypoxic tumor cells, pimonidazole is reduced at its nitro group, followed by conjugation with GSH. PMID:27580239

  18. Imaging Mass Spectrometry Revealed the Accumulation Characteristics of the 2-Nitroimidazole-Based Agent "Pimonidazole" in Hypoxia.

    PubMed

    Masaki, Yukiko; Shimizu, Yoichi; Yoshioka, Takeshi; Feng, Fei; Zhao, Songji; Higashino, Kenichi; Numata, Yoshito; Kuge, Yuji

    2016-01-01

    Hypoxia, or low oxygen concentration, is a key factor promoting tumor progression and angiogenesis and resistance of cancer to radiotherapy and chemotherapy. 2-Nitroimidazole-based agents have been widely used in pathological and nuclear medicine examinations to detect hypoxic regions in tumors; in particular, pimonidazole is used for histochemical staining of hypoxic regions. It is considered to accumulate in hypoxic cells via covalent binding with macromolecules or by forming reductive metabolites after reduction of its nitro group. However, the detailed mechanism of its accumulation remains unknown. In this study, we investigated the accumulation mechanism of pimonidazole in hypoxic tumor tissues in a mouse model by mass spectrometric analyses including imaging mass spectrometry (IMS). Pimonidazole and its reductive metabolites were observed in the tumor tissues. However, their locations in the tumor sections were not similar to the positively stained areas in pimonidazole-immunohistochemistry, an area considered hypoxic. The glutathione conjugate of reduced pimonidazole, a low-molecular-weight metabolite of pimonidazole, was found in tumor tissues by LC-MS analysis, and our IMS study determined that the intratumor localization of the glutathione conjugate was consistent with the area positively immunostained for pimonidazole. We also found complementary localization of the glutathione conjugate and reduced glutathione (GSH), implying that formation of the glutathione conjugate occurred in the tumor tissue. These results suggest that in hypoxic tumor cells, pimonidazole is reduced at its nitro group, followed by conjugation with GSH.

  19. Three-dimensional contrast enhanced ultrasound score and dynamic contrast-enhanced magnetic resonance imaging score in evaluating breast tumor angiogenesis: correlation with biological factors.

    PubMed

    Jia, Wan-Ru; Chai, Wei-Min; Tang, Lei; Wang, Yi; Fei, Xiao-Chun; Han, Bao-San; Chen, Man

    2014-07-01

    To explore the clinical value of three-dimensional contrast enhanced ultrasound (3D-CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) score systems in evaluating breast tumor angiogenesis by comparing their diagnostic efficacy and correlation with biological factors. 3D-CEUS was performed in 183 patients with breast tumors by Esaote Mylab90 with SonoVue (Bracco, Italy), DCE-MRI was performed on a dedicated breast magnetic resonance imaging (DBMRI) system (Aurora Dedicated Breast MRI Systems, USA) with a dedicated breast coil. 3D-CEUS and DCE-MRI score systems were created based on tumor perfusion and vascular characteristics. Microvessel density (MVD), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) expression were measured by immunohistochemistry. Pathological results showed 35 benign and 148 malignant breast tumors. MVD (P=0.000, r=0.76), VEGF (P=0.000, r=0.55), MMP-2 (P=0.000, r=0.39) and MMP-9 (P=0.000, r=0.41) expression were all significantly different between benignity and malignancy. Regarding 3D-CEUS 4 points as cutoff value, the sensitivity, specificity and accuracy were 85.1%, 94.3% and 86.9%, respectively, and correlated well with MVD (P=0.000, r=0.50), VEGF (P=0.000, r=0.50), MMP-2 (P=0.000, r=0.50) and MMP-9 (P=0.000, r=0.66). Taking DCE-MRI 5 points as cutoff value, the sensitivity, specificity and accuracy were 86.5%, 94.3% and 88.0%, respectively and also correlated well with MVD (P=0.000, r=0.52), VEGF (P=0.000, r=0.44), MMP-2 (P=0.000, r=0.42) and MMP-9 (P=0.000, r=0.35). 3D-CEUS score system displays inspiring diagnostic performance and good agreement with DCE-MRI scoring. Moreover, both score systems correlate well with MVD, VEGF, MMP-2 and MMP-9 expression, and thus have great potentials in tumor angiogenesis evaluation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. High-Resolution Ultrasound-Switchable Fluorescence Imaging in Centimeter-Deep Tissue Phantoms with High Signal-To-Noise Ratio and High Sensitivity via Novel Contrast Agents

    PubMed Central

    Cheng, Bingbing; Bandi, Venugopal; Wei, Ming-Yuan; Pei, Yanbo; D’Souza, Francis; Nguyen, Kytai T.; Hong, Yi; Yuan, Baohong

    2016-01-01

    For many years, investigators have sought after high-resolution fluorescence imaging in centimeter-deep tissue because many interesting in vivo phenomena—such as the presence of immune system cells, tumor angiogenesis, and metastasis—may be located deep in tissue. Previously, we developed a new imaging technique to achieve high spatial resolution in sub-centimeter deep tissue phantoms named continuous-wave ultrasound-switchable fluorescence (CW-USF). The principle is to use a focused ultrasound wave to externally and locally switch on and off the fluorophore emission from a small volume (close to ultrasound focal volume). By making improvements in three aspects of this technique: excellent near-infrared USF contrast agents, a sensitive frequency-domain USF imaging system, and an effective signal processing algorithm, for the first time this study has achieved high spatial resolution (~ 900 μm) in 3-centimeter-deep tissue phantoms with high signal-to-noise ratio (SNR) and high sensitivity (3.4 picomoles of fluorophore in a volume of 68 nanoliters can be detected). We have achieved these results in both tissue-mimic phantoms and porcine muscle tissues. We have also demonstrated multi-color USF to image and distinguish two fluorophores with different wavelengths, which might be very useful for simultaneously imaging of multiple targets and observing their interactions in the future. This work has opened the door for future studies of high-resolution centimeter-deep tissue fluorescence imaging. PMID:27829050

  1. High-Resolution Ultrasound-Switchable Fluorescence Imaging in Centimeter-Deep Tissue Phantoms with High Signal-To-Noise Ratio and High Sensitivity via Novel Contrast Agents.

    PubMed

    Cheng, Bingbing; Bandi, Venugopal; Wei, Ming-Yuan; Pei, Yanbo; D'Souza, Francis; Nguyen, Kytai T; Hong, Yi; Yuan, Baohong

    2016-01-01

    For many years, investigators have sought after high-resolution fluorescence imaging in centimeter-deep tissue because many interesting in vivo phenomena-such as the presence of immune system cells, tumor angiogenesis, and metastasis-may be located deep in tissue. Previously, we developed a new imaging technique to achieve high spatial resolution in sub-centimeter deep tissue phantoms named continuous-wave ultrasound-switchable fluorescence (CW-USF). The principle is to use a focused ultrasound wave to externally and locally switch on and off the fluorophore emission from a small volume (close to ultrasound focal volume). By making improvements in three aspects of this technique: excellent near-infrared USF contrast agents, a sensitive frequency-domain USF imaging system, and an effective signal processing algorithm, for the first time this study has achieved high spatial resolution (~ 900 μm) in 3-centimeter-deep tissue phantoms with high signal-to-noise ratio (SNR) and high sensitivity (3.4 picomoles of fluorophore in a volume of 68 nanoliters can be detected). We have achieved these results in both tissue-mimic phantoms and porcine muscle tissues. We have also demonstrated multi-color USF to image and distinguish two fluorophores with different wavelengths, which might be very useful for simultaneously imaging of multiple targets and observing their interactions in the future. This work has opened the door for future studies of high-resolution centimeter-deep tissue fluorescence imaging.

  2. TEM8 May Be a Better Anti-Angiogenesis Target | Center for Cancer Research

    Cancer.gov

    Anti-angiogenesis agents have improved the efficacy of many treatment strategies for solid tumors, but their ability to inhibit tumor vasculature is often incomplete and comes at a price, namely, side effects that can harm normal tissues including blood vessels. As a result, tumor angiogenesis is seldom completely halted, and both angiogenesis and tumor growth inevitably progress.

  3. Combining dynamic contrast enhanced magnetic resonance imaging and microvessel density to assess the angiogenesis after PEI in a rabbit VX2 liver tumor model.

    PubMed

    Chen, Juan; Qian, Ting; Zhang, Huanhuan; Wei, Chunxiao; Meng, Fanhua; Yin, Huabin

    2016-02-01

    To evaluate the correlation between parameters of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and microvessel density (MVD) measurements in rabbit VX2 liver tumor models after percutaneous ethanol injection (PEI) and to observe influence of PEI on angiogenesis in a rabbit VX2 liver tumor model with dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Forty five New Zealand white rabbits were used in this study. VX2 tumor tissue blocks were implanted in the left lobe of liver by percutaneous puncture under CT guidance. 2 weeks later, all rabbits underwent conventional MRI (T1WI, T2WI) to determine the successful models. Then those successful implanted VX2 liver tumor models in the study were randomly divided into the control group and the experimental group, the former did not have processing, and the latter underwent PEI under CT guidance. MRI (T1WI, T2WI and DCE-MRI) was performed 1 week later again, the parameters of DCE-MRI (Ktrans, Kep, Ve and iAUC60) of viable tumor portions were observed. Then all the liver samples were processed for hematoxylin and eosin (H&E) staining and immunohistochemical staining for CD31 to determine MVD. At last, data (including DCE-MRI perfusion parameters and MVD) were compared between experimental and control groups, correlation of DCE-MRI perfusion parameters and MVD was evaluated. Twenty six VX2 liver tumor models underwent all examinations (thirteen models for each group) 1 week later after PEI. For the experimental group, the parameters Ktrans (r=0.6382, P=0.0189) and iAUC60 (r=0.6591, P=0.0143) in viable tumor portions were positively moderately correlated with MVD, whereas the parameters Kep (r=0.4656, P=0.1088) and Ve (r=0.2918, P=0.3333) were not correlated with MVD. For the control group, the parameters Ktrans (r=0.6385, P=0.0188) and iAUC60 (r=0.6391, P=0.0187) in viable tumor portions were also positively moderately correlated with MVD, while the parameters Kep (r=0.5518, P=0.0506) and Ve (r

  4. Multimeric Near IR–MR Contrast Agent for Multimodal In Vivo Imaging

    PubMed Central

    2015-01-01

    Multiple imaging modalities are often required for in vivo imaging applications that require both high probe sensitivity and excellent spatial and temporal resolution. In particular, MR and optical imaging are an attractive combination that can be used to determine both molecular and anatomical information. Herein, we describe the synthesis and in vivo testing of two multimeric NIR–MR contrast agents that contain three Gd(III) chelates and an IR-783 dye moiety. One agent contains a PEG linker and the other a short alkyl linker. These agents label cells with extraordinary efficacy and can be detected in vivo using both imaging modalities. Biodistribution of the PEGylated agent shows observable fluorescence in xenograft MCF7 tumors and renal clearance by MR imaging. PMID:26083313

  5. Positron emission tomography imaging of tumor angiogenesis with a (61/64)Cu-labeled F(ab')(2) antibody fragment.

    PubMed

    Hong, Hao; Zhang, Yin; Orbay, Hakan; Valdovinos, Hector F; Nayak, Tapas R; Bean, Jero; Theuer, Charles P; Barnhart, Todd E; Cai, Weibo

    2013-02-04

    The objective of this study was to characterize the in vitro and in vivo properties of the F(ab')(2) fragment of TRC105, a human/murine chimeric IgG1 monoclonal antibody that binds with high avidity to human and murine CD105 (i.e., endoglin), and investigate its potential for positron emission tomography (PET) imaging of tumor angiogenesis after (61/64)Cu-labeling. TRC105-F(ab')(2) of high purity was produced by pepsin digestion of TRC105, which was confirmed by SDS-PAGE, HPLC analysis, and mass spectrometry. (61/64)Cu-labeling of NOTA-TRC105-F(ab')(2) (NOTA denotes 1,4,7-triazacyclononane-1,4,7-triacetic acid) was achieved with yields of >75% (specific activity: ∼115 GBq/μmol). PET imaging revealed rapid tumor uptake of (64)Cu-NOTA-TRC105-F(ab')(2) in the 4T1 murine breast cancer model (5.8 ± 0.8, 7.6 ± 0.6, 5.6 ± 0.4, 5.0 ± 0.6, and 3.8 ± 0.7% ID/g at 0.5, 3, 16, 24, and 48 h postinjection respectively; n = 4). Since tumor uptake peaked at 3 h postinjection, (61)Cu-NOTA-TRC105-F(ab')(2) also gave good tumor contrast at 3 and 8 h postinjection. CD105 specificity of the tracers was confirmed by blocking studies and histopathology. In conclusion, the use of a F(ab')(2) fragment led to more rapid tumor uptake (which peaked at 3 h postinjection) than radiolabeled intact antibody (which often peaked after 24 h postinjection), which may allow for same day immunoPET imaging in future clinical studies.

  6. Cannabidiol inhibits angiogenesis by multiple mechanisms

    PubMed Central

    Solinas, M; Massi, P; Cantelmo, AR; Cattaneo, MG; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, LM; Noonan, DM; Albini, A; Parolaro, D

    2012-01-01

    BACKGROUND AND PURPOSE Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. EXPERIMENTAL APPROACH Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability – through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis – and in vitro motility – both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. KEY RESULTS CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. CONCLUSIONS AND IMPLICATIONS This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. PMID:22624859

  7. Ultrasound contrast agent imaging: Real-time imaging of the superharmonics

    NASA Astrophysics Data System (ADS)

    Peruzzini, D.; Viti, J.; Tortoli, P.; Verweij, M. D.; de Jong, N.; Vos, H. J.

    2015-10-01

    Currently, in medical ultrasound contrast agent (UCA) imaging the second harmonic scattering of the microbubbles is regularly used. This scattering is in competition with the signal that is caused by nonlinear wave propagation in tissue. It was reported that UCA imaging based on the third or higher harmonics, i.e. "superharmonic" imaging, shows better contrast. However, the superharmonic scattering has a lower signal level compared to e.g. second harmonic signals. This study investigates the contrast-to-tissue ratio (CTR) and signal to noise ratio (SNR) of superharmonic UCA scattering in a tissue/vessel mimicking phantom using a real-time clinical scanner. Numerical simulations were performed to estimate the level of harmonics generated by the microbubbles. Data were acquired with a custom built dual-frequency cardiac phased array probe. Fundamental real-time images were produced while beam formed radiofrequency (RF) data was stored for further offline processing. The phantom consisted of a cavity filled with UCA surrounded by tissue mimicking material. The acoustic pressure in the cavity of the phantom was 110 kPa (MI = 0.11) ensuring non-destructivity of UCA. After processing of the acquired data from the phantom, the UCA-filled cavity could be clearly observed in the images, while tissue signals were suppressed at or below the noise floor. The measured CTR values were 36 dB, >38 dB, and >32 dB, for the second, third, and fourth harmonic respectively, which were in agreement with those reported earlier for preliminary contrast superharmonic imaging. The single frame SNR values (in which `signal' denotes the signal level from the UCA area) were 23 dB, 18 dB, and 11 dB, respectively. This indicates that noise, and not the tissue signal, is the limiting factor for the UCA detection when using the superharmonics in nondestructive mode.

  8. Ultrasound contrast agent imaging: Real-time imaging of the superharmonics

    SciTech Connect

    Peruzzini, D.; Viti, J.; Tortoli, P.; Verweij, M. D.; Jong, N. de; Vos, H. J.

    2015-10-28

    Currently, in medical ultrasound contrast agent (UCA) imaging the second harmonic scattering of the microbubbles is regularly used. This scattering is in competition with the signal that is caused by nonlinear wave propagation in tissue. It was reported that UCA imaging based on the third or higher harmonics, i.e. “superharmonic” imaging, shows better contrast. However, the superharmonic scattering has a lower signal level compared to e.g. second harmonic signals. This study investigates the contrast-to-tissue ratio (CTR) and signal to noise ratio (SNR) of superharmonic UCA scattering in a tissue/vessel mimicking phantom using a real-time clinical scanner. Numerical simulations were performed to estimate the level of harmonics generated by the microbubbles. Data were acquired with a custom built dual-frequency cardiac phased array probe. Fundamental real-time images were produced while beam formed radiofrequency (RF) data was stored for further offline processing. The phantom consisted of a cavity filled with UCA surrounded by tissue mimicking material. The acoustic pressure in the cavity of the phantom was 110 kPa (MI = 0.11) ensuring non-destructivity of UCA. After processing of the acquired data from the phantom, the UCA-filled cavity could be clearly observed in the images, while tissue signals were suppressed at or below the noise floor. The measured CTR values were 36 dB, >38 dB, and >32 dB, for the second, third, and fourth harmonic respectively, which were in agreement with those reported earlier for preliminary contrast superharmonic imaging. The single frame SNR values (in which ‘signal’ denotes the signal level from the UCA area) were 23 dB, 18 dB, and 11 dB, respectively. This indicates that noise, and not the tissue signal, is the limiting factor for the UCA detection when using the superharmonics in nondestructive mode.

  9. X-ray spatial frequency heterodyne imaging of protein-based nanobubble contrast agents

    PubMed Central

    Rand, Danielle; Uchida, Masaki; Douglas, Trevor; Rose-Petruck, Christoph

    2014-01-01

    Spatial Frequency Heterodyne Imaging (SFHI) is a novel x-ray scatter imaging technique that utilizes nanoparticle contrast agents. The enhanced sensitivity of this new technique relative to traditional absorption-based x-ray radiography makes it promising for applications in biomedical and materials imaging. Although previous studies on SFHI have utilized only metal nanoparticle contrast agents, we show that nanomaterials with a much lower electron density are also suitable. We prepared protein-based “nanobubble” contrast agents that are comprised of protein cage architectures filled with gas. Results show that these nanobubbles provide contrast in SFHI comparable to that of gold nanoparticles of similar size. PMID:25321797

  10. X-ray spatial frequency heterodyne imaging of protein-based nanobubble contrast agents.

    PubMed

    Rand, Danielle; Uchida, Masaki; Douglas, Trevor; Rose-Petruck, Christoph

    2014-09-22

    Spatial Frequency Heterodyne Imaging (SFHI) is a novel x-ray scatter imaging technique that utilizes nanoparticle contrast agents. The enhanced sensitivity of this new technique relative to traditional absorption-based x-ray radiography makes it promising for applications in biomedical and materials imaging. Although previous studies on SFHI have utilized only metal nanoparticle contrast agents, we show that nanomaterials with a much lower electron density are also suitable. We prepared protein-based "nanobubble" contrast agents that are comprised of protein cage architectures filled with gas. Results show that these nanobubbles provide contrast in SFHI comparable to that of gold nanoparticles of similar size.

  11. Platelets and angiogenesis in malignancy.

    PubMed

    Sierko, Ewa; Wojtukiewicz, Marek Z

    2004-02-01

    There is increasing evidence that platelets play an important role in the process of tumor angiogenesis. Thrombocytosis is a frequent finding in cancer patients (10-57%). Although the mechanisms underlying thrombocytosis are not yet fully elucidated, tumor-derived factors with thrombopoietin-like activity and growth factors, platelet-derived microparticles, and factors secreted from bone marrow endothelial cells, as well as growth factors released by megakaryocytes (acting via an autocrine loop), are postulated to influence this process. The progression of cancer is associated with hypercoagulability, which results from direct influences of tumor cells and diverse indirect mechanisms. Activated platelets serve as procoagulant surfaces amplifying the coagulation reactions. It is well known that hemostatic proteins are involved in different steps of the angiogenic process. Furthermore, platelets adhering to endothelium facilitate adhesion of mononuclear cells (which exert various proangiogenic activities) to endothelial cells and their transmigration to the extravascular space. It was also documented that platelets induce angiogenesis in vivo. Platelets are a rich source of proangiogenic factors. They also store and release angiogenesis inhibitors. In addition, platelets express surface growth factor receptors, which may regulate the process of angiogenesis. Platelets also contribute directly to the process of basement membrane and extracellular matrix proteolysis by releasing proteinases, or indirectly via inducing endothelial cells and tumor cells to release proteolytic enzymes, as well as through the proteolytic activities of platelet-derived growth factors. The multidirectional activities of platelets in the process of new blood vessel formation during tumor development and metastasis formation may create the possibility of introducing antiplatelet agents for antiangiogenic therapy in cancer patients. Thus far experimental studies employing inhibitors of

  12. Soliton driven angiogenesis

    NASA Astrophysics Data System (ADS)

    Bonilla, L. L.; Carretero, M.; Terragni, F.; Birnir, B.

    2016-08-01

    Angiogenesis is a multiscale process by which blood vessels grow from existing ones and carry oxygen to distant organs. Angiogenesis is essential for normal organ growth and wounded tissue repair but it may also be induced by tumours to amplify their own growth. Mathematical and computational models contribute to understanding angiogenesis and developing anti-angiogenic drugs, but most work only involves numerical simulations and analysis has lagged. A recent stochastic model of tumour-induced angiogenesis including blood vessel branching, elongation, and anastomosis captures some of its intrinsic multiscale structures, yet allows one to extract a deterministic integropartial differential description of the vessel tip density. Here we find that the latter advances chemotactically towards the tumour driven by a soliton (similar to the famous Korteweg-de Vries soliton) whose shape and velocity change slowly. Analysing these collective coordinates paves the way for controlling angiogenesis through the soliton, the engine that drives this process.

  13. Experimental characterization, comparison and image quality assessment of two ultrasound contrast agents: Optison and Definity

    NASA Astrophysics Data System (ADS)

    Hughes, Amy C.; Day, Steven W.; Linte, Cristian A.; Schwarz, Karl Q.

    2016-04-01

    Microbubble-based contrast agents are commonly used in ultrasound imaging to help differentiate the blood pool from the endocardial wall. It is essential to use an agent which produces high image intensity relative to the surrounding tissue, commonly referred to contrast effect. When exposed to ultrasound waves, microbubbles produce an intense backscatter signal in addition to the contrast produced by the fluctuating size of the microbubbles. However, over time, the microbubble concentration depletes, leading to reduced visual enhancement. The retention time associated with contrast effect varies according to the frequency and power level of the ultrasound wave, as well as the contrast agent used. The primary objective of this study was to investigate and identify the most appropriate image acquisition parameters that render optimal contrast effect for two intravenous contrast agents, Optison™ and Definity™. Several controlled in vitro experiments were conducted using an experimental apparatus that featured a perfused tissue-emulating phantom. A continuous flow of contrast agent was imaged using ultrasound at different frequencies and power levels, while a pulse wave Doppler device was used to monitor the concentration of the contrast agent solution. The contrast effect was determined based on the image intensity inside the flow pipe mimicking the blood-pool relative to the intensity of the surrounding phantom material mimicking cardiac tissue. To identify the combination of parameters that yielded optimal visualization for each contrast agent tested, the contrast effect was assessed at different microbubble concentrations and different ultrasound imaging frequencies and transmission power levels.

  14. Melanin-Based Contrast Agents for Biomedical Optoacoustic Imaging and Theranostic Applications

    PubMed Central

    Longo, Dario Livio; Aime, Silvio

    2017-01-01

    Optoacoustic imaging emerged in early 1990s as a new biomedical imaging technology that generates images by illuminating tissues with short laser pulses and detecting resulting ultrasound waves. This technique takes advantage of the spectroscopic approach to molecular imaging, and delivers high-resolution images in the depth of tissue. Resolution of the optoacoustic imaging is scalable, so that biomedical systems from cellular organelles to large organs can be visualized and, more importantly, characterized based on their optical absorption coefficient, which is proportional to the concentration of absorbing chromophores. Optoacoustic imaging was shown to be useful in both preclinical research using small animal models and in clinical applications. Applications in the field of molecular imaging offer abundant opportunities for the development of highly specific and effective contrast agents for quantitative optoacoustic imaging. Recent efforts are being made in the direction of nontoxic biodegradable contrast agents (such as nanoparticles made of melanin) that are potentially applicable in clinical optoacoustic imaging. In order to increase the efficiency and specificity of contrast agents and probes, they need to be made smart and capable of controlled accumulation in the target cells. This review was written in recognition of the potential breakthroughs in medical optoacoustic imaging that can be enabled by efficient and nontoxic melanin-based optoacoustic contrast agents. PMID:28783106

  15. Dynamic Contrast-Enhanced Magnetic Resonance Imaging Reveals Stress-Induced Angiogenesis in MCF7 Human Breast Tumors

    NASA Astrophysics Data System (ADS)

    Furman-Haran, Edna; Margalit, Raanan; Grobgeld, Dov; Degani, Hadassa

    1996-06-01

    The mechanism of contrast enhancement of tumors using magnetic resonance imaging was investigated in MCF7 human breast cancer implanted in nude mice. Dynamic contrast-enhanced images recorded at high spatial resolution were analyzed by an image analysis method based on a physiological model, which included the blood circulation, the tumor, the remaining tissues, and clearance via the kidneys. This analysis enabled us to map in rapidly enhancing regions within the tumor, the capillary permeability factor (capillary permeability times surface area per voxel volume) and the fraction of leakage space. Correlation of these maps with T2-weighted spin echo images, with histopathology, and with immunohistochemical staining of endothelial cells demonstrated the presence of dense permeable microcapillaries in the tumor periphery and in intratumoral regions that surrounded necrotic loci. The high leakage from the intratumoral permeable capillaries indicated an induction of a specific angiogenic process associated with stress conditions that cause necrosis. This induction was augmented in tumors responding to tamoxifen treatment. Determination of the distribution and extent of this stress-induced angiogenic activity by contrast-enhanced MRI might be of diagnostic and of prognostic value.

  16. Microscopic validation of whole mouse micro-metastatic tumor imaging agents using cryo-imaging and sliding organ image registration

    NASA Astrophysics Data System (ADS)

    Liu, Yiqiao; Zhou, Bo; Qutaish, Mohammed; Wilson, David L.

    2016-03-01

    We created a metastasis imaging, analysis platform consisting of software and multi-spectral cryo-imaging system suitable for evaluating emerging imaging agents targeting micro-metastatic tumor. We analyzed CREKA-Gd in MRI, followed by cryo-imaging which repeatedly sectioned and tiled microscope images of the tissue block face, providing anatomical bright field and molecular fluorescence, enabling 3D microscopic imaging of the entire mouse with single metastatic cell sensitivity. To register MRI volumes to the cryo bright field reference, we used our standard mutual information, non-rigid registration which proceeded: preprocess --> affine --> B-spline non-rigid 3D registration. In this report, we created two modified approaches: mask where we registered locally over a smaller rectangular solid, and sliding organ. Briefly, in sliding organ, we segmented the organ, registered the organ and body volumes separately and combined results. Though sliding organ required manual annotation, it provided the best result as a standard to measure other registration methods. Regularization parameters for standard and mask methods were optimized in a grid search. Evaluations consisted of DICE, and visual scoring of a checkerboard display. Standard had accuracy of 2 voxels in all regions except near the kidney, where there were 5 voxels sliding. After mask and sliding organ correction, kidneys sliding were within 2 voxels, and Dice overlap increased 4%-10% in mask compared to standard. Mask generated comparable results with sliding organ and allowed a semi-automatic process.

  17. Spectral Imaging Technology-Based Evaluation of Radiation Treatment Planning to Remove Contrast Agent Artifacts.

    PubMed

    Yi-Qun, Xu; Wei, Liu; Xin-Ye, Ni

    2016-10-01

    This study employs dual-source computed tomography single-spectrum imaging to evaluate the effects of contrast agent artifact removal and the computational accuracy of radiotherapy treatment planning improvement. The phantom, including the contrast agent, was used in all experiments. The amounts of iodine in the contrast agent were 30, 15, 7.5, and 0.75 g/100 mL. Two images with different energy values were scanned and captured using dual-source computed tomography (80 and 140 kV). To obtain a fused image, 2 groups of images were processed using single-energy spectrum imaging technology. The Pinnacle planning system was used to measure the computed tomography values of the contrast agent and the surrounding phantom tissue. The difference between radiotherapy treatment planning based on 80 kV, 140 kV, and energy spectrum image was analyzed. For the image with high iodine concentration, the quality of the energy spectrum-fused image was the highest, followed by that of the 140-kV image. That of the 80-kV image was the worst. The difference in the radiotherapy treatment results among the 3 models was significant. When the concentration of iodine was 30 g/100 mL and the distance from the contrast agent at the dose measurement point was 1 cm, the deviation values (P) were 5.95% and 2.20% when image treatment planning was based on 80 and 140 kV, respectively. When the concentration of iodine was 15 g/100 mL, deviation values (P) were -2.64% and -1.69%. Dual-source computed tomography single-energy spectral imaging technology can remove contrast agent artifacts to improve the calculated dose accuracy in radiotherapy treatment planning. © The Author(s) 2015.

  18. Green Synthesis of Sub-10 nm Gadolinium-Based Nanoparticles for Sparkling Kidneys, Tumor, and Angiogenesis of Tumor-Bearing Mice in Magnetic Resonance Imaging.

    PubMed

    Zhang, Bingbo; Yang, Weitao; Yu, Jiani; Guo, Weisheng; Wang, Jun; Liu, Shiyuan; Xiao, Yi; Shi, Donglu

    2017-02-01

    Gadolinium (Gd)-based nanoparticles are known for their high potential in magnetic resonance imaging (MRI). However, further MRI applications of these nanoparticles are hampered by their relatively large sizes resulting in poor organ/tumor targeting. In this study, ultrafine sub-10 nm and biocompatible Gd-based nanoparticles are synthesized in a bioinspired, environmentally benign, and straightforward fashion. This novel green synthetic strategy is developed for growing dextran-coated Gd-based nanoparticles (GdNPs@Dex). The as-prepared GdNPs@Dex is not only biocompatible but also stable with a sub-10 nm size. It exhibits higher longitudinal and transverse relaxivities in water (r1 and r2 values of 5.43 and 7.502 s(-1) × 10(-3) m(-1) of Gd(3+) , respectively) than those measured for Gd-DTPA solution (r1 and r2 values of 3.42 and 3.86 s(-1) × 10(-3) m(-1) of Gd(3+) , respectively). In vivo dynamic T1 -weighted MRI in tumor-bearing mice shows GdNPs@Dex can selectively target kidneys and tumor, in addition to liver and spleen. GdNPs@Dex is found particularly capable for determining the tumor boundary with clearly enhanced tumor angiogenesis. GdNPs@Dex is also found cleared from body gradually mainly via hepatobiliary and renal processing with no obvious systemic toxicity. With this green synthesis strategy, the sub-10 nm GdNPs@Dex presents promising potentials for translational biomedical imaging applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. A New F-18 Labeled PET Agent For Imaging Alzheimer's Plaques

    SciTech Connect

    Kulkarni, Padmakar V.; Hao Guiyang; Arora, Veera; Long, Michael; Slavine, Nikolai; Chiguru, Srinivas; Qu Baoxi; Sun Xiankai; Bennett, Michael; Antich, Peter P.; Bonte, Frederick J.; Vasdev, Neil

    2011-06-01

    Amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD). Advances in development of imaging agents have focused on targeting amyloid plaques. Notable success has been the development of C-11 labeled PIB (Pittsburgh Compound) and a number of studies have demonstrated the utility of this agent. However, the short half life of C-11 (t1/2: 20 min), is a limitation, thus has prompted the development of F-18 labeled agents. Most of these agents are derivatives of amyloid binding dyes; Congo red and Thioflavin. Some of these agents are in clinical trials with encouraging results. We have been exploring new class of agents based on 8-hydroxy quinoline, a weak metal chelator, targeting elevated levels of metals in plaques. Iodine-123 labeled clioquinol showed affinity for amyloid plaques however, it had limited brain uptake and was not successful in imaging in intact animals and humans. We have been successful in synthesizing F-18 labeled 8-hydroxy quinoline. Small animal PET/CT imaging studies with this agent showed high (7-10% ID/g), rapid brain uptake and fast washout of the agent from normal mice brains and delayed washout from transgenic Alzheimer's mice. These promising results encouraged us in further evaluation of this class of compounds for imaging AD plaques.

  20. A New F-18 Labeled PET Agent For Imaging Alzheimer's Plaques

    NASA Astrophysics Data System (ADS)

    Kulkarni, Padmakar V.; Vasdev, Neil; Hao, Guiyang; Arora, Veera; Long, Michael; Slavine, Nikolai; Chiguru, Srinivas; Qu, Bao Xi; Sun, Xiankai; Bennett, Michael; Antich, Peter P.; Bonte, Frederick J.

    2011-06-01

    Amyloid plaques and neurofibrillary tangles are hallmarks of Alzheimer's disease (AD). Advances in development of imaging agents have focused on targeting amyloid plaques. Notable success has been the development of C-11 labeled PIB (Pittsburgh Compound) and a number of studies have demonstrated the utility of this agent. However, the short half life of C-11 (t1/2: 20 min), is a limitation, thus has prompted the development of F-18 labeled agents. Most of these agents are derivatives of amyloid binding dyes; Congo red and Thioflavin. Some of these agents are in clinical trials with encouraging results. We have been exploring new class of agents based on 8-hydroxy quinoline, a weak metal chelator, targeting elevated levels of metals in plaques. Iodine-123 labeled clioquinol showed affinity for amyloid plaques however, it had limited brain uptake and was not successful in imaging in intact animals and humans. We have been successful in synthesizing F-18 labeled 8-hydroxy quinoline. Small animal PET/CT imaging studies with this agent showed high (7-10% ID/g), rapid brain uptake and fast washout of the agent from normal mice brains and delayed washout from transgenic Alzheimer's mice. These promising results encouraged us in further evaluation of this class of compounds for imaging AD plaques.

  1. Object oriented image analysis based on multi-agent recognition system

    NASA Astrophysics Data System (ADS)

    Tabib Mahmoudi, Fatemeh; Samadzadegan, Farhad; Reinartz, Peter

    2013-04-01

    In this paper, the capabilities of multi-agent systems are used in order to solve object recognition difficulties in complex urban areas based on the characteristics of WorldView-2 satellite imagery and digital surface model (DSM). The proposed methodology has three main steps: pre-processing of dataset, object based image analysis and multi-agent object recognition. Classified regions obtained from object based image analysis are used as input datasets in the proposed multi-agent system in order to modify/improve results. In the first operational level of the proposed multi-agent system, various kinds of object recognition agents modify initial classified regions based on their spectral, textural and 3D structural knowledge. Then, in the second operational level, 2D structural knowledge and contextual relations are used by agents for reasoning and modification. Evaluation of the capabilities of the proposed object recognition methodology is performed on WorldView-2 imagery over Rio de Janeiro (Brazil) which has been collected in January 2010. According to the obtained results of the object based image analysis process, contextual relations and structural descriptors have high potential to modify general difficulties of object recognition. Using knowledge based reasoning and cooperative capabilities of agents in the proposed multi-agent system in this paper, most of the remaining difficulties are decreased and the accuracy of object based image analysis results is improved for about three percent.

  2. MULTIFUNCTIONAL SYNTHETIC POLY(L-GLUTAMIC ACID)-BASED CANCER THERAPEUTIC AND IMAGING AGENTS

    PubMed Central

    Melancon, Marites P.

    2012-01-01

    Modern polymer chemistry has led to the generation of a number of biocompatible synthetic polymers have been increasingly studied as efficient carriers for drugs and imaging agents. Synthetic biocompatible polymers have been used to improve the efficacy of both small-molecular-weight therapeutics and imaging agents. Furthermore, multiple targeted anticancer agents and/or imaging reporters can be attached to a single polymer chain, allowing multifunctional and/or multimodality therapy and molecular imaging. Having both an anticancer drug and an imaging reporter in a single polymer chain allows noninvasive real-time visualization of the pharmacokinetics of polymeric drug delivery systems, which can uncover and explain the complicated mechanisms of in vivo drug delivery and their correlation to pharmacodynamics. This review examines use of the synthetic biocompatible polymer poly(L-glutamic acid) (PG) as an efficient carrier of cancer therapeutics and imaging agents. This review will summarize and update our recent research on use of PG as a platform for drug delivery and molecular imaging, including recent clinical findings with respect to PG-paclitaxel (PG-TXL); the combination of PG-TXL with radiotherapy; mechanisms of action of PG-TXL; and noninvasive visualization of in vivo delivery of polymeric conjugates with contrast-enhanced magnetic resonance imaging (MRI), optical imaging, and multimodality imaging. PMID:21303613

  3. Targeting Angiogenesis for Treatment of Human Cancer

    PubMed Central

    Somani, R. R.; Bhanushali, U. V.

    2013-01-01

    Recent advances in cancer research highlighted the importance of target-specific drug discovery. In view of these advances, the most important mechanism in tumour growth is its ability to stimulate the formation of blood capillaries around itself called tumour-driven angiogenesis. Hence targeting the angiogenesis, inhibits the growth of blood vessels around it and responsible for death of the tumour due to starvation and accumulation of toxic waste. The therapy, thus, indirectly cytotoxic to the tumour cells by targeting newly developing blood vessels. In this review, we summarised the various antiangiogenic agents with their clinical uses and current status. PMID:23901154

  4. Isonitrile radionuclide complexes for labelling and imaging agents

    DOEpatents

    Jones, Alun G.; Davison, Alan; Abrams, Michael J.

    1984-06-04

    A coordination complex of an isonitrile ligand and radionuclide such as Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta, is useful as a diagnostic agent for labelling liposomes or vesicles, and selected living cells containing lipid membranes, such as blood clots, myocardial tissue, gall bladder tissue, etc.

  5. Isonitrile radionuclide complexes for labelling and imaging agents

    SciTech Connect

    Jones, A.G.; Abrams, M.J.; Davison, A.

    1984-06-05

    A coordination complex of an isonitrile ligand and radionuclide such as Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta, is useful as a diagnostic agent for labelling liposomes or vesicles, and selected living cells containing lipid membranes, such as blood clots, myocardial tissue, gall bladder tissue, etc.

  6. Radioiodinated glucose analogues for use as imaging agents

    DOEpatents

    Goodman, Mark M.; Knapp, Jr., Furn F.

    1988-01-01

    A radioiodinated branched carbohydrate for tissue imaging. Iodine-123 is stabilized in the compound by attaching it to a vinyl functional group that is on the carbohydrate. The compound exhibits good uptake and retention and is promising in the development of radiopharmaceuticals for brain, heart and tumor imaging.

  7. Advances in CNS Imaging Agents: Focus on PET and SPECT Tracers in Experimental and Clinical Use.

    PubMed

    George, Noble; Gean, Emily G; Nandi, Ayon; Frolov, Boris; Zaidi, Eram; Lee, Ho; Brašić, James R; Wong, Dean F

    2015-04-01

    The physiological functioning of the brain is not well-known in current day medicine and the pathologies of many neuropsychiatric disorders are still not yet fully understood. With our aging population and better life expectancies, it has become imperative to find better biomarkers for disease progression as well as receptor target engagements. In the last decade, these major advances in the field of molecular CNS imaging have been made available with tools such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and neuroreceptor-targeted positron emission tomography (PET). These tools have given researchers, pharmaceutical companies, and clinical physicians a better method of understanding CNS dysfunctions, and the ability to employ improved therapeutic agents. This review is intended to provide an update on brain imaging agents that are currently used in clinical and translational research toward treatment of CNS disorders. The review begins with amyloid and tau imaging, the former of which has at least three [(18)F] agents that have been recently approved and will soon be available for clinical use for specific indications in the USA and elsewhere. Other prevalent PET and SPECT neurotransmitter system agents, including those newly US FDA-approved imaging agents related to the dopaminergic system, are included. A review of both mature and potentially growing PET imaging agents, including those targeting serotonin and opiate receptor systems, is also provided.

  8. Evaluating tumor angiogenesis.

    PubMed

    Uh, Minji K; Kandel, Jessica; Kitajewski, Jan

    2013-01-01

    The evaluation of tumor angiogenesis in pancreatic cancers involves determining the status of tumor vasculature and hypoxia in the tumor. Describing the nature and extent of tumor angiogenesis involves evaluating the expression of endothelial and perivascular cells within the tumor, and the expression of angiogenesis-related genes in tumor vasculature. Here we describe the methodology for assessment of tumor vasculature in murine mouse models of cancer. Specifically, we provide methodology for the evaluation of tumor hypoxia, tumor vessel perfusion, and chromogenic and fluorescent immunohistochemistry applied to tumor vascular analysis.

  9. Macromolecular Imaging Agents Containing Lanthanides: Can Conceptual Promise Lead to Clinical Potential?

    PubMed Central

    Bryson, Joshua; Reineke, Jeffrey W.; Reineke, Theresa M.

    2012-01-01

    Macromolecular magnetic resonance imaging (MRI) contrast agents are increasingly being used to improve the resolution of this noninvasive diagnostic technique. All clinically-approved T1 contrast agents are small molecule chelates of gadolinium [Gd(III)] that affect bound water proton relaxivity. Both the small size and monomeric nature of these agents ultimately limits the image resolution enhancement that can be achieved for both contrast enhancement and pharmacokinetic/biodistribution reasons. The multimeric nature of macromolecules, such as polymers, dendrimers, and noncovalent complexes of small molecule agents with proteins, have been shown to significantly increase the image contrast and resolution due to their large size and ability to incorporate multiple Gd(III) chlelation sites. Also, macromolecular agents are advantageous as they have the ability to be designed to be nontoxic, hydrophilic, easily purified, aggregation-resistant, and have controllable three-dimensional macromolecular structure housing the multiple lanthanide chelation sites. For these reasons, large molecule diagnostics have the ability to significantly increase the relaxivity of water protons within the targeted tissues and thus the image resolution for many diagnostic applications. The FDA approval of a contrast agent that consists of a reversible, non-covalent coupling of a small Gd(III) chelate with serum albumin for blood pool imaging (marketed under the trade names of Vasovist and Ablivar) proved to be one of the first diagnostic agent to capitalize on these benefits from macromolecular association in humans. However, much research and development is necessary to optimize the safety of these unique agents for in vivo use and potential clinical development. To this end, recent work in the field of polymer, dendrimer, and noncovalent complex-based imaging agents are reviewed herein and the future outlook of this field is discussed. PMID:23467737

  10. Small animal imaging platform for quantitative assessment of short-wave infrared-emitting contrast agents

    NASA Astrophysics Data System (ADS)

    Hu, Philip; Mingozzi, Marco; Higgins, Laura M.; Ganapathy, Vidya; Zevon, Margot; Riman, Richard E.; Roth, Charles M.; Moghe, Prabhas V.; Pierce, Mark C.

    2015-03-01

    We report the design, calibration, and testing of a pre-clinical small animal imaging platform for use with short-wave infrared (SWIR) emitting contrast agents. Unlike materials emitting at visible or near-infrared wavelengths, SWIR-emitting agents require detection systems with sensitivity in the 1-2 μm wavelength region, beyond the range of commercially available small animal imagers. We used a collimated 980 nm laser beam to excite rare-earth-doped NaYF4:Er,Yb nanocomposites, as an example of a SWIR emitting material under development for biomedical imaging applications. This beam was raster scanned across the animal, with fluorescence in the 1550 nm wavelength region detected by an InGaAs area camera. Background adjustment and intensity non-uniformity corrections were applied in software. The final SWIR fluorescence image was overlaid onto a standard white-light image for registration of contrast agent uptake with respect to anatomical features.

  11. Dynamic imaging of lymphatic vessels and lymph nodes using a bimodal nanoparticulate contrast agent.

    PubMed

    Mounzer, Rawad; Shkarin, Pavel; Papademetris, Xenophon; Constable, Todd; Ruddle, Nancy H; Fahmy, Tarek M

    2007-01-01

    Evaluation of lymphedema and lymph node metastasis in humans has relied primarily on invasive or radioactive modalities. While noninvasive technologies such as magnetic resonance imaging (MRI) offer the potential for true three-dimensional imaging of lymphatic structures, invasive modalities, such as optical fluorescence microscopy, provide higher resolution and clearer delineation of both lymph nodes and lymphatic vessels. Thus, contrast agents that image lymphatic vessels and lymph nodes by both fluorescence and MRI may further enhance our understanding of the structure and function of the lymphatic system. Recent applications of bimodal (fluorescence and MR) contrast agents in mice have not achieved clear visualization of lymphatic vessels and nodes. Here the authors describe the development of a nanoparticulate contrast agent that is taken up by lymphatic vessels to draining lymph nodes and detected by both modalities. A unique nanoparticulate contrast agent composed of a polyamidoamine dendrimer core conjugated to paramagnetic contrast agents and fluorescent probes was synthesized. Anesthetized mice were injected with the nanoparticulates in the hind footpads and imaged by MR and fluorescence microscopy. High resolution MR and fluorescence images were obtained and compared to traditional techniques for lymphatic visualization using Evans blue dye. Lymph nodes and lymphatic vessels were clearly observed by both MRI and fluorescence microscopy using the bimodal nanoparticulate contrast agent. Characteristic tail-lymphatics were also visualized by both modalities. Contrast imaging yielded a higher resolution than the traditional method employing Evans blue dye. MR data correlated with fluorescence and Evans blue dye imaging. A bimodal nanoparticulate contrast agent facilitates the visualization of lymphatic vessels and lymph nodes by both fluorescence microscopy and MRI with strong correlation between the two modalities. This agent may translate to applications

  12. GADOLINIUM(Gd)-BASED and Ion Oxide Nanoparticle Contrast Agents for Pre-Clinical and Clinical Magnetic Resonance Imaging (mri) Research

    NASA Astrophysics Data System (ADS)

    Ng, Thian C.

    2012-06-01

    It is known that one strength of MRI is its excellent soft tissue discrimination. It naturally provides sufficient contrast between the structural differences of normal and pathological tissues, their spatial extent and progression. However, to further extend its applications and enhance even more contrast for clinical studies, various Gadolinium (Gd)-based contrast agents have been developed for different organs (brain strokes, cancer, cardio-MRI, etc). These Gd-based contrast agents are paramagnetic compounds that have strong T1-effect for enhancing the contrast between tissue types. Gd-contrast can also enhance magnetic resonance angiography (CE-MRA) for studying stenosis and for measuring perfusion, vascular susceptibility, interstitial space, etc. Another class of contrast agents makes use of ferrite iron oxide nanoparticles (including Superparamagnetic Ion Oxide (SPIO) and Ultrasmall Superparamagnetic Iron Oxide (USPIO)). These nanoparticles have superior magnetic susceptibility effect and produce a drop in signal, namely in T2*-weighted images, useful for the determination of lymph nodes metastases, angiogenesis and arteriosclerosis plaques.

  13. Tumor imaging with novel radiogallium (67/68Ga) labeled agents

    NASA Astrophysics Data System (ADS)

    Kulkarni, P. V.; Antich, P. P.; Constantinescu, A.; Ranney, D. F.; Fernando, J. L.; Xiong, R.; Oz, O.; Parkey, R. W.

    1997-02-01

    Gallium-67 (t1/2: 78 h) has played an important role in tumor imaging. It is produced in a cyclotron and is commercially available for routine clinical use. 68Ga (t1/2: 68 min), a positron emitter, suitable for positron emission tomographic (PET) imaging, is obtained from a generator with long lived parent 68Ge (t1/2: 288 d). Radiogallium has been used mostly, as gallium citrate in imaging studies. Recently, receptor specific agents labeled with gallium have been developed. These include, agents to image somatostatin and folate receptors. We have shown that a new class of agents based on glycosaminoglycoans (GLYCOS) target a variety of tumors. Gallium labeled deferroxamine (DF) bound to sulfated glycosaminoglycans has the ability to rapidly target and permeate a wide variety of solid animal tumors and also undergo rapid blood clearance almost exclusively by the renal route. We have been able to image (within 5 min to 1 hr), prostate adenocarcinoma (AT-1 tumor) grown in surgically prepared pedicles of Copenhagen male rats and breast tumor in pedicles of Fisher female rats. 67Ga labeled agent was used in single photon imaging mode and 68Ga labeled agent was used in PET mode with a small animal PET imaging device built in our laboratory with plastic scintillating optical fibers.

  14. Phase-Change Contrast Agents for Imaging and Therapy

    PubMed Central

    Sheeran, Paul S.; Dayton, Paul A.

    2016-01-01

    Phase-change contrast agents (PCCAs) for ultrasound-based applications have resulted in novel ways of approaching diagnostic and therapeutic techniques beyond what is possible with microbubble contrast agents and liquid emulsions. When subjected to sufficient pressures delivered by an ultrasound transducer, stabilized droplets undergo a phase-transition to the gaseous state and a volumetric expansion occurs. This phenomenon, termed acoustic droplet vaporization, has been proposed as a means to address a number of in vivo applications at the microscale and nanoscale. In this review, the history of PCCAs, physical mechanisms involved, and proposed applications are discussed with a summary of studies demonstrated in vivo. Factors that influence the design of PCCAs are discussed, as well as the need for future studies to characterize potential bioeffects for administration in humans and optimization of ultrasound parameters. PMID:22352770

  15. Angiogenesis assays using chick chorioallantoic membrane.

    PubMed

    West, D C; Thompson, W D; Sells, P G; Burbridge, M F

    2001-01-01

    The study of the angiogenic process and the search for novel therapeutic agents to inhibit, or stimulate, angiogenesis has employed a wide range of in vivo 'angiogenesis' assays (reviewed in 1-3). These differ greatly in their difficulty, quantitative nature, rapidity, and cost. The classical in vivo models include the rabbit ear chamber, hamster cheek pouch, dorsal skin chamber, dorsal skin and air-sac model, anterior chamber/iris and avascular corneal pocket assay, and the chick embryo chorioallantoic membrane (CAM) assay. More recent methods involve the implantation of preloaded Matrigel or alginate plugs, or collagen or poly vinyl sponges (1). Largely owing to its simplicity and low cost, the CAM is the most widely used in vivo model for the study of both angiogenesis and antiangiogenesis (1,4).

  16. Magnetic nanobeads as potential contrast agents for magnetic resonance imaging.

    PubMed

    Pablico-Lansigan, Michele H; Hickling, William J; Japp, Emily A; Rodriguez, Olga C; Ghosh, Anup; Albanese, Chris; Nishida, Maki; Van Keuren, Edward; Fricke, Stanley; Dollahon, Norman; Stoll, Sarah L

    2013-10-22

    Metal-oxo clusters have been used as building blocks to form hybrid nanomaterials and evaluated as potential MRI contrast agents. We have synthesized a biocompatible copolymer based on a water stable, nontoxic, mixed-metal-oxo cluster, Mn8Fe4O12(L)16(H2O)4, where L is acetate or vinyl benzoic acid, and styrene. The cluster alone was screened by NMR for relaxivity and was found to be a promising T2 contrast agent, with r1 = 2.3 mM(-1) s(-1) and r2 = 29.5 mM(-1) s(-1). Initial cell studies on two human prostate cancer cell lines, DU-145 and LNCap, reveal that the cluster has low cytotoxicity and may be potentially used in vivo. The metal-oxo cluster Mn8Fe4(VBA)16 (VBA = vinyl benzoic acid) can be copolymerized with styrene under miniemulsion conditions. Miniemulsion allows for the formation of nanometer-sized paramagnetic beads (~80 nm diameter), which were also evaluated as a contrast agent for MRI. These highly monodispersed, hybrid nanoparticles have enhanced properties, with the option for surface functionalization, making them a promising tool for biomedicine. Interestingly, both relaxivity measurements and MRI studies show that embedding the Mn8Fe4 core within a polymer matrix decreases r2 effects with little effect on r1, resulting in a positive T1 contrast enhancement.

  17. Modeling angiogenesis with micro- and nanotechnology.

    PubMed

    Chen, Li-Jiun; Kaji, Hirokazu

    2017-10-05

    Angiogenesis plays an important role not only in the growth and regeneration of tissues in humans but also in pathological conditions such as inflammation, degenerative disease and the formation of tumors. Angiogenesis is also vital in thick engineered tissues and constructs, such as those for the heart and bone, as these can face difficulties in successful implantation if they are insufficiently vascularized or unable to connect to the host vasculature. Considerable research has been carried out on angiogenic processes using a variety of approaches. Pathological angiogenesis has been analyzed at the cellular level through investigation of cell migration and interactions, modeling tissue level interactions between engineered blood vessels and whole organs, and elucidating signaling pathways involved in different angiogenic stimuli. Approaches to regenerative angiogenesis in ischemic tissues or wound repair focus on the vascularization of tissues, which can be broadly classified into two categories: scaffolds to direct and facilitate tissue growth and targeted delivery of genes, cells, growth factors or drugs that promote the regeneration. With technological advancement, models have been designed and fabricated to recapitulate the innate microenvironment. Moreover, engineered constructs provide not only a scaffold for tissue ingrowth but a reservoir of agents that can be controllably released for therapeutic purposes. This review summarizes the current approaches for modeling pathological and regenerative angiogenesis in the context of micro-/nanotechnology and seeks to bridge these two seemingly distant aspects of angiogenesis. The ultimate aim is to provide insights and advances from various models in the realm of angiogenesis studies that can be applied to clinical situations.

  18. High-Relaxivity MRI Contrast Agents: Where Coordination Chemistry Meets Medical Imaging

    SciTech Connect

    Werner, Eric J.; Datta, Ankona; Jocher, Christoph J.; Raymond, Kenneth N.

    2008-01-15

    The desire to improve and expand the scope of clinical magnetic resonance imaging (MRI) has prompted the search for contrast agents of higher efficiency. The development of better agents requires consideration of the fundamental coordination chemistry of the gadolinium(III) ion and the parameters that affect its efficacy as a proton relaxation agent. In optimizing each parameter, other practical issues such as solubility and in vivo toxicity must also be addressed, making the attainment of safe, high-relaxivity agents a challenging goal. Here we present recent advances in the field, with an emphasis on the hydroxypyridinone family of Gd{sup III} chelates.

  19. Galectins in tumor angiogenesis

    PubMed Central

    Griffioen, Arjan W.

    2014-01-01

    The expansion of solid tumors depends on the continuous ingrowth of new blood vessels out of pre-existing capillaries. Consequently, tumor neovascularization or tumor angiogenesis is considered a hallmark of cancer and an attractive target for cancer therapy. Tumor angiogenesis is mainly carried out by endothelial cells (EC), i.e., the cells lining the luminal vessel wall. These cells have to take on different functional activities in order to successfully make new tumor blood vessels. In the last decade it has become apparent that galectins are important regulators of tumor angiogenesis. In the present review we summarize the current knowledge regarding the role galectins in tumor angiogenesis focussing on the endothelial galectins, i.e., gal-1/-3/-8/-9. PMID:25405165

  20. Magnetic resonance contrast media sensing in vivo molecular imaging agents: an overview.

    PubMed

    Amanlou, Massoud; Siadat, Seyed Davar; Norouzian, Dariush; Ebrahimi, Seyed Esmaeil Sadat; Aghasadeghi, Mohammad Reza; Ghorbani, Masoud; Alavidjeh, Mohammad Shafiee; Inanlou, Davoud Nouri; Arabzadeh, Ali Jabbari; Ardestani, Mehdi Shafiee

    2011-01-01

    Metabolic imaging is commonly performed by nuclear medicine facilities such as PET or SPECT, etc. The production and biomedical applications of bio-molecular sensing in vivo MRI metabolic contrast agents has recently become of great universal research interest, which follows its great success as a potential cost effective, less radioactive, nuclear medicine alternative. Temperature, redox potential, enzyme activity, free radial/metal ion responsive and/or pH sensitive molecular metabolic MR contrast agents are among the famous instances exemplified, which basically promote MR image contrast enhancement ability to distinguish molecular metabolic/gene expression features. Overall, these MRI contrast agents provide a framework to achieve a greater degree of accuracy from MRI as a low cost, more available facility, non radioactive radiation producing and highly sensitive biomedical tool to propound as a new suggesting opponent for PET nuclear medicine imaging. In the present review, the design, development, examination and future of the above agents will be discussed in detail.

  1. High-Accuracy Ultrasound Contrast Agent Detection Method for Diagnostic Ultrasound Imaging Systems.

    PubMed

    Ito, Koichi; Noro, Kazumasa; Yanagisawa, Yukari; Sakamoto, Maya; Mori, Shiro; Shiga, Kiyoto; Kodama, Tetsuya; Aoki, Takafumi

    2015-12-01

    An accurate method for detecting contrast agents using diagnostic ultrasound imaging systems is proposed. Contrast agents, such as microbubbles, passing through a blood vessel during ultrasound imaging are detected as blinking signals in the temporal axis, because their intensity value is constantly in motion. Ultrasound contrast agents are detected by evaluating the intensity variation of a pixel in the temporal axis. Conventional methods are based on simple subtraction of ultrasound images to detect ultrasound contrast agents. Even if the subject moves only slightly, a conventional detection method will introduce significant error. In contrast, the proposed technique employs spatiotemporal analysis of the pixel intensity variation over several frames. Experiments visualizing blood vessels in the mouse tail illustrated that the proposed method performs efficiently compared with conventional approaches. We also report that the new technique is useful for observing temporal changes in microvessel density in subiliac lymph nodes containing tumors. The results are compared with those of contrast-enhanced computed tomography.

  2. Polypyrrole Hollow Microspheres as Echogenic Photothermal Agent for Ultrasound Imaging Guided Tumor Ablation

    PubMed Central

    Zha, Zhengbao; Wang, Jinrui; Qu, Enze; Zhang, Shuhai; Jin, Yushen; Wang, Shumin; Dai, Zhifei

    2013-01-01

    Ultrasound (US) imaging provides a valuable opportunity to administer photothermal therapy (PTT) of cancer with real-time guidance to ensure proper targeting, but only a few theranostic agents were developed by physically grafting near infrared (NIR)-absorbing inorganic nanomaterials to ready-made ultrasound contrast agents (UCAs) for US imaging guided PTT. In this paper, NIR absorbing hollow microspheres were generated from polypyrrole merely using a facile one-step microemulsion method. It was found that the obtained polypyrrole hollow microspheres (PPyHMs) can act as an efficient theranostic agent not only to enhance US imaging greatly, but also exhibit excellent photohyperthermic effects. The contrast consistently sustained the echo signals for no less than 5 min and the NIR laser light ablated the tumor completely within two weeks in the presence of PPyHMs. More importantly, no use of additional NIR absorber substantially minimizes an onetime dose of the theranostic agent. PMID:23912977

  3. Modifying the size distribution of microbubble contrast agents for high-frequency subharmonic imaging

    PubMed Central

    Shekhar, Himanshu; Rychak, Joshua J.; Doyley, Marvin M.

    2013-01-01

    Purpose: Subharmonic imaging is of interest for high frequency (>10 MHz) nonlinear imaging, because it can specifically detect the response of ultrasound contrast agents (UCA). However, conventional UCA produce a weak subharmonic response at high frequencies, which limits the sensitivity of subharmonic imaging. We hypothesized that modifying the size distribution of the agent can enhance its high-frequency subharmonic response. The overall goal of this study was to investigate size-manipulated populations of the agent to determine the range of sizes that produce the strongest subharmonic response at high frequencies (in this case, 20 MHz). A secondary goal was to assess whether the number or the volume-weighted size distribution better represents the efficacy of the agent for high-frequency subharmonic imaging. Methods: The authors created six distinct agent size distributions from the native distribution of a commercially available UCA (Targestar-P®). The median (number-weighted) diameter of the native agent was 1.63 μm, while the median diameters of the size-manipulated populations ranged from 1.35 to 2.99 μm. The authors conducted acoustic measurements with native and size-manipulated agent populations to assess their subharmonic response to 20 MHz excitation (pulse duration 1.5 μs, pressure amplitudes 100–398 kPa). Results: The results showed a considerable difference between the subharmonic response of the agent populations that were investigated. The subharmonic response peaked for the agent population with a median diameter of 2.15 μm, which demonstrated a subharmonic signal that was 8 dB higher than the native agent. Comparing the subharmonic response of different UCA populations indicated that microbubbles with diameters between 1.3 and 3 μm are the dominant contributors to the subharmonic response at 20 MHz. Additionally, a better correlation was observed between the subharmonic response of the agent and the number-weighted size-distribution (R2

  4. Effects of nonlinear propagation in ultrasound contrast agent imaging.

    PubMed

    Tang, Meng-Xing; Kamiyama, Naohisa; Eckersley, Robert J

    2010-03-01

    This paper investigates two types of nonlinear propagation and their effects on image intensity and contrast-to-tissue ratio (CTR) in contrast ultrasound images. Previous studies have shown that nonlinear propagation can occur when ultrasound travels through tissue and microbubble clouds, making tissue farther down the acoustic path appear brighter in pulse inversion (PI) images, thus reducing CTR. In this study, the effect of nonlinear propagation through tissue or microbubbles on PI image intensity and CTR are compared at low mechanical index. A combination of simulation and experiment with SonoVue microbubbles were performed using a microbubble dynamics model, a laboratory ultrasound system and a clinical prototype scanner. The results show that, close to the bubble resonance frequency, nonlinear propagation through a bubble cloud of a few centimeter thickness with a modest concentration (1:10000 dilution of SonoVue microbubbles) is much more significant than through tissue-mimicking material. Consequently, CTR in regions distal to the imaging probe is greatly reduced for nonlinear propagation through the bubble cloud, with as much as a 12-dB reduction compared with nonlinear propagation through tissue-mimicking material. Both types of nonlinear propagation cause only a small change in bubble PI signals at the bubble resonance frequency. When the driving frequency increases beyond bubble resonance, nonlinear propagation through bubbles is greatly reduced in absolute values. However because of a greater reduction in nonlinear scattering from bubbles at higher frequencies, the corresponding CTR is much lower than that at bubble resonance frequency.

  5. PSMA-targeted contrast agents for intraoperative imaging of prostate cancer.

    PubMed

    Bao, Kai; Lee, Jeong Heon; Kang, Homan; Park, G Kate; El Fakhri, Georges; Choi, Hak Soo

    2017-02-04

    Prostate-specific membrane antigen (PSMA) can serve as a molecular cell surface target for the detection and treatment of prostate cancer. Near-infrared (NIR) fluorescence imaging enables highly sensitive, rapid, and non-radioactive imaging of PSMA, though specific targeting still remains a challenge because no optimized contrast agents exist.

  6. An activatable, polarity dependent, dual-luminescent imaging agent with a long luminescence lifetime.

    PubMed

    Rood, Marcus T M; Oikonomou, Maria; Buckle, Tessa; Raspe, Marcel; Urano, Yasuteru; Jalink, Kees; Velders, Aldrik H; van Leeuwen, Fijs W B

    2014-09-04

    In this proof-of-concept study, a new activatable imaging agent based on two luminophores and two different quenching mechanisms is reported. Both partial and total activation of the luminescence signal can be achieved, either in solution or in vitro. Bond cleavage makes the compound suitable for luminescence lifetime imaging.

  7. Synthesis and evaluation of a targeted nanoglobular dual-modal imaging agent for MR imaging and image-guided surgery of prostate cancer.

    PubMed

    Tan, Mingqian; Ye, Zhen; Lindner, Daniel; Brady-Kalnay, Susann M; Lu, Zheng-Rong

    2014-06-01

    To synthesize and evaluate a peptide targeted nanoglobular dual modal imaging agent specific to a cancer biomarker in tumor stroma for MRI and fluorescence visualization of prostate tumor in image-guided surgery. A peptide (CGLIIQKNEC, CLT1) targeted generation 2 nanoglobular (polylysine dendrimer with a silsesquioxane core) dual modal imaging agent, CLT1-G2-(Gd-DOTA-MA)-Cy5, was synthesized by stepwise conjugation of Gd-DOTA-MA, Cy5 and peptide to the dendrimer. Contrast enhanced MR imaging of the targeted dual imaging agent was evaluated on a Bruker 7T animal scanner with male athymic nude mice bearing orthotopic PC3-GFP prostate tumor. Fluorescence tumor imaging of the agent was carried out on a Maestro fluorescence imaging system. The targeted agent CLT1-G2-(Gd-DOTA-MA)-Cy5 produced greater contrast enhancement in the tumor tissue than the control agent KAREC-G2-(Gd-DOTA-MA)-Cy5 at a dose of 30 μmol-Gd/kg in the MR images of the tumor bearing mice. Signal-to-noise ratio (SNR) of CLT1-G2-(Gd-DOTA-MA)-Cy5 in the tumor tissue was approximately 2 fold of that of the control agent in the first 15 min post-injection. The targeted agent also resulted in bright fluorescence signals in the tumor tissue. The CLT1 peptide targeted nanoglobular dual-imaging agent CLT1-G2-(Gd-DOTA-MA)-Cy5 has a potential for MRI and fluorescence visualization of prostate tumor.

  8. Research into europium complexes as magnetic resonance imaging contrast agents (Review)

    PubMed Central

    HAN, GUOCAN; DENG, YANGWEI; SUN, JIHONG; LING, JUN; SHEN, ZHIQUAN

    2015-01-01

    Europium (Eu) is a paramagnetic lanthanide element that possesses an outstanding luminescent property. Eu complexes are ideal fluorescence imaging (FI) agents. Eu2+ has satisfactory relaxivity and optical properties, and can realize magnetic resonance (MRI)-FI dual imaging applications when used with appropriate cryptands that render it oxidatively stable. By contrast, based on the chemical exchange saturation transfer (CEST) mechanism, Eu3+ complexes can provide enhanced MRI sensitivity when used with optimal cryptands, incorporated into polymeric CEST agents or blended with Gd3+. Eu complexes are promising in MRI-FI dual imaging applications and have a bright future. PMID:26136858

  9. Combined ultrasound and photoacoustic imaging of pancreatic cancer using nanocage contrast agents

    NASA Astrophysics Data System (ADS)

    Homan, Kimberly; Shah, Jignesh; Gomez, Sobeyda; Gensler, Heidi; Karpiouk, Andrei; Brannon-Peppas, L.; Emelianov, Stanislav

    2009-02-01

    A new metallodielectric nanoparticle consisting of a silica core and silver outer cage was developed for the purpose of enhancing photoacoustic imaging contrast in pancreatic tissue. These nanocages were injected into an ex vivo porcine pancreas and imaged using a combined photoacoustic and ultrasound (PAUS) assembly. This custom-designed PAUS assembly delivered 800 nm light through a fiber optical light delivery system integrated with 128 element linear array transducer operating at 7.5 MHz center frequency. Imaging results prove that the nanocage contrast agents have the ability to enhance photoacoustic imaging contrast. Furthermore, the value of the combined PAUS imaging modality was demonstrated as the location of nanocages against background native tissue was evident. Future applications of these nanocage contrast agents could include targeting them to pancreatic cancer for enhancement of photoacoustic imaging for diagnosis and therapy.

  10. Motion corrected photoacoustic difference imaging of fluorescent contrast agents

    NASA Astrophysics Data System (ADS)

    Märk, Julia; Wagener, Asja; Pönick, Sarah; Grötzinger, Carsten; Zhang, Edward; Laufer, Jan

    2016-03-01

    In fluorophores, such as exogenous dyes and genetically expressed proteins, the excited state lifetime can be modulated using pump-probe excitation at wavelengths corresponding to the absorption and fluorescence spectra. Simultaneous pump-probe pulses induce stimulated emission (SE) which, in turn, modulates the thermalized energy, and hence the photoacoustic (PA) signal amplitude. For time-delayed pulses, by contrast, SE is suppressed. Since this is not observed in endogenous chromophores, the location of the fluorophore can be determined by subtracting images acquired using simultaneous and time-delayed pump-probe excitation. This simple experimental approach exploits a fluorophorespecific contrast mechanism, and has the potential to enable deep-tissue molecular imaging at fluences below the MPE. In this study, some of the challenges to its in vivo implementation are addressed. First, the PA signal amplitude generated in fluorophores in vivo is often much smaller than that in blood. Second, tissue motion can give rise to artifacts that correspond to endogenous chromophores in the difference image. This would not allow the unambiguous detection of fluorophores. A method to suppress motion artifacts based on fast switching between simultaneous and time-delayed pump-probe excitation was developed. This enables the acquisition of PA signals using the two excitation modes with minimal time delay (20 ms), thus minimizing the effects of tissue motion. The feasibility of this method is demonstrated by visualizing a fluorophore (Atto680) in tissue phantoms, which were moved during the image acquisition to mimic tissue motion.

  11. Bisphosphonate-Based Contrast Agents for Radiological Imaging of Microcalcifications

    DTIC Science & Technology

    2006-03-01

    treatment of patients with bone metastases [5]. Two such commercially available compounds are pamidronate disodium, available as Aredia® from...reaction has superior yield (>70%) to the 18-21% yield for pamidronate - IRDye-78 (LI-COR) conjugation reported previously [6]. Representative images are

  12. Development of contrast enhancing agents in magnetic resonance imaging.

    PubMed

    Lex, L

    1989-01-01

    Magnetic Resonance Imaging (MRI) is a powerful new diagnostic tool in medicine. In MRI there is a great need to improve the specific identification of different tissues i.e. to enhance the contrast between them. This review tries to cover most of the approaches known for solving this problem.

  13. A novel four-step system for screening angiogenesis inhibitors.

    PubMed

    Zhou, Qin; Qi, Cui-Ling; Li, Yan; He, Xiao-Dong; Li, Jiang-Chao; Zhang, Qian-Qian; Tian, Lan; Zhang, Ming; Han, Zhe; Wang, Huiping; Yang, Xuesong; Wang, Li-Jing

    2013-12-01

    Angiogenesis exhibits a significant effect on tumor progression. Inhibiting angiogenesis may provide significant advantages over currently available therapeutics for cancer therapies thus, the development of a system of screening angiogenesis is essential. In the present study, a novel available system of screening angiogenesis inhibitors by four steps was developed. The chorioallantoic membrane (CAM), yolk sac membrane and early chick embryo blood island assay were initially performed to obtain possible antitumor compounds. The MMTV‑PyMT transgenic breast cancer mouse model was used for final screening and to confirm potential antitumor effects. Four angiogenesis inhibitors were isolated from 480 compounds, which were obtained from ICCB known bioactives library, by a combination of the CAM, yolk sac membrane and early chick embryo blood island assay. The MMTV‑PyMT mouse was treated with one of four agents and it was demonstrated that the tumor volume was significantly inhibited. These results demonstrate that the four‑step screening system is feasible.

  14. Gold nanoclusters as contrast agents for fluorescent and X-ray dual-modality imaging.

    PubMed

    Zhang, Aili; Tu, Yu; Qin, Songbing; Li, Yan; Zhou, Juying; Chen, Na; Lu, Qiang; Zhang, Bingbo

    2012-04-15

    Multimodal imaging technique is an alternative approach to improve sensitivity of early cancer diagnosis. In this study, highly fluorescent and strong X-ray absorption coefficient gold nanoclusters (Au NCs) are synthesized as dual-modality imaging contrast agents (CAs) for fluorescent and X-ray dual-modality imaging. The experimental results show that the as-prepared Au NCs are well constructed with ultrasmall sizes, reliable fluorescent emission, high computed tomography (CT) value and fine biocompatibility. In vivo imaging results indicate that the obtained Au NCs are capable of fluorescent and X-ray enhanced imaging. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Fluorescent guided surgical resection of glioma using targeted molecular imaging agents: a literature review

    PubMed Central

    Craig, Sonya E.L.; Wright, James; Sloan, Andrew E.; Brady-Kalnay, Susann M.

    2016-01-01

    The median life expectancy following a diagnosis of glioblastoma (GBM) is 15 months. While chemotherapeutics may someday cure GBM by killing the highly dispersive malignant cells, the most important contribution that clinicians can currently offer to improve survival is by maximizing the extent of resection and providing concurrent chemo-radiation, which has become standard. Strides have been made in this area with the advent and implementation of methods of improved intraoperative tumor visualization. One of these techniques, optical fluorescent imaging with targeted molecular imaging agents, allows the surgeon to view fluorescently labeled tumor tissue during surgery with the use of special microscopy – thereby highlighting where to resect, and indicating when tumor-free margins have been obtained. This advantage is especially important at the difficult to observe margins where tumor cells infiltrate normal tissue. Targeted fluorescent agents also may be valuable for identifying tumor versus non-tumor tissue. In this review, we briefly summarize non-targeted fluorescent tumor imaging agents before discussing several novel targeted fluorescent agents being developed for glioma imaging in the context of fluorescent guided surgery or live molecular navigation. Many of these agents are currently undergoing preclinical testing. As the agents become available, however, it is necessary to understand the strengths and weaknesses of each. PMID:26915698

  16. HER2 Targeted Molecular MR Imaging Using a De Novo Designed Protein Contrast Agent

    PubMed Central

    Qiao, Jingjuan; Li, Shunyi; Wei, Lixia; Jiang, Jie; Long, Robert; Mao, Hui; Wei, Ling; Wang, Liya; Yang, Hua; Grossniklaus, Hans E.; Liu, Zhi-Ren; Yang, Jenny J.

    2011-01-01

    The application of magnetic resonance imaging (MRI) to non-invasively assess disease biomarkers has been hampered by the lack of desired contrast agents with high relaxivity, targeting capability, and optimized pharmacokinetics. We have developed a novel MR imaging probe targeting to HER2, a biomarker for various cancer types and a drug target for anti-cancer therapies. This multimodal HER20targeted MR imaging probe integrates a de novo designed protein contrast agent with a high affinity HER2 affibody and a near IR fluorescent dye. Our probe can differentially monitor tumors with different expression levels of HER2 in both human cell lines and xenograft mice models. In addition to its 100-fold higher dose efficiency compared to clinically approved non-targeting contrast agent DTPA, our developed agent also exhibits advantages in crossing the endothelial boundary, tissue distribution, and tumor tissue retention over reported contrast agents as demonstrated by even distribution of the imaging probe across the entire tumor mass. This contrast agent will provide a powerful tool for quantitative assessment of molecular markers, and improved resolution for diagnosis, prognosis and drug discovery. PMID:21455310

  17. Combined blood pool and extracellular contrast agents for pediatric and young adult cardiovascular magnetic resonance imaging.

    PubMed

    Johnson, Joyce T; Robinson, Joshua D; Deng, Jie; Rigsby, Cynthia K

    2016-12-01

    A comprehensive cardiac magnetic resonance (cardiac MR) study including both late gadolinium enhancement (LGE) and MR angiography may be indicated for patients with a history of acquired or congenital heart disease. To study the novel use of an extracellular agent for assessment of LGE combined with a blood pool contrast agent for detailed MR angiography evaluation to yield a comprehensive cardiac MR study in these patients. We reviewed clinical cardiac MR studies utilizing extracellular and blood pool contrast agents and noted demographics, clinical data and adverse events. We rated LGE image quality and MR angiography image quality for each vascular segment and calculated inter-rater variability. We also quantified contrast-to-noise ratio (CNR). Thirty-three patients (mean age 13.9 ± 3 years) received an extracellular contrast agent (10 gadobenate dimeglumine, 23 gadopentetate dimeglumine) and blood pool contrast agent (33 gadofosveset trisodium). No adverse events were reported. MRI indications included Kawasaki disease (8), cardiomyopathy and coronary anatomy (15), repaired congenital heart disease (8), and other (2). Mean LGE quality was 2.6 ± 0.6 with 97% diagnostic imaging. LGE quality did not vary by type of contrast agent given (P = 0.07). Mean MR angiography quality score was 4.7 ± 0.6, with high inter-rater agreement (k = 0.6-0.8, P < 0.002). MR angiography quality did not vary by type of contrast agent used (P = 0.6). Cardiac MR studies utilizing both extracellular and blood pool contrast agents are feasible and safe and provide excellent-quality LGE and MR angiography images. The use of two contrast agents allows for a comprehensive assessment of both myocardial viability and vascular anatomy during the same exam.

  18. Towards a framework for agent-based image analysis of remote-sensing data.

    PubMed

    Hofmann, Peter; Lettmayer, Paul; Blaschke, Thomas; Belgiu, Mariana; Wegenkittl, Stefan; Graf, Roland; Lampoltshammer, Thomas Josef; Andrejchenko, Vera

    2015-04-03

    Object-based image analysis (OBIA) as a paradigm for analysing remotely sensed image data has in many cases led to spatially and thematically improved classification results in comparison to pixel-based approaches. Nevertheless, robust and transferable object-based solutions for automated image analysis capable of analysing sets of images or even large image archives without any human interaction are still rare. A major reason for this lack of robustness and transferability is the high complexity of image contents: Especially in very high resolution (VHR) remote-sensing data with varying imaging conditions or sensor characteristics, the variability of the objects' properties in these varying images is hardly predictable. The work described in this article builds on so-called rule sets. While earlier work has demonstrated that OBIA rule sets bear a high potential of transferability, they need to be adapted manually, or classification results need to be adjusted manually in a post-processing step. In order to automate these adaptation and adjustment procedures, we investigate the coupling, extension and integration of OBIA with the agent-based paradigm, which is exhaustively investigated in software engineering. The aims of such integration are (a) autonomously adapting rule sets and (b) image objects that can adopt and adjust themselves according to different imaging conditions and sensor characteristics. This article focuses on self-adapting image objects and therefore introduces a framework for agent-based image analysis (ABIA).

  19. Towards a framework for agent-based image analysis of remote-sensing data

    PubMed Central

    Hofmann, Peter; Lettmayer, Paul; Blaschke, Thomas; Belgiu, Mariana; Wegenkittl, Stefan; Graf, Roland; Lampoltshammer, Thomas Josef; Andrejchenko, Vera

    2015-01-01

    Object-based image analysis (OBIA) as a paradigm for analysing remotely sensed image data has in many cases led to spatially and thematically improved classification results in comparison to pixel-based approaches. Nevertheless, robust and transferable object-based solutions for automated image analysis capable of analysing sets of images or even large image archives without any human interaction are still rare. A major reason for this lack of robustness and transferability is the high complexity of image contents: Especially in very high resolution (VHR) remote-sensing data with varying imaging conditions or sensor characteristics, the variability of the objects’ properties in these varying images is hardly predictable. The work described in this article builds on so-called rule sets. While earlier work has demonstrated that OBIA rule sets bear a high potential of transferability, they need to be adapted manually, or classification results need to be adjusted manually in a post-processing step. In order to automate these adaptation and adjustment procedures, we investigate the coupling, extension and integration of OBIA with the agent-based paradigm, which is exhaustively investigated in software engineering. The aims of such integration are (a) autonomously adapting rule sets and (b) image objects that can adopt and adjust themselves according to different imaging conditions and sensor characteristics. This article focuses on self-adapting image objects and therefore introduces a framework for agent-based image analysis (ABIA). PMID:27721916

  20. Neurosurgical confocal endomicroscopy: A review of contrast agents, confocal systems, and future imaging modalities

    PubMed Central

    Zehri, Aqib H.; Ramey, Wyatt; Georges, Joseph F.; Mooney, Michael A.; Martirosyan, Nikolay L.; Preul, Mark C.; Nakaji, Peter

    2014-01-01

    Background: The clinical application of fluorescent contrast agents (fluorescein, indocyanine green, and aminolevulinic acid) with intraoperative microscopy has led to advances in intraoperative brain tumor imaging. Their properties, mechanism of action, history of use, and safety are analyzed in this report along with a review of current laser scanning confocal endomicroscopy systems. Additional imaging modalities with potential neurosurgical utility are also analyzed. Methods: A comprehensive literature search was performed utilizing PubMed and key words: In vivo confocal microscopy, confocal endomicroscopy, fluorescence imaging, in vivo diagnostics/neoplasm, in vivo molecular imaging, and optical imaging. Articles were reviewed that discussed clinically available fluorophores in neurosurgery, confocal endomicroscopy instrumentation, confocal microscopy systems, and intraoperative cancer diagnostics. Results: Current clinically available fluorescent contrast agents have specific properties that provide microscopic delineation of tumors when imaged with laser scanning confocal endomicroscopes. Other imaging modalities such as coherent anti-Stokes Raman scattering (CARS) microscopy, confocal reflectance microscopy, fluorescent lifetime imaging (FLIM), two-photon microscopy, and second harmonic generation may also have potential in neurosurgical applications. Conclusion: In addition to guiding tumor resection, intraoperative fluorescence and microscopy have the potential to facilitate tumor identification and complement frozen section analysis during surgery by providing real-time histological assessment. Further research, including clinical trials, is necessary to test the efficacy of fluorescent contrast agents and optical imaging instrumentation in order to establish their role in neurosurgery. PMID:24872922

  1. Neurosurgical confocal endomicroscopy: A review of contrast agents, confocal systems, and future imaging modalities.

    PubMed

    Zehri, Aqib H; Ramey, Wyatt; Georges, Joseph F; Mooney, Michael A; Martirosyan, Nikolay L; Preul, Mark C; Nakaji, Peter

    2014-01-01

    The clinical application of fluorescent contrast agents (fluorescein, indocyanine green, and aminolevulinic acid) with intraoperative microscopy has led to advances in intraoperative brain tumor imaging. Their properties, mechanism of action, history of use, and safety are analyzed in this report along with a review of current laser scanning confocal endomicroscopy systems. Additional imaging modalities with potential neurosurgical utility are also analyzed. A COMPREHENSIVE LITERATURE SEARCH WAS PERFORMED UTILIZING PUBMED AND KEY WORDS: In vivo confocal microscopy, confocal endomicroscopy, fluorescence imaging, in vivo diagnostics/neoplasm, in vivo molecular imaging, and optical imaging. Articles were reviewed that discussed clinically available fluorophores in neurosurgery, confocal endomicroscopy instrumentation, confocal microscopy systems, and intraoperative cancer diagnostics. Current clinically available fluorescent contrast agents have specific properties that provide microscopic delineation of tumors when imaged with laser scanning confocal endomicroscopes. Other imaging modalities such as coherent anti-Stokes Raman scattering (CARS) microscopy, confocal reflectance microscopy, fluorescent lifetime imaging (FLIM), two-photon microscopy, and second harmonic generation may also have potential in neurosurgical applications. In addition to guiding tumor resection, intraoperative fluorescence and microscopy have the potential to facilitate tumor identification and complement frozen section analysis during surgery by providing real-time histological assessment. Further research, including clinical trials, is necessary to test the efficacy of fluorescent contrast agents and optical imaging instrumentation in order to establish their role in neurosurgery.

  2. Functional imaging using the retinal function imager: direct imaging of blood velocity, achieving fluorescein angiography-like images without any contrast agent, qualitative oximetry, and functional metabolic signals.

    PubMed

    Izhaky, David; Nelson, Darin A; Burgansky-Eliash, Zvia; Grinvald, Amiram

    2009-07-01

    The Retinal Function Imager (RFI; Optical Imaging, Rehovot, Israel) is a unique, noninvasive multiparameter functional imaging instrument that directly measures hemodynamic parameters such as retinal blood-flow velocity, oximetric state, and metabolic responses to photic activation. In addition, it allows capillary perfusion mapping without any contrast agent. These parameters of retinal function are degraded by retinal abnormalities. This review delineates the development of these parameters and demonstrates their clinical applicability for noninvasive detection of retinal function in several modalities. The results suggest multiple clinical applications for early diagnosis of retinal diseases and possible critical guidance of their treatment.

  3. PSMA-Activated Imaging Agents for Prostate Cancer

    DTIC Science & Technology

    2010-02-01

    PSMA-14 was observed in the cell extract , consistent with the ability of the highly charged carrier peptide to keep the agent out of cells, figure 2A...LNCaP Cell extract LNCaP 300nM JHD9784 Cell extract LNCaP 1uM JHD9784 pe rc en ta ge PSA-15 (JHD9784) cleavage assay Ph12ADT PhL12ADT JHD9784 0...10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Media, JHD9783 no cells Media + 300nM JHD9783, LNCaP Media + 1uM JHD9783, LNCaP Cell extract LNCaP

  4. Magnetic conjugated polymer nanoparticles as bimodal imaging agents.

    PubMed

    Howes, Philip; Green, Mark; Bowers, Alex; Parker, David; Varma, Gopal; Kallumadil, Mathew; Hughes, Mary; Warley, Alice; Brain, Anthony; Botnar, Rene

    2010-07-21

    Hybrid nanoparticles which incorporate multiple functionalities, such as fluorescence and magnetism, can exhibit enhanced efficiency and versatility by performing several tasks in parallel. In this study, magnetic-fluorescent semiconductor polymer nanospheres (MF-SPNs) have been synthesized by encapsulation of hydrophobic conjugated polymers and iron oxide nanoparticles in phospholipid micelles. Four fluorescent conjugated polymers were used, yielding aqueous dispersions of nanoparticles which emit across the visible spectrum. The MF-SPNs were shown to be magnetically responsive and simultaneously fluorescent. In MRI studies, they were seen to have a shortening effect on the transverse T(2)* relaxation time, which demonstrates their potential as an MR contrast agent. Finally, successful uptake of the MF-SPNs by SH-SY5Y neuroblastoma cells was demonstrated, and they were seen to behave as bright and stable fluorescent markers. There was no evidence of toxicity or adverse affect on cell growth.

  5. Amphetamines and pH-shift agents for brain imaging

    SciTech Connect

    Biersack, H.J.; Winkler, C.

    1986-01-01

    This book gives a review of the results of experimental and clinical research on both I-amphetamine derivatives and pH-shift agents. Virtually all relevant working groups from the USA and Europe have contributed to this volume. The pharmacology of amphetamine and the corresponding receptor theories are described in detail, whereas other chapters deal with the labeling as well as the metabolic process of this drug. In addition to this, new amphetamine derivatives are presented together with other essential products which play a significant role in scintigraphy of the brain function. Finally, there are two chapters on instrumentation problems followed by eight contributions on the clinical results of amphetamine scintigraphy in cerebral vascular diseases, epilepsy, migraine and brain tumors.

  6. Adaptive angiogenesis in placentas of heavy smokers.

    PubMed

    Pfarrer, C; Macara, L; Leiser, R; Kingdom, J

    1999-07-24

    Smoking in pregnancy increases perinatal morbidity and mortality, suggesting impaired placental function, though placental weight is increased. We used scanning electron microscopy to show adaptive angiogenesis in term placental villi from smokers (n=4) and non-smokers (n=4). These images may aid communication of the dangers of smoking in pregnancy.

  7. A dual function theranostic agent for near-infrared photoacoustic imaging and photothermal therapy

    NASA Astrophysics Data System (ADS)

    Upputuri, Paul Kumar; Huang, Shuo; Wang, Mingfeng; Pramanik, Manojit

    2016-03-01

    Theranostic, defined as combining diagnostic and therapeutic agents, has attracted more attention in biomedical application. It is essential to monitor diseased tissue before treatment. Photothermal therapy (PTT) is a promising treatment of cancer tissue due to minimal invasion, unharmful to normal tissue and high efficiency. Photoacoustic tomography (PAT) is a hybrid nonionizing biomedical imaging modality that combines rich optical contrast and high ultrasonic resolution in a single imaging modality. The near infra-red (NIR) wavelengths, usually used in PAT, can provide deep penetration at the expense of reduced contrast, as the blood absorption drops in the NIR range. Exogenous contrast agents with strong absorption in the NIR wavelength range can enhance the photoacoustic imaging contrast as well as imaging depth. Most theranostic agents incorporating PAT and PTT are inorganic nanomaterials that suffer from poor biocompatibility and biodegradability. Herein, we present an benzo[1,2-c;4,5-c'] bis[1,2,5] thiadiazole (BBT), based theranostic agent which not only acts as photoacoustic contrast agent but also a photothermal therapy agent. Experiments were performed on animal blood and organic nanoparticles embedded in a chicken breast tissue using PAT imaging system at ~803 nm wavelengths. Almost ten time contrast enhancement was observed from the nanoparticle in suspension. More than 6.5 time PA signal enhancement was observed in tissue at 3 cm depth. HeLa cell lines was used to test photothermal effect showing 90% cells were killed after 10 min laser irradiation. Our results indicate that the BBT - based naoparticles are promising theranostic agents for PAT imaging and cancer treatment by photothermal therapy.

  8. Correlating Molecular Character of NIR Imaging Agents with Tissue-Specific Uptake

    PubMed Central

    Owens, Eric A.; Hyun, Hoon; Tawney, Joseph G.; Choi, Hak Soo; Henary, Maged

    2015-01-01

    Near-infrared (NIR) fluorescent contrast agents are emerging in optical imaging as sensitive, cost-effective, and nonharmful alternatives to current agents that emit harmful ionizing radiation. Developing spectrally distinct NIR fluorophores to visualize sensitive vital tissues to selectively avoid them during surgical resection of diseased tissue is of great significance. Herein, we report the synthetic variation of pentamethine cyanine fluorophores with modifications of physicochemical properties toward prompting tissue-specific uptake into sensitive tissues (i.e., endocrine glands). Tissue-specific targeting and biodistribution studies revealed localization of contrast agents in the adrenal and pituitary glands, pancreas, and lymph nodes with dependence on molecular characteristics. Incorporation of hydrophobic heterocyclic rings, alkyl groups, and halogens allowed a fine-tuning capability to the hydrophobic character and dipole moment for observing perturbation in biological activity in response to minor structural alterations. These NIR contrast agents have potential for clinical translation for intraoperative imaging in the delineation of delicate glands. PMID:25923454

  9. Synthesis and characterization of ethosomal contrast agents containing iodine for computed tomography (CT) imaging applications.

    PubMed

    Shin, Hanjin; Cho, Young-Min; Lee, Kangtaek; Lee, Chang-Ha; Choi, Byoung Wook; Kim, Bumsang

    2014-06-01

    As a first step in the development of novel liver-specific contrast agents using ethosomes for computed tomography (CT) imaging applications, we entrapped iodine within ethosomes, which are phospholipid vesicular carriers containing relatively high alcohol concentrations, synthesized using several types of alcohol, such as methanol, ethanol, and propanol. The iodine containing ethosomes that were prepared using methanol showed the smallest vesicle size (392 nm) and the highest CT density (1107 HU). The incorporation of cholesterol into the ethosomal contrast agents improved the stability of the ethosomes but made the vesicle size large. The ethosomal contrast agents were taken up well by macrophage cells and showed no cellular toxicity. The results demonstrated that ethosomes containing iodine, as prepared in this study, have potential as contrast agents for applications in CT imaging.

  10. Diagnosis of Popliteal Venous Entrapment Syndrome by Magnetic Resonance Imaging Using Blood-Pool Contrast Agents

    SciTech Connect

    Beitzke, Dietrich Wolf, Florian; Juelg, Gregor; Lammer, Johannes; Loewe, Christian

    2011-02-15

    Popliteal vascular entrapment syndrome is caused by aberrations or hypertrophy of the gastrocnemius muscles, which compress the neurovascular structures of the popliteal fossa, leading to symptoms of vascular and degeneration as well as aneurysm formation. Imaging of popliteal vascular entrapment may be performed with ultrasound, magnetic resonance imaging (MRI), computed tomography angiography, and conventional angiography. The use of blood-pool contrast agents in MRI when popliteal vascular entrapment is suspected offers the possibility to perform vascular imaging with first-pass magnetic resonance angiographic, high-resolution, steady-state imaging and allows functional tests all within one examination with a single dose of contrast agent. We present imaging findings in a case of symptomatic popliteal vein entrapment diagnosed by the use of blood pool contrast-enhanced MRI.

  11. Nicotine and pathological angiogenesis.

    PubMed

    Lee, Jieun; Cooke, John P

    2012-11-27

    This paper describes the role of endothelial nicotinic acetylcholine receptors (nAChR) in diseases where pathological angiogenesis plays a role. An extensive review of the literature was performed, focusing on studies that investigated the effect of nicotine upon angiogenesis. Nicotine induces pathological angiogenesis at clinically relevant concentrations (i.e. at tissue and plasma concentrations similar to those of a light to moderate smoker). Nicotine promotes endothelial cell migration, proliferation, survival, tube formation and nitric oxide (NO) production in vitro, mimicking the effect of other angiogenic growth factors. These in vitro findings indicate that there may be an angiogenic component to the pathophysiology of major tobacco related diseases such as carcinoma, atherosclerosis, and age-related macular degeneration. Indeed, nicotine stimulates pathological angiogenesis in pre-clinical models of these disorders. Subsequently, it has been demonstrated that nicotine stimulates nAChRs on the endothelium to induce angiogenic processes, that these nAChRs are largely of the α7 homomeric type, and that there are synergistic interactions between the nAChRs and angiogenic growth factor receptors at the phosphoproteomic and genomic levels. These findings are of potential clinical relevance, and provide mechanistic insights into tobacco-related disease. Furthermore, these findings may lead to novel therapies for diseases characterized by insufficient or inappropriate angiogenesis. Copyright © 2012. Published by Elsevier Inc.

  12. The use of contrast agents with fast field-cycling magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Hógáin, Dara Ó.; Davies, Gareth R.; Baroni, Simona; Aime, Silvio; Lurie, David J.

    2011-01-01

    Fast field-cycling (FFC) MRI allows switching of the magnetic field during an imaging scan. FFC-MRI takes advantage of the T1 dispersion properties of contrast agents to improve contrast, thus enabling more sensitive detection of the agent. A new contrast agent designed specifically for use with FFC was imaged using both a homebuilt FFC-MRI system and a 3 T Philips clinical MRI scanner. T1 dispersion curves were obtained using a commercial relaxometer which showed large changes in relaxation rate between fields. A model of magnetization behaviour was used to predict optimum evolution times for the maximum T1 contrast between samples at each field. Images were processed and analysed to create maps of R1 values using a set of images at each field. The R1 maps produced at two different fields were then subtracted from each other in order to create a map of ΔR1 in which pixel values depend on the change in R1 of the sample between the two fields. The dispersion properties of the agent resulted in higher contrast in a ΔR1 image compared with a standard T1-weighted image.

  13. The use of contrast agents with fast field-cycling magnetic resonance imaging.

    PubMed

    Hógáin, Dara O; Davies, Gareth R; Baroni, Simona; Aime, Silvio; Lurie, David J

    2011-01-07

    Fast field-cycling (FFC) MRI allows switching of the magnetic field during an imaging scan. FFC-MRI takes advantage of the T(1) dispersion properties of contrast agents to improve contrast, thus enabling more sensitive detection of the agent. A new contrast agent designed specifically for use with FFC was imaged using both a homebuilt FFC-MRI system and a 3 T Philips clinical MRI scanner. T(1) dispersion curves were obtained using a commercial relaxometer which showed large changes in relaxation rate between fields. A model of magnetization behaviour was used to predict optimum evolution times for the maximum T(1) contrast between samples at each field. Images were processed and analysed to create maps of R(1) values using a set of images at each field. The R(1) maps produced at two different fields were then subtracted from each other in order to create a map of ΔR(1) in which pixel values depend on the change in R(1) of the sample between the two fields. The dispersion properties of the agent resulted in higher contrast in a ΔR(1) image compared with a standard T(1)-weighted image.

  14. In vivo photothermal optical coherence tomography for non-invasive imaging of endogenous absorption agents.

    PubMed

    Makita, Shuichi; Yasuno, Yoshiaki

    2015-05-01

    In vivo photothermal optical coherence tomography (OCT) is demonstrated for cross-sectional imaging of endogenous absorption agents. In order to compromise the sensitivity, imaging speed, and sample motion immunity, a new photothermal detection scheme and phase processing method are developed. Phase-resolved swept-source OCT and fiber-pigtailed laser diode (providing excitation at 406 nm) are combined to construct a high-sensitivity photothermal OCT system. OCT probe and excitation beam coaxially illuminate and are focused on tissues. The photothermal excitation and detection procedure is designed to obtain high efficiency of photothermal effect measurement. The principle and method of depth-resolved cross-sectional imaging of absorption agents with photothermal OCT has been derived. The phase-resolved thermal expansion detection algorithm without motion artifact enables in vivo detection of photothermal effect. Phantom imaging with a blood phantom and in vivo human skin imaging are conducted. A phantom with guinea-pig blood as absorber has been scanned by the photothermal OCT system to prove the concept of cross-sectional absorption agent imaging. An in vivo human skin measurement is also performed with endogenous absorption agents.

  15. Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study

    PubMed Central

    Ghasemian, Zeinab; Shahbazi-Gahrouei, Daryoush; Manouchehri, Sohrab

    2015-01-01

    Background: Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents. Methods: Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents. Results: Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM−1 s−1), respectively. Conclusion: The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works. PMID:26140183

  16. Cobalt Zinc Ferrite Nanoparticles as a Potential Magnetic Resonance Imaging Agent: An In vitro Study.

    PubMed

    Ghasemian, Zeinab; Shahbazi-Gahrouei, Daryoush; Manouchehri, Sohrab

    2015-01-01

    Magnetic Nanoparticles (MNP) have been used for contrast enhancement in Magnetic Resonance Imaging (MRI). In recent years, research on the use of ferrite nanoparticles in T2 contrast agents has shown a great potential application in MR imaging. In this work, Co0.5Zn0.5Fe2O4 and Co0.5Zn0.5Fe2O4-DMSA magnetic nanoparticles, CZF-MNPs and CZF-MNPs-DMSA, were investigated as MR imaging contrast agents. Cobalt zinc ferrite nanoparticles and their suitable coating, DMSA, were investigated under in vitro condition. Human prostate cancer cell lines (DU145 and PC3) with bare (uncoated) and coated magnetic nanoparticles were investigated as nano-contrast MR imaging agents. Using T2-weighted MR images identified that signal intensity of bare and coated MNPs was enhanced with increasing concentration of MNPs in water. The values of 1/T2 relaxivity (r2) for bare and coated MNPs were found to be 88.46 and 28.80 (mM (-1) s(-1)), respectively. The results show that bare and coated MNPs are suitable as T2-weighted MR imaging contrast agents. Also, the obtained r2/r1 values (59.3 and 50) for bare and coated MNPs were in agreement with the results of other previous relevant works.

  17. In vivo photothermal optical coherence tomography for non-invasive imaging of endogenous absorption agents

    PubMed Central

    Makita, Shuichi; Yasuno, Yoshiaki

    2015-01-01

    In vivo photothermal optical coherence tomography (OCT) is demonstrated for cross-sectional imaging of endogenous absorption agents. In order to compromise the sensitivity, imaging speed, and sample motion immunity, a new photothermal detection scheme and phase processing method are developed. Phase-resolved swept-source OCT and fiber-pigtailed laser diode (providing excitation at 406 nm) are combined to construct a high-sensitivity photothermal OCT system. OCT probe and excitation beam coaxially illuminate and are focused on tissues. The photothermal excitation and detection procedure is designed to obtain high efficiency of photothermal effect measurement. The principle and method of depth-resolved cross-sectional imaging of absorption agents with photothermal OCT has been derived. The phase-resolved thermal expansion detection algorithm without motion artifact enables in vivo detection of photothermal effect. Phantom imaging with a blood phantom and in vivo human skin imaging are conducted. A phantom with guinea-pig blood as absorber has been scanned by the photothermal OCT system to prove the concept of cross-sectional absorption agent imaging. An in vivo human skin measurement is also performed with endogenous absorption agents. PMID:26137374

  18. Poly(Lactic-co-Glycolic) Acid as a Carrier for Imaging Contrast Agents

    PubMed Central

    Doiron, Amber L.; Homan, Kimberly A.; Emelianov, Stanislav; Brannon-Peppas, Lisa

    2010-01-01

    Purpose With the broadening field of nanomedicine poised for future molecular level therapeutics, nano-and microparticles intended for the augmentation of either single- or multimodal imaging are created with PLGA as the chief constituent and carrier. Methods Emulsion techniques were used to encapsulate hydrophilic and hydrophobic imaging contrast agents in PLGA particles. The imaging contrast properties of these PLGA particles were further enhanced by reducing silver onto the PLGA surface, creating a silver cage around the polymeric core. Results The MRI contrast agent Gd-DTPA and the exogenous dye rhodamine 6G were both encapsulated in PLGA and shown to enhance MR and fluorescence contrast, respectively. The silver nanocage built around PLGA nanoparticles exhibited strong near infrared light absorbance properties, making it a suitable contrast agent for optical imaging strategies such as photoacoustic imaging. Conclusions The biodegradable polymer PLGA is an extremely versatile nano- and micro-carrier for several imaging contrast agents with the possibility of targeting diseased states at a molecular level. PMID:19034628

  19. Utilization of nanoparticles as X-ray contrast agents for diagnostic imaging applications.

    PubMed

    De La Vega, José Carlos; Häfeli, Urs O

    2015-01-01

    Among all the diagnostic imaging modalities, X-ray imaging techniques are the most commonly used owing to their high resolution and low cost. The improvement of these techniques relies heavily on the development of novel X-ray contrast agents, which are molecules that enhance the visibility of internal structures within the body in X-ray imaging. To date, clinically used X-ray contrast agents consist mainly of small iodinated molecules that might cause severe adverse effects (e.g. allergies, cardiovascular diseases and nephrotoxicity) in some patients owing to the large and repeated doses that are required to achieve good contrast. For this reason, there is an increasing interest in the development of alternative X-ray contrast agents utilizing elements with high atomic numbers (e.g. gold, bismuth, ytterbium and tantalum), which are well known for exhibiting high absorption of X-rays. Nanoparticles (NPs) made from these elements have been reported to have better imaging properties, longer blood circulation times and lower toxicity than conventional iodinated X-ray contrast agents. Additionally, the combination of two or more of these elements into a single carrier allows for the development of multimodal and hybrid contrast agents. Herein, the limitations of iodinated X-ray contrast agents are discussed and the parameters that influence the efficacy of X-ray contrast agents are summarized. Several examples of the design and production of both iodinated and iodine-free NP-based X-ray contrast agents are then provided, emphasizing the studies performed to evaluate their X-ray attenuation capabilities and their toxicity in vitro and in vivo.

  20. Mechanisms of ZnII-Activated Magnetic Resonance Imaging Agents

    PubMed Central

    Major, Jody L.; Boiteau, Rene M.; Meade, Thomas J.

    2009-01-01

    We report on the mechanism of a series of ZnII-activated magnetic resonance contrast agents that modulate the access of water to a paramagnetic GdIII ion to create an increase in relaxivity upon binding of ZnII. In the absence and presence of ZnII, the coordination at the GdIII center is modulated by appended ZnII binding groups. These groups were systematically varied to optimize the change in coordination upon ZnII binding. We observe that at least one appended aminoacetate must be present as a coordinating group to bind GdIII and effectively inhibit access of water. At least two binding groups are required to efficiently bind ZnII, creating an unsaturated complex and allowing access of water. 13C isotopic labeling of the acetate binding groups for NMR spectroscopy provides evidence of a change in the metal coordination of these groups upon the addition of ZnII supporting our proposed mechanism of activation as presented. PMID:18928280

  1. K-edge ratio method for identification of multiple nanoparticulate contrast agents by spectral CT imaging

    PubMed Central

    Ghadiri, H; Ay, M R; Shiran, M B; Soltanian-Zadeh, H

    2013-01-01

    Objective: Recently introduced energy-sensitive X-ray CT makes it feasible to discriminate different nanoparticulate contrast materials. The purpose of this work is to present a K-edge ratio method for differentiating multiple simultaneous contrast agents using spectral CT. Methods: The ratio of two images relevant to energy bins straddling the K-edge of the materials is calculated using an analytic CT simulator. In the resulting parametric map, the selected contrast agent regions can be identified using a thresholding algorithm. The K-edge ratio algorithm is applied to spectral images of simulated phantoms to identify and differentiate up to four simultaneous and targeted CT contrast agents. Results: We show that different combinations of simultaneous CT contrast agents can be identified by the proposed K-edge ratio method when energy-sensitive CT is used. In the K-edge parametric maps, the pixel values for biological tissues and contrast agents reach a maximum of 0.95, whereas for the selected contrast agents, the pixel values are larger than 1.10. The number of contrast agents that can be discriminated is limited owing to photon starvation. For reliable material discrimination, minimum photon counts corresponding to 140 kVp, 100 mAs and 5-mm slice thickness must be used. Conclusion: The proposed K-edge ratio method is a straightforward and fast method for identification and discrimination of multiple simultaneous CT contrast agents. Advances in knowledge: A new spectral CT-based algorithm is proposed which provides a new concept of molecular CT imaging by non-iteratively identifying multiple contrast agents when they are simultaneously targeting different organs. PMID:23934964

  2. Ytterbium-based PARACEST agent: feasibility of CEST imaging on a clinical MR scanner.

    PubMed

    Takayama, Yukihisa; Yoshiura, Takashi; Nishie, Akihiro; Nakayama, Tomohiro; Hatakenaka, Masamitsu; Kato, Naoki; Yoshise, Satoshi; Keupp, Jochen; Burdinski, Dirk; Honda, Hiroshi

    2012-01-01

    We investigated the feasibility of performing chemical exchange saturation transfer (CEST) imaging using ytterbium-based paramagnetic CEST (PARACEST) agents on a clinical magnetic resonance (MR) scanner. We prepared solutions of 3 different ytterbium-based PARACEST agents at concentrations of 5, 10, 20, and 50 mM at a pH of 7.4 and at a concentration of 50 mM at pHs of 3.0, 5.0, 7.4, and 9.5. We acquired images with a turbo spin echo technique using a quadrature head coil and a clinical 3.0-tesla MR system in accordance with the safety limits of the specific absorption rate (SAR). We acquired CEST images with presaturation offset frequencies from -5,000 Hz (-39.1 ppm) to 5,000 Hz (39.1 ppm) with an interval of 500 Hz (3.9 ppm) for each condition. We repeated each scan 3 times and then calculated the mean and standard deviations of the magnitude of the CEST effect at different concentrations and pH values for each agent. We used one-way analysis of variance and Tukey's honestly significant difference post hoc test to compare mean values of the magnitude of the CEST effect obtained at different concentrations and pH values. P < 0.05 was considered significant. PARACEST agents showed a strong CEST effect at their specific presaturation offset frequencies. For each agent, the CEST effect showed significant concentration dependency (P < 0.05), increasing with agent concentration, and significant pH dependency (P < 0.05), with strong effect near physiological pH. CEST imaging using ytterbium-based PARACEST agents might be feasible on a clinical MR scanner with further modifications, such as adjustments of the presaturation radiofrequency pulse and imaging protocols.

  3. Development of new brain imaging agents based upon nocaine-modafinil hybrid monoamine transporter inhibitors.

    PubMed

    Musachio, John L; Hong, Jinsoo; Ichise, Masanori; Seneca, Nicholas; Brown, Amira K; Liow, Jeih-San; Halldin, Christer; Innis, Robert B; Pike, Victor W; He, Rong; Zhou, Jia; Kozikowski, Alan P

    2006-06-15

    11C-labeled (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]ethanol ([11C]5) and (+)-trans-2-[[(3R,4S)-4-(4-chlorophenyl)-1-methylpiperidin-3-yl]methylsulfanyl]-1-(piperidin-1-yl)ethanone ([11C]6) were synthesized and evaluated as new imaging agents for the norepinephrine transporter (NET). [11C]5 and [11C]6 display high affinity for the NET in vitro (Ki = 0.94 and 0.68 nM, respectively) and significant selectivity over the dopamine (DAT) and serotonin transporters (SERT). Because of their high affinity and favorable transporter selectivities we speculated that these ligands might serve as useful PET agents for imaging NET in vivo. Contrary to our expectations, both of these ligands provided brain images that were more typical of those shown by agents binding to the DAT.

  4. Gd-based macromolecules and nanoparticles as magnetic resonance contrast agents for molecular imaging

    PubMed Central

    Huang, Ching-Hui; Tsourkas, Andrew

    2013-01-01

    As we move towards an era of personalized medicine, molecular imaging contrast agents are likely to see an increasing presence in routine clinical practice. Magnetic resonance (MR) imaging has garnered particular interest as a platform for molecular imaging applications due its ability to monitor anatomical changes concomitant with physiologic and molecular changes. One promising new direction in the development of MR contrast agents involves the labeling and/or loading of nanoparticles with gadolinium (Gd). These nanoplatforms are capable of carrying large payloads of Gd, thus providing the requisite sensitivity to detect molecular signatures within disease pathologies. In this review, we discuss some of the progress that has recently been made in the development of Gd-based macromolecules and nanoparticles and outline some of the physical and chemical properties that will be important to incorporate into the next generation of contrast agents, including high Gd chelate stability, high “relaxivity per particle” and “relaxivity density”, and biodegradability. PMID:23432004

  5. Nano-sized Contrast Agents to Non-Invasively Detect Renal Inflammation by Magnetic Resonance Imaging

    PubMed Central

    Thurman, Joshua M.; Serkova, Natalie J.

    2013-01-01

    Several molecular imaging methods have been developed that employ nano-sized contrast agents to detect markers of inflammation within tissues. Renal inflammation contributes to disease progression in a wide range of autoimmune and inflammatory diseases, and a biopsy is currently the only method of definitively diagnosing active renal inflammation. However, the development of new molecular imaging methods that employ contrast agents capable of detecting particular immune cells or protein biomarkers will allow clinicians to evaluate inflammation throughout the kidneys, and to assess a patient's response to immunomodulatory drugs. These imaging tools will improve our ability to validate new therapies and to optimize the treatment of individual patients with existing therapies. This review describes the clinical need for new methods of monitoring renal inflammation, and recent advances in the development of nano-sized contrast agents for detection of inflammatory markers of renal disease. PMID:24206601

  6. Intravenous ultrasound contrast agents versus other imaging methods in pediatric patients with neoplastic diseases - a comparison.

    PubMed

    Piskunowicz, Maciej; Kosiak, Wojciech; Batko, Tomasz; Adamkiewicz-Drożyńska, Elżbieta; Szarmach, Arkadiusz

    2013-12-01

    The lack of registration of ultrasound contrast agents for use in patients below the age of 18 is a significant limitation of their usage. Despite this, examinations with the use of contrast agents are conducted in numerous centers, mainly as part of the diagnostic process of vesicoureteral reflux. Examinations after an intravenous administration of contrast agents are conducted rarely. The reason for this is not only the lack of registration, but also the lack of studies on their safety profile in paediatric patients or no guidelines concerning the dosage. It seems that imaging with the use of such agents could help solve certain clinical problems when other diagnostic methods fail. The paper presents selected cases of pediatric patients treated in oncological departments, in whom the examination with the use of ultrasound contrast agents had a considerable influence on the diagnostic and therapeutic process.

  7. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  8. 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

  9. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    PubMed Central

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-01-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents. PMID:27147293

  10. Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design

    NASA Astrophysics Data System (ADS)

    Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily; Thurber, Greg M.

    2016-05-01

    Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared – non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.

  11. SRF in angiogenesis

    PubMed Central

    Franco, Claudio A

    2009-01-01

    Cell cytoskeleton proteins are fundamental to cell shape, cell adhesion and cell motility, and therefore play an important role during angiogenesis. One of the major regulators of cytoskeletal protein expression is serum response factor (SRF), a MADS-box transcription factor that regulates multiple genes implicated in cell growth, migration, cytoskeletal organization, energy metabolism and myogenesis. Recent data have demonstrated a crucial role of SRF downstream of VEGF and FGF signalling during sprouting angiogenesis, regulating endothelial cell (EC) migration, actin polymerisation, tip cell morphology, EC junction assembly and vascular integrity. Here, we review the role of SRF in the regulation of angiogenesis and EC function, integrate SRF function into a broader mechanism regulating branching morphogenesis, and discuss future directions and perspectives of SRF in EC biology. PMID:19287204

  12. Submicron polycaprolactone particles as a carrier for imaging contrast agent for in vitro applications.

    PubMed

    Iqbal, Muhammad; Robin, Sophie; Humbert, Philippe; Viennet, Céline; Agusti, Geraldine; Fessi, Hatem; Elaissari, Abdelhamid

    2015-12-01

    Fluorescent materials have recently attracted considerable attention due to their unique properties and high performance as imaging agent in biomedical fields. Different imaging agents have been encapsulated in order to restrict its delivery to a specific area. In this study, a fluorescent contrast agent was encapsulated for in vitro application by polycaprolactone (PCL) polymer. The encapsulation was performed using modified double emulsion solvent evaporation technique with sonication. Fluorescent nanoparticles (20 nm) were incorporated in the inner aqueous phase of double emulsion. A number of samples were fabricated using different concentrations of fluorescent contrast agent. The contrast agent-containing submicron particle was characterized by a zetasizer for average particle size, SEM and TEM for morphology observations and fluorescence spectrophotometer for encapsulation efficiency. Moreover, contrast agent distribution in the PCL matrix was determined by confocal microscopy. The incorporation of contrast agent in different concentrations did not affect the physicochemical properties of PCL particles and the average size of encapsulated particles was found to be in the submicron range. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Poly(iohexol) nanoparticles as contrast agents for in vivo X-ray computed tomography imaging.

    PubMed

    Yin, Qian; Yap, Felix Y; Yin, Lichen; Ma, Liang; Zhou, Qin; Dobrucki, Lawrence W; Fan, Timothy M; Gaba, Ron C; Cheng, Jianjun

    2013-09-18

    Biocompatible poly(iohexol) nanoparticles, prepared through cross-linking of iohexol and hexamethylene diisocyanate followed by coprecipitation of the resulting cross-linked polymer with mPEG-polylactide, were utilized as contrast agents for in vivo X-ray computed tomography (CT) imaging. Compared to conventional small-molecule contrast agents, poly(iohexol) nanoparticles exhibited substantially protracted retention within the tumor bed and a 36-fold increase in CT contrast 4 h post injection, which makes it possible to acquire CT images with improved diagnosis accuracy over a broad time frame without multiple administrations.

  14. Effects of the Magnetic Resonance Imaging Contrast Agent Gd-DTPA on Plant Growth and Root Imaging in Rice

    PubMed Central

    Liu, Binmei; Wang, Qi; Ni, Xiaoyu; Dong, Yaling; Zhong, Kai; Wu, Yuejin

    2014-01-01

    Although paramagnetic contrast agents have a wide range of applications in medical studies involving magnetic resonance imaging (MRI), these agents are seldom used to enhance MRI images of plant root systems. To extend the application of MRI contrast agents to plant research and to develop related techniques to study root systems, we examined the applicability of the MRI contrast agent Gd-DTPA to the imaging of rice roots. Specifically, we examined the biological effects of various concentrations of Gd-DTPA on rice growth and MRI images. Analysis of electrical conductivity and plant height demonstrated that 5 mmol Gd-DTPA had little impact on rice in the short-term. The results of signal intensity and spin-lattice relaxation time (T1) analysis suggested that 5 mmol Gd-DTPA was the appropriate concentration for enhancing MRI signals. In addition, examination of the long-term effects of Gd-DTPA on plant height showed that levels of this compound up to 5 mmol had little impact on rice growth and (to some extent) increased the biomass of rice. PMID:24945975

  15. Effects of the magnetic resonance imaging contrast agent Gd-DTPA on plant growth and root imaging in rice.

    PubMed

    Liu, Zan; Qian, Junchao; Liu, Binmei; Wang, Qi; Ni, Xiaoyu; Dong, Yaling; Zhong, Kai; Wu, Yuejin

    2014-01-01

    Although paramagnetic contrast agents have a wide range of applications in medical studies involving magnetic resonance imaging (MRI), these agents are seldom used to enhance MRI images of plant root systems. To extend the application of MRI contrast agents to plant research and to develop related techniques to study root systems, we examined the applicability of the MRI contrast agent Gd-DTPA to the imaging of rice roots. Specifically, we examined the biological effects of various concentrations of Gd-DTPA on rice growth and MRI images. Analysis of electrical conductivity and plant height demonstrated that 5 mmol Gd-DTPA had little impact on rice in the short-term. The results of signal intensity and spin-lattice relaxation time (T1) analysis suggested that 5 mmol Gd-DTPA was the appropriate concentration for enhancing MRI signals. In addition, examination of the long-term effects of Gd-DTPA on plant height showed that levels of this compound up to 5 mmol had little impact on rice growth and (to some extent) increased the biomass of rice.

  16. From angiogenesis to neuropathology

    NASA Astrophysics Data System (ADS)

    Greenberg, David A.; Jin, Kunlin

    2005-12-01

    Angiogenesis - the growth of new blood vessels - is a crucial force for shaping the nervous system and protecting it from disease. Recent advances have improved our understanding of how the brain and other tissues grow new blood vessels under normal and pathological conditions. Angiogenesis factors, especially vascular endothelial growth factor, are now known to have roles in the birth of new neurons (neurogenesis), the prevention or mitigation of neuronal injury (neuroprotection), and the pathogenesis of stroke, Alzheimer's disease and motor neuron disease. As our understanding of pathophysiology grows, these developments may point the way towards new molecular and cell-based therapies.

  17. ER Stress and Angiogenesis.

    PubMed

    Binet, François; Sapieha, Przemyslaw

    2015-10-06

    Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

  18. REGULATION OF VASCULOGENESIS AND ANGIOGENESIS

    EPA Science Inventory

    Regulation of vasculogenesis and angiogenesis.
    B.D. Abbott
    Reproductive Toxicology Division, Environmental Protection Agency, Research Triangle Park, North Carolina, USA
    Vasculogenesis and angiogenesis are regulated by a complex, interactive family of receptors and lig...

  19. REGULATION OF VASCULOGENESIS AND ANGIOGENESIS

    EPA Science Inventory

    Regulation of vasculogenesis and angiogenesis.
    B.D. Abbott
    Reproductive Toxicology Division, Environmental Protection Agency, Research Triangle Park, North Carolina, USA
    Vasculogenesis and angiogenesis are regulated by a complex, interactive family of receptors and lig...

  20. Notch in Pathological Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2012-05-01

    agent known as Notch1 decoy (hN1DFc). Activation or inactivation of Notch changes the gene profile of LEC and changes their in vitro behavior. An...induced transcripts for direct targets such as Hey1 and Hey2 (data not shown), as well as the LEC gene VEGFR-3 (Figure 2a). Interestingly, Notch...activity may interfere with tumor (lymph)angiogenesis by disrupting expression and activity of EC genes . To that end, we have created a treatment

  1. Optimization of oral contrast agents for MR imaging of the small bowel.

    PubMed

    Lauenstein, Thomas C; Schneemann, Herbert; Vogt, Florian M; Herborn, Christoph U; Ruhm, Stefan G; Debatin, Jorg F

    2003-07-01

    Effect on small-bowel distention of additives to water as contrast agents for magnetic resonance (MR) imaging was assessed. Oral contrast agents included water and water in combination with mannitol, a bulk fiber laxative, locust bean gum, and a combination of mannitol and locust bean gum. Filling of the small bowel was quantified on coronal images obtained with two-dimensional true fast imaging with steady-state precession sequence; bowel diameters were measured. Ingestion of water with locust bean gum and mannitol provided the best distention of the small bowel. MR imaging of the small bowel with oral administration of water can be improved with addition of osmotic and nonosmotic substances that lead to decreased water resorption.

  2. Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents.

    PubMed

    Estelrich, Joan; Sánchez-Martín, María Jesús; Busquets, Maria Antònia

    2015-01-01

    Magnetic resonance imaging (MRI) has become one of the most widely used and powerful tools for noninvasive clinical diagnosis owing to its high degree of soft tissue contrast, spatial resolution, and depth of penetration. MRI signal intensity is related to the relaxation times (T 1, spin-lattice relaxation and T 2, spin-spin relaxation) of in vivo water protons. To increase contrast, various inorganic nanoparticles and complexes (the so-called contrast agents) are administered prior to the scanning. Shortening T 1 and T 2 increases the corresponding relaxation rates, 1/T 1 and 1/T 2, producing hyperintense and hypointense signals respectively in shorter times. Moreover, the signal-to-noise ratio can be improved with the acquisition of a large number of measurements. The contrast agents used are generally based on either iron oxide nanoparticles or ferrites, providing negative contrast in T 2-weighted images; or complexes of lanthanide metals (mostly containing gadolinium ions), providing positive contrast in T 1-weighted images. Recently, lanthanide complexes have been immobilized in nanostructured materials in order to develop a new class of contrast agents with functions including blood-pool and organ (or tumor) targeting. Meanwhile, to overcome the limitations of individual imaging modalities, multimodal imaging techniques have been developed. An important challenge is to design all-in-one contrast agents that can be detected by multimodal techniques. Magnetoliposomes are efficient multimodal contrast agents. They can simultaneously bear both kinds of contrast and can, furthermore, incorporate targeting ligands and chains of polyethylene glycol to enhance the accumulation of nanoparticles at the site of interest and the bioavailability, respectively. Here, we review the most important characteristics of the nanoparticles or complexes used as MRI contrast agents.

  3. Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents

    PubMed Central

    Estelrich, Joan; Sánchez-Martín, María Jesús; Busquets, Maria Antònia

    2015-01-01

    Magnetic resonance imaging (MRI) has become one of the most widely used and powerful tools for noninvasive clinical diagnosis owing to its high degree of soft tissue contrast, spatial resolution, and depth of penetration. MRI signal intensity is related to the relaxation times (T1, spin–lattice relaxation and T2, spin–spin relaxation) of in vivo water protons. To increase contrast, various inorganic nanoparticles and complexes (the so-called contrast agents) are administered prior to the scanning. Shortening T1 and T2 increases the corresponding relaxation rates, 1/T1 and 1/T2, producing hyperintense and hypointense signals respectively in shorter times. Moreover, the signal-to-noise ratio can be improved with the acquisition of a large number of measurements. The contrast agents used are generally based on either iron oxide nanoparticles or ferrites, providing negative contrast in T2-weighted images; or complexes of lanthanide metals (mostly containing gadolinium ions), providing positive contrast in T1-weighted images. Recently, lanthanide complexes have been immobilized in nanostructured materials in order to develop a new class of contrast agents with functions including blood-pool and organ (or tumor) targeting. Meanwhile, to overcome the limitations of individual imaging modalities, multimodal imaging techniques have been developed. An important challenge is to design all-in-one contrast agents that can be detected by multimodal techniques. Magnetoliposomes are efficient multimodal contrast agents. They can simultaneously bear both kinds of contrast and can, furthermore, incorporate targeting ligands and chains of polyethylene glycol to enhance the accumulation of nanoparticles at the site of interest and the bioavailability, respectively. Here, we review the most important characteristics of the nanoparticles or complexes used as MRI contrast agents. PMID:25834422

  4. Multimodality PET/MR imaging agents targeted to activated macrophages

    PubMed Central

    Tu, Chuqiao; Ng, Thomas S. C.; Jacobs, Russell E.; Louie, Angelique Y.

    2013-01-01

    The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles (IONPs) have become a popular platform for the fabrication of PET/MRI probes due to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this paper, we report the synthesis of dextran coated iron oxide nanoparticles labeled with the positron emitter 64Cu to generate a PET/MRI probe, and modified with small molecular maleic anhydride to increase negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-64Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand-receptor found on activated macrophages but not on normal vessel walls. MDIO-64Cu-DOTA has an average iron oxide core size of 7-8 nm, an average hydrodynamic diameter of 62.7 nm, an r1 relaxivity of 16.8 mM−1·s−1, and an r2 relaxivity of 83.9 mM−1·s−1 (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the non-modified analog, the accumulation of maleylated DIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-64Cu-DOTA for identification of vulnerable atherosclerotic plaques (VAP) via the targeting of macrophages. PMID:24166283

  5. Cyanine dyes as contrast agents for near-infrared imaging in vivo: acute tolerance, pharmacokinetics, and fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Ebert, Bernd; Riefke, Björn; Sukowski, Uwe; Licha, Kai

    2011-06-01

    We compare pharmacokinetic, tolerance, and imaging properties of two near-IR contrast agents, indocyanine green (ICG) and 1,1'-bis-(4-sulfobutyl) indotricarbocyanine-5,5'-dicarboxylic acid diglucamide monosodium salt (SIDAG). ICG is a clinically approved imaging agent, and its derivative SIDAG is a more hydrophilic counterpart that has recently shown promising imaging properties in preclinical studies. The rather lipophilic ICG has a very short plasma half-life, thus limiting the time available to image body regions during its vascular circulation (e.g., the breast in optical mammography where scanning over several minutes is required). In order to change the physicochemical properties of the indotricarbocyanine dye backbone, several derivatives were synthesized with increasing hydrophilicity. The most hydrophilic dye SIDAG is selected for further biological characterization. The acute tolerance of SIDAG in mice is increased up to 60-fold compared to ICG. Contrary to ICG, the pharmacokinetic properties of SIDAG are shifted toward renal elimination, caused by the high hydrophilicity of the molecule. N-Nitrosomethylurea (NMU)-induced rat breast carcinomas are clearly demarcated, both immediately and 24 h after intravenous administration of SIDAG, whereas ICG shows a weak tumor contrast under the same conditions. Our findings demonstrate that SIDAG is a high potential contrast agent for optical imaging, which could increase the sensitivity for detection of inflamed regions and tumors.

  6. Carbon Dots as Nontoxic and High-Performance Fluorescence Imaging Agents

    PubMed Central

    Yang, Sheng-Tao; Wang, Xin; Wang, Haifang; Lu, Fushen; Luo, Pengju G.; Cao, Li; Meziani, Mohammed J.; Liu, Jia-Hui; Liu, Yuanfang; Chen, Min; Huang, Yipu; Sun, Ya-Ping

    2009-01-01

    Fluorescent carbon dots (small carbon nanoparticles with the surface passivated by oligomeric PEG molecules) were evaluated for their cytotoxicity and in vivo toxicity and also for their optical imaging performance in reference to that of the commercially supplied CdSe/ZnS quantum dots. The results suggested that the carbon dots were biocompatible, and their performance as fluorescence imaging agents was competitive. The implication to the use of carbon dots for in vitro and in vivo applications is discussed. PMID:20357893

  7. Technetium-99m Labeled Duramycin: A Novel Molecular Imaging Agent to Detect Apoptosis in Cardiovascular Pathologies

    NASA Astrophysics Data System (ADS)

    Chaudhry, Farhan

    Apoptosis underlines atherosclerosis and myocardial infarction/reperfusion (IR) injury. An imaging agent targeting apoptosis would increase the specificity of non-invasive imaging of apoptosis in these pathologies. Duramycin binds to phosphatidylethanolamine (PE) on the surface of apoptotic cells and can thus target apoptosis. In this study, technetium-99m labeled duramycin (TcD) was used to image both atherosclerosis and IR injury in rabbits using SPECT/CT. Rabbits were inflicted with atherosclerotic damage, IR injury, or were unmanipulated (control). Also, to assess for detection of therapeutic changes, a cardioprotective agent (minocycline) was used in IR rabbits. TcD, 99mTc-Annexin A5 (positive control), and linear TcD (Duramycin without the binding head to PE) were all imaged using SPECT/CT. Aortic or heart samples were collected with their respective organ samples for gamma counting and histopathology. After correlating the imaging, sample gamma counts, and the histopathology, TcD is a feasible imaging agent for apoptosis in atherosclerotic and IR injury.

  8. Palladium nanosheets as highly stable and effective contrast agents for in vivo photoacoustic molecular imaging

    NASA Astrophysics Data System (ADS)

    Nie, Liming; Chen, Mei; Sun, Xiaolian; Rong, Pengfei; Zheng, Nanfeng; Chen, Xiaoyuan

    2014-01-01

    A stable and efficient contrast agent is highly desirable for photoacoustic (PA) imaging applications. Recently gold nanostructures have been widely reported and studied for PA imaging and photothermal therapy. However, the structures of the nonspherical gold nanoparticles are easily destroyed after laser irradiation and thus may fail to complete the intended tasks. In this study, we propose to apply palladium nanosheets (PNSs), with strong optical absorption in the near-infrared (NIR) region, as a new class of exogenous PA contrast agents. PA and ultrasound (US) images were acquired sequentially by a portable and fast photoacoustic tomography (PAT) system with a hand-held transducer. Significant and long-lasting imaging enhancement in SCC7 head and neck squamous cell carcinoma was successfully observed in mice by PAT over time after tail vein administration of PNSs. The morphology and functional perfusion of the tumors were delineated in PA images due to the nanoparticle accumulation. PAT of the main organs was also conducted ex vivo to trace the fate of PNSs, which was further validated by inductively coupled plasma atomic emission spectrometry (ICP-AES). No obvious toxic effect was observed by in vitro MTT assay and ex vivo histological examination 7 days after PNS administration. With the combination of a portable imaging instrument and signal specificity, PNSs might be applied as stable and effective agents for photoacoustic cancer detection, diagnosis and treatment guidance.

  9. Gadolinium-Based Contrast Agents for Vessel Wall Magnetic Resonance Imaging (MRI) of Atherosclerosis

    PubMed Central

    Calcagno, Claudia; Ramachandran, Sarayu; Millon, Antoine; Robson, Philip M.; Mani, Venkatesh

    2012-01-01

    Cardiovascular disease due to atherosclerosis is the number one killer in the Western world, and threatens to become the major cause of morbidity and mortality worldwide. It is therefore paramount to develop non-invasive methods for the detection of high-risk, asymptomatic individuals before the onset of clinical symptoms or events. In the recent past, great strides have been made in the understanding of the pathological mechanisms involved in the atherosclerotic cascade down to the molecular details. This has allowed the development of contrast agents that can aid in the in vivo characterization of these processes. Gadolinium chelates are among the contrast media most commonly used in MR imaging. Originally used for MR angiography for the detection and quantification of vascular stenosis, more recently they have been applied to improve characterization of atherosclerotic plaques. In this manuscript, we will briefly review gadolinium-chelates (Gd) based contrast agents for non-invasive MR imaging of atherosclerosis. We will first describe Gd-based non-targeted FDA approved agents, used routinely in clinical practice for the evaluation of neovascularization in other diseases. Secondly, we will describe non-specific and specific targeted contrast agents, which have great potential for dissecting specific biological processes in the atherosclerotic cascade. Lastly, we will briefly compare Gd-based agents to others commonly used in MRI and to other imaging modalities. PMID:23539505

  10. Gadolinium-Based Contrast Agents for Vessel Wall Magnetic Resonance Imaging (MRI) of Atherosclerosis.

    PubMed

    Calcagno, Claudia; Ramachandran, Sarayu; Millon, Antoine; Robson, Philip M; Mani, Venkatesh; Fayad, Zahi

    2013-02-01

    Cardiovascular disease due to atherosclerosis is the number one killer in the Western world, and threatens to become the major cause of morbidity and mortality worldwide. It is therefore paramount to develop non-invasive methods for the detection of high-risk, asymptomatic individuals before the onset of clinical symptoms or events. In the recent past, great strides have been made in the understanding of the pathological mechanisms involved in the atherosclerotic cascade down to the molecular details. This has allowed the development of contrast agents that can aid in the in vivo characterization of these processes. Gadolinium chelates are among the contrast media most commonly used in MR imaging. Originally used for MR angiography for the detection and quantification of vascular stenosis, more recently they have been applied to improve characterization of atherosclerotic plaques. In this manuscript, we will briefly review gadolinium-chelates (Gd) based contrast agents for non-invasive MR imaging of atherosclerosis. We will first describe Gd-based non-targeted FDA approved agents, used routinely in clinical practice for the evaluation of neovascularization in other diseases. Secondly, we will describe non-specific and specific targeted contrast agents, which have great potential for dissecting specific biological processes in the atherosclerotic cascade. Lastly, we will briefly compare Gd-based agents to others commonly used in MRI and to other imaging modalities.

  11. Microbubbles as x-ray scattering contrast agents using analyzer-based imaging.

    PubMed

    Arfelli, F; Rigon, L; Menk, R H

    2010-03-21

    Conventional contrast agents utilized in diagnostic radiology are based on x-ray absorption properties; alternative physical principles capable of providing a contrast enhancement in radiographs have never been applied. This study exploits the possibility of using a novel type of contrast media based on x-ray scattering. The contrast agents consist of microbubble echo-enhancing agents, usually applied in ultrasound examinations, which are invisible with conventional x-ray absorption techniques. The experiment was carried out at the medical beamline of the synchrotron radiation laboratory ELETTRA in Trieste, Italy. A flat silicon analyzer crystal typically used for diffraction-enhanced imaging was utilized as a tool for detecting the scattering properties of the contrast agents. In analyzer-based imaging, it is possible to detect the scattering properties of the sample by shifting the analyzer crystal to selected positions of its reflectivity curve. In particular, when the sample consists of a large number of micro-particles an overall effect can be observed. Phantoms containing contrast agents based on microbubbles were imaged at different angular positions of the analyzer crystal. High visibility of the details was demonstrated, and a strong contrast enhancement was measured compared to normal x-ray absorption techniques.

  12. How phototherapy affects angiogenesis

    NASA Astrophysics Data System (ADS)

    Dyson, Mary

    2007-02-01

    Angiogenesis is essential for normal growth, tissue repair and regeneration. Its stimulation accelerates repair and regeneration including wound healing where these processes are delayed. Its inhibition can reduce the rate of growth of solid tumors. Phototherapy can accelerate the resolution of acute inflammation with the result that the proliferative phase of tissue repair, when angiogenesis occurs, begins earlier than in sham-irradiated controls. Evidence that angiogenesis is enhanced in dermal repair, tendon repair and bone regeneration in rodents is presented. The cellular mechanisms that control angiogenesis involve the interaction of endothelial cells, macrophages, pericytes and other cells in response, for example, to changes in the availability of oxygen in the local environment. Pericytes and macrophages modulate endothelial cell proliferation; pericytes guide endothelial cell migration. The stimulation of endothelial cell proliferation in vitro following exposure to red (660 nm) and infrared (820 nm) radiation, 15 mW, at 2-8 J/cm2 is presented. 1J/cm2 was ineffective. 820 nm irradiation, 15 mW, at 8 J/cm2 was observed to inhibit pericyte proliferation in vitro. Indirect effects on endothelial cell and pericyte proliferation followed stimulation of soluble mediator production by macrophages following exposure to red and infrared radiation. The potential clinical significance of the results obtained is discussed and the necessity of clinical trials emphasized.

  13. The Harvard angiogenesis story.

    PubMed

    Miller, Joan W

    2014-01-01

    I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.

  14. Automatic extraction of angiogenesis bioprocess from text

    PubMed Central

    Wang, Xinglong; McKendrick, Iain; Barrett, Ian; Dix, Ian; French, Tim; Tsujii, Jun'ichi; Ananiadou, Sophia

    2011-01-01

    Motivation: Understanding key biological processes (bioprocesses) and their relationships with constituent biological entities and pharmaceutical agents is crucial for drug design and discovery. One way to harvest such information is searching the literature. However, bioprocesses are difficult to capture because they may occur in text in a variety of textual expressions. Moreover, a bioprocess is often composed of a series of bioevents, where a bioevent denotes changes to one or a group of cells involved in the bioprocess. Such bioevents are often used to refer to bioprocesses in text, which current techniques, relying solely on specialized lexicons, struggle to find. Results: This article presents a range of methods for finding bioprocess terms and events. To facilitate the study, we built a gold standard corpus in which terms and events related to angiogenesis, a key biological process of the growth of new blood vessels, were annotated. Statistics of the annotated corpus revealed that over 36% of the text expressions that referred to angiogenesis appeared as events. The proposed methods respectively employed domain-specific vocabularies, a manually annotated corpus and unstructured domain-specific documents. Evaluation results showed that, while a supervised machine-learning model yielded the best precision, recall and F1 scores, the other methods achieved reasonable performance and less cost to develop. Availability: The angiogenesis vocabularies, gold standard corpus, annotation guidelines and software described in this article are available at http://text0.mib.man.ac.uk/~mbassxw2/angiogenesis/ Contact: xinglong.wang@gmail.com PMID:21821664

  15. The influence of bonding agents in improving interactions in composite propellants determined using image analysis.

    PubMed

    Dostanić, J; Husović, T V; Usćumlić, G; Heinemann, R J; Mijin, D

    2008-12-01

    Binder-oxidizer interactions in rocket composite propellants can be improved using adequate bonding agents. In the present work, the effectiveness of different 1,3,5-trisubstituted isocyanurates was determined by stereo and metallographic microscopy and using the software package Image-Pro Plus. The chemical analysis of samples was performed by a scanning electron microscope equipped for energy dispersive spectrometry.

  16. Amphetamines and pH-shift agents for brain imaging: Basic research and clinical results

    SciTech Connect

    Biersack, H.J.; Winkler, C.

    1986-01-01

    This book contains 18 selections. Some of the titles are: Labelling of amphetamines with /sup 123/I: Receptors for amphetamines; New amphetamine derivatives; Potential new approaches for the development of brain imaging agents for single-photon applications; and IM SPECT with the pinhole collimator.

  17. Hetero-bivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen (PSMA) and Hepsin

    DTIC Science & Technology

    2013-09-01

    Simultaneous Targeting Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin PRINCIPAL INVESTIGATOR: Youngjoo Byun, Ph. D. CONTRACTING...SUBTITLE 5a. CONTRACT NUMBER Hetero-bivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen ( PSMA ) and Hepsin 5b...prostate cancer by targeting simultaneously PSMA and hepsin, which are highly expressed in advanced and metastatic prostate cancer. In Year 3, we

  18. Synthesis of PSA Inhibitors as SPECT- and PET-Based Imaging Agents for Prostate Cancer

    DTIC Science & Technology

    2011-06-01

    for their ability to inhibit PSA and chymotrypsin. 15. SUBJECT TERMS Prostate cancer , PSA inhibitors, boronic acids, peptidomimetics, serine protease...prostate cancer . First, all men undergoing androgen ablation, eventually relapse and no longer respond to hormone treatment . Therefore, there is an...Imaging Agents for Prostate Cancer PRINCIPAL INVESTIGATOR: Maya Kostova, Ph.D. CONTRACTING ORGANIZATION: Johns Hopkins University

  19. Fluorine-19 MRI Contrast Agents for Cell Tracking and Lung Imaging

    PubMed Central

    Fox, Matthew S.; Gaudet, Jeffrey M.; Foster, Paula J.

    2015-01-01

    Fluorine-19 (19F)-based contrast agents for magnetic resonance imaging stand to revolutionize imaging-based research and clinical trials in several fields of medical intervention. First, their use in characterizing in vivo cell behavior may help bring cellular therapy closer to clinical acceptance. Second, their use in lung imaging provides novel noninvasive interrogation of the ventilated airspaces without the need for complicated, hard-to-distribute hardware. This article reviews the current state of 19F-based cell tracking and lung imaging using magnetic resonance imaging and describes the link between the methods across these fields and how they may mutually benefit from solutions to mutual problems encountered when imaging 19F-containing compounds, as well as hardware and software advancements. PMID:27042089

  20. A high-affinity, high-stability photoacoustic agent for imaging gastrin-releasing peptide receptor in prostate cancer.

    PubMed

    Levi, Jelena; Sathirachinda, Ataya; Gambhir, Sanjiv S

    2014-07-15

    To evaluate the utility of targeted photoacoustic imaging (PAI) in providing molecular information to complement intrinsic functional and anatomical details of the vasculature within prostate lesion. We developed a PAI agent, AA3G-740, that targets gastrin-releasing peptide receptor (GRPR), found to be highly overexpressed in prostate cancer. The binding specificity of the agent was evaluated in human prostate cancer cell lines, PC3 and LNCaP, and antagonist properties determined by cell internalization and intracellular calcium mobilization studies. The imaging sensitivity was assessed for the agent itself and for the PC3 cells labeled with agent. The in vivo stability of the agent was determined in human plasma and in the blood of living mice. The in vivo binding of the agent was evaluated in PC3 prostate tumor models in mice, and was validated ex vivo by optical imaging. AA3G-740 demonstrated strong and specific binding to GRPR. The sensitivity of detection in vitro indicated suitability of the agent to image very small lesions. In mice, the agent was able to bind to GRPR even in poorly vascularized tumors leading to nearly 2-fold difference in photoacoustic signal relative to the control agent. The ability to image both vasculature and molecular profile outside the blood vessels gives molecular PAI a unique advantage over currently used imaging techniques. The imaging method presented here can find application both in diagnosis and in image-guided biopsy. ©2014 American Association for Cancer Research.

  1. Phthalocyanine photosensitizers as contrast agents for in vivo photoacoustic tumor imaging.

    PubMed

    Attia, Amalina Bte Ebrahim; Balasundaram, Ghayathri; Driessen, Wouter; Ntziachristos, Vasilis; Olivo, Malini

    2015-02-01

    There is a need for contrast agents for non-invasive diagnostic imaging of tumors. Herein, Multispectral Optoacoustic Tomography (MSOT) was employed to evaluate phthalocyanines commonly used in photodynamic therapy as photoacoustic contrast agents. We studied the photoacoustic activity of three water-soluble phthalocyanine photosensitizers: phthalocyanine tetrasulfonic acid (PcS4), Zn(II) phthalocyanine tetrasulfonic acid (ZnPcS4) and Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) in phantom and in tumor-bearing mice to investigate the biodistribution and fate of the phthalocyanines in the biological tissues. PcS4 was observed to grant good contrast between the different reticuloendothelial organs and accumulate in the tumor within an hour of post-administration. ZnPcS4 and AlPcS4 offered little contrast in photoacoustic signals between the organs. PcS4 is a promising photoacoustic contrast agent and can be exploited as a photodiagnostic agent.

  2. Glucosamine and N-acetyl glucosamine as new CEST MRI agents for molecular imaging of tumors

    PubMed Central

    Rivlin, Michal; Navon, Gil

    2016-01-01

    The efficacy of glucosamine (GlcN) and N-acetyl glucosamine (GlcNAc) as agents for chemical exchange saturation transfer (CEST) magnetic resonance molecular imaging of tumors is demonstrated. Both agents reflect the metabolic activity and malignancy of the tumors. The method was tested in two types of tumors implanted orthotopically in mice: 4T1 (mouse mammary cancer cells) and MCF7 (human mammary cancer cells). 4T1 is a more aggressive type of tumor than MCF7 and exhibited a larger CEST effect. Two methods of administration of the agents, intravenous (IV) and oral (PO), gave similar results. The CEST MRI observation of lung metastasis was confirmed by histology. The potential of the clinical application of CEST MRI with these agents for cancer diagnosis is strengthened by their lack of toxicity as can be indicated from their wide use as food supplements. PMID:27600054

  3. Imaging specificity of MR-optical imaging agents following the masking of surface charge by poly(ethylene glycol).

    PubMed

    Wu, Shou-Cheng; Lin, Kun-Liang; Wang, Tzu-Pin; Tzou, Shey-Cherng; Singh, Gyan; Chen, Ming-Hung; Cheng, Tian-Lu; Chen, Chiao-Yun; Liu, Gin-Chung; Lee, Te-Wei; Hu, Shao-Hwa; Wang, Yun-Ming

    2013-05-01

    The coupling of specific antibodies to imaging agents often improves imaging specificity. However, free amine groups designed for the coupling can cause nonspecific binding of the imaging agents. We report here development of a nanocarrier, MnMEIO-silane-NH2-mPEG nanoparticles (NPs), consisting of a manganese-doped iron oxide nanoparticle core (MnMEIO), a copolymer shell of silane and amine-functionalized poly(ethylene glycol) (silane-EA-mPEG). The key feature in MnMEIO-silane-NH2-mPEG is the flexible PEG, which masks the non-conjugated reactive amine groups (-NH2 ↔ -NH3(+)) and reduces nonspecific binding of MnMEIO-silane-NH2-mPEG to cells. The amine groups on MnMEIO-silane-NH2-mPEG were conjugated with the fluorescent dye, Cy777 or antibodies [Erbitux (Erb)] to form a MR-optical imaging contrast agent (MnMEIO-silane-NH2-(Erb)-mPEG) for EGFR-expressing tumors. Confocal microscopic and flow cytometric analyses showed that MnMEIO-silane-NH2-(Erb)-mPEG displayed low nonspecific binding. Moreover, TEM images showed that MnMEIO-silane-NH2-(Erb)-mPEG were endocytosed by EGFR-expressing cells. In line with their EGFR expression levels, A431, PC-3, and Colo-205 tumors treated with MnMEIO-silane-NH2-(Erb)-mPEG NPs showed -97.1%, -49.7%, and -2.8% contrast enhancement, respectively, in in vitro T2-weighted MR imaging. In vivo T2-weighted MR imaging and optical images showed that MnMEIO-silane-NH2-(Erb)-mPEG could specifically and effectively target to EGFR-expressing tumors in nude mice; the relative contrast enhancements were 7.94 (at 2 h) and 7.59 (at 24 h) fold higher in A431 tumors as compared to the EGFR-negative Colo-205 tumors. On the contrary, MnMEIO-silane-NH2-(Erb) NPs showed only 1.44 (at 2 h) and 1.52 (at 24 h) fold higher in EGFR-positive tumors as compared to the EGFR-negative tumors. Finally, antibodies can be readily changed to allow imaging of other tumors bearing different antigens. These data indicate that masking surface charges on contrast

  4. Perylene-diimide-based nanoparticles as highly efficient photoacoustic agents for deep brain tumor imaging in living mice.

    PubMed

    Fan, Quli; Cheng, Kai; Yang, Zhen; Zhang, Ruiping; Yang, Min; Hu, Xiang; Ma, Xiaowei; Bu, Lihong; Lu, Xiaomei; Xiong, Xiaoxing; Huang, Wei; Zhao, Heng; Cheng, Zhen

    2015-02-04

    In order to promote preclinical and clinical applications of photoacoustic imaging, novel photoacoustic contrast agents are highly desired for molecular imaging of diseases, especially for deep tumor imaging. Here, perylene-3,4,9,10-tetracarboxylic diiimide-based near-infrared-absorptive organic nanoparticles are reported as an efficient agent for photoacoustic imaging of deep brain tumors in living mice with enhanced permeability and retention effect.

  5. Perylene-diimide-based nanoparticles as highly efficient photoacoustic agents for deep brain tumor imaging in living mice

    DOE PAGES

    Fan, Quli; Cheng, Kai; Yang, Zhen; ...

    2014-11-06

    In order to promote preclinical and clinical applications of photoacoustic imaging, novel photoacoustic contrast agents are highly desired for molecular imaging of diseases, especially for deep tumor imaging. In this paper, perylene-3,4,9,10-tetracarboxylic diiimide-based near-infrared-absorptive organic nanoparticles are reported as an efficient agent for photoacoustic imaging of deep brain tumors in living mice with enhanced permeability and retention effect

  6. Oxidation-Responsive, EuII/III-Based, Multimodal Contrast Agent for Magnetic Resonance and Photoacoustic Imaging

    PubMed Central

    2017-01-01

    We report, for the first time, a multimodal, oxidation-responsive contrast agent for magnetic resonance imaging and photoacoustic imaging that uses the differences in the properties between Eu in the +2 and +3 oxidation states. The enhancement of contrast in T1-weighted magnetic resonance and photoacoustic imaging was observed in the +2 but not in the +3 oxidation state, and the complex is a known chemical exchange saturation transfer agent for magnetic resonance imaging in the +3 oxidation state. PMID:28393130

  7. Notch in Pathological Angiogenesis and Lymphangiogenesis

    DTIC Science & Technology

    2011-05-01

    have created a treatment agent known as Notch1 decoy (hN1DFc). Activation of Notch changes the gene profile of LEC and changes their in vitro...and lymphangiogenesis by disrupting expression and activity of EC genes . To that end, we have created a treatment agent known as Notch1 decoy (hN1DFc...We hypothesized that inhibiting Notch activity may disrupt tumor (lymph)angiogenesis by changing expression and activity of EC genes . To that end, we

  8. Photoacoustic imaging and surface-enhanced Raman spectroscopy using dual modal contrast agents

    NASA Astrophysics Data System (ADS)

    Park, Sungjo; Lee, Seunghyun; Cha, Myeonggeun; Jeong, Cheolhwan; Kang, Homan; Park, So Yeon; Lee, Yoon-sik; Jeong, Daehong; Kim, Chulhong

    2016-03-01

    Recently, photoacoustic tomography (PAT) has emerged as a remarkable non-invasive imaging modality that provides a strong optical absorption contrast, high ultrasonic resolution, and great penetration depth. Thus, PAT has been widely used as an in vivo preclinical imaging tool. Surface-enhanced Raman spectroscopy (SERS) is another attractive sensing technology in biological research because it offers highly sensitive chemical analyses and multiplexed detection. By performing dual-modal imaging of SERS and PAT, high-resolution structural PAT imaging and high-sensitivity SERS sensing can be achieved. At the same time, it is equally important to develop a dual modal contrast agent for this purpose. To perform both PAT and SERS, we synthesized PEGylated silver bumpy nanoshells (AgBSs). The AgBSs generate strong PA signals owing to their strong optical absorption properties as well as sensitive SERS signals because of the surface plasmon resonance effect. Then, multiplexed Raman chemicals were synthesized to enhance the sensitivity of Raman. We have photoacoustically imaged the sentinel lymph nodes of small animals after intradermal injection of multiplexed agents. Furthermore, the chemical composition of each agent has been distinguished through SERS.

  9. Gold nanoparticles as a contrast agent for in vivo tumor imaging with photoacoustic tomography

    NASA Astrophysics Data System (ADS)

    Zhang, Q.; Iwakuma, N.; Sharma, P.; Moudgil, B. M.; Wu, C.; McNeill, J.; Jiang, H.; Grobmyer, S. R.

    2009-09-01

    Photoacoustic tomography (PAT) is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. The ability to quantitatively and non-invasively image nanoparticles has important implications for the development of nanoparticles as in vivo cancer diagnostic and therapeutic agents. In this study, the ability of systemically administered poly(ethylene glycol)-coated (PEGylated) gold nanoparticles as a contrast agent for in vivo tumor imaging with PAT has been evaluated. We demonstrate that gold nanoparticles (20 and 50 nm) have high photoacoustic contrast as compared to mouse tissue ex vivo. Gold nanoparticles can be visualized in mice in vivo following subcutaneous administration using PAT. Following intravenous administration of PEGylated gold nanoparticles to tumor-bearing mice, accumulation of gold nanoparticles in tumors can be effectively imaged with PAT. With gold nanoparticles as a contrast agent, PAT has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

  10. Mathematical Models of Contrast Transport Kinetics for Cancer Diagnostic Imaging: A Review.

    PubMed

    Turco, Simona; Wijkstra, Hessel; Mischi, Massimo

    2016-01-01

    Angiogenesis plays a fundamental role in cancer growth and the formation of metastasis. Novel cancer therapies aimed at inhibiting angiogenic processes and/or disrupting angiogenic tumor vasculature are currently being developed and clinically tested. The need for earlier and improved cancer diagnosis, and for early evaluation and monitoring of therapeutic response to angiogenic treatment, have led to the development of several imaging methods for in vivo noninvasive assessment of angiogenesis. The combination of dynamic contrast-enhanced imaging with mathematical modeling of the contrast agent kinetics enables quantitative assessment of the structural and functional changes in the microvasculature that are associated with tumor angiogenesis. In this paper, we review quantitative imaging of angiogenesis with dynamic contrast-enhanced magnetic resonance imaging, computed tomography, and ultrasound.

  11. Fe-based nanoparticulate metallic alloys as contrast agents for magnetic resonance imaging.

    PubMed

    Bomatí-Miguel, Oscar; Morales, María P; Tartaj, Pedro; Ruiz-Cabello, Jesús; Bonville, Pierre; Santos, Martín; Zhao, Xinqing; Veintemillas-Verdaguer, Sabino

    2005-10-01

    Pharmaceutical grade magnetic colloidal dispersions have been prepared from iron alloys synthesized by laser pyrolysis. The colloids were obtained by simultaneous dispersion and coating of the particles with dextran in a strong alkaline solution. Both powders and dispersions have been analyzed in terms of microstructural characteristics, chemical composition and magnetic properties. The powders consist of uniform spherical nanoparticles (12 nm of diameter) showing a metallic core encapsulated into an iron-oxide shell. On the other hand, the colloidal dispersions consist of magnetic particles-aggregates with hydrodynamic sizes of approximately 75 nm. Magnetic resonance images of rats were taken after the intravenously administration of the Fe colloidal dispersions, and compared with those obtained using a commercial iron oxide magnetic resonance imaging contrast agent. The results showed a contrast improvement of 60% in the liver with respect to the commercial sample, which suggests that this product could be a suitable contrast agent for NMR imaging of liver and spleen.

  12. Experimental studies of the physiologic properties of technetium-99m agents: Myocardial transport of perfusion imaging agents

    SciTech Connect

    Meerdink, D.J.; Leppo, J.A. )

    1990-10-16

    The physiologic properties of new technetium-99m-labeled myocardial imaging agents (Tc-99m sestamibi, an isonitrile; and Tc-99m teboroxime, a boronic acid adduct of technetium dioxime) are discussed and compared to thallium-201 (Tl-201). Studies with isolated hearts, subcellular fractions and cell cultures indicate that Tc-99m sestamibi, Tc-99m teboroxime and Tl-201 do not share common transport or sequestration mechanisms. Although peak Tc-99m sestamibi myocardial extraction over time is about half that of Tl-201 at equivalent coronary blood flows, the amount of Tc-99m sestamibi that remains in the heart is similar to that of Tl-201 because of its higher retention efficiency. The high retention efficiency for Tc-99m sestamibi also results in minimal redistribution. In contrast, Tc-99m teboroxime myocardial extraction is higher than that of Tl-201, but its retention is less efficient, resulting in relatively rapid washout characteristics which may quickly result in tracer redistribution. During reperfusion after a no-flow period, Tc-99m sestamibi extraction and retention increase, but for Tc-99m teboroxime and Tl-201 these values tend to decrease. All tracers show adequate transport characteristics for perfusion imaging, and differences in transport and retention should lead to the development of new clinical protocols.27 references.

  13. Semimetal Nanomaterials of Antimony as Highly Efficient Agent for Photoacoustic Imaging and Photothermal Therapy

    PubMed Central

    Li, Wanwan; Rong, Pengfei; Yang, Kai; Huang, Peng; Sun, Kang; Chen, Xiaoyuan

    2017-01-01

    In this study we report semimetal naonmaterials of antimony (Sb) as highly efficient agent for photoacoustic imaging (PAI) and photothermal therapy (PTT). The Sb nanorod bundles have been synthesized through a facile route by mixing 1-octadecane (ODE) and oleyl amine (OAm) as the solvent. The aqueous dispersion of PEGylated Sb NPs, due to its broad and strong photoabsorption ranging from ultraviolet (UV) to near-infrared (NIR) wavelengths, is applicable as a photothermal agent driven by 808 nm laser with photothermal conversion efficiency up to 41%, noticeably higher than most of the PTT agents reported before. Our in vitro experiments also showed that cancer cell ablation effect of PEGylated Sb NPs was dependent on laser power. By intratumoral administration of PEGylated Sb NPs, 100% tumor ablation can be realized by using NIR laser irradiation with a lower power of 1 W/cm2 for 5 min (or 0.5 W/cm2 for 10 min) and no obvious toxic side effect is identified after photothermal treatment. Moreover, intense PA signal was also observed after intratumoral injection of PEGylated Sb NPs and NIR laser irradiation due to their strong NIR photoabsorption, suggesting PEGylated Sb NPs as a potential NIR PA agent. Based on the findings of this work, futher development of using other smimetal nanocrystals as highly efficient NIR agents can be achieved for vivo tumor imaging and PTT. PMID:25662491

  14. 3D Multi-Object Segmentation of Cardiac MSCT Imaging by using a Multi-Agent Approach

    PubMed Central

    Fleureau, Julien; Garreau, Mireille; Boulmier, Dominique; Hernandez, Alfredo

    2007-01-01

    We propose a new technique for general purpose, semi-interactive and multi-object segmentation in N-dimensional images, applied to the extraction of cardiac structures in MultiSlice Computed Tomography (MSCT) imaging. The proposed approach makes use of a multi-agent scheme combined with a supervised classification methodology allowing the introduction of a priori information and presenting fast computing times. The multi-agent system is organised around a communicating agent which manages a population of situated agents which segment the image through cooperative and competitive interactions. The proposed technique has been tested on several patient data sets. Some typical results are finally presented and discussed. PMID:18003382

  15. 3D multi-object segmentation of cardiac MSCT imaging by using a multi-agent approach.

    PubMed

    Fleureau, Julien; Garreau, Mireille; Boulmier, Dominique; Hernández, Alfredo

    2007-01-01

    We propose a new technique for general purpose, semi-interactive and multi-object segmentation in N-dimensional images, applied to the extraction of cardiac structures in MultiSlice Computed Tomography (MSCT) imaging. The proposed approach makes use of a multi-agent scheme combined with a supervised classification methodology allowing the introduction of a priori information and presenting fast computing times. The multi-agent system is organised around a communicating agent which manages a population of situated agents which segment the image through cooperative and competitive interactions. The proposed technique has been tested on several patient data sets. Some typical results are finally presented and discussed.

  16. Monitoring/Imaging and Regenerative Agents for Enhancing Tissue Engineering Characterization and Therapies

    PubMed Central

    Santiesteban, Daniela Y.; Kubelick, Kelsey; Dhada, Kabir S.; Dumani, Diego; Suggs, Laura; Emelianov, Stanislav

    2016-01-01

    The past three decades have seen numerous advances in tissue engineering and regenerative medicine (TERM) therapies. However, despite the successes there is still much to be done before TERM therapies become commonplace in clinic. One of the main obstacles is the lack of knowledge regarding complex tissue engineering processes. Imaging strategies, in conjunction with exogenous contrast agents, can aid in this endeavor by assessing in vivo therapeutic progress. The ability to uncover real-time treatment progress will help shed light on the complex tissue engineering processes and lead to development of improved, adaptive treatments. More importantly, the utilized exogenous contrast agents can double as therapeutic agents. Proper use of these Monitoring/Imaging and Regenerative Agents (MIRAs) can help increase TERM therapy successes and allow for clinical translation. While other fields have exploited similar particles for combining diagnostics and therapy, MIRA research is still in its beginning stages with much of the current research being focused on imaging or therapeutic applications, separately. Advancing MIRA research will have numerous impacts on achieving clinical translations of TERM therapies. Therefore, it is our goal to highlight current MIRA progress and suggest future research that can lead to effective TERM treatments. PMID:26692081

  17. Gold nanoparticles as contrast agents in x-ray imaging and computed tomography.

    PubMed

    Cole, Lisa E; Ross, Ryan D; Tilley, Jennifer Mr; Vargo-Gogola, Tracy; Roeder, Ryan K

    2015-01-01

    Computed tomography enables 3D anatomic imaging at a high spatial resolution, but requires delivery of an x-ray contrast agent to distinguish tissues with similar or low x-ray attenuation. Gold nanoparticles (AuNPs) have gained recent attention as an x-ray contrast agent due to exhibiting a high x-ray attenuation, nontoxicity and facile synthesis and surface functionalization for colloidal stability and targeted delivery. Potential diagnostic applications include blood pool imaging, passive targeting and active targeting, where actively targeted AuNPs could enable molecular imaging by computed tomography. This article summarizes the current state of knowledge for AuNP x-ray contrast agents within a paradigm of key structure-property-function relationships in order to provide guidance for the design of AuNP contrast agents to meet the necessary functional requirements in a particular application. Functional requirements include delivery to the site of interest (e.g., blood, tumors or microcalcifications), nontoxicity during delivery and clearance, targeting or localization at the site of interest and contrast enhancement for the site of interest compared with surrounding tissues. Design is achieved by strategically controlling structural characteristics (composition, mass concentration, size, shape and surface functionalization) for optimized properties and functional performance. Examples from the literature are used to highlight current design trade-offs that exist between the different functional requirements.

  18. Differential structured illumination microendoscopy for in vivo imaging of molecular contrast agents

    PubMed Central

    Keahey, Pelham; Ramalingam, Preetha; Schmeler, Kathleen

    2016-01-01

    Fiber optic microendoscopy has shown promise for visualization of molecular contrast agents used to study disease in vivo. However, fiber optic microendoscopes have limited optical sectioning capability, and image contrast is limited by out-of-focus light generated in highly scattering tissue. Optical sectioning techniques have been used in microendoscopes to remove out-of-focus light but reduce imaging speed or rely on bulky optical elements that prevent in vivo imaging. Here, we present differential structured illumination microendoscopy (DSIMe), a fiber optic system that can perform structured illumination in real time for optical sectioning without any opto-mechanical components attached to the distal tip of the fiber bundle. We demonstrate the use of DSIMe during in vivo fluorescence imaging in patients undergoing surgery for cervical adenocarcinoma in situ. Images acquired using DSIMe show greater contrast than standard microendoscopy, improving the ability to detect cellular atypia associated with neoplasia. PMID:27621464

  19. Erratum to: Ungersma SE, Pacheco G, Ho C, Yee SF, Ross J, van Bruggen N, Peale FV Jr, Ross S, Carano RA. Vessel imaging with viable tumor analysis for quantification of tumor angiogenesis. Magn Reson Med 2010;63:1637–1647.

    PubMed

    Ungersma, Sharon E; Pacheco, Glenn; Ho, Calvin; Yee, Sharon Fong; Ross, Jed; van Bruggen, Nicholas; Peale, Franklin V; Ross, Sarajane; Carano, Richard A D

    2011-03-01

    Imaging of tumor microvasculature has become an important tool for studying angiogenesis and monitoring antiangiogenic therapies. Ultrasmall paramagnetic iron oxide contrast agents for indirect imaging of vasculature offer a method for quantitative measurements of vascular biomarkers such as vessel size index, blood volume, and vessel density (Q). Here, this technique is validated with direct comparisons to ex vivo micro-computed tomography angiography and histologic vessel measurements, showing significant correlations between in vivo vascular MRI measurements and ex vivo structural vessel measurements. The sensitivity of the MRI vascular parameters is also demonstrated, in combination with a multispectral analysis technique for segmenting tumor tissue to restrict the analysis to viable tumor tissue and exclude regions of necrosis. It is shown that this viable tumor segmentation increases sensitivity for detection of significant effects on blood volume and Q by two antiangiogenic therapeutics [anti-vascular endothelial growth factor (anti-VEGF) and anti-neuropilin-1] on an HM7 colorectal tumor model. Anti-vascular endothelial growth factor reduced blood volume by 36±3% (p<0.0001) and Q by 52±3% (p<0.0001) at 48 h post-treatment; the effects of anti-neuropilin-1 were roughly half as strong with a reduction in blood volume of 18±6% (p<0.05) and a reduction in Q of 33±5% (p<0.05) at 48 h post-treatment.

  20. Spectral and fluorescence imaging of immune system and tissue response to an immunogenic agent

    NASA Astrophysics Data System (ADS)

    Choe, Se-woon; Acharya, Abhinav; Keselowsky, Benjamin G.; Sorg, Brian S.

    2009-05-01

    Imaging of immune system and tissue response to immunogenic agents can be important to the development of new biomaterials. Additionally, quantitative functional imaging can be useful for testing and evaluation of methods to alter or control the immune system response to implanted materials. In this preliminary study, we employ spectral imaging and fluorescence imaging to measure immune system and tissue response to implanted immunogenic agents. Poly (D,L lactide-co-glycolide) (PLGA) with a 50:50 composition was used to create immunogenic microparticles (MPs). Lipopolysaccharide (LPS) encapsulated in the MPs was used to provoke a tissue immune response in mice and encapsulated fluorescein isothiocyanate (FITC) was used to fluorescently label the MPs for imaging. Control MPs did not contain LPS. The MPs were delivered at 50 particles/μL in a total volume of 20μL by subcutaneous injection in the skin of a nude mouse in a dorsal skin-fold window chamber preparation. Cultured immune cells from a mouse leukemic monocyte macrophage cell line were exogenously labeled with the fluorescent dye DiD in solution at a concentration of 8000cells/μL. Immediately after window chamber surgery and implantation of the MPs, 100μL of the fluorescent macrophage solution was administered via the tail vein. Fluorescence imaging was used to track MPs and macrophages while spectral imaging was used for imaging and measurement of hemoglobin saturation in the tissue microvasculature. Imaging was performed periodically over about three days. The spectral and fluorescence imaging combination enabled detailed observations of the macrophage response and functional effects on the tissue.

  1. Injectable microbubbles as contrast agents for diagnostic ultrasound imaging: the key role of perfluorochemicals.

    PubMed

    Schutt, Ernest G; Klein, David H; Mattrey, Robert M; Riess, Jean G

    2003-07-21

    Ultrasonography has, until recently, lacked effective contrast-enhancing agents. Micrometer-sized gas bubbles that resonate at a diagnostic frequency are ideal reflectors for ultrasound. However, simple air bubbles, when injected into the blood stream, disappear within seconds through the combined effects of Laplace pressure, blood pressure, and exposure to ultrasound energy. Use of fluorocarbon vapor, by extending the persistence of microbubbles in vivo from seconds to minutes, propelled contrast ultrasonography into clinical practice. Imaging techniques that selectively suppress tissue, but not microbubble signal, further increase image contrast. Approved products consist of C3F8 or SF6 microbubbles, and N2 microbubbles osmotically stabilized with C6F14. These agents allow the detection and characterization of cardiovascular abnormalities and solid organ lesions, such as tumors. By providing higher quality images, they improve the accuracy and confidence of disease diagnosis, and can play a decisive role in clinical decision making. New objectives include agents that target specific cells for the molecular imaging of disease, and drug and gene delivery, including ultrasound-triggered delivery.

  2. Positron emitting [68Ga]Ga-based imaging agents: chemistry and diversity.

    PubMed

    Velikyan, Irina

    2011-09-01

    Positron Emission Tomography (PET) field and, in particular utilization of (68)Ga radiometal is getting momentum. The development of new imaging agents for targeted, pre-targeted, non-targeted imaging and their clinical applications is accelerating worldwide. The pharmacopoeia monographs regarding generator produced (68)Ga radionuclide and (68)Ga-labeled somatostatin (SST) analogues are in progress. The number of commercial generators and automated synthesizers for (68)Ga-labeling chemistry is increasing constantly. Development of a molecular imaging agent is a complex process including identification of the biological target, respective lead compound, synthesis of the imaging agent, its chemical characterization, pre-clinical, and clinical evaluation. The introduction of new radiopharmaceuticals and their accessibility are important factors determining the expansion of clinical nuclear medicine for early disease detection and personalized medicine with higher therapeutic efficiency. Further, the availability of the technology for GMP compliant automated tracer production can facilitate the introduction of new radiopharmaceuticals due to the ability to conduct standardized and harmonized multi-center studies for regulatory approval. This review reflects on the current status of (68)Ga in PET field with the focus on the achievements in the chemistry as well as diversity and potential of the resulting tracers.

  3. Uptake of perfusion imaging agents by transplanted hearts: an experimental study in rats

    SciTech Connect

    Bergsland, J.; Carr, E.A. Jr.; Carroll, M.; Feldman, M.J.; Kung, H.; Wright, J.R.

    1989-02-01

    There is a need for a reliable noninvasive marker of rejection in transplanted hearts. Endomyocardial biopsy is now the universally accepted diagnostic method of choice, but the invasiveness of the procedure and the limited size of the sample obtained makes this method far from ideal. As coronary blood flow may be expected to decrease during acute rejection, there has been interest in thallium-201 chloride (T1), a perfusion marker, as an imaging agent for diagnosing cardiac rejection. Hexakis(t-butylisonitrile)-technetium (Tc-TBI) is a representative of a new class of radiopharmaceuticals proposed as perfusion markers. We have compared the uptake of these imaging agents in a rat model of cardiac transplantation. Uptake of Tc-TBI as well as of T1 was significantly lower in rejecting than in nonrejecting hearts. This change was found in both left (LV) and right (RV) ventricles. Allografts in animals treated with cyclosporine (CyA) showed less severe rejection and higher uptakes of both imaging agents as compared to unmodified rejection. Our results suggest that perfusion imaging with these radionuclides is a potentially useful approach to the problem of detecting allograft rejection.

  4. A naturally occurring contrast agent for OCT imaging of smokers' lung

    NASA Astrophysics Data System (ADS)

    Yang, Ying; Bagnaninchi, Pierre O.; Whiteman, Suzanne C.; Gey van Pittius, Daniel; El Haj, Alicia J.; Spiteri, Monica A.; Wang, Ruikang K.

    2005-08-01

    Optical coherence tomography (OCT) offers great potential for clinical applications in terms of its cost, safety and real-time imaging capability. Improvement of its resolution for revealing sub-layers or sub-cellular components within a tissue will further widen its application. In this study we report that carbon pigment, which is frequently present in the lungs of smokers, could be used as a contrast agent to improve the OCT imaging of lung tissue. Carbon produced an intense bright OCT image at a relatively deep location. The parallel histopathological section analysis confirmed the presence of carbon pigment in such tissues. The underlying mechanism of the OCT image formation has been discussed based on a model system in which carbon particles were dispersed in agar gel. Calculations and in-depth intensity profiles of OCT revealed that higher refractive index particles with a size close to or smaller than the wavelength would greatly increase backscattering and generate a sharp contrast, while a particle size several times larger than the wavelength would absorb or obstruct the light path. The naturally occurring contrast agent could provide a diagnostic biomarker of lung tissue in smokers. Furthermore, carbon under such circumstances, can be used as an effective exogenous contrast agent, with which specific components or tissues exhibiting early tumour formation can be optically labelled to delineate the location and boundary, providing potential for early cancer detection and its treatment.

  5. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    DOE PAGES

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; ...

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form anmore » image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.« less

  6. Small animal optoacoustic tomography system for molecular imaging of contrast agents

    NASA Astrophysics Data System (ADS)

    Su, Richard; Liopo, Anton; Ermilov, Sergey A.; Oraevsky, Alexander A.

    2016-03-01

    We developed a new and improved Laser Optoacoustic Imaging System, LOIS-3D for preclinical research applications in small animal models. The advancements include (i) a new stabilized imaging module with a more homogeneous illumination of the mouse yielding a better spatial resolution (<0.2 mm) and (ii) a new low noise amplifier incorporated into the ultrasonic probe and providing the noise equivalent pressure around 2 Pa resulting in increased signal-to-noise ratio and the optical absorption sensitivity of about 0.15 cm-1. We also improved scan time and the image reconstruction times. This prototype has been commercialized for a number of biomedical research applications, such as imaging vascularization and measuring hemoglobin / oxyhemoglobin distribution in the organs as well as imaging exogenous or endogenous optoacoustic contrast agents. As examples, we present in vivo experiments using phantoms and mice with and without tumor injected with contrast agents with indocyanine green (ICG). LOIS-3D was capable of detecting ~1-2 pmole of the ICG, in tissues with relatively low blood content. With its high sensitivity and excellent spatial resolution LOIS-3D is an advanced alternative to fluorescence and bioluminescence based modalities for molecular imaging in live mice.

  7. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    SciTech Connect

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-29

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. As a result, the enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  8. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    PubMed Central

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging. PMID:26511147

  9. X-ray Scatter Imaging of Hepatocellular Carcinoma in a Mouse Model Using Nanoparticle Contrast Agents

    NASA Astrophysics Data System (ADS)

    Rand, Danielle; Derdak, Zoltan; Carlson, Rolf; Wands, Jack R.; Rose-Petruck, Christoph

    2015-10-01

    Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and is almost uniformly fatal. Current methods of detection include ultrasound examination and imaging by CT scan or MRI; however, these techniques are problematic in terms of sensitivity and specificity, and the detection of early tumors (<1 cm diameter) has proven elusive. Better, more specific, and more sensitive detection methods are therefore urgently needed. Here we discuss the application of a newly developed x-ray imaging technique called Spatial Frequency Heterodyne Imaging (SFHI) for the early detection of HCC. SFHI uses x-rays scattered by an object to form an image and is more sensitive than conventional absorption-based x-radiography. We show that tissues labeled in vivo with gold nanoparticle contrast agents can be detected using SFHI. We also demonstrate that directed targeting and SFHI of HCC tumors in a mouse model is possible through the use of HCC-specific antibodies. The enhanced sensitivity of SFHI relative to currently available techniques enables the x-ray imaging of tumors that are just a few millimeters in diameter and substantially reduces the amount of nanoparticle contrast agent required for intravenous injection relative to absorption-based x-ray imaging.

  10. Evaluation of a targeted nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Li, Chunfang; Shen, Chunxu; Liu, Haijuan; Wu, Kaizhi; Zhou, Qibing; Ding, Mingyue

    2015-03-01

    Targeted nanobubbles have been reported to improve the contrast effect of ultrasound imaging due to the enhanced permeation and retention effects at tumor vascular leaks. In this work, the contrast enhancement abilities and the tumor targeting potential of a self-made VEGFR2-targeted nanobubble ultrasound contrast agent was evaluated in-vitro and in-vivo. Size distribution and zeta potential were assessed. Then the contrast-enhanced ultrasound imaging of the VEGFR2 targeted nanobubbles were evaluated with a custom-made experimental apparatus and in normal Wistar rats. Finally, the in-vivo tumor-targeting ability was evaluated on nude mice with subcutaneous tumor. The results showed that the target nanobubbles had uniform distribution with the average diameter of 208.1 nm, polydispersity index (PDI) of 0.411, and zeta potential of -13.21 mV. Significant contrast enhancement was observed in both in-vitro and in-vivo ultrasound imaging, demonstrating that the self-made target nanobubbles can enhance the contrast effect of ultrasound imaging efficiently. Targeted tumor imaging showed less promising result, due to the fact that the targeted nanobubbles arriving and permeating through tumor vessels were not many enough to produce significant enhancement. Future work will focus on exploring new imaging algorithm which is sensitive to targeted nanobubbles, so as to correctly detect the contrast agent, particularly at a low bubble concentration.

  11. Experimental design and instability analysis of coaxial electrospray process for microencapsulation of drugs and imaging agents

    PubMed Central

    Si, Ting; Zhang, Leilei; Li, Guangbin; Roberts, Cynthia J.; Yin, Xiezhen

    2013-01-01

    Abstract. Recent developments in multimodal imaging and image-guided therapy requires multilayered microparticles that encapsulate several imaging and therapeutic agents in the same carrier. However, commonly used microencapsulation processes have multiple limitations such as low encapsulation efficiency and loss of bioactivity for the encapsulated biological cargos. To overcome these limitations, we have carried out both experimental and theoretical studies on coaxial electrospray of multilayered microparticles. On the experimental side, an improved coaxial electrospray setup has been developed. A customized coaxial needle assembly combined with two ring electrodes has been used to enhance the stability of the cone and widen the process parameter range of the stable cone-jet mode. With this assembly, we have obtained poly(lactide-co-glycolide) microparticles with fine morphology and uniform size distribution. On the theoretical side, an instability analysis of the coaxial electrified jet has been performed based on the experimental parameters. The effects of process parameters on the formation of different unstable modes have been studied. The reported experimental and theoretical research represents a significant step toward quantitative control and optimization of the coaxial electrospray process for microencapsulation of multiple drugs and imaging agents in multimodal imaging and image-guided therapy. PMID:23864011

  12. Experimental design and instability analysis of coaxial electrospray process for microencapsulation of drugs and imaging agents.

    PubMed

    Si, Ting; Zhang, Leilei; Li, Guangbin; Roberts, Cynthia J; Yin, Xiezhen; Xu, Ronald

    2013-07-01

    Recent developments in multimodal imaging and image-guided therapy requires multilayered microparticles that encapsulate several imaging and therapeutic agents in the same carrier. However, commonly used microencapsulation processes have multiple limitations such as low encapsulation efficiency and loss of bioactivity for the encapsulated biological cargos. To overcome these limitations, we have carried out both experimental and theoretical studies on coaxial electrospray of multilayered microparticles. On the experimental side, an improved coaxial electrospray setup has been developed. A customized coaxial needle assembly combined with two ring electrodes has been used to enhance the stability of the cone and widen the process parameter range of the stable cone-jet mode. With this assembly, we have obtained poly(lactide-co-glycolide) microparticles with fine morphology and uniform size distribution. On the theoretical side, an instability analysis of the coaxial electrified jet has been performed based on the experimental parameters. The effects of process parameters on the formation of different unstable modes have been studied. The reported experimental and theoretical research represents a significant step toward quantitative control and optimization of the coaxial electrospray process for microencapsulation of multiple drugs and imaging agents in multimodal imaging and image-guided therapy.

  13. Hypoxia-Induced Angiogenesis

    PubMed Central

    Krock, Bryan L.; Skuli, Nicolas

    2011-01-01

    The vascular network delivers oxygen (O2) and nutrients to all cells within the body. It is therefore not surprising that O2 availability serves as a primary regulator of this complex organ. Most transcriptional responses to low O2 are mediated by hypoxia-inducible factors (HIFs), highly conserved transcription factors that control the expression of numerous angiogenic, metabolic, and cell cycle genes. Accordingly, the HIF pathway is currently viewed as a master regulator of angiogenesis. HIF modulation could provide therapeutic benefit for a wide array of pathologies, including cancer, ischemic heart disease, peripheral artery disease, wound healing, and neovascular eye diseases. Hypoxia promotes vessel growth by upregulating multiple pro-angiogenic pathways that mediate key aspects of endothelial, stromal, and vascular support cell biology. Interestingly, recent studies show that hypoxia influences additional aspects of angiogenesis, including vessel patterning, maturation, and function. Through extensive research, the integral role of hypoxia and HIF signaling in human disease is becoming increasingly clear. Consequently, a thorough understanding of how hypoxia regulates angiogenesis through an ever-expanding number of pathways in multiple cell types will be essential for the identification of new therapeutic targets and modalities. PMID:22866203

  14. Ferrite Nanoparticles in Pharmacological Modulation of Angiogenesis

    NASA Astrophysics Data System (ADS)

    Deshmukh, Aparna; Radha, S.; Khan, Y.; Tilak, Priya

    2011-07-01

    Nanoparticles are being explored in the targeted drug delivery of pharmacological agents : angiogenesis being one such novel application which involves formation of new blood vessels or branching of existing ones. The present study involves the use of ferrite nanoparticles for precise therapeutic modulation of angiogenesis. The ferrite nanoparticles synthesized by co-precipitation of ferrous and ferric salts by a suitable base, were found to be 10-20 nm from X-ray diffraction and TEM measurements. The magnetization measurements showed superparamagnetic behavior of the uncoated nanoparticles. These ferrite nanoparticles were found to be bio-compatible with lymphocytes and neural cell lines from the biochemical assays. The chick chorioallantoic membrane(CAM) from the shell of fertile white Leghorn eggs was chosen as a model to study angiogenic activity. An enhancement in the angiogenic activity in the CAM due to addition of uncoated ferrite nanoparticles was observed.

  15. Contrast-Enhanced Digital Mammography and Angiogenesis

    SciTech Connect

    Rosado-Mendez, I.; Palma, B. A.; Villasenor, Y.; Benitez-Bribiesca, L.; Brandan, M. E.

    2007-11-26

    Angiogenesis could be a means for pouring contrast media around tumors. In this work, optimization of radiological parameters for contrast-enhanced subtraction techniques in mammography has been performed. A modification of Lemacks' analytical formalism was implemented to model the X-ray absorption in the breast with contrast medium and detection by a digital image receptor. Preliminary results of signal-to-noise ratio analysis show the advantage of subtracting two images taken at different energies, one prior and one posterior to the injection of contrast medium. Preliminary experimental results using a custom-made phantom have shown good agreement with calculations. A proposal is presented for the clinical application of the optimized technique, which aims at finding correlations between angiogenesis indicators and dynamic variables of contrast medium uptake.

  16. MRI texture analysis parameters of contrast-enhanced T1-weighted images of Crohn's disease differ according to the presence or absence of histological markers of hypoxia and angiogenesis.

    PubMed

    Bhatnagar, Gauraang; Makanyanga, Jesica; Ganeshan, Balaji; Groves, Ashley; Rodriguez-Justo, Manuel; Halligan, Steve; Taylor, Stuart A

    2016-07-01

    To investigate if texture analysis parameters of contrast-enhanced MRI differ according to the presence of histological markers of hypoxia and angiogenesis in Crohn's disease (CD). Seven CD patients (mean age 38 (19-75), 3 male)) undergoing ileal resection underwent 3T MR enterography including axial ultrafast spoiled gradient-echo T1 post IV gadolinium chelate. Regions of interest were placed in bowel destined for resection and registered to trans-mural histological sections (n = 28 across 7 bowel sections) via MRI of the resected specimen. Microvessel density (MVD) and staining for markers of hypoxia (HIF 1α) and angiogenesis (VEGF) were performed. Texture analysis features were derived utilizing an image filtration-histogram technique at spatial scaling factor (SSF) 0-6 mm, including mean, standard deviation, mean of positive pixels, entropy, kurtosis and skewness and compared according to the presence or absence of histological markers of hypoxia/angiogenesis using Mann-Whitney U/Kruskal-Wallis tests and with the log of MVD using simple linear regression. Mean, standard deviation and mean of positive pixels were significantly lower in sections expressing VEGF. For example at SSF 6 mm, median (inter-quartile range) of mean, standard deviation and mean of positive pixels in those with VEGF expression were 150.1 (134.7), 132.4 (49.2) and 184.0 (91.4) vs. 362.5 (150.2), 216.3 (100.1) and 416.6 (80.0) in those without (p = 0.001, p = 0.004 and p = 0.001), respectively. There was a significant association between skewness and MVD (ratio 1.97 (1.15-3.41)) at SSF = 2 mm. Contrast-enhanced MRI texture analysis features significantly differ according to the presence or absence of histological markers of hypoxia and angiogenesis in CD.

  17. 1.5 Harmonic Imaging Sonography with microbubble contrast agent improves characterization of hepatocellular carcinoma

    PubMed Central

    Yamamoto, Kouji; Shiraki, Katsuya; Nakanishi, Shigeo; Fuke, Hiroyuki; Nakano, Takeshi; Hashimoto, Akira; Shimizu, Atsuya; Hamataki, Toshinobu

    2005-01-01

    AIM: To investigate the usefulness of 1.5 Harmonic Imaging Sonography with the use of the contrast agent Levovist for the diagnosis of hepatocellular carcinoma (HCC) and for the evaluation of therapeutic response. METHODS: Phantom experiments were performed to compare the contrast effects of 2nd harmonic imaging and 1.5 Harmonic Imaging Sonography. 1.5 Harmonic Imaging Sonography was employed to examine 36 patients with HCC (42 nodules) before and after the treatment and to compare against the findings obtained using other diagnostic imaging modalities. RESULTS: In 1.5 Harmonic Imaging Sonography, the tumor vessels of HCCs were clearly identified during the early phase, and late-phase images clearly demonstrated the differences in contrast enhancement between the tumor and surrounding hepatic parenchyma. Blood flow within the tumor was detected in 36 nodules (85.7%) during the early phase and in all 42 nodules (100%) during the late phase using 1.5 Harmonic Imaging Sonography, in 38 nodules (90.5%) using contrast-enhanced CT, in 34 nodules (81.0%) using digital subtraction angiography (DSA), and in 42 nodules (100%) using US CO2 angiography. Following transcatheter arterial embolization, 1.5 Harmonic Imaging Sonography detected blood flow and contrast enhancement within the tumors that were judged to contain viable tissue in 20 of 42 nodules (47.6%). However, 6 of these 20 cases were not judged in contrast-enhanced CT. 1.5 Harmonic Imaging Sonography was compared with the US CO2 angiography findings as the gold standard, and the sensitivity and specificity of these images for discerning viable and nonviable HCC after transcatheter arterial embolization were 100% and 100%, respectively. CONCLUSION: 1.5 Harmonic Imaging Sonography permits the vascular structures of HCCs to be identified and blood flow within the tumor to be clearly demonstrated. Furthermore, 1.5 Harmonic Imaging Sonography is potentially useful for evaluating the therapeutic effects of transcatheter

  18. Review of Long-Wavelength Optical and NIR Imaging Materials: Contrast Agents, Fluorophores and Multifunctional Nano Carriers

    PubMed Central

    Pansare, Vikram; Hejazi, Shahram; Faenza, William; Prud’homme, Robert K.

    2012-01-01

    The importance of long wavelength and near infra-red (NIR) imaging has dramatically increased due to the desire to perform whole animal and deep tissue imaging. The adoption of NIR imaging is also growing rapidly due to the availability of targeted biological agents for diagnosis and basic medical research that can be imaged in vivo. The wavelength range of 650–1450 nm falls in the region of the spectrum with the lowest absorption in tissue and therefore enables the deepest tissue penetration. This is the wavelength range we focus on with this review. To operate effectively the imaging agents must both be excited and must emit in this long-wavelength window. We review the agents used both for imaging by absorption, scattering, and excitation (such as fluorescence). Imaging agents comprise both aqueous soluble and insoluble species, both organic and inorganic, and unimolecular and supramolecular constructs. The interest in multi-modal imaging, which involves delivery of actives, targeting, and imaging, requires nanocarriers or supramolecular assemblies. Nanoparticles for diagnostics also have advantages in increasing circulation time and increased imaging brightness relative to single molecule imaging agents. This has led to rapid advances in nanocarriers for long-wavelength, NIR imaging. PMID:22919122

  19. New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy.

    PubMed

    Zarrabi, Kevin; Fang, Chunhui; Wu, Shenhong

    2017-02-02

    Angiogenesis is a critical process in the progression of advanced renal cell carcinoma. Agents targeting angiogenesis have played a primary role in the treatment of metastatic renal cell carcinoma. However, resistance to anti-angiogenesis therapy almost always occurs, and major progress has been made in understanding its underlying molecular mechanism. Axitinib and everolimus have been used extensively in patients whom have had disease progression after prior anti-angiogenesis therapy. Recently, several new agents have been shown to improve overall survival in comparison with everolimus. This review provides an in-depth summary of drugs employable in the clinical setting, the rationale to their use, and the studies conducted leading to their approval for use and provides perspective on the paradigm shift in the treatment of renal cell carcinoma. Highlighted are the newly approved agents cabozantinib, nivolumab, and lenvatinib for advanced renal cell carcinoma patients treated with prior anti-angiogenesis therapy.

  20. Imaging of hemorrhagic fever with renal syndrome: a potential bioterrorism agent of military significance.

    PubMed

    Bui-Mansfield, Liem T; Cressler, Dana K

    2011-11-01

    Hemorrhagic fever with renal syndrome (HFRS) is a potentially fatal infectious disease with worldwide distribution. Its etiologic agents are viruses of the genus Hantavirus of the virus family Bunyaviridae. Hypothetical ease of production and distribution of these agents, with their propensity to incapacitate victims and overwhelm health care resources, lend themselves as significant potential biological agents of terrorism. HFRS has protean clinical manifestations, which may mimic upper respiratory tract infection, nephrolithiasis, and Hantavirus pulmonary syndrome and may delay proper treatment. Sequelae of HFRS, such as hemorrhage, acute renal failure, retroperitoneal edema, pancreatitis, pulmonary edema, and neurologic symptoms, can be detected by different imaging modalities. Medical providers caring for HFRS patients must be aware of its radiologic features, which may help to confirm its clinical diagnosis. In this article, the authors review the epidemiology, pathophysiology, clinical presentation, diagnosis, treatment, and complications of HFRS.

  1. Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging

    PubMed Central

    Wang, Yi-Xiang J

    2015-01-01

    Five types of superparamagnetic iron oxide (SPIO), i.e. Ferumoxides (Feridex® IV, Berlex Laboratories), Ferucarbotran (Resovist®, Bayer Healthcare), Ferumoxtran-10 (AMI-227 or Code-7227, Combidex®, AMAG Pharma; Sinerem®, Guerbet), NC100150 (Clariscan®, Nycomed,) and (VSOP C184, Ferropharm) have been designed and clinically tested as magnetic resonance contrast agents. However, until now Resovist® is current available in only a few countries. The other four agents have been stopped for further development or withdrawn from the market. Another SPIO agent Ferumoxytol (Feraheme®) is approved for the treatment of iron deficiency in adult chronic kidney disease patients. Ferumoxytol is comprised of iron oxide particles surrounded by a carbohydrate coat, and it is being explored as a potential imaging approach for evaluating lymph nodes and certain liver tumors. PMID:26715826

  2. Development of nanostars as a biocompatible tumor contrast agent: toward in vivo SERS imaging

    PubMed Central

    D’Hollander, Antoine; Mathieu, Evelien; Jans, Hilde; Vande Velde, Greetje; Stakenborg, Tim; Van Dorpe, Pol; Himmelreich, Uwe; Lagae, Liesbet

    2016-01-01

    The need for sensitive imaging techniques to detect tumor cells is an important issue in cancer diagnosis and therapy. Surface-enhanced Raman scattering (SERS), realized by chemisorption of compounds suitable for Raman spectroscopy onto gold nanoparticles, is a new method for detecting a tumor. As a proof of concept, we studied the use of biocompatible gold nanostars as sensitive SERS contrast agents targeting an ovarian cancer cell line (SKOV3). Due to a high intracellular uptake of gold nanostars after 6 hours of exposure, they could be detected and located with SERS. Using these nanostars for passive targeting after systemic injection in a xenograft mouse model, a detectable signal was measured in the tumor and liver in vivo. These signals were confirmed by ex vivo SERS measurements and darkfield microscopy. In this study, we established SERS nanostars as a highly sensitive contrast agent for tumor detection, which opens the potential for their use as a theranostic agent against cancer. PMID:27536107

  3. Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging.

    PubMed

    Wang, Yi-Xiang J

    2015-12-21

    Five types of superparamagnetic iron oxide (SPIO), i.e. Ferumoxides (Feridex(®) IV, Berlex Laboratories), Ferucarbotran (Resovist(®), Bayer Healthcare), Ferumoxtran-10 (AMI-227 or Code-7227, Combidex(®), AMAG Pharma; Sinerem(®), Guerbet), NC100150 (Clariscan(®), Nycomed,) and (VSOP C184, Ferropharm) have been designed and clinically tested as magnetic resonance contrast agents. However, until now Resovist(®) is current available in only a few countries. The other four agents have been stopped for further development or withdrawn from the market. Another SPIO agent Ferumoxytol (Feraheme(®)) is approved for the treatment of iron deficiency in adult chronic kidney disease patients. Ferumoxytol is comprised of iron oxide particles surrounded by a carbohydrate coat, and it is being explored as a potential imaging approach for evaluating lymph nodes and certain liver tumors.

  4. Synthesis of cytocompatible Fe3O4@ZSM-5 nanocomposite as magnetic resonance imaging contrast agent

    NASA Astrophysics Data System (ADS)

    Atashi, Zahra; Divband, Baharak; Keshtkar, Ahmad; Khatamian, Maasoumeh; Farahmand-Zahed, Farzane; Nazarlo, Ali Kiani; Gharehaghaji, Nahideh

    2017-09-01

    In this study, ZSM-5 nano zeolite was used as a support material for iron oxide nanoparticles and the potential ability of the nanocomposite for magnetic resonance imaging (MRI) contrast agent was investigated. The nanocomposite was synthesized by hydrothermal method and characterized using X-ray diffraction and scanning electron microscopy. MRI was carried out by use of a 1.5 Tesla clinical scanner. The T2 weighted images were prepared and the r2 relaxivity was calculated. The sizes of Fe3O4 nanoparticles and related nanocomposite were 13-24 nm and 80-150 nm, respectively. Results of MTT assay confirmed that the prepared nanocomposite is cytocompatible. The r2 relaxivity of the Fe3O4@ZSM-5 nanocomposite was 457.1 mM-1 s-1. This study suggests that the Fe3O4@ZSM-5 nanocomposite has potential to use as an MRI T2 contrast agent.

  5. Silica-coated gold nanoplates as stable photoacoustic contrast agents for sentinel lymph node imaging

    NASA Astrophysics Data System (ADS)

    Luke, Geoffrey P.; Bashyam, Ashvin; Homan, Kimberly A.; Makhija, Suraj; Chen, Yun-Sheng; Emelianov, Stanislav Y.

    2013-11-01

    A biopsy of the first lymph node to which a tumor drains—the sentinel lymph node (SLN)—is commonly performed to identify micrometastases. Image guidance of the SLN biopsy procedure has the potential to improve its accuracy and decrease its morbidity. We have developed a new stable contrast agent for photoacoustic image-guided SLN biopsy: silica-coated gold nanoplates (Si-AuNPs). The Si-AuNPs exhibit high photothermal stability when exposed to pulsed and continuous wave laser irradiation. This makes them well suited for in vivo photoacoustic imaging. Furthermore, Si-AuNPs are shown to have low cytotoxicity. We tested the Si-AuNPs for SLN mapping in a mouse model where they exhibited a strong, sustained photoacoustic signal. Real-time ultrasound and photoacoustic imaging revealed that the Si-AuNPs quickly drain to the SLN, gradually spreading throughout a large portion of the node.

  6. Gold nanoparticle contrast agents in advanced X-ray imaging technologies.

    PubMed

    Ahn, Sungsook; Jung, Sung Yong; Lee, Sang Joon

    2013-05-17

    Recently, there has been significant progress in the field of soft- and hard-X-ray imaging for a wide range of applications, both technically and scientifically, via developments in sources, optics and imaging methodologies. While one community is pursuing extensive applications of available X-ray tools, others are investigating improvements in techniques, including new optics, higher spatial resolutions and brighter compact sources. For increased image quality and more exquisite investigation on characteristic biological phenomena, contrast agents have been employed extensively in imaging technologies. Heavy metal nanoparticles are excellent absorbers of X-rays and can offer excellent improvements in medical diagnosis and X-ray imaging. In this context, the role of gold (Au) is important for advanced X-ray imaging applications. Au has a long-history in a wide range of medical applications and exhibits characteristic interactions with X-rays. Therefore, Au can offer a particular advantage as a tracer and a contrast enhancer in X-ray imaging technologies by sensing the variation in X-ray attenuation in a given sample volume. This review summarizes basic understanding on X-ray imaging from device set-up to technologies. Then this review covers recent studies in the development of X-ray imaging techniques utilizing gold nanoparticles (AuNPs) and their relevant applications, including two- and three-dimensional biological imaging, dynamical processes in a living system, single cell-based imaging and quantitative analysis of circulatory systems and so on. In addition to conventional medical applications, various novel research areas have been developed and are expected to be further developed through AuNP-based X-ray imaging technologies.

  7. Angiogenesis in Inflammatory Bowel Disease

    PubMed Central

    Alkim, Canan; Alkim, Huseyin; Koksal, Ali Riza; Boga, Salih; Sen, Ilker

    2015-01-01

    Angiogenesis is an important component of pathogenesis of inflammatory bowel disease (IBD). Chronic inflammation and angiogenesis are two closely related processes. Chronic intestinal inflammation is dependent on angiogenesis and this angiogenesis is modulated by immune system in IBD. Angiogenesis is a very complex process which includes multiple cell types, growth factors, cytokines, adhesion molecules, and signal transduction. Lymphangiogenesis is a new research area in the pathogenesis of IBD. While angiogenesis supports inflammation via leukocyte migration, carrying oxygen and nutrients, on the other hand, it has a major role in wound healing. Angiogenic molecules look like perfect targets for the treatment of IBD, but they have risk for serious side effects because of their nature. PMID:26839731

  8. Highly stabilized gadolinium chelates functionalized on metal nanoparticles as magnetic resonance imaging contrast agent

    NASA Astrophysics Data System (ADS)

    Siddiqui, Talha S.

    Magnetic resonance imaging (MRI) is a non-invasive method for imaging and diagnosing tissue damage, organ function and the vascular system. Magnevist(TM) a complex of diethylenetriaminepentaacetic acid (DTPA) and Gd3+ is a clinically approved contrast agent for MRI. A derivative of DTPA was formed by the addition of two cysteine groups (DTPA-L-Cys) through amide linkage. The Gd complex of this ligand bonds with the silver surfaces through the cysteine thiols. GdDTPA-L-Cys was bound to ˜10nm diameter Ag nanoparticles for use as a multifunctional MRI contrast agent. The ligand and complex were characterized by 1H and 13C NMR, ESI-MS and IR spectroscopy. The silver construct was characterized by TEM, TGA and UV-Vis absorption spectra. The per metal complex r1 relaxivity of GdDTPA-L-Cys{Ag} greater than that of Magnavist(TM) with the same molarity for both compounds. The synthesis of a DTPA derivative is described that allows it to bind to silver or gold nanoparticles through a single thiol linkage (DTPASH). The resulting Gd complex, GdDTPASH, was bound to Ag nanoparticles to create a single monolayer on the surface. The construct was further stabilized in buffered solution with the addition of a thiolated PEG chain. The highly stabilized nanoparticle construct delivers a high payload of Gd compelex and is an effective T1 brightening agent. The production of this type of construct opens the way for engineered multimodal MRI contrast agents.

  9. Hypoxia targeted carbon nanotubes as a sensitive contrast agent for photoacoustic imaging of tumors

    NASA Astrophysics Data System (ADS)

    Zanganeh, Saeid; Aguirre, Andres; Biswal, Nrusingh C.; Pavlik, Christopher; Smith, Michael B.; Alqasemi, Umar; Li, Hai; Zhu, Quing

    2011-03-01

    Development of new and efficient contrast agents is of fundamental importance to improve detection sensitivity of smaller lesions. Within the family of nanomaterials, carbon nanotubes (CNT) not only have emerged as a new alternative and efficient transporter and translocater of therapeutic molecules but also as a photoacoustic molecular imaging agent owing to its strong optical absorption in the near-infrared region. Drugs, Antibodies and nucleic acids could functionalize the CNT and prepare an appropriate system for delivering the cargos to cells and organs. In this work, we present a novel photoacoustic contrast agent which is based on a unique hypoxic marker in the near infrared region, 2-nitroimidazole -bis carboxylic acid derivative of Indocyanine Green conjugated to single walled carbon nanotube (SWCNT-2nitroimidazole-ICG). The 2-nitroimidazole-ICG has an absorption peak at 755 nm and an extinction coefficient of 20,5222 M-1cm-1. The conjugation of this marker with SWCNT shows more than 25 times enhancement of optical absorption of carbon nanotubes in the near infrared region. This new conjugate has been optically evaluated and shows promising results for high contrast photoacoustic imaging of deeply located tumors. The conjugate specifically targets tumor hypoxia, an important indicator of tumor metabolism and tumor therapeutic response. The detection sensitivity of the new contrast agent has been evaluated in-vitro cell lines and with in-vivo tumors in mice.

  10. An in vitro study of a microbubble contrast agent using a clinical ultrasound imaging system

    NASA Astrophysics Data System (ADS)

    Sboros, V.; Moran, C. M.; Pye, S. D.; McDicken, W. N.

    2004-01-01

    Optimal insonation settings for contrast imaging are yet to be specified, mainly due to the lack of good understanding of the behaviour of the microbubbles. A satisfactory model that explains the behaviour of individual contrast agent scatterers has not yet been reported in the literature. An in vitro system based on a commercial scanner (ATL HDI3000) has been developed to investigate the backscatter of such agents. Suspensions of Definity® were introduced in an anechoic tank. The frequency of transmitted ultrasound varied from 1 to 5 MHz, pulse period from 2 to 10 periods and peak negative acoustic pressure from 0.08 to 1.7 MPa. The backscatter at the fundamental and second harmonic frequency windows from the agent was normalized in terms of the corresponding components of backscatter from a blood mimicking fluid suspension. The agent provided a dominant resonance effect at 1.6 MHz transmit frequency. Second harmonic normalized backscatter averaged around 9 dB higher than the fundamental. The normalized fundamental backscatter intensity was linear with peak negative pressure. The second harmonic at resonance peaked at 0.5 MPa suggestive of bubble disruption above such pressure. The system proved capable of illustrating the ultrasonic behaviour of Definity® in vitro, and the investigation suggested particular insonation conditions for optimal image enhancement using Definity®.

  11. Polypyrrole coated phase-change contrast agents for sono-photoacoustic imaging (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Li, David S.; Yoon, Soon Joon; Matula, Thomas J.; O'Donnell, Matthew; Pozzo, Lilo D.

    2017-03-01

    A new light and sound sensitive nanoemulsion contrast agent is presented. The agents feature a low boiling point liquid perfluorocarbon core and a broad light spectrum absorbing polypyrrole (PPy) polymer shell. The PPy coated nanoemulsions can reversibly convert from liquid to gas phase upon cavitation of the liquid perfluorocarbon core. Cavitation can be initiated using a sufficiently high intensity acoustic pulse or from heat generation due to light absorption from a laser pulse. The emulsions can be made between 150 and 350 nm in diameter and PPy has a broad optical absorption covering both the visible spectrum and extending into the near-infrared spectrum (peak absorption 1053 nm). The size, structure, and optical absorption properties of the PPy coated nanoemulsions were characterized and compared to PPy nanoparticles (no liquid core) using dynamic light scattering, ultraviolet-visible spectrophotometry, transmission electron microscopy, and small angle X-ray scattering. The cavitation threshold and signal intensity were measured as a function of both acoustic pressure and laser fluence. Overlapping simultaneous transmission of an acoustic and laser pulse can significantly reduce the activation energy of the contrast agents to levels lower than optical or acoustic activation alone. We also demonstrate that simultaneous light and sound cavitation of the agents can be used in a new sono-photoacoustic imaging method, which enables greater sensitivity than traditional photoacoustic imaging.

  12. Targeting Angiogenesis in Metastatic Breast Cancer

    PubMed Central

    Reddy, Sangeetha; Raffin, Michael

    2012-01-01

    Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC. PMID:22843553

  13. Research on image fusion of missile team based on multi-agent cooperative blackboard model

    NASA Astrophysics Data System (ADS)

    Sen, Guo; Munan, Li

    The target of cooperative engagement of missile teams is to furthest improve hit rate of target according to communication and cooperation among missiles. In this paper the problems of image fusion between missile teams in complex combat environment was analyzed, after which an muti-agent blackboard cooperative model was presented and a public information platform of missile team is built according to this model. Through these, the fusion of images taken from muti-sensor of missiles can be realized and the hit rate of attacking target will be improved. At last, an simulation experiment were performed, and the feasibility of the method is proved by simulation experiment.

  14. Gd-Si Oxide Nanoparticles as Contrast Agents in Magnetic Resonance Imaging

    PubMed Central

    Cabrera-García, Alejandro; Vidal-Moya, Alejandro; Bernabeu, Ángela; Pacheco-Torres, Jesús; Checa-Chavarria, Elisa; Fernández, Eduardo; Botella, Pablo

    2016-01-01

    We describe the synthesis, characterization and application as contrast agents in magnetic resonance imaging of a novel type of magnetic nanoparticle based on Gd-Si oxide, which presents high Gd3+ atom density. For this purpose, we have used a Prussian Blue analogue as the sacrificial template by reacting with soluble silicate, obtaining particles with nanorod morphology and of small size (75 nm). These nanoparticles present good biocompatibility and higher longitudinal and transversal relaxivity values than commercial Gd3+ solutions, which significantly improves the sensitivity of in vivo magnetic resonance images. PMID:28335240

  15. Imaging translucent cell bodies in the living mouse retina without contrast agents

    PubMed Central

    Guevara-Torres, A.; Williams, D. R.; Schallek, J. B.

    2015-01-01

    The transparency of most retinal cell classes typically precludes imaging them in the living eye; unless invasive methods are used that deploy extrinsic contrast agents. Using an adaptive optics scanning light ophthalmoscope (AOSLO) and capitalizing on the large numerical aperture of the mouse eye, we enhanced the contrast from otherwise transparent cells by subtracting the left from the right half of the light distribution in the detector plane. With this approach, it is possible to image the distal processes of photoreceptors, their more proximal cell bodies and the mosaic of horizontal cells in the living mouse retina. PMID:26114032

  16. Imaging translucent cell bodies in the living mouse retina without contrast agents.

    PubMed

    Guevara-Torres, A; Williams, D R; Schallek, J B

    2015-06-01

    The transparency of most retinal cell classes typically precludes imaging them in the living eye; unless invasive methods are used that deploy extrinsic contrast agents. Using an adaptive optics scanning light ophthalmoscope (AOSLO) and capitalizing on the large numerical aperture of the mouse eye, we enhanced the contrast from otherwise transparent cells by subtracting the left from the right half of the light distribution in the detector plane. With this approach, it is possible to image the distal processes of photoreceptors, their more proximal cell bodies and the mosaic of horizontal cells in the living mouse retina.

  17. New generation ICG-based contrast agents for ultrasound-switchable fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Yu, Shuai; Cheng, Bingbing; Yao, Tingfeng; Xu, Cancan; Nguyen, Kytai T.; Hong, Yi; Yuan, Baohong

    2016-10-01

    Recently, we developed a new technology, ultrasound-switchable fluorescence (USF), for high-resolution imaging in centimeter-deep tissues via fluorescence contrast. The success of USF imaging highly relies on excellent contrast agents. ICG-encapsulated poly(N-isopropylacrylamide) nanoparticles (ICG-NPs) are one of the families of the most successful near-infrared (NIR) USF contrast agents. However, the first-generation ICG-NPs have a short shelf life (<1 month). This work significantly increases the shelf life of the new-generation ICG-NPs (>6 months). In addition, we have conjugated hydroxyl or carboxyl function groups on the ICG-NPs for future molecular targeting. Finally, we have demonstrated the effect of temperature-switching threshold (Tth) and the background temperature (TBG) on the quality of USF images. We estimated that the Tth of the ICG-NPs should be controlled at ~38-40 °C (slightly above the body temperature of 37 °C) for future in vivo USF imaging. Addressing these challenges further reduces the application barriers of USF imaging.

  18. New generation ICG-based contrast agents for ultrasound-switchable fluorescence imaging

    PubMed Central

    Yu, Shuai; Cheng, Bingbing; Yao, Tingfeng; Xu, Cancan; Nguyen, Kytai T.; Hong, Yi; Yuan, Baohong

    2016-01-01

    Recently, we developed a new technology, ultrasound-switchable fluorescence (USF), for high-resolution imaging in centimeter-deep tissues via fluorescence contrast. The success of USF imaging highly relies on excellent contrast agents. ICG-encapsulated poly(N-isopropylacrylamide) nanoparticles (ICG-NPs) are one of the families of the most successful near-infrared (NIR) USF contrast agents. However, the first-generation ICG-NPs have a short shelf life (<1 month). This work significantly increases the shelf life of the new-generation ICG-NPs (>6 months). In addition, we have conjugated hydroxyl or carboxyl function groups on the ICG-NPs for future molecular targeting. Finally, we have demonstrated the effect of temperature-switching threshold (Tth) and the background temperature (TBG) on the quality of USF images. We estimated that the Tth of the ICG-NPs should be controlled at ~38–40 °C (slightly above the body temperature of 37 °C) for future in vivo USF imaging. Addressing these challenges further reduces the application barriers of USF imaging. PMID:27775014

  19. Tracking contrast agents using real-time 2D photoacoustic imaging system for cardiac applications

    NASA Astrophysics Data System (ADS)

    Olafsson, Ragnar; Montilla, Leonardo; Ingram, Pier; Witte, Russell S.

    2009-02-01

    Photoacoustic (PA) imaging is a rapidly developing imaging modality that can detect optical contrast agents with high sensitivity. While detectors in PA