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Sample records for image contrast agent

  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. PMID

  2. 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.

  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. 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.

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

    PubMed

    Sinharay, Sanhita; Pagel, Mark D

    2016-06-12

    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 (13)C to detect the agent with outstanding sensitivity. These hyperpolarized (13)C 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

  6. 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

  7. Modified natural nanoparticles as contrast agents for medical imaging

    PubMed Central

    Cormode, David P.; Jarzyna, Peter A.; Mulder, Willem J. M.; Fayad, Zahi A.

    2009-01-01

    The development of novel and effective contrast agents is one of the drivers of the ongoing improvement in medical imaging. Many of the new agents reported are nanoparticle-based. There are a variety of natural nanoparticles known, e.g. lipoproteins, viruses or ferritin. Natural nanoparticles have advantages as delivery platforms such as biodegradability. In addition, our understanding of natural nanoparticles is quite advanced, allowing their adaptation as contrast agents. They can be labeled with small molecules or ions such as Gd3+ to act as contrast agents for magnetic resonance imaging, 18F to act as positron emission tomography contrast agents or fluorophores to act as contrast agents for fluorescence techniques. Additionally, inorganic nanoparticles such as iron oxide, gold nanoparticles or quantum dots can be incorporated to add further contrast functionality. Furthermore, these natural nanoparticle contrast agents can be rerouted from their natural targets via the attachment of targeting molecules. In this review, we discuss the various modified natural nanoparticles that have been exploited as contrast agents. PMID:19900496

  8. 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

  9. Contrast agents in diagnostic imaging: Present and future.

    PubMed

    Caschera, Luca; Lazzara, Angelo; Piergallini, Lorenzo; Ricci, Domenico; Tuscano, Bruno; Vanzulli, Angelo

    2016-08-01

    Specific contrast agents have been developed for x ray examinations (mainly CT), sonography and Magnetic Resonance Imaging. Most of them are extracellular agents which create different enhancement on basis of different vascularization or on basis of different interstitial network in tissues, but some can be targeted to a particular cell line (e.g. hepatocyte). Microbubbles can be used as carrier for therapeutic drugs which can be released in specific targets under sonographic guidance, decreasing systemic toxicity and increasing therapeutic effect. Radiologists have to choose a particular contrast agent knowing its physical and chemical properties and the possibility of adverse reactions and balancing them with the clinical benefits of a more accurate diagnosis. As for any drug, contrast agents can cause adverse events, which are more frequent with Iodine based CA, but also with Gd based CA and even with sonographic contrast agents hypersensitivity reaction can occur. PMID:27168225

  10. 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. PMID:23983210

  11. 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

  12. 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

  13. Selective imaging of adherent targeted ultrasound contrast agents

    PubMed Central

    Zhao, S; Kruse, D E; Ferrara, K W; Dayton, P A

    2007-01-01

    The goal of ultrasonic molecular imaging is the detection of targeted contrast agents bound to receptors on endothelial cells. We propose imaging methods that can distinguish adherent microbubbles from tissue and from freely circulating microbubbles, each of which would otherwise obscure signal from molecularly targeted adherent agents. The methods are based on a harmonic signal model of the returned echoes over a train of pulses. The first method utilizes an ‘image–push–image’ pulse sequence where adhesion of contrast agents is rapidly promoted by acoustic radiation force and the presence of adherent agents is detected by the signal change due to targeted microbubble adhesion. The second method rejects tissue echoes using a spectral high-pass filter. Free agent signal is suppressed by a pulse-to-pulse low-pass filter in both methods. An overlay of the adherent and/or flowing contrast agents on B-mode images can be readily created for anatomical reference. Contrast-to-tissue ratios from adherent microbubbles exceeding 30 dB and 20 dB were achieved for the two methods proposed, respectively. The performance of these algorithms is compared, emphasizing the significance and potential applications in ultrasonic molecular imaging. PMID:17404455

  14. Dual-frequency transducer for nonlinear contrast agent imaging.

    PubMed

    Guiroy, Axel; Novell, Anthony; Ringgaard, Erling; Lou-Moeller, Rasmus; Grégoire, Jean-Marc; Abellard, André-Pierre; Zawada, Tomasz; Bouakaz, Ayache; Levassort, Franck

    2013-12-01

    Detection of high-order nonlinear components issued from microbubbles has emerged as a sensitive method for contrast agent imaging. Nevertheless, the detection of these high-frequency components, including the third, fourth, and fifth harmonics, remains challenging because of the lack of transducer sensitivity and bandwidth. In this context, we propose a new design of imaging transducer based on a simple fabrication process for high-frequency nonlinear imaging. The transducer is composed of two elements: the outer low-frequency (LF) element was centered at 4 MHz and used in transmit mode, whereas the inner high-frequency (HF) element centered at 14 MHz was used in receive mode. The center element was pad-printed using a lead zirconate titanate (PZT) paste. The outer element was molded using a commercial PZT, and curved porous unpoled PZT was used as backing. Each piezoelectric element was characterized to determine the electromechanical performance with thickness coupling factor around 45%. After the assembly of the two transducer elements, hydrophone measurements (electroacoustic responses and radiation patterns) were carried out and demonstrated a large bandwidth (70% at -3 dB) of the HF transducer. Finally, the transducer was evaluated for contrast agent imaging using contrast agent microbubbles. The results showed that harmonic components (up to the sixth harmonic) of the microbubbles were successfully detected. Moreover, images from a flow phantom were acquired and demonstrated the potential of the transducer for high-frequency nonlinear contrast imaging. PMID:24297028

  15. Multifunctional Photosensitizer-Based Contrast Agents for Photoacoustic Imaging

    PubMed Central

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

    2014-01-01

    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. PMID:24938638

  16. Microbubbles as contrast agent for in-line x-ray phase-contrast imaging

    SciTech Connect

    Xi Yan; Zhao Jun; Tang Rongbiao; Wang Yujie

    2011-07-04

    In the present study, we investigated the potential of gas-filled microbubbles as contrast agents for in-line x-ray phase-contrast imaging (PCI) in biomedical applications. When imaging parameters are optimized, the microbubbles function as microlenses that focus the incoming x-rays to form bright spots, which can significantly enhance the image contrast. Since microbubbles have been shown to be safe contrast agents in clinical ultrasonography, this contrast-enhancement procedure for PCI may have promising utility in biomedical applications, especially when the dose of radiation is a serious concern. In this study, we performed both numerical simulations and ex vivo experiments to investigate the formation of the contrast and the effectiveness of microbubbles as contrast agents in PCI.

  17. 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

  18. Hepatobiliary MR Imaging with Gadolinium Based Contrast Agents

    PubMed Central

    Frydrychowicz, Alex; Lubner, Meghan G.; Brown, Jeffrey J.; Merkle, Elmar M.; Nagle, Scott K.; Rofsky, Neil M.; Reeder, Scott B.

    2011-01-01

    The advent of gadolinium-based “hepatobiliary” contrast agents offers new opportunities for diagnostic MRI and has triggered a great interest for innovative imaging approaches to the liver and bile ducts. In this review article we will discuss the imaging properties of the two gadolinium-based hepatobiliary contrast agents currently available in the USA, gadobenate dimeglumine and gadoxetic acid, as well as important pharmacokinetic differences that affect their diagnostic performance. We will review potential applications, protocol optimization strategies, as well as diagnostic pitfalls. A variety of illustrative case examples will be used to demonstrate the role of these agents in detection and characterization of liver lesions as well as for imaging the biliary system. Changes in MR protocols geared towards optimizing workflow and imaging quality will also be discussed. It is our aim that the information provided in this article will facilitate the optimal utilization of these agents, and will stimulate the reader‘s pursuit of new applications for future benefit. PMID:22334493

  19. Molecular nanomagnets as contrast agents for Magnetic Resonance Imaging

    NASA Astrophysics Data System (ADS)

    Rodríguez, Elisenda; Roig, Anna; Molins, Elies; Arús, Carles; Cabañas, Miquel; Quintero, María Rosa; Cerdán, Sebastián; Sanfeliu, Coral

    2003-03-01

    Magnetic resonance imaging (MRI) is a non-invasive technique used in medicine to produce high quality images of human body slices. In order to enhance the contrast between different organs or to reveal altered portions of them such necrosis or tumors, the administration of a contrast agent is highly convenient. Currently Gd-DTPA, a paramagnetic complex, is the most widely administered compound. In this context, we have assayed molecular nanomagnets as MRI contrast agents. The complex [(tacn)_6Fe_8(μ_3-O)_2(μ_2-OH)_12]Br_8·9H_2O^1(Fe8 in brief) has been evaluated and shorter relaxation times, T1 and T_2, have been obtained for Fe8 than those obtained for the commercial Gd-DTPA. No toxic effects have been observed at concentrations up to 1 mM of Fe8 in cultured cells. Phantom studies with T_1-weighted MRI at 9.4 Tesla suggest that Fe8 can have potentiality as T_1-contrast agent. ^1Wieghardt K Angew Chem Intl Ed Engl 23 1 (1984) 77

  20. 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.

  1. Screening CEST contrast agents using ultrafast CEST imaging.

    PubMed

    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. PMID:26969814

  2. Exogenous contrast agents for thermoacoustic imaging: An investigation into the underlying sources of contrast

    SciTech Connect

    Ogunlade, Olumide Beard, Paul

    2015-01-15

    Purpose: Thermoacoustic imaging at microwave excitation frequencies is limited by the low differential contrast exhibited by high water content tissues. To overcome this, exogenous thermoacoustic contrast agents based on gadolinium compounds, iron oxide, and single wall carbon nanotubes have previously been suggested and investigated. However, these previous studies did not fully characterize the electric, magnetic, and thermodynamic properties of these agents thus precluding identification of the underlying sources of contrast. To address this, measurements of the complex permittivity, complex permeability, DC conductivity, and Grüneisen parameter have been made. These measurements allowed the origins of the contrast provided by each substance to be identified. Methods: The electric and magnetic properties of the contrast agents were characterized at 3 GHz using two rectangular waveguide cavities. The DC conductivity was measured separately using a conductivity meter. Thermoacoustic signals were then acquired and compared to those generated in water. Finally, 3D electromagnetic simulations were used to decouple the different contributions to the absorbed power density. Results: It was found that the gadolinium compounds provided appreciable electric contrast but not originating from the gadolinium itself. The contrast was either due to dissociation of the gadolinium salt which increased ionic conductivity or its nondissociated polar fraction which increased dielectric polarization loss or a combination of both. In addition, very high concentrations were required to achieve appreciable contrast, to the extent that the Grüneisen parameter increased significantly and became a source of contrast. Iron oxide particles were found to produce low but measurable dielectric contrast due to dielectric polarization loss, but this is attributed to the coating of the particles not the iron oxide. Single wall carbon nanotubes did not provide measurable contrast of any type

  3. 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.

  4. 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.

  5. 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

  6. Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging.

    PubMed

    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

  7. 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.

  8. 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. PMID:25321797

  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. 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.

  11. 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

  12. Tumor Characterization with Dynamic Contrast Enhanced Magnetic Resonance Imaging and Biodegradable Macromolecular Contrast Agents in Mice

    PubMed Central

    Wu, Xueming; Feng, Yi; Jeong, Eun-Kee; Emerson, Lyska; Lu, Zheng-Rong

    2009-01-01

    Purpose To investigate the efficacy of polydisulfide-based biodegradable macromolecular contrast agents of different degradability and molecular weight for tumor characterization based on angiogenesis using dynamic contrast enhanced MRI (DCE-MRI). Methods Biodegradable macromolecular MRI contrast agents, GDCC and GDCP, with molecular weight of 20 and 70 KDa were evaluated for tumor characterization. The DCE-MRI studies were performed in nude mice bearing MDA PCa 2b and PC-3 human prostate tumor xenografts. Tumor angiogenic kinetic parameters, endothelium transfer coefficient (Ktrans) and fractional tumor plasma volume (fPV), were calculated from the DCE-MRI data using a two-compartment model. Results There was no significant difference in the fPV values between two tumor models estimated with the same agent except for GDCC-70. The Ktrans values in both tumor models decreased with increasing molecular weight of the agents. GDCC-70 showed a higher Ktrans values than GDCP-70 due to high degradability of the former in both tumor models (p < 0.05). The Ktrans values of MDA PCa 2b tumors were significantly higher than those of PC-3 tumors estimated by Gd(DTPA-BMA), GDCC-20, GDCC-70, GDCP-70, and albumin-(Gd-DTPA) (p < 0.05). Conclusions The polydisulfide based biodegradable macromolecular MRI contrast agents are promising in tumor characterization with dynamic contrast enhanced MRI. PMID:19597972

  13. 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

  14. 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.

  15. Dynamic manipulation of magnetic contrast agents in photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Jia, Congxian; Xia, Jinjun; Pelivanov, Ivan M.; Seo, Chi Hyung; Hu, Xiaoge; Jin, Yongdong; Gao, Xiaohu; O'Donnell, Matthew

    2011-03-01

    Magnetic nanoparticles (MNPs) have been used extensively ex vivo for cellular and molecular separations. We recently showed that a coupled nanoparticle combining a superparamagnetic core with a thin, isolated gold shell providing strong absorption in the near infrared can be used for magnetomotive photoacoustic imaging (mmPA), a new technique in which magnetic manipulation of the particle during PA imaging greatly enhances molecular contrast specificity. This particle can also be biologically targeted for in vivo applications, where mmPA imaging provides a spatially localized readout of magnetic manipulations. As an initial test of potential in vivo molecular assays and integrated molecular therapeutics using magnetic manipulation of nanoparticles, we present experiments demonstrating PA readout of trapped magnetic particles in a flow field. An aqueous solution containing a concentration of 0.05-mg/ml 10-μM superparamagnetic iron oxide particles flowed in a 1.65-mm diameter Zeus PTFE (Teflon) sublite wall tubing at three velocities of 0.8, 1.5 and 3.0-mm/s. Opposed permanent magnets separated by 40-mm were positioned on both sides of the tube. As expected, the targeted objects can be magnetically captured and accumulated locally. By translating the magnets, a dynamic magnetic field (0.1-0.3-T) was alternately generated on the side of the tube closest to one of the magnets and created a synchronous PA motion from accumulated targeted objects. This synchronized motion can be used to differentiate the stationary background or other PA sources moving asynchronously with magnetic manipulations (e.g., moving blood) from targeted cells moving synchronously with the magnetic field. This technology can potentially provide sensitive molecular assays of cellular targets travelling in the vasculature (e.g., metastatic tumor cells).

  16. Acoustic radiation pressure: A 'phase contrast' agent for x-ray phase contrast imaging

    SciTech Connect

    Bailat, Claude J.; Hamilton, Theron J.; Rose-Petruck, Christoph; Diebold, Gerald J.

    2004-11-08

    We show that the radiation pressure exerted by a beam of ultrasound can be used for contrast enhancement in high-resolution x-ray imaging of tissue and soft materials. Interfacial features of objects are highlighted as a result of both the displacement introduced by the ultrasound and the inherent sensitivity of x-ray phase contrast imaging to density variations. The potential of the method is demonstrated by imaging microscopic tumor phantoms embedded into tissue with a thickness typically presented in mammography. The detection limit of micrometer size masses exceeds the resolution of currently available mammography imaging systems. The directionality of the acoustic radiation force and its localization in space permits the imaging of ultrasound-selected tissue volumes. The results presented here suggest that the method may permit the detection of tumors in soft tissue in their early stage of development.

  17. Microbubble embedded with upconversion nanoparticles as a bimodal contrast agent for fluorescence and ultrasound imaging

    NASA Astrophysics Data System (ADS)

    Jin, Birui; Lin, Min; You, Minli; Zong, Yujin; Wan, Mingxi; Xu, Feng; Duan, Zhenfeng; Lu, Tianjian

    2015-08-01

    Bimodal imaging offers additional imaging signal thus finds wide spread application in clinical diagnostic imaging. Fluorescence/ultrasound bimodal imaging contrast agent using fluorescent dyes or quantum dots for fluorescence signal has emerged as a promising method, which however requires visible light or UV irradiation resulting in photobleaching, photoblinking, auto-fluorescence and limited tissue penetration depth. To surmount these problems, we developed a novel bimodal contrast agent using layer-by-layer assembly of upconversion nanoparticles onto the surface of microbubbles. The resulting microbubbles with average size of 2 μm provide enhanced ultrasound echo for ultrasound imaging and upconversion emission upon near infrared irradiation for fluorescence imaging. The developed bimodal contrast agent holds great potential to be applied in ultrasound target technique for targeted diseases diagnostics and therapy.

  18. 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

  19. 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.

  20. Magnetic Resonance Imaging with Hyperpolarized 13C Contrast Agents

    NASA Astrophysics Data System (ADS)

    Gordon, Jeremy W.

    Hyperpolarized 13C substrates offer the potential to non-invasively image metabolism and enzymatic activity. However, hyperpolarization introduces a number of difficulties, and imaging is hampered by non-equilibrium magnetization and the need for spectral encoding. There is therefore a need for fast and RF efficient spectral imaging techniques. This work presents a number of new methods that can be used to improve polarization, increase RF efficiency and improve modeling accuracy in hyperpolarized 13C experiments. In particular, a novel encoding and reconstruction algorithm is presented that can generate spatially and spectrally resolved images with a single RF excitation and echo time. This reconstruction framework increases data acquisition efficiency, enabling accelerated acquisition speed, preserved polarization, and/or improved temporal or spatial resolution. Overall, the methods enumerated in this dissertation have the potential to improve modeling accuracy and to mitigate the conventional tradeoffs between SNR, spatial resolution, and temporal resolution that govern image quality in hyperpolarized 13C experiments.

  1. 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

  2. Evaluation of microbubble contrast agents for dynamic imaging with x-ray phase contrast

    PubMed Central

    Millard, T. P.; Endrizzi, M.; Everdell, N.; Rigon, L.; Arfelli, F.; Menk, R. H.; Stride, E.; Olivo, A.

    2015-01-01

    X-rays are commonly used as a means to image the inside of objects opaque to visible light, as their short wavelength allows penetration through matter and the formation of high spatial resolution images. This physical effect has found particular importance in medicine where x-ray based imaging is routinely used as a diagnostic tool. Increasingly, however, imaging modalities that provide functional as well as morphological information are required. In this study the potential to use x-ray phase based imaging as a functional modality through the use of microbubbles that can be targeted to specific biological processes is explored. We show that the concentration of a microbubble suspension can be monitored quantitatively whilst in flow using x-ray phase contrast imaging. This could provide the basis for a dynamic imaging technique that combines the tissue penetration, spatial resolution, and high contrast of x-ray phase based imaging with the functional information offered by targeted imaging modalities. PMID:26219661

  3. Superparamagnetic And Paramagnetic MRI Contrast Agents: Application Of Rapid Magnetic Resonance Imaging To Assess Renal Function

    NASA Astrophysics Data System (ADS)

    Carvlin, Mark J.; Renshaw, Perry F.; Arger, Peter; Kundel, Harold L.; Dougherty, Larry; Axel, Leon; Kassab, Eleanor; Moore, Bethanne

    1988-06-01

    The paramagnetic chelate complex, gadolinium-diethylene-triamine-pentaacetic acid, Gd-DTPA, and superparamagnetic particles, such as those composed of dextran coated magnetite, function as magnetic resonance contrast agents by changing the relaxation rates, 1/T1 and 1/T2. The effects that these agents have upon MR signal intensity are determined by: the inherent biophysical properties of the tissue being imaged, the concentration of the contrast agent and the data acquisition scheme (pulse sequence parameters) employed. Following the time course of MR signal change in the first minutes after the injection of contrast agent(s) allows a dynamic assessment of organ functions in a manner analogous to certain nuclear medicine studies. In order to study renal function, sequential MR fast scan images, gradient echo (TR=35/TE=7 msec, flip angle=25 degrees), were acquired, one every 12 seconds, after intravenous injection of Gd-DTPA and/or dextran-magnetite. Gd-DTPA, which is freely filtered at the glomerulus and is neither secreted nor reabsorbed, provides information concerning renal perfusion, glomerular filtration and tubular concentrating ability. Dextran-magnetite (200 A diameter), which is primarily contained within the intravascular space shortly after injection, provides information on blood flow to and distribution within the kidney. The MR signal change observed after administration of contrast agents varied dramatically depending upon the agents injected and the imaging parameters used. Hence a broad range of physiolgic processes may be described using these techniques, i.e. contrast agent enhanced functional MR examinations.

  4. 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. PMID:24188576

  5. 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.

  6. 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.

  7. 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

  8. Quantitative imaging of cell-permeable magnetic resonance contrast agents using x-ray fluorescence.

    PubMed

    Endres, Paul J; Macrenaris, Keith W; Vogt, Stefan; Allen, Matthew J; Meade, Thomas J

    2006-01-01

    The inability to transduce cellular membranes is a limitation of current magnetic resonance imaging probes used in biologic and clinical settings. This constraint confines contrast agents to extracellular and vascular regions of the body, drastically reducing their viability for investigating processes and cycles in developmental biology. Conversely, a contrast agent with the ability to permeate cell membranes could be used in visualizing cell patterning, cell fate mapping, gene therapy, and, eventually, noninvasive cancer diagnosis. Therefore, we describe the synthesis and quantitative imaging of four contrast agents with the capability to cross cell membranes in sufficient quantity for detection. Each agent is based on the conjugation of a Gd(III) chelator with a cellular transduction moiety. Specifically, we coupled Gd(III)-diethylenetriaminepentaacetic acid DTPA and Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid with an 8-amino acid polyarginine oligomer and an amphipathic stilbene molecule, 4-amino-4'-(N,N-dimethylamino)stilbene. The imaging modality that provided the best sensitivity and spatial resolution for direct detection of the contrast agents is synchrotron radiation x-ray fluorescence (SR-XRF). Unlike optical microscopy, SR-XRF provides two-dimensional images with resolution 10(3) better than (153)Gd gamma counting, without altering the agent by organic fluorophore conjugation. The transduction efficiency of the intracellular agents was evaluated by T(1) analysis and inductively coupled plasma mass spectrometry to determine the efficacy of each chelate-transporter combination. PMID:17150161

  9. Graphene Meets Microbubbles: A Superior Contrast Agent for Photoacoustic Imaging.

    PubMed

    Toumia, Yosra; Domenici, Fabio; Orlanducci, Silvia; Mura, Francesco; Grishenkov, Dmitry; Trochet, Philippe; Lacerenza, Savino; Bordi, Federico; Paradossi, Gaio

    2016-06-29

    Coupling graphene with a soft polymer surface offers the possibility to build hybrid constructs with new electrical, optical, and mechanical properties. However, the low reactivity of graphene is a hurdle in the synthesis of such systems which is often bypassed by oxidizing its carbon planar structure. However, the defects introduced with this process jeopardize the properties of graphene. In this paper we present a different approach, applicable to many different polymer surfaces, which uses surfactant assisted ultrasonication to exfoliate, and simultaneously suspend, graphene in water in its intact form. Tethering pristine graphene sheets to the surfaces is accomplished by using suitable reactive functional groups of the surfactant scaffold. We focused on applying this approach to the fabrication of a hybrid system, made of pristine graphene tethered to poly(vinyl alcohol) based microbubbles (PVA MBs), designed for enhancing photoacoustic signals. Photoacoustic imaging (PAI) is a powerful preclinical diagnostic tool which provides real time images at a resolution of 40 μm. The leap toward clinical imaging has so far been hindered by the limited tissues penetration of near-infrared (NIR) pulsed laser radiation. Many academic and industrial research laboratories have met this challenge by designing devices, each with pros and cons, to enhance the photoacoustic (PA) signal. The major advantages of the hybrid graphene/PVA MBs construct, however, are (i) the preservation of graphene properties, (ii) biocompatibility, a consequence of the robust anchoring of pristine graphene to the bioinert surface of the PVA bubble, and (iii) a very good enhancement in a NIR spectral region of the PA signal, which does not overlap with the signals of PA active endogenous molecules such as hemoglobin. PMID:27269868

  10. Nuclear magnetic resonance contrast agents

    DOEpatents

    Smith, Paul H.; Brainard, James R.; Jarvinen, Gordon D.; Ryan, Robert R.

    1997-01-01

    A family of contrast agents for use in magnetic resonance imaging and a method of enhancing the contrast of magnetic resonance images of an object by incorporating a contrast agent of this invention into the object prior to forming the images or during formation of the images. A contrast agent of this invention is a paramagnetic lanthanide hexaazamacrocyclic molecule, where a basic example has the formula LnC.sub.16 H.sub.14 N.sub.6. Important applications of the invention are in medical diagnosis, treatment, and research, where images of portions of a human body are formed by means of magnetic resonance techniques.

  11. Nuclear magnetic resonance contrast agents

    DOEpatents

    Smith, P.H.; Brainard, J.R.; Jarvinen, G.D.; Ryan, R.R.

    1997-12-30

    A family of contrast agents for use in magnetic resonance imaging and a method of enhancing the contrast of magnetic resonance images of an object by incorporating a contrast agent of this invention into the object prior to forming the images or during formation of the images. A contrast agent of this invention is a paramagnetic lanthanide hexaazamacrocyclic molecule, where a basic example has the formula LnC{sub 16}H{sub 14}N{sub 6}. Important applications of the invention are in medical diagnosis, treatment, and research, where images of portions of a human body are formed by means of magnetic resonance techniques. 10 figs.

  12. 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.

  13. 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. PMID:26454055

  14. 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.

  15. 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

  16. 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.

  17. A spatially-distributed computational model to quantify behaviour of contrast agents in MR perfusion imaging

    PubMed Central

    Cookson, A.N.; Lee, J.; Michler, C.; Chabiniok, R.; Hyde, E.; Nordsletten, D.; Smith, N.P.

    2014-01-01

    Contrast agent enhanced magnetic resonance (MR) perfusion imaging provides an early, non-invasive indication of defects in the coronary circulation. However, the large variation of contrast agent properties, physiological state and imaging protocols means that optimisation of image acquisition is difficult to achieve. This situation motivates the development of a computational framework that, in turn, enables the efficient mapping of this parameter space to provide valuable information for optimisation of perfusion imaging in the clinical context. For this purpose a single-compartment porous medium model of capillary blood flow is developed which is coupled with a scalar transport model, to characterise the behaviour of both blood-pool and freely-diffusive contrast agents characterised by their ability to diffuse through the capillary wall into the extra-cellular space. A parameter space study is performed on the nondimensionalised equations using a 2D model for both healthy and diseased myocardium, examining the sensitivity of system behaviour to Peclet number, Damköhler number (Da), diffusivity ratio and fluid porosity. Assuming a linear MR signal response model, sample concentration time series data are calculated, and the sensitivity of clinically-relevant properties of these signals to the model parameters is quantified. Both upslope and peak values display significant non-monotonic behaviour with regard to the Damköhler number, with these properties showing a high degree of sensitivity in the parameter range relevant to contrast agents currently in use. However, the results suggest that signal upslope is the more robust and discerning metric for perfusion quantification, in particular for correlating with perfusion defect size. Finally, the results were examined in the context of nonlinear signal response, flow quantification via Fermi deconvolution and perfusion reserve index, which demonstrated that there is no single best set of contrast agent parameters

  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. Development and application of a multimodal contrast agent for SPECT/CT hybrid imaging.

    PubMed

    Criscione, Jason M; Dobrucki, Lawrence W; Zhuang, Zhen W; Papademetris, Xenophon; Simons, Michael; Sinusas, Albert J; Fahmy, Tarek M

    2011-09-21

    Hybrid or multimodality imaging is often applied in order to take advantage of the unique and complementary strengths of individual imaging modalities. This hybrid noninvasive imaging approach can provide critical information about anatomical structure in combination with physiological function or targeted molecular signals. While recent advances in software image fusion techniques and hybrid imaging systems have enabled efficient multimodal imaging, accessing the full potential of this technique requires development of a new toolbox of multimodal contrast agents that enhance the imaging process. Toward that goal, we report the development of a hybrid probe for both single photon emission computed tomography (SPECT) and X-ray computed tomography (CT) imaging that facilitates high-sensitivity SPECT and high spatial resolution CT imaging. In this work, we report the synthesis and evaluation of a novel intravascular, multimodal dendrimer-based contrast agent for use in preclinical SPECT/CT hybrid imaging systems. This multimodal agent offers a long intravascular residence time (t(1/2) = 43 min) and sufficient contrast-to-noise for effective serial intravascular and blood pool imaging with both SPECT and CT. The colocalization of the dendritic nuclear and X-ray contrasts offers the potential to facilitate image analysis and quantification by enabling correction for SPECT attenuation and partial volume errors at specified times with the higher resolution anatomic information provided by the circulating CT contrast. This may allow absolute quantification of intramyocardial blood volume and blood flow and may enable the ability to visualize active molecular targeting following clearance from the blood. PMID:21851119

  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. Targeted Multifunctional Multimodal Protein-Shell Microspheres as Cancer Imaging Contrast Agents

    PubMed Central

    John, Renu; Nguyen, Freddy T.; Kolbeck, Kenneth J.; Chaney, Eric J.; Marjanovic, Marina; Suslick, Kenneth S.; Boppart, Stephen A.

    2012-01-01

    Purpose In this study, protein-shell microspheres filled with a suspension of iron oxide nanoparticles in oil are demonstrated as multimodal contrast agents in magnetic resonance imaging (MRI), magnetomotive optical coherence tomography (MM-OCT), and ultrasound imaging. The development, characterization, and use of multifunctional multimodal microspheres are described for targeted contrast and therapeutic applications. Procedures A preclinical rat model was used to demonstrate the feasibility of the multimodal multifunctional microspheres as contrast agents in ultrasound, MM-OCT and MRI. Microspheres were functionalized with the RGD peptide ligand, which is targeted to αvβ3 integrin receptors that are over-expressed in tumors and atherosclerotic lesions. Results These microspheres, which contain iron oxide nanoparticles in their cores, can be modulated externally using a magnetic field to create dynamic contrast in MM-OCT. With the presence of iron oxide nanoparticles, these agents also show significant negative T2 contrast in MRI. Using ultrasound B-mode imaging at a frequency of 30 MHz, a marked enhancement of scatter intensity from in vivo rat mammary tumor tissue was observed for these targeted protein microspheres. Conclusions Preliminary results demonstrate multimodal contrast-enhanced imaging of these functionalized microsphere agents with MRI, MM-OCT, ultrasound imaging, and fluorescence microscopy, including in vivo tracking of the dynamics of these microspheres in real-time using a high-frequency ultrasound imaging system. These targeted oil-filled protein microspheres with the capacity for high drug-delivery loads offer the potential for local delivery of lipophilic drugs under image guidance. PMID:21298354

  2. 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

  3. Nanoparticles as magnetic resonance imaging contrast agents for vascular and cardiac diseases

    PubMed Central

    Chen, Wei; Cormode, David P.; Fayad, Zahi A.; Mulder, Willem J. M.

    2011-01-01

    Advances in nanoparticle contrast agents for molecular imaging have made magnetic resonance imaging a promising modality for noninvasive visualization and assessment of vascular and cardiac disease processes. This review provides a description of the various nanoparticles exploited for imaging cardiovascular targets. Nanoparticle probes detecting inflammation, apoptosis, extracellular matrix, and angiogenesis may provide tools for assessing the risk of progressive vascular dysfunction and heart failure. The utility of nanoparticles as multimodal probes and/or theranostic agents has also been investigated. Although clinical application of these nanoparticles is largely unexplored, the potential for enhancing disease diagnosis and treatment is considerable. PMID:20967875

  4. Experimental and theoretical x-ray imaging performance comparison of iodine and lanthanide contrast agents.

    PubMed

    Cardinal, H N; Holdsworth, D W; Drangova, M; Hobbs, B B; Fenster, A

    1993-01-01

    Contrast agents based on the lanthanide elements gadolinium and holmium have recently been developed for magnetic resonance imaging (MRI). Because of the increased atomic number of these elements relative to iodine, these new compounds, used as x-ray contrast agents, may yield higher radiographic contrast, and hence improved x-ray image quality, relative to conventional iodinated compounds, for clinically useful x-ray spectra. This possibility has been investigated, in independent experimental and theoretical studies, for two x-ray imaging systems: a digital radiographic system, using an x-ray image intensifier (XRII) and charge-coupled device (CCD) detector; and a conventional screen/film system, using a Lanex Regular screen. Iodine, gadolinium, and holmium contrast agents were investigated over a wide range of concentration-thickness products (0.1-0.6 M cm) and diagnostic x-ray spectra (60-120 kVp). A simple theoretical model of x-ray detector response predicts the experimental radiographic contrast measurements with a mean absolute error of 8.0% for the XRII/CCD system and 5.9% for the screen/film system, and shows that the radiographic contrast for these two systems is representative of all XRII and screen/film systems. An index of image quality is defined, and its dependence on radiographic contrast, x-ray fluence per unit dose, and detective quantum efficiency (DQE) is shown. Theoretical values of the index, predicted by our model, are then used to compare the performance of the three contrast agents for the two systems investigated. In general, iodine performance decreases steadily with increasing kVp, gadolinium performance has a broad maximum near 85 kVp, and gadolinium outperforms holmium. Gadolinium outperforms iodine for spectra above (and vice versa below) about 72 kVp, depending slightly on spectrum filtration, object thickness, and detector type. Thus, raising the kVp to shorten exposure times or reduce x-ray tube heat loading results in a loss of

  5. Brain nuclear magnetic resonance imaging enhanced by a paramagnetic nitroxide contrast agent: preliminary report. [Dogs

    SciTech Connect

    Brasch, R.C.; Nitecki, D.E.; Brant-Zawadzki, M.; Enzmann, D.R.; Wesbey, G.E.; Tozer, T.N.; Tuck, L.D.; Cann, C.E.; Fike, J.R.; Sheldon, P.

    1983-11-01

    Contrast-enhancing agents for demonstrating abnormalities of the blood-brain barrier may extend the diagnostic utility of proton nuclear magnetic resonance (NMR) imaging. TES, a nitroxide stable free radical derivative, was tested as a central nervous system contrast enhancer in dogs with experimentally induced unilateral cerebritis or radiation cerebral damage. After intravenous injection of TES, the normal brain showed no change in NMR appearance, but areas of disease demonstrated a dramatic increase (up to 45%) in spin-echo intensity and a decrease in T/sub 1/, relaxation times. The areas of disease defined by TES enhancement were either not evident on the nonenhanced NMR images or were better defined after contrast administration. In-depth tests of toxicity, stability, and metabolism of this promising NMR contrast agent are now in progress.

  6. 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. PMID:22289255

  7. Directed evolution of a magnetic resonance imaging contrast agent for noninvasive imaging of dopamine

    PubMed Central

    Shapiro, Mikhail G; Westmeyer, Gil G; Romero, Philip A; Szablowski, Jerzy O; Küster, Benedict; Shah, Ameer; Otey, Christopher R; Langer, Robert; Arnold, Frances H; Jasanoff, Alan

    2011-01-01

    The development of molecular probes that allow in vivo imaging of neural signaling processes with high temporal and spatial resolution remains challenging. Here we applied directed evolution techniques to create magnetic resonance imaging (MRI) contrast agents sensitive to the neurotransmitter dopamine. The sensors were derived from the heme domain of the bacterial cytochrome P450-BM3 (BM3h). Ligand binding to a site near BM3h’s paramagnetic heme iron led to a drop in MRI signal enhancement and a shift in optical absorbance. Using an absorbance-based screen, we evolved the specificity of BM3h away from its natural ligand and toward dopamine, producing sensors with dissociation constants for dopamine of 3.3–8.9 μM. These molecules were used to image depolarization-triggered neurotransmitter release from PC12 cells and in the brains of live animals. Our results demonstrate the feasibility of molecular-level functional MRI using neural activity–dependent sensors, and our protein engineering approach can be generalized to create probes for other targets. PMID:20190737

  8. 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.

  9. 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. PMID:26114032

  10. 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

  11. Evaluation of chirp reversal power modulation sequence for contrast agent imaging

    NASA Astrophysics Data System (ADS)

    Novell, A.; Sennoga, CA; Escoffre, JM; Chaline, J.; Bouakaz, A.

    2014-09-01

    Over the last decade, significant research effort has been focused on the use of chirp for contrast agent imaging because chirps are known to significantly increase imaging contrast-to-noise ratio (CNR). New imaging schemes, such as chirp reversal (CR), have been developed to improve contrast detection by increasing non-linear microbubble responses. In this study we evaluated the contrast enhancement efficiency of various chirped imaging sequences in combination with well-established imaging schemes such as power modulation (PM) and pulse inversion (PI). The imaging schemes tested were implemented on a fully programmable open scanner and evaluated by ultrasonically scanning (excitation frequency of 2.5 MHz amplitude of 350 kPa) a tissue-mimicking flow phantom comprising a 4 mm diameter tube through which aqueous dispersions (dilution fraction of 1/2000) of the commercial ultrasound contrast agent, SonoVue® were continuously circulated. The recovery of non-linear microbubble responses after chirp compression requires the development and the optimization of a specific filter. A compression filter was therefore designed and used to compress and extract several non-linear components from the received microbubble responses. The results showed that using chirps increased the image CNR by approximately 10 dB, as compared to conventional Gaussian apodized sine burst excitation but degraded the axial resolution by a factor of 1.4, at -3 dB. We demonstrated that the highest CNR and contrast-to-noise ratio (CTR) were achievable when CR was combined with PM as compared to other imaging schemes such as PI.

  12. Sub-second Proton Imaging of 13C Hyperpolarized Contrast Agents in Water

    PubMed Central

    Truong, Milton L.; Coffey, Aaron M.; Shchepin, Roman V.; Waddell, Kevin W.; Chekmenev, Eduard Y.

    2014-01-01

    Indirect proton detection of 13C hyperpolarized contrast agents potentially enables greater sensitivity. Presented here is a study of sub-second projection imaging of hyperpolarized 13C contrast agent addressing the obstacle posed by water suppression for indirect detection in vivo. Sodium acetate phantoms were used to develop and test water suppression and sub-second imaging with frequency selective RF pulses using spectroscopic and imaging indirect proton detection. A 9.8 mM aqueous solution of 13C PHIP hyperpolarized 2-hydroxyethyl-13C-propionate-d2,3,3 (HEP),

    ~25% was used for demonstration of indirect proton sub-second imaging detection. Balanced 2D FSSFP (Fast Steady State Free Precession) allowed recording proton images with FOV = 64×64 mm2 and spatial resolution 2×2 mm2 with total acquisition time of less than 0.2 s. In thermally polarized sodium 1-13C-acetate, 13C to 1H polarization transfer efficiency of 45.1% of the theoretically predicted values was observed in imaging detection corresponding to an 11 fold of overall sensitivity improvement compared to direct 13C FSSFP imaging. 13C to 1H polarization transfer efficiency of 27% was observed in imaging detection corresponding to a 3.25 fold sensitivity improvement compared to direct 13C FSSFP imaging with hyperpolarized HEP. The range of potential applications and limitations of this sub-second and ultra-sensitive imaging approach are discussed. PMID:24753438

  13. Gold-coated iron oxide nanoparticles as a T2 contrast agent in magnetic resonance imaging.

    PubMed

    Ahmad, Tanveer; Bae, Hongsub; Rhee, Ilsu; Chang, Yongmin; Jin, Seong-Uk; Hong, Sungwook

    2012-07-01

    Gold-coated iron oxide (Fe3O4) nanoparticles were synthesized for use as a T2 contrast agent in magnetic resonance imaging (MRI). The coated nanoparticles were spherical in shape with an average diameter of 20 nm. The gold shell was about 2 nm thick. The bonding status of the gold on the nanoparticle surfaces was checked using a Fourier transform infrared spectrometer (FTIR). The FTIR spectra confirmed the attachment of homocysteine, in the form of thiolates, to the Au shell of the Au-Fe3O4 nanoparticles. The relaxivity ratio, R2/R1, for the coated nanoparticles was 3-fold higher than that of a commercial contrast agent, Resovist, which showed the potential for their use as a T2 contrast agent with high efficacy. In animal experiments, the presence of the nanoparticles in rat liver resulted in a 71% decrease in signal intensity in T2-weighted MR images, indicating that our gold-coated iron oxide nanoparticles are suitable for use as a T2 contrast agent in MRI. PMID:22966533

  14. 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.

  15. Preclinical evaluation of biodegradable macromolecular contrast agents for magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Feng, Yi

    Macromolecular contrast agents have been shown to be superior to small molecular weight contrast agents for MRI in blood pool imaging, tumor diagnosis and grading. However, none has been approved by the FDA because they circulate in the bloodstream much longer than small molecular weight contrast agents and result in high tissue accumulation of toxic Gd(III) ions. Biodegradable macromolecular contrast agents (BMCA) were invented to alleviate the toxic accumulation. They have a cleavable disulfide bond based backbone that can be degraded in vivo and excreted out of the body via renal filtration. Furthermore, the side chain of the backbone can be modified to achieve various degradation rates. Three BMCA, (Gd-DTPA)-cystamine copolymers (GDCC), Gd-DTPA cystine copolymers (GDCP), and Gd-DTPA cystine diethyl ester copolymers (GDCEP), were evaluated as blood pool contrast agents in a rat model. They have excellent blood pool enhancement, preferred pharmacokinetics, and only minimal long-term tissue retention of toxic Gd(III) ions. GDCC and GDCP, the lead agents with desired degradation rates, with molecular weights of 20 KDa and 70 KDa, were chosen for dynamic contrast enhanced MRI (DCE-MRI) to differentiate human prostate tumor models of different malignancy and growth rates. GDCC and GDCP could differentiate these tumor models, providing more accurate estimations of plasma volume, flow leakage rate, and permeability surface area product than a small molecular weight contrast agent Gd-DTPA-BMA when compared to the prototype macromolecular contrast agent albumin-Gd-DTPA. GDCC was favored for its neutral charge side chain and reasonable uptake rate by the tumors. GDCC with a molecular weight of 40 KDa (GDCC-40, above the renal filtration cutoff size) was used to assess the efficacy of two photothermal therapies (interstitial and indocyanine green enhanced). GDCC-40 provided excellent tumor enhancement shortly after its injection. Acute tumor response (4 hr) after therapies

  16. Study of suspending agents for gadolinium(III)-exchanged hectorite. An oral magnetic resonance imaging contrast agent

    SciTech Connect

    Balkus, K.J. Jr.; Shi, J.

    1996-12-25

    Clays modified with paramagnetic ions have been shown to be effective magnetic resonance imaging contrast agents. The efficacy in part relies on the suspension of the small clay particles in aqueous solution. In this study a series of macromolecules were eveluated as suspending agents for Gd(III) ion exchanged hectorite clay in water. The room temperature relaxivities for the Gd-hectorite clays were enhanced by the addition of poly(ethylene oxide), poly(ethylene glycol), cyclodextrins, and cholic acid to aqueous suspensions. Additionally, there was no evidence of free Gd(III) in solution in the presence of these suspending agents. In contrast the combination of alginic acid or poly(sodium 4-styrenesulfonate) with the clays resulted in release of the Gd(III) into solution. Xanthan gum, which is often used as an emulsifier and stabilizer in food products, forms a viscous suspension but also reacts with free Gd(III) ions. 25 refs., 10 figs., 2 tabs.

  17. 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.

  18. Development of nanostars as a biocompatible tumor contrast agent: toward in vivo SERS imaging.

    PubMed

    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

  19. 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

  20. Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents

    PubMed Central

    Palekar, Rohun U; Jallouk, Andrew P; Lanza, Gregory M; Pan, Hua; Wickline, Samuel A

    2015-01-01

    As atherosclerosis remains one of the most prevalent causes of patient mortality, the ability to diagnose early signs of plaque rupture and thrombosis represents a significant clinical need. With recent advances in nanotechnology, it is now possible to image specific molecular processes noninvasively with MRI, using various types of nanoparticles as contrast agents. In the context of cardiovascular disease, it is possible to specifically deliver contrast agents to an epitope of interest for detecting vascular inflammatory processes, which serve as predecessors to atherosclerotic plaque development. Herein, we review various applications of nanotechnology in detecting atherosclerosis using MRI, with an emphasis on perfluorocarbon nanoparticles and fluorine imaging, along with theranostic prospects of nanotechnology in cardiovascular disease. PMID:26080701

  1. Octapod iron oxide nanoparticles as high-performance T₂ contrast agents for magnetic resonance imaging.

    PubMed

    Zhao, Zhenghuan; Zhou, Zijian; Bao, Jianfeng; Wang, Zhenyu; Hu, Juan; Chi, Xiaoqin; Ni, Kaiyuan; Wang, Ruifang; Chen, Xiaoyuan; Chen, Zhong; Gao, Jinhao

    2013-01-01

    Spherical superparamagnetic iron oxide nanoparticles have been developed as T2-negative contrast agents for magnetic resonance imaging in clinical use because of their biocompatibility and ease of synthesis; however, they exhibit relatively low transverse relaxivity. Here we report a new strategy to achieve high transverse relaxivity by controlling the morphology of iron oxide nanoparticles. We successfully fabricate size-controllable octapod iron oxide nanoparticles by introducing chloride anions. The octapod iron oxide nanoparticles (edge length of 30 nm) exhibit an ultrahigh transverse relaxivity value (679.3 ± 30 mM(-1) s(-1)), indicating that these octapod iron oxide nanoparticles are much more effective T2 contrast agents for in vivo imaging and small tumour detection in comparison with conventional iron oxide nanoparticles, which holds great promise for highly sensitive, early stage and accurate detection of cancer in the clinic. PMID:23903002

  2. A nano-sized PARACEST-fluorescence imaging contrast agent facilitates & validates in vivo CEST MRI detection of glioma

    PubMed Central

    Ali, Meser M; Bhuiyan, Mohammed PI; Janic, Branislava; Varma, Nadimpalli RS; Mikkelsen, Tom; Ewing, James R; Knight, Robert A; Pagel, Mark D; Arbab, Ali S

    2012-01-01

    Aim The authors have investigated the usefulness of in vivo chemical exchange saturation transfer MRI for detecting gliomas using a dual-modality imaging contrast agent. Materials & methods A paramagnetic chemical exchange saturation transfer MRI contrast agent, Eu-1,4,7,10-tetraazacclododecane-1,4,7,10-tetraacetic acid-Gly4 and a fluorescent agent, DyLight® 680, were conjugated to a generation 5 polyamidoamine dendrimer to create the dual-modality, nano-sized imaging contrast agent. Results The agent was detected with in vivo chemical exchange saturation transfer MRI in an U87 glioma model. These results were validated using in vivo and ex vivo fluorescence imaging. Conclusion This study demonstrated the merits of using a nano-sized imaging contrast agent for detecting gliomas and using a dual-modality agent for detecting gliomas at different spatial scales. PMID:22891866

  3. 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.

  4. Dual Contrast Agent for Computed Tomography and Magnetic Resonance Hard Tissue Imaging

    PubMed Central

    Ventura, Manuela; Sun, Yi; Rusu, Viorel; Laverman, Peter; Borm, Paul; Heerschap, Arend; Oosterwijk, Egbert; Boerman, Otto C.; Walboomers, X. Frank

    2013-01-01

    Calcium phosphate cements (CPCs) are commonly used bone substitute materials, which closely resemble the composition of the mineral phase of bone. However, this high similarity to natural bone also results in difficult discrimination from the bone tissue by common imaging modalities, that is, plain X-ray radiography and three-dimensional computed tomography (CT). In addition, new imaging techniques introduced for bone tissue visualization, like magnetic resonance imaging (MRI), face a similar problem. Even at high MRI resolution, the lack of contrast between CPCs and surrounding bone is evident. Therefore, this study aimed to evaluate the feasibility of a dual contrast agent, traceable with both CT and MRI as enhancers of CPC/bone tissue contrast. Our formulation is based on the use of silica beads as vectors, which encapsulate and carry contrast-enhancing nanoparticles, in our case, colloidal Gold and Superparamagnetic Iron oxide particles (SPIO). The bead suspension was incorporated within a calcium phosphate powder. The resultant cements were then tested both in vitro and in vivo in a femoral condyle defect model in rats. Results showed that the mechanical properties of the cement were not significantly affected by the inclusion of the beads. Both in vitro and in vivo data proved the homogeneous incorporation of the contrast within the cement and its visual localization, characterized by a short-term CT contrast enhancement and a long-term MR effect recognizable by the characteristic blooming shape. Finally, no signs of adverse tissue reactions were noticed in vivo. In conclusion, this study proved the feasibility of a multimodal contrast agent as an inert and biocompatible enhancer of CaP cement versus bone tissue contrast. PMID:23259682

  5. Thermal dependence of ultrasound contrast agents scattering efficiency for echographic imaging techniques

    NASA Astrophysics Data System (ADS)

    Biagioni, Angelo; Bettucci, Andrea; Passeri, Daniele; Alippi, Adriano

    2015-06-01

    Ultrasound contrast agents are used in echographic imaging techniques to enhance image contrast. In addition, they may represent an interesting solution to the problem of non-invasive temperature monitoring inside the human body, based on some thermal variations of their physical properties. Contrast agents, indeed, are inserted into blood circulation and they reach the most important organs inside the human body; consequently, any thermometric property that they may possess, could be exploited for realizing a non-invasive thermometer. They essentially are a suspension of microbubbles containing a gas enclosed in a phospholipid membrane; temperature variations induce structural modifications of the microbubble phospholipid shell, thus causing thermal dependence of contrast agent's elastic characteristics. In this paper, the acoustic scattering efficiency of a bulk suspension of of SonoVue® (Bracco SpA Milan, Italy) has been studied using a pulse-echo technique in the frequency range 1-17 MHz, as it depends upon temperatures between 25 and 65°C. Experimental data confirm that the ultrasonic attenuation coefficient of SonoVue® depends on temperature between 25 and 60°C. Chemical composition of the bubble shell seem to support the hypothesis that a phase transition in the microstructure of lipid-coated microbubbles could play a key role in explaining such effect.

  6. 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 imaging have traditionally been single element ultrasound transducers, use of array systems is desirable because they potentially provide high frame rates to capture dynamic events, such as injection and distribution of contrast in clinical applications. We present preliminary data consisting of 40 second sequences of coregistered pulse-echo (PE) and PA images acquired simultaneously in real time using a clinical ultrasonic machine. Using a 7 MHz linear array, the scanner allowed simultaneous acquisition of inphase-quadrature (IQ) data on 64 elements at a rate limited by the illumination source (Q-switched laser at 20 Hz) with spatial resolution determined to be 0.6 mm (axial) and 0.4 mm (lateral). PA images had a signal-to-noise ratio of approximately 35 dB without averaging. The sequences captured the injection and distribution of an infrared-absorbing contrast agent into a cadaver rat heart. From these data, a perfusion time constant of 0.23 s-1 was estimated. After further refinement, the system will be tested in live animals. Ultimately, an integrated system in the clinic could facilitate inexpensive molecular screening for coronary artery disease.

  7. Novel receptor-targeted contrast agents for optical imaging of tumors

    NASA Astrophysics Data System (ADS)

    Becker, Andreas; Hessenius, Carsten; Bhargava, Sarah; Ebert, Bernd; Sukowski, Uwe; Rinneberg, Herbert H.; Wiedenmann, Bertram; Semmler, Wolfhard; Licha, Kai

    2000-04-01

    Many gastroenteropancreatic tumors express receptors for somatostatin (SST) and/or vasoactive intestinal peptide (VIP). These receptors can be used as molecular targets for the delivery of contrast agents for tumor diagnostics. We have synthesized conjugates consisting of a cyanine dye and an SST analogue or VIP for use as contrast agents in optical imaging. Receptor binding and internalization of these compounds were examined with optical methods in transfected RIN38 tumor cells expressing the SST2 receptor or a GFP- labeled VIP (VPAC1) receptor. Furthermore, biodistribution of the conjugates was examined by laser-induced fluorescence imaging in nude mice bearing SST2 or VPAC1 receptor- expressing tumors. After incubation of RIN38 SSTR2 cells in the presence of 100 nM indotricarbocyanine-SST analogue, cell-associated fluorescence increased, whereas no increase was observed when receptor-medicated endocytosis was inhibited. Indodicarbocyanine-VIP accumulated in RIN38 VPAC1 cells and co-localization with the GFP-labeled VPAC1 receptor was observed. After injection of indotricarbocyanine-SST analogue into tumor-bearing nude mice, SST2 receptor-positive tumors could be visualized for a time period from 10 min to at least 48 h. After application of indodicarbocyanine-VIP, a fluorescence signal in VIP1 receptor-expressing tumors was only detected during the first hour. We conclude that cyanine dye-labeled VIP and SST analogue are novel, targeted contrast agents for the optical imaging of tumors expressing the relevant receptor.

  8. Development of Ultrasound-switchable Fluorescence Imaging Contrast Agents based on Thermosensitive Polymers and Nanoparticles

    PubMed Central

    Cheng, Bingbing; Wei, Ming-Yuan; Liu, Yuan; Pitta, Harish; Xie, Zhiwei; Hong, Yi; Nguyen, Kytai T.; Yuan, Baohong

    2015-01-01

    In this work we first introduced a recently developed high-resolution, deep-tissue imaging technique, ultrasound-switchable fluorescence (USF). The imaging principles based on two types of USF contrast agents were reviewed. To improve USF imaging techniques further, excellent USF contrast agents were developed based on high-performance thermoresponsive polymers and environment-sensitive fluorophores. Herein, such contrast agents were synthesized and characterized with five key parameters: (1) peak excitation and emission wavelengths (λex and λem), (2) the fluorescence intensity ratio between on and off states (IOn/IOff), (3) the fluorescence lifetime ratio between on and off states (τOn/τOff), (4) the temperature threshold to switch on fluorophores (Tth), and (5) the temperature transition bandwidth (TBW). We mainly investigated fluorescence intensity and lifetime changes of four environment-sensitive dyes [7-(2-Aminoethylamino)-N,N-dimethyl-4-benzofurazansulfonamide (DBD-ED), St633, Sq660, and St700] as a function of temperature, while the dye was attached to poly(N-isopropylacrylamide) linear polymers or encapsulated in nanoparticles. Six fluorescence resonance energy transfer systems were invented in which both the donor (DBD-ED or ST425) and the acceptor (Sq660) were adopted. Our results indicate that three Förster resonance energy transfer systems, where both IOn/IOff and τOn/τOff are larger than 2.5, are promising for application in future surface tissue bioimaging by USF technique. PMID:26052192

  9. Peptidyl Molecular Imaging Contrast Agents Using a New Solid Phase Peptide Synthesis Approach

    PubMed Central

    Yoo, Byunghee; Pagel, Mark D.

    2008-01-01

    A versatile method is disclosed for solid phase peptide synthesis (SPPS) of molecular imaging contrast agents. A DO3A moiety was derivatized to introduce a CBZ-protected amino group and then coupled to a polymeric support. CBZ cleavage with Et2AlCl/thioanisole was optimized for SPPS. Amino acids were then coupled to the aminoDOTA loaded resin using conventional step-wise Fmoc SPPS to create a product with DOTA coupled to the C-terminus of the peptide. In a second study, the DO3A moiety was coupled to a glycine-loaded polymeric support, and amino acids were then coupled to the amino-DOTA-peptide loaded resin using SPPS, to incorporate DOTA within the peptide sequence. The peptide-(Tm3+-DOTA) amide showed a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) effect, which demonstrated the utility of this contrast agent for molecular imaging. These results demonstrate the advantages of exploiting SPPS methodologies through the development of unique DOTA derivatives to create peptide-based molecular imaging contrast agents. PMID:17330953

  10. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-01

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors.

  11. The fabrication of novel nanobubble ultrasound contrast agent for potential tumor imaging.

    PubMed

    Xing, Zhanwen; Wang, Jinrui; Ke, Hengte; Zhao, Bo; Yue, Xiuli; Dai, Zhifei; Liu, Jibin

    2010-04-01

    Novel biocompatible nanobubbles were fabricated by ultrasonication of a mixture of Span 60 and polyoxyethylene 40 stearate (PEG40S) followed by differential centrifugation to isolate the relevant subpopulation from the parent suspensions. Particle sizing analysis and optical microscopy inspection indicated that the freshly generated micro/nanobubble suspension was polydisperse and the size distribution was bimodal with large amounts of nanobubbles. To develop a nano-sized contrast agent that is small enough to leak through tumor pores, a fractionation to extract smaller bubbles by variation in the time of centrifugation at 20g (relative centrifuge field, RCF) was suggested. The results showed that the population of nanobubbles with a precisely controlled mean diameter could be sorted from the initial polydisperse suspensions to meet the specified requirements. The isolated bubbles were stable over two weeks under the protection of perfluoropropane gas. The acoustic behavior of the nano-sized contrast agent was evaluated using power Doppler imaging in a normal rabbit model. An excellent power Doppler enhancement was found in vivo renal imaging after intravenous injection of the obtained nanobubbles. Given the broad spectrum of potential clinical applications, the nano-sized contrast agent may provide a versatile adjunct for ultrasonic imaging enhancement and/or treatment of tumors. PMID:20220227

  12. 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

  13. Gadolinium-phthalein complexone as a contrast agent for hepatobiliary MR imaging

    SciTech Connect

    Kawamura, Y.; Endo, K.; Koizumi, M.; Watanabe, Y.; Saga, T.; Konishi, J.; Horiuchi, K.; Yokoyama, A.

    1989-01-01

    Gadolinium-phthalein complexone (Gd-PC) was developed as a hepatobiliary magnetic resonance (MR) contrast agent. Phthalein complexone is one of the iminodiacetic acid derivatives and a structural analogue of bromosulfophthalein. Gadolinium-PC substantially enhanced signal intensity of normal functioning livers on T1-weighted MR images. Contrast enhancement of rabbit liver and gradual accumulation of high intensity bile in the gallbladder were observed after intravenous injection of 0.05 and 0.1 mmol/kg Gd-PC. However, 0.1 mmol/kg of Gd-DTPA caused little effect on liver MR.

  14. 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.

  15. X-ray scatter imaging of hepatocellular carcinoma in a mouse model using nanoparticle contrast agents

    DOE PAGESBeta

    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 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

  16. 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.

  17. 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

  18. 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.

  19. Copper oxide nanoparticles as contrast agents for MRI and ultrasound dual-modality imaging

    NASA Astrophysics Data System (ADS)

    Perlman, Or; Weitz, Iris S.; Azhari, Haim

    2015-08-01

    Multimodal medical imaging is gaining increased popularity in the clinic. This stems from the fact that data acquired from different physical phenomena may provide complementary information resulting in a more comprehensive picture of the pathological state. In this context, nano-sized contrast agents may augment the potential sensitivity of each imaging modality and allow targeted visualization of physiological points of interest (e.g. tumours). In this study, 7 nm copper oxide nanoparticles (CuO NPs) were synthesized and characterized. Then, in vitro and phantom specimens containing CuO NPs ranging from 2.4 to 320 μg · mL-1 were scanned, using both 9.4 T MRI and through-transmission ultrasonic imaging. The results show that the CuO NPs induce shortening of the magnetic T1 relaxation time on the one hand, and increase the speed of sound and ultrasonic attenuation coefficient on the other. Moreover, these visible changes are NP concentration-dependent. The change in the physical properties resulted in a substantial increase in the contrast-to-noise ratio (3.4-6.8 in ultrasound and 1.2-19.3 in MRI). In conclusion, CuO NPs are excellent candidates for MRI-ultrasound dual imaging contrast agents. They offer radiation-free high spatial resolution scans by MRI, and cost-effective high temporal resolution scans by ultrasound.

  20. Chitosan-coated nickel-ferrite nanoparticles as contrast agents in magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Ahmad, Tanveer; Bae, Hongsub; Iqbal, Yousaf; Rhee, Ilsu; Hong, Sungwook; Chang, Yongmin; Lee, Jaejun; Sohn, Derac

    2015-05-01

    We report evidence for the possible application of chitosan-coated nickel-ferrite (NiFe2O4) nanoparticles as both T1 and T2 contrast agents in magnetic resonance imaging (MRI). The coating of nickel-ferrite nanoparticles with chitosan was performed simultaneously with the synthesis of the nickel-ferrite nanoparticles by a chemical co-precipitation method. The coated nanoparticles were cylindrical in shape with an average length of 17 nm and an average width of 4.4 nm. The bonding of chitosan onto the ferrite nanoparticles was confirmed by Fourier transform infrared spectroscopy. The T1 and T2 relaxivities were 0.858±0.04 and 1.71±0.03 mM-1 s-1, respectively. In animal experimentation, both a 25% signal enhancement in the T1-weighted mage and a 71% signal loss in the T2-weighted image were observed. This demonstrated that chitosan-coated nickel-ferrite nanoparticles are suitable as both T1 and T2 contrast agents in MRI. We note that the applicability of our nanoparticles as both T1 and T2 contrast agents is due to their cylindrical shape, which gives rise to both inner and outer sphere processes of nanoparticles.

  1. Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

    PubMed Central

    Yang, Hua; Qiao, Jingjuan; Pu, Fan; Jiang, Jie; Hubbard, Kendra; Hekmatyar, Khan; Langley, Jason; Salarian, Mani; Long, Robert C.; Bryant, Robert G.; Hu, Xiaoping Philip; Grossniklaus, Hans E.; Liu, Zhi-Ren; Yang, Jenny J.

    2015-01-01

    With available MRI techniques, primary and metastatic liver cancers that are associated with high mortality rates and poor treatment responses are only diagnosed at late stages, due to the lack of highly sensitive contrast agents without Gd3+ toxicity. We have developed a protein contrast agent (ProCA32) that exhibits high stability for Gd3+ and a 1011-fold greater selectivity for Gd3+ over Zn2+ compared with existing contrast agents. ProCA32, modified from parvalbumin, possesses high relaxivities (r1/r2: 66.8 mmol−1⋅s−1/89.2 mmol−1⋅s−1 per particle). Using T1- and T2-weighted, as well as T2/T1 ratio imaging, we have achieved, for the first time (to our knowledge), robust MRI detection of early liver metastases as small as ∼0.24 mm in diameter, much smaller than the current detection limit of 10–20 mm. Furthermore, ProCA32 exhibits appropriate in vivo preference for liver sinusoidal spaces and pharmacokinetics for high-quality imaging. ProCA32 will be invaluable for noninvasive early detection of primary and metastatic liver cancers as well as for monitoring treatment and guiding therapeutic interventions, including drug delivery. PMID:25971726

  2. NIR-activated iron oxides as a new multi-functional contrast agent of photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Ting, Pei-Hsien; Huang, Chih-Chia; Li, Meng-Lin

    2014-03-01

    Iron oxide nanoparticles are commonly used contrast agents for theranostic nanomedicines because of their advantages of good biocompatibility, high stability in physiological conditions, low cytotoxicity and excellent safety record in clinical settings for human use. In this study, we developed a NIR-activated iron oxide (NIR-Fe3O4) nanoparticle as a new multi-functional contrast agent of photoacoustic (PA) imaging. Unlike traditional iron oxides, the developed NIR-Fe3O4 owns biocompatibility and optical tunability capable of providing strong optical absorption in the NIR range for PA signal generation. Its intrinsic magnetic property enables the active magnetic tumor targeting. Phantom experiments were performed to confirm the tunability of NIR-Fe3O4's optical absorption in NIR and demonstrate its magnetic targeting capability. The PA signal response of NIR-Fe3O4 as a function of concentration was also investigated. The results showed that the PA signal of NIR-Fe3O4 with OD=1.25 was comparable to that of blood at 715 nm - the wavelength of peak absorption of the used NIR-Fe3O4. Moreover, the PA signal from NIR-Fe3O4 could be further improved by magnetic targeting. Overall, we proved that the potential of the developed NIR-Fe3O4 as a good tumor targeting contrast agent of PA imaging.

  3. On-chip preparation of nanoscale contrast agents towards high-resolution ultrasound imaging.

    PubMed

    Peyman, Sally A; McLaughlan, James R; Abou-Saleh, Radwa H; Marston, Gemma; Johnson, Benjamin R G; Freear, Steven; Coletta, P Louise; Markham, Alexander F; Evans, Stephen D

    2016-02-21

    Micron-sized lipid-stabilised bubbles of heavy gas have been utilised as contrast agents for diagnostic ultrasound (US) imaging for many years. Typically bubbles between 1 and 8 μm in diameter are produced to enhance imaging in US by scattering sound waves more efficiently than surrounding tissue. A potential area of interest for Contrast Enhanced Ultrasound (CEUS) are bubbles with diameters <1 μm or 'nanobubbles.' As bubble diameter decreases, ultrasonic resonant frequency increases, which could lead to an improvement in resolution for high-frequency imaging applications when using nanobubbles. In addition, current US contrast agents are limited by their size to the vasculature in vivo. However, molecular-targeted nanobubbles could penetrate into the extra-vascular space of cancerous tissue providing contrast in regions inaccessible to traditional microbubbles. This paper reports a new microfluidic method for the generation of sub-micron sized lipid stabilised particles containing perfluorocarbon (PFC). The nanoparticles are produced in a unique atomisation-like flow regime at high production rates, in excess of 10(6) particles per s and at high concentration, typically >10(11) particles per mL. The average particle diameter appears to be around 100-200 nm. These particles, suspected of being a mix of liquid and gaseous C4F10 due to Laplace pressure, then phase convert into nanometer sized bubbles on the application of US. In vitro ultrasound characterisation from these nanoparticle populations showed strong backscattering compared to aqueous filled liposomes of a similar size. The nanoparticles were stable upon injection and gave excellent contrast enhancement when used for in vivo imaging, compared to microbubbles with an equivalent shell composition. PMID:26689151

  4. Bismuth@US-tubes as a Potential Contrast Agent for X-ray Imaging Applications

    PubMed Central

    Rivera, Eladio J.; Tran, Lesa A.; Hernández-Rivera, Mayra; Yoon, Diana; Mikos, Antonios G.; Rusakova, Irene A.; Cheong, Benjamin Y.; Cabreira-Hansen, Maria da Graça; Willerson, James T.; Perin, Emerson C.; Wilson, Lon J.

    2013-01-01

    The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking. PMID:24288589

  5. 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. PMID:26715826

  6. Dextran coated bismuth-iron oxide nanohybrid contrast agents for computed tomography and magnetic resonance imaging

    PubMed Central

    Naha, Pratap C.; Zaki, Ajlan Al; Hecht, Elizabeth; Chorny, Michael; Chhour, Peter; Blankemeyer, Eric; Yates, Douglas M.; Witschey, Walter R. T.; Litt, Harold I.; Tsourkas, Andrew; Cormode, David P.

    2014-01-01

    Bismuth nanoparticles have been proposed as a novel CT contrast agent, however few syntheses of biocompatible bismuth nanoparticles have been achieved. We herein report the synthesis of composite bismuth-iron oxide nanoparticles (BION) that are based on a clinically approved, dextran-coated iron oxide formulation; the particles have the advantage of acting as contrast agents for both CT and MRI. BION were synthesized and characterized using various analytical methods. BION CT phantom images revealed that the X-ray attenuation of the different formulations was dependent upon the amount of bismuth present in the nanoparticle, while T2-weighted MRI contrast decreased with increasing bismuth content. No cytotoxicity was observed in Hep G2 and BJ5ta cells after 24 hours incubation with BION. The above properties, as well as the yield of synthesis and bismuth inclusion efficiency, led us to select the Bi-30 formulation for in vivo experiments, performed in mice using a micro-CT and a 9.4 T MRI system. X-ray contrast was observed in the heart and blood vessels over a 2 hour period, indicating that Bi-30 has a prolonged circulation half-life. Considerable signal loss in T2-weighted MR images was observed in the liver compared to pre-injection scans. Evaluation of the biodistribution of Bi-30 revealed that bismuth is excreted via the urine, with significant concentrations found in the kidneys and urine. In vitro experiments confirmed the degradability of Bi-30. In summary, dextran coated BION are biocompatible, biodegradable, possess strong X-ray attenuation properties and also can be used as T2-weighted MR contrast agents. PMID:25485115

  7. Silica-Coated Gold Nanoplates as Stable Photoacoustic Contrast Agents for Sentinel Lymph Node Imaging

    PubMed Central

    Luke, Geoffrey P.; Bashyam, Ashvin; Homan, Kimberly A.; Makhija, Suraj; Chen, Yun-Sheng; Emelianov, Stanislav Y.

    2013-01-01

    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. PMID:24121616

  8. Metal-oxo containing polymer nanobeads as potential contrast agents for magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Pablico, Michele Huelar

    Magnetic resonance imaging (MRI) has greatly revolutionized the way diseases are detected and treated, as it is a non-invasive imaging modality solely based on the interaction of radiowaves and hydrogen nuclei in the presence of an external magnetic field. It is widely used today for the diagnosis of diseases as it offers an efficient method of mapping structure and function of soft tissues in the body. Most MRI examinations utilize paramagnetic materials known as contrast agents, which enhance the MR signal by decreasing the longitudinal (T1) and transverse (T2) relaxation times of the surrounding water protons in biological systems. This results into increased signal intensity differences thereby allowing better interpretation and analysis of pathological tissues. Contrast agents function by lowering the T1 or lowering the T2, resulting into bright and dark contrasts, respectively. The most common MRI contrast agents that are in clinical use today are gadolinium chelates and superparamagnetic iron oxide nanoparticles, both of which have their own advantages in terms of contrast enhancement properties. In the past few years, however, there has been interest in utilizing metal-containing clusters for MRI contrast enhancement as these materials bridge the gap between the constrained structure and magnetic properties of the gadolinium chelates with the superparamagnetic behavior of the iron oxide nanoparticles. Recently, metallic clusters containing Mn and Fe metal centers have received increased attention mainly because of their potential for high spin states and benign nature. In the quest to further develop novel imaging agents, this research has focused on investigating the use of metal-oxo clusters as potential contrast agents for MRI. The primary goal of this project is to identify clusters that meet the following criteria: high paramagnetic susceptibility, water-soluble, stable, cheap, contain environmentally benign metals, and easily derivatized. This work is

  9. Simultaneous imaging of multiple contrast agents using full-spectrum micro-CT

    NASA Astrophysics Data System (ADS)

    Clark, D. P.; Touch, M.; Barber, W.; Badea, C. T.

    2015-03-01

    One of the major challenges for in vivo, micro-computed tomography (CT) imaging is poor soft tissue contrast. To increase contrast, exogenous contrast agents can be used as imaging probes. Combining these probes with a photon counting x-ray detector (PCXD) allows energy-sensitive CT and probe material decomposition from a series of images associated with different x-ray energies. We have implemented full-spectrum micro-CT using a PCXD and 2 keV energy sampling. We then decomposed multiple k-edge contrast materials present in an object (iodine, barium, and gadolinium) from water. Since the energy bins were quite narrow, the projection data was very noisy. This noise and further spectral distortions amplify errors in post-reconstruction material decompositions. Here, we propose and demonstrate a novel post-reconstruction denoising scheme which jointly enforces local and global gradient sparsity constraints, improving the contrast-to-noise ratio in full-spectrum micro-CT data and resultant material decompositions. We performed experiments using both calibration phantoms and ex vivo mouse data. Denoising increased the material contrast-to-noise ratio by an average of 13 times relative to filtered backprojection reconstructions. The relative decomposition error after denoising was 21%. To further improve material decomposition accuracy in future work, we also developed a model of the spectral distortions caused by PCXD imaging using known spectra from radioactive isotopes (109Cd, 133Ba). In future work, we plan to combine this model with the proposed denoising algorithm, enabling material decomposition with higher sensitivity and accuracy.

  10. Environmentally responsive MRI contrast agents

    PubMed Central

    Davies, Gemma-Louise; Kramberger, Iris; Davis, Jason J.

    2015-01-01

    Biomedical imaging techniques can provide a vast amount of anatomical information, enabling diagnosis and the monitoring of disease and treatment profile. MRI uniquely offers convenient, non-invasive, high resolution tomographic imaging. A considerable amount of effort has been invested, across several decades, in the design of non toxic paramagnetic contrast agents capable of enhancing positive MRI signal contrast. Recently, focus has shifted towards the development of agents capable of specifically reporting on their local biochemical environment, where a switch in image contrast is triggered by a specific stimulus/biochemical variable. Such an ability would not only strengthen diagnosis but also provide unique disease-specific biochemical insight. This feature article focuses on recent progress in the development of MRI contrast switching with molecular, macromolecular and nanoparticle-based agents. PMID:24040650

  11. Mesoporous silica nanoparticles as a breast cancer targeting contrast agent for ultrasound imaging

    NASA Astrophysics Data System (ADS)

    Milgroom, Andrew Carson

    Current clinical use of ultrasound for breast cancer diagnostics is strictly limited to a role as a supplementary detection method to other modalities, such as mammography or MRI. A major reason for ultrasound’s role as a secondary method is its inability to discern between cancerous and non-cancerous bodies of similar density, like dense calcifications or benign fibroadenomas. Its detection capabilities are further diminished by the variable density of the surrounding breast tissue with the progression of age. Preliminary studies suggest that mesoporous silica nanoparticles (MSNs) are a good candidate as an in situ contrast agent for ultrasound. By tagging the silica particle surface with the cancer-targeting antibody trastuzumab (Herceptin), suspect regions of interest can be better identified in real time with standard ultrasound equipment. Once the silica-antibody conjugate is injected into the bloodstream and enters the cancerous growth’s vasculature, the antibody arm will bind to HER2, a cell surface receptor known to be dysfunctional or overexpressed in certain types of breast cancer. As more particles aggregate at the cell surface, backscatter of the ultrasonic waves increases as a result of the higher porous silica concentration. This translates to an increased contrast around the lesion boundary. Tumor detection through ultrasound contrast enhancement provides a tremendous advantage over current cancer diagnostics because is it significantly cheaper and can be monitored in real time. Characterization of MCM-41 type MSNs suggests that these particles have sufficient stability and particle size distribution to penetrate through fenestrated tumor vasculature and accumulate in HER2+ breast cancer cells through the enhanced permeation and retention (EPR) effect. A study of acoustic properties showed that particle concentration is linearly correlated to image contrast in clinical frequency-range ultrasound, although less pronounced than typical microbubble

  12. Open-Source Automated Parahydrogen Hyperpolarizer for Molecular Imaging Using (13)C Metabolic Contrast Agents.

    PubMed

    Coffey, Aaron M; Shchepin, Roman V; Truong, Milton L; Wilkens, Ken; Pham, Wellington; Chekmenev, Eduard Y

    2016-08-16

    An open-source hyperpolarizer producing (13)C hyperpolarized contrast agents using parahydrogen induced polarization (PHIP) for biomedical and other applications is presented. This PHIP hyperpolarizer utilizes an Arduino microcontroller in conjunction with a readily modified graphical user interface written in the open-source processing software environment to completely control the PHIP hyperpolarization process including remotely triggering an NMR spectrometer for efficient production of payloads of hyperpolarized contrast agent and in situ quality assurance of the produced hyperpolarization. Key advantages of this hyperpolarizer include: (i) use of open-source software and hardware seamlessly allowing for replication and further improvement as well as readily customizable integration with other NMR spectrometers or MRI scanners (i.e., this is a multiplatform design), (ii) relatively low cost and robustness, and (iii) in situ detection capability and complete automation. The device performance is demonstrated by production of a dose (∼2-3 mL) of hyperpolarized (13)C-succinate with %P13C ∼ 28% and 30 mM concentration and (13)C-phospholactate at %P13C ∼ 15% and 25 mM concentration in aqueous medium. These contrast agents are used for ultrafast molecular imaging and spectroscopy at 4.7 and 0.0475 T. In particular, the conversion of hyperpolarized (13)C-phospholactate to (13)C-lactate in vivo is used here to demonstrate the feasibility of ultrafast multislice (13)C MRI after tail vein injection of hyperpolarized (13)C-phospholactate in mice. PMID:27478927

  13. Ultrasmall Nanoplatforms as Calcium-Responsive Contrast Agents for Magnetic Resonance Imaging.

    PubMed

    Moussaron, Albert; Vibhute, Sandip; Bianchi, Andrea; Gündüz, Serhat; Kotb, Shady; Sancey, Lucie; Motto-Ros, Vincent; Rizzitelli, Silvia; Crémillieux, Yannick; Lux, Francois; Logothetis, Nikos K; Tillement, Olivier; Angelovski, Goran

    2015-10-01

    The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle-based, calcium-responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA-USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA-USRPs on a multigram scale. The resulting platforms display the desired MRI activity—i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca(2+). Cell viability is probed with the MTT assay using HEK-293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA-USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl2 is also administrated. Laser-induced breakdown spectroscopy experiments confirm accumulation of SCA-USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium-sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium-dependent physiological and pathological processes in a dynamic manner. PMID:26179212

  14. Ultrasound contrast agent fabricated from microbubbles containing instant adhesives, and its ultrasound imaging ability

    NASA Astrophysics Data System (ADS)

    Makuta, T.; Tamakawa, Y.

    2012-04-01

    Non-invasive surgery techniques and drug delivery system with acoustic characteristics of ultrasound contrast agent have been studied intensively in recent years. Ultrasound contrast agent collapses easily under the blood circulating and the ultrasound irradiating because it is just a stabilized bubble without solid-shell by surface adsorption of surfactant or lipid. For improving the imaging stability, we proposed the fabrication method of the hollow microcapsule with polymer shell, which can be fabricated just blowing vapor of commonly-used instant adhesive (Cyanoacrylate monomer) into water as microbubbles. Therefore, the cyanoacrylate vapor contained inside microbubble initiates polymerization on the gasliquid interface soon after microbubbles are generated in water. Consequently, hollow microspheres coated by cyanoacrylate thin film are generated. In this report, we revealed that diameter distributions of microbubbles and microcapsules were approximately same and most of them were less than 10 μm, that is, smaller than blood capillary. In addition, we also revealed that hollow microcapsules enhanced the acoustic signal especially in the harmonic contrast imaging and were broken or agglomerated under the ultrasound field. As for the yield of hollow microcapsules, we revealed that sodium dodecyl sulfate addition to water phase instead of deoxycolic acid made the fabrication yield increased.

  15. A novel functional CT contrast agent for molecular imaging of cancer

    NASA Astrophysics Data System (ADS)

    Li, Ji; Chaudhary, Ahmed; Chmura, Steven J.; Pelizzari, Charles; Rajh, Tijana; Wietholt, Christian; Kurtoglu, Metin; Aydogan, Bulent

    2010-08-01

    The purpose of this study was to investigate the feasibility of using a 2-deoxy-d-glucose (2-DG) labeled gold nanoparticle (AuNP-2-DG) as a functionally targeted computed tomography (CT) contrast agent to obtain high-resolution metabolic and anatomic information of tumor in a single CT scan. Gold nanoparticles (AuNPs) were fabricated and were conjugated with 1-DG or 2-DG. 1-DG provides an excellent comparison since it is known to interfere with the ability of the glucose transporter to recognize the sugar moiety. The human alveolar epithelial cancer cell line, A-549, was chosen for the in vitro cellular uptake assay. Three groups of cell samples were incubated with the 1-DG or 2-DG labeled AuNP and the unlabeled AuNP. Following the incubation, the cells were washed with sterile phosphate buffered saline to remove the excess AuNPs and spun using a centrifuge. The cell pellets were imaged using a microCT scanner immediately after the centrifugation. Internalization of AuNP-2-DG is verified using transmission electron microscopy imaging. Significant contrast enhancement in the cell samples incubated with the AuNP-2-DG with respect to the cell samples incubated with the unlabeled AuNP and the AuNP-1-DG was observed in multiple CT slices. Results from our in vitro experiments suggest that the AuNP-2-DG may be used as a functional CT contrast agent to provide high-resolution metabolic and anatomic information in a single CT scan. These results justify further in vitro and in vivo experiments to study the feasibility of using the AuNP-2-DG as a functional CT contrast agent in radiation therapy settings.

  16. Tunable, biodegradable gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging.

    PubMed

    Cheheltani, Rabee; Ezzibdeh, Rami M; Chhour, Peter; Pulaparthi, Kumidini; Kim, Johoon; Jurcova, Martina; Hsu, Jessica C; Blundell, Cassidy; Litt, Harold I; Ferrari, Victor A; Allcock, Harry R; Sehgal, Chandra M; Cormode, David P

    2016-09-01

    Gold nanoparticles (AuNP) have been proposed for many applications in medicine. Although large AuNP (>5.5 nm) are desirable for their longer blood circulation and accumulation in diseased tissues, small AuNP (<5.5 nm) are required for excretion via the kidneys. We present a novel platform where small, excretable AuNP are encapsulated into biodegradable poly di(carboxylatophenoxy)phosphazene (PCPP) nanospheres. These larger nanoparticles (Au-PCPP) can perform their function as contrast agents, then subsequently break down into harmless byproducts and release the AuNP for swift excretion. Homogeneous Au-PCPP were synthesized using a microfluidic device. The size of the Au-PCPP can be controlled by the amount of polyethylene glycol-polylysine (PEG-PLL) block co-polymer in the formulation. Synthesis of Au-PCPP nanoparticles and encapsulation of AuNP in PCPP were evaluated using transmission electron microscopy and their biocompatibility and biodegradability confirmed in vitro. The Au-PCPP nanoparticles were found to produce strong computed tomography contrast. The UV-Vis absorption peak of Au-PCPP can be tuned into the near infrared region via inclusion of varying amounts of AuNP and controlling the nanoparticle size. In vitro and in vivo experiments demonstrated the potential of Au-PCPP as contrast agents for photoacoustic imaging. Therefore, Au-PCPP nanoparticles have high potency as contrast agents for two imaging modalities, as well as being biocompatible and biodegradable, and thus represent a platform with potential for translation into the clinic. PMID:27322961

  17. Experimental evaluation of a hyperspectral imager for near-infrared fluorescent contrast agent studies

    NASA Astrophysics Data System (ADS)

    Luthman, A. S.; Bohndiek, Sarah E.

    2015-03-01

    Hyperspectral imaging (HSI) systems have the potential to combine morphological and spectral information to provide detailed and high sensitivity readouts in biological and medical applications. As HSI enables simultaneous detection in several spectral bands, the technology has significant potential for use in real-time multiplexed contrast agent studies. Examples include tumor detection in intraoperative and endoscopic imaging as well as histopathology. A multiplexed readout from multiple disease targets, such as cell surface receptors overexpressed in cancer cells, could improve both sensitivity and specificity of tumor identification. Here, we evaluate a commercial, compact, near-infrared HSI sensor that has the potential to enable low cost, video rate HSI for multiplexed fluorescent contrast agent studies in biomedical applications. The hyperspectral imager, based on a monolithically integrated Fabry-Perot etalon, has 70 spectral bands between 600-900 nm, making it ideal for this application. Initial calibration of the imager was performed to determine wavelength band response, quantum efficiency and the effect of F-number on the spectral response. A platform for wide-field fluorescence imaging in reflectance using fluorophore specific LED excitation was then developed. The applicability of the imaging platform for simultaneous readout of multiple fluorophore signals was demonstrated using a dilution series of Alexa Fluor 594 and Alexa Fluor 647, showing that nanomolar fluorophore concentrations can be detected. Our results show that the HSI system can clearly resolve the emission spectra of the two fluorophores in mixtures of concentrations across several orders of magnitude, indicating a high dynamic range performance. We therefore conclude that the HSI sensor tested here is suitable for detecting fluorescence in biomedical imaging applications.

  18. Evaluation of a novel gadolinium-based contrast agent for intraoperative magnetic resonance imaging

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Wu, Genevieve N.; Chow, Rayland; Kim, Sung-Yop; Hirschberg, Henry

    2008-02-01

    The aim of this experimental study was to determine whether Motexafin Gadolinium (MGd) could serve as an efficient intraoperative contrast agent avoiding problems that arise with surgically-induced intracranial enhancement. F98 orthotopic brain tumors or surgical lesions were induced in Fisher rats. T1-weighted MRI studies were performed with either a single or multiple daily doses of MGd. The last contrast dose was administered either 7 or 24 h prior to scanning in both tumor-bearing and surgically treated animals. Animals receiving either 30 or 60 mg/kg MGd i.v. developed clinical signs of impaired motor activity, and increasing lethargy. MGd given i.p. was tolerated up to a dose of 140 mg/kg. Despite multiple dosages, and several administration modes (i.p. and i.v.), no significant enhancement was observed if the scans were performed 7 or 24 h following the last MGd dose. Clear enhancement was observed if the scans were performed 30 min. following MGd administration. Scans of necrotic lesions were positive 7 h post MGd injection. MGd scans showed no significant enhancement following surgically-induced lesions while scans with conventional contrast agents showed both meningeal and intraparenchymal enhancement. This study suggests that MGd is not sequestered in viable tumor for the necessary time interval required to allow delayed imaging in this model. The agent does seem to remain in necrotic tissue for longer time intervals. MGd therefore would not be suitable as a contrast agent in iMRI for the detection of residual tumor tissue during surgery.

  19. Nanosized Ultrasound Enhanced-Contrast Agent for in Vivo Tumor Imaging via Intravenous Injection.

    PubMed

    Kim, Manse; Lee, Jong Hyun; Kim, Se Eun; Kang, Seong Soo; Tae, Giyoong

    2016-04-01

    To enhance the detection limit of ultrasound (US) imaging, ultrasound enhanced-contrast agents (UECAs) that can go preferentially to the target tissue such as a tumor and amplify the US signal have been developed. However, nanosized UECAs among various UECAs developed are very limited to clearly demonstrate proper ability for selective tumor detection by US imaging upon their intravenous injection. In this study, we prepared CaCO3 nanoparticles that were formed inside a flexible and biocompatible pluronic-based nanocarrier. This nanosized UECA was stable in serum-containing media and generated CO2, more preferentially at low pH; thus, it could be detected by US imaging. After intravenous injection into tumor-bearing mice, this nanosized UECA showed a significant US contrast enhancement at the tumor site in 1 h, in contrast to no change in the liver, followed by a rapid clearance from the body in 24 h. Therefore, the present nanosized UECA could be applied as an effective diagnostic modality for in vivo tumor imaging by ultrasonography. PMID:27010717

  20. Cleaved iron oxide nanoparticles as T2 contrast agents for magnetic resonance imaging.

    PubMed

    Jeon, Sung Lan; Chae, Min Kyung; Jang, Eun Ju; Lee, Chulhyun

    2013-03-25

    Iron oxide nanoparticles as contrast agents are reported to effectively improve magnetic resonance imaging of tissues and cells. In this work, cleaved iron oxide nanoparticles (CIONPs) were generated from hydrophobic FeO nanoparticles (HIONPs) by coating their surfaces with PEG-phospholipids, oxidizing them under water, and slowly removing the residual FeO phase in phthalate buffer. The synthesized CIONPs showed good r2 values of up to 258 s(-1)  mM(-1). Thus, the CIONPs can be employed as vectors for drug delivery due to their unique structure with an empty inner space, which enables their use in a wide range of applications. PMID:23345158

  1. Virus-mimicking nano-constructs as a contrast agent for near infrared photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Gupta, Sharad; Chatni, Muhammad R.; Rao, Ayala L. N.; Vullev, Valentine I.; Wang, Lihong V.; Anvari, Bahman

    2013-02-01

    We report the first proof-of-principle demonstration of photoacoustic imaging using a contrast agent composed of a plant virus protein shell, which encapsulates indocyanine green (ICG), the only FDA-approved near infrared chromophore. These nano-constructs can provide higher photoacoustic signals than blood in tissue phantoms, and display superior photostability compared to non-encapsulated ICG. Our preliminary results suggest that the constructs do not elicit an acute immunogenic response in healthy mice.We report the first proof-of-principle demonstration of photoacoustic imaging using a contrast agent composed of a plant virus protein shell, which encapsulates indocyanine green (ICG), the only FDA-approved near infrared chromophore. These nano-constructs can provide higher photoacoustic signals than blood in tissue phantoms, and display superior photostability compared to non-encapsulated ICG. Our preliminary results suggest that the constructs do not elicit an acute immunogenic response in healthy mice. Electronic supplemental information (ESI) available: Information on experimental procedure for fabrication of the nano-constructs, photoacoustic imaging, and immunogenic studies. See DOI: 10.1039/c3nr34124k

  2. 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.

  3. High-resolution wide-field imaging of perfused capillaries without the use of contrast agent

    PubMed Central

    Nelson, Darin A; Burgansky-Eliash, Zvia; Barash, Hila; Loewenstein, Anat; Barak, Adiel; Bartov, Elisha; Rock, Tali; Grinvald, Amiram

    2011-01-01

    Purpose: Assessment of capillary abnormalities facilitates early diagnosis, treatment, and follow-up of common retinal pathologies. Injected contrast agents like fluorescein are widely used to image retinal capillaries, but this highly effective procedure has a few disadvantages, such as untoward side effects, inconvenience of injection, and brevity of the time window for clear visualization. The retinal function imager (RFI) is a tool for monitoring retinal functions, such as blood velocity and oximetry, based on intrinsic signals. Here we describe the clinical use of hemoglobin in red blood cells (RBCs) as an intrinsic motion-contrast agent in the generation of detailed noninvasive capillary-perfusion maps (nCPMs). Patients and methods: Multiple series of nCPM images were acquired from 130 patients with diabetic retinopathy, vein occlusion, central serous retinopathy, age-related macular degeneration, or metabolic syndrome, as well as from 37 healthy subjects. After registration, pixel value distribution parameters were analyzed to locate RBC motion. Results: The RFI yielded nCPMs demonstrating microvascular morphology including capillaries in exquisite detail. Maps from the same subject were highly reproducible in repeated measurements, in as much detail and often better than that revealed by the very best fluorescein angiography. In patients, neovascularization and capillary nonperfusion areas were clearly observed. Foveal avascular zones (FAZ) were sharply delineated and were larger in patients with diabetic retinopathy than in controls (FAZ diameter: 641.5 ± 82.3 versus 463.7 ± 105 μm; P < 0.001). Also visible were abnormal vascular patterns, such as shunts and vascular loops. Conclusion: Optical imaging of retinal capillaries in human patients based on motion contrast is noninvasive, comfortable, safe, and can be repeated as often as required for early diagnosis, treatment guidance, and follow up of retinal disease progression. PMID:21887088

  4. Self-assembled microbubbles as contrast agents for ultrasound/magnetic resonance dual-modality imaging.

    PubMed

    Song, Sheng; Guo, Heze; Jiang, Zequan; Jin, Yuqing; Wu, Ying; An, Xiao; Zhang, Zhaofeng; Sun, Kang; Dou, Hongjing

    2015-09-01

    In this work, superparamagnetic self-assembled microbubbles (SAMBs) consisting of "Poly(acrylic acid)-Iron oxide nanoparticles-Polyamine" sandwich-like shells and tetradecafluorohexane cores were fabricated by a template-free self-assembly approach. The SAMBs exhibit not only magnetic resonance (MR) T2 imaging functionality, but also ultrasound (US) image contrast, showing great potential as US/MR dual contrast agents. The diameters of the SAMBs can be tuned easily from 450nm to 1300nm by changing the precursor ratio, and this size variation directly affects their in vitro MRI and US signals. The SAMBs also exhibit in vivo contrast enhancement capabilities in rat liver with injection through portal vein, for both MR and US imaging. Additionally, the biodistribution of SAMBs over time suggests normal systemic metabolic activity through the spleen. The results show that the Fe content in rat liver reduces to a level of which Fe cannot be detected in 45days. The SAMBs exhibit no obvious damage to the primary organs of rat during the metabolic process, indicating their good biocompatibility in vivo. PMID:26112374

  5. Long-Lasting and Efficient Tumor Imaging Using a High Relaxivity Polysaccharide Nanogel Magnetic Resonance Imaging Contrast Agent.

    PubMed

    Chan, Minnie; Lux, Jacques; Nishimura, Tomoki; Akiyoshi, Kazunari; Almutairi, Adah

    2015-09-14

    Clinically approved small-molecule magnetic resonance imaging (MRI) contrast agents are all rapidly cleared from the body and offer weak signal enhancement. To avoid repeated administration of contrast agent and improve signal-to-noise ratios, agents with stronger signal enhancement and better retention in tumors are needed. Therefore, we focused on hydrogels because of their excellent water accessibility and biodegradability. Gadolinium (Gd)-chelating cross-linkers were incorporated into self-assembled pullulan nanogels to both impart magnetic properties and to stabilize this material that has been extensively studied for medical applications. We show that these Gd-chelating pullulan nanogels (Gd-CHPOA) have the highest reported relaxivity for any hydrogel-based particles and accumulate in the 4T1 tumors in mice at high levels 4 h after injection. This combination offers high signal enhancement and lasts up to 7 days to delineate the tumor clearly for longer imaging time scales. Importantly, this long-term accumulation does not cause any damage or toxicity in major organs up to three months after injection. Our work highlights the clinical potential of Gd-CHPOA as a tumor-imaging MRI contrast agent, permitting tumor identification and assessment with a high signal-to-background ratio. PMID:26278775

  6. Porous silicon nanoparticles as biocompatible contrast agents for magnetic resonance imaging

    SciTech Connect

    Gongalsky, M. B. Kargina, Yu. V.; Osminkina, L. A.; Perepukhov, A. M.; Maximychev, A. V.; Gulyaev, M. V.; Vasiliev, A. N.; Pirogov, Yu. A.; Timoshenko, V. Yu.

    2015-12-07

    We propose porous silicon nanoparticles (PSi NPs) with natural oxide coating as biocompatible and bioresorbable contrast agents for magnetic resonant imaging (MRI). A strong shortening of the transversal proton relaxation time (T{sub 2}) was observed for aqueous suspensions of PSi NPs, whereas the longitudinal relaxation time (T{sub 1}) changed moderately. The longitudinal and transversal relaxivities are estimated to be 0.03 and 0.4 l/(g·s), respectively, which are promising for biomedical studies. The proton relaxation is suggested to undergo via the magnetic dipole-dipole interaction with Si dangling bonds on surfaces of PSi NPs. MRI experiments with phantoms have revealed the remarkable contrasting properties of PSi NPs for medical diagnostics.

  7. Generation of superparamagnetic liposomes revealed as highly efficient MRI contrast agents for in vivo imaging.

    PubMed

    Martina, Marie-Sophie; Fortin, Jean-Paul; Ménager, Christine; Clément, Olivier; Barratt, Gillian; Grabielle-Madelmont, Cécile; Gazeau, Florence; Cabuil, Valérie; Lesieur, Sylviane

    2005-08-01

    Maghemite (gamma-Fe2O3) nanocrystals stable at neutral pH and in isotonic aqueous media were synthesized and encapsulated within large unilamellar vesicles of egg phosphatidylcholine (EPC) and distearoyl-SN-glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG(2000), 5 mol %), formed by film hydration coupled with sequential extrusion. The nonentrapped particles were removed by flash gel exclusion chromatography. The magnetic-fluid-loaded liposomes (MFLs) were homogeneous in size (195 +/- 33 hydrodynamic diameters from quasi-elastic light scattering). Iron loading was varied from 35 up to 167 Fe(III)/lipid mol %. Physical and superparamagnetic characteristics of the iron oxide particles were preserved after liposome encapsulation as shown by cryogenic transmission electron microscopy and magnetization curve recording. In biological media, MFLs were highly stable and avoided ferrofluid flocculation while being nontoxic toward the J774 macrophage cell line. Moreover, steric stabilization ensured by PEG-surface-grafting significantly reduced liposome association with the macrophages. The ratios of the transversal (r2) and longitudinal (r1) magnetic resonance (MR) relaxivities of water protons in MFL dispersions (6 < r2/r1 < 18) ranked them among the best T2 contrast agents, the higher iron loading the better the T2 contrast enhancement. Magnetophoresis demonstrated the possible guidance of MFLs by applying a magnetic field gradient. Mouse MR imaging assessed MFLs efficiency as contrast agents in vivo: MR angiography performed 24 h after intravenous injection of the contrast agent provided the first direct evidence of the stealthiness of PEG-ylated magnetic-fluid-loaded liposomes. PMID:16045355

  8. Confocal microendoscopy: Characterization of imaging bundles, fluorescent contrast agents, and early clinical results

    NASA Astrophysics Data System (ADS)

    Udovich, Joshua Anthony

    . No significant difference was determined between the groups. These data provide preliminary results on determining the effect of these dyes on living tissues. Preliminary results of a clinical trial are presented showing in-vivo use of the CME for imaging of the ovaries. This is the first portion of a two part study to demonstrate the clinical diagnosis potential of the CME system. A mobile version of the bench-top CME was modified to be used in the clinic. Fluorescein sodium is used as an initial contrast agent in these studies to demonstrate fluorescence imaging. Twenty patients were successfully imaged, and results of this study have allowed progression to a clinical validation study showing the diagnostic capabilities of the CME.

  9. Two-photon luminescence imaging of cancerous tissue using gold nanorods as bright contrast agents

    NASA Astrophysics Data System (ADS)

    Durr, Nicholas J.; Holfeld, Benjamin A.; Larson, Timothy; Smith, Danielle K.; Korgel, Brian A.; Sokolova, Konstantin; Ben-Yakar, Adela

    2007-07-01

    We demonstrate the use of gold nanorods as molecularly targeted contrast agents for two-photon luminescence (TPL) imaging of cancerous cells 150 µm deep inside a tissue phantom. We synthesized gold nanorods of 50 nm x 15 nm size with a longitudinal surface plasmon resonance of 760 nm. Gold nanorods were conjugated to antibodies against epidermal growth factor receptor (EGFR) and labeled to A431 human epithelial skin cancer cells in a collagen matrix tissue phantom. Using a 1.4 NA oil immersion objective lens, we found that excitation power needed for similar emission intensity in TPL imaging of labeled cells was up to 64 times less than that needed for two-photon autofluorescence (TPAF) imaging of unlabeled cells, which would correspond to a more than 4,000 times increase in emission intensity under equal excitation energy. However, the aberrations due to refractive index mismatch of the immersion oil and the sample limit imaging depth to 75 µm. Using a 0.95 NA water immersion objective lens, we observe robust two-photon emission signal from gold nanorods in the tissue phantoms from at depths of up to 150 µm. Furthermore, the increase in excitation energy required to maintain a constant emission signal intensity as imaging depth was increased was the same in both labeled and unlabeled phantom, suggesting that at the concentrations used, the addition of gold nanorods did not appreciably increase the bulk scattering coefficient of the sample. The remarkable TPL brightness of gold nanorods in comparison to TPAF signal makes them an attractive contrast agent for early detection of cutaneous melanoma.

  10. Fluorescent Heterodoped Nanotetrapods as Synergistically Enhancing Positive and Negative Magnetic Resonance Imaging Contrast Agents.

    PubMed

    Sharma, V K; Alipour, A; Soran-Erdem, Z; Kelestemur, Y; Aykut, Z G; Demir, H V

    2016-05-18

    In this work, we report Mn-Fe heterodoped ZnSe tetrapod nanocrystals (NCs) synthesized to synergistically enhance contrast in both T1- and T2-weighted magnetic resonance imaging (MRI). The proposed NCs were prepared using a customized heteroarchitecture such that the manganese (Mn) is confined in the core and iron (Fe) in the branches of the tetrapods. The elemental composition and profile of these NCs were studied using X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, and inductively coupled plasma mass spectroscopy. Photoluminescence quantum yield of these heterodoped NCs in water is ∼30%. Magnetic measurements reveal the simultaneous presence of superparamagnetic and paramagnetic behavior in these NCs because of the coexistence of Mn(2+) and Fe(2+) dopants. Their potential as simultaneous positive and negative MRI contrast agents was demonstrated by relaxivity measurements and in vivo MRI. From the in vivo studies, we also found that these NCs (with a hydrodynamic diameter of 20 nm) are excreted from the body within 24 h after the injection. Therefore, these heterodoped tetrapods NCs, while being fluorescent and safe, hold great future as a synergistically enhancing dual-modal MRI contrast agent. PMID:27139918

  11. Gadofullerene MRI contrast agents.

    PubMed

    Bolskar, Robert D

    2008-04-01

    A promising new class of MRI contrast-enhancing agents with high relaxivities is based on gadolinium-containing metallofullerenes, which are also termed gadofullerenes. Detailed study of the water-proton relaxivity properties and intermolecular nanoclustering behavior of gadofullerene derivatives has revealed valuable information about their relaxivity mechanisms and given a deeper understanding of this new class of paramagnetic contrast agent. Here, the latest findings on water-solubilized gadofullerene materials and how these findings relate to their future applications in MRI are reviewed and discussed. PMID:18373426

  12. A novel use of near-infrared fluorescence imaging during robotic surgery without contrast agents.

    PubMed

    Hockenberry, Mark S; Smith, Zachary L; Mucksavage, Phillip

    2014-05-01

    We describe a novel use of near-infrared fluorescence (NIRF) imaging without contrast agents, like indocyanine green, to identify otherwise obscured intraluminal areas of interest during robot-assisted laparoscopic (RAL) surgery marked by the white light (WL) of endoscopic instruments. By filtering light wavelengths below near-infrared, NIRF imaging causes the WL of the endoscopes to illuminate green while allowing simultaneous vision of the surrounding tissues. With this visualization, intraoperative ureteroscopy was used to identify the extent of a ureteral stricture in a patient undergoing RAL partial ureterectomy. Cystoscopy was used to identify bladder diverticula and tumor locations in three patients undergoing RAL partial cystectomy with or without diverticulectomy and the ureteral orifice in another patient undergoing RAL nephroureterectomy. This technique enabled more precise identification of important areas and successful completion of RAL surgery in these five patients, which serves as proof of concept for broader applications in RAL surgery. PMID:24354630

  13. 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

  14. Engineered Iron-Oxide-Based Nanoparticles as Enhanced T1 Contrast Agents for Efficient Tumor Imaging

    PubMed Central

    Zhou, Zijian; Wang, Lirong; Chi, Xiaoqin; Bao, Jianfeng; Yang, Lijiao; Zhao, Wenxiu; Chen, Zhong; Wang, Xiaomin; Chen, Xiaoyuan; Gao, Jinhao

    2013-01-01

    We report the design and synthesis of small-sized zwitterion-coated gadolinium-embedded iron oxide (GdIO) nanoparticles, which exhibit a strong T1 contrast effect for tumor imaging through enhanced permeation and retention effect and the ability to clear out of the body in living subjects. The combination of spin-canting effects and the collection of gadolinium species within small-sized GdIO nanoparticles led to a significantly enhanced T1 contrast effect. For example, GdIO nanoparticles with a diameter of ~4.8 nm exhibited a high r1 relaxivity of 7.85 mM−1 · S−1 and a low r2/r1 ratio of 5.24. After being coated with zwitterionic dopamine sulfonate molecules, the 4.8 nm GdIO nanoparticles showed a steady hydrodynamic diameter (~5.2 nm) in both PBS buffer and fetal bovine serum solution, indicating a low nonspecific protein absorption. This study provides a valuable strategy for the design of highly sensitive iron-oxide-based T1 contrast agents with relatively long circulation half-lives (~50 min), efficient tumor passive targeting (SKOV3, human ovarian cancer xenograft tumor as a model), and the possibility of rapid renal clearance after tumor imaging. PMID:23473444

  15. Crimson carrier, a long-acting contrast agent for in vivo near-infrared imaging of injured and diseased muscle.

    PubMed

    Prajapati, Suresh I; Martinez, Carlo O; Abraham, Jinu; McCleish, Amanda T; Michalek, Joel E; McManus, Linda M; Rubin, Brian P; Shireman, Paula K; Keller, Charles

    2010-08-01

    The near-infrared wavelengths (700-900 nm) are the most suitable optical window for light penetration and deep tissue imaging in small animals. Herein we report a near-infrared fluorescent contrast agent, crimson carrier, which acts as a blood pool contrast agent to detect and quantify injury and disease in live animals. After determining the excitation-emission spectra and pharmacokinetics, crimson carrier was injected into myoinjured mice to monitor their recovery. Crimson carrier was also used to image transgenic mice with spontaneous tumors. Crimson carrier has maximal excitation and emission wavelengths of 745 nm and 820 nm, respectively. Elimination occurs predominantly via urinary excretion. We demonstrate the utility of this contrast agent for serial imaging of traumatized muscle as well as muscle tumors. The unique long-acting pharmacokinetics and urinary excretion route characteristics make crimson carrier a contrast agent of choice for the visualization of tumors and injured muscle or other tissues in live animal studies. PMID:20544935

  16. Preliminary Results on Different Impedance Contrast Agents for Pulmonary Perfusion Imaging with Electrical Impedance Tomography

    NASA Astrophysics Data System (ADS)

    Nguyen, D. T.; Kosobrodov, R.; Barry, M. A.; Chik, W.; Pouliopoulos, J.; Oh, T. I.; Thiagalingam, A.; McEwan, A.

    2013-04-01

    Recent studies in animal models suggest that the use of small volume boluses of NaCl as an impedance contrast agent can significantly improve pulmonary perfusion imaging by Electrical Impedance Tomography (EIT). However, these studies used highly concentrated NaCl solution (20%) which may have adverse effects on the patients. In a pilot experiment, we address this problem by comparing a number of different Impedance Contrast Boluses (ICBs). Conductivity changes in the lungs of a sheep after the injection of four different ICBs were compared, including three NaCl-based ICBs and one glucose-based ICB. The following procedure was followed for each ICB. Firstly, ventilation was turned off to provide an apneic window of approximately 40s to image the conductivity changes due to the ICB. Each ICB was then injected through a pig-tail catheter directly into the right atrium. EIT images were acquired throughout the apnea to capture the conductivity change. For each ICB, the experiment was repeated three times. The three NaCl-based ICB exhibited similar behaviour in which following the injection of each of these ICBs, the conductivity of each lung predictably increased. The effect of the ICB of 5% glucose solution was inconclusive. A small decrease in conductivity in the left lung was observed in two out of three cases and none was discernible in the right lung.

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

    PubMed

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

    2015-01-01

    Nanobubbles (NBs), as novel ultrasound contrast agents (UCAs), have attracted increasing attention in the field of molecular ultrasound imaging for tumors. However, the preparation of uniform-sized NBs is considered to be controversial, and poor tumor selectivity in in vivo imaging has been reported. In this study, we fabricated uniform nano-sized NBs (478.2 ± 29.7 nm with polydispersity index of 0.164 ± 0.044, n = 3) using a thin-film hydration method by controlling the thickness of phospholipid films; we then conjugated the NBs with Affibody molecules to produce nano-sized UCAs referred to as NB-Affibody with specific affinity to human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors. NB-Affibody presented good ultrasound enhancement, demonstrating a peak intensity of 104.5 ± 2.1 dB under ultrasound contrast scanning. Ex vivo experiments further confirmed that the NB-Affibody conjugates were capable of targeting HER2-expressing tumor cells in vivo with high affinity. The newly prepared nano-sized NB-Affibody conjugates were observed to be novel targeted UCAs for efficient and safe specific molecular imaging and may have potential applications in early cancer quantitative diagnosis and targeted therapy in the future. PMID:25453958

  18. Strategies for Optimizing Water-Exchange Rates of Lanthanide-Based Contrast Agents for Magnetic Resonance Imaging

    PubMed Central

    Siriwardena-Mahanama, Buddhima N.; Allen, Matthew J.

    2013-01-01

    This review describes recent advances in strategies for tuning the water-exchange rates of contrast agents for magnetic resonance imaging (MRI). Water-exchange rates play a critical role in determining the efficiency of contrast agents; consequently, optimization of water-exchange rates, among other parameters, is necessary to achieve high efficiencies. This need has resulted in extensive research efforts to modulate water-exchange rates by chemically altering the coordination environments of the metal complexes that function as contrast agents. The focus of this review is coordination-chemistry-based strategies used to tune the water-exchange rates of lanthanide(III)-based contrast agents for MRI. Emphasis will be given to results published in the 21st century, as well as implications of these strategies on the design of contrast agents. PMID:23921796

  19. Polycatechol Nanoparticle MRI Contrast Agents.

    PubMed

    Li, Yiwen; Huang, Yuran; Wang, Zhao; Carniato, Fabio; Xie, Yijun; Patterson, Joseph P; Thompson, Matthew P; Andolina, Christopher M; Ditri, Treffly B; Millstone, Jill E; Figueroa, Joshua S; Rinehart, Jeffrey D; Scadeng, Miriam; Botta, Mauro; Gianneschi, Nathan C

    2016-02-01

    Amphiphilic triblock copolymers containing Fe(III) -catecholate complexes formulated as spherical- or cylindrical-shaped micellar nanoparticles (SMN and CMN, respectively) are described as new T1-weighted agents with high relaxivity, low cytotoxicity, and long-term stability in biological fluids. Relaxivities of both SMN and CMN exceed those of established gadolinium chelates across a wide range of magnetic field strengths. Interestingly, shape-dependent behavior is observed in terms of the particles' interactions with HeLa cells, with CMN exhibiting enhanced uptake and contrast via magnetic resonance imaging (MRI) compared with SMN. These results suggest that control over soft nanoparticle shape will provide an avenue for optimization of particle-based contrast agents as biodiagnostics. The polycatechol nanoparticles are proposed as suitable for preclinical investigations into their viability as gadolinium-free, safe, and effective imaging agents for MRI contrast enhancement. PMID:26681255

  20. Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery

    PubMed Central

    Paefgen, Vera; Doleschel, Dennis; Kiessling, Fabian

    2015-01-01

    Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles’ shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given. PMID:26441654

  1. Evolution of contrast agents for ultrasound imaging and ultrasound-mediated drug delivery.

    PubMed

    Paefgen, Vera; Doleschel, Dennis; Kiessling, Fabian

    2015-01-01

    Ultrasound (US) is one of the most frequently used diagnostic methods. It is a non-invasive, comparably inexpensive imaging method with a broad spectrum of applications, which can be increased even more by using bubbles as contrast agents (CAs). There are various different types of bubbles: filled with different gases, composed of soft- or hard-shell materials, and ranging in size from nano- to micrometers. These intravascular CAs enable functional analyses, e.g., to acquire organ perfusion in real-time. Molecular analyses are achieved by coupling specific ligands to the bubbles' shell, which bind to marker molecules in the area of interest. Bubbles can also be loaded with or attached to drugs, peptides or genes and can be destroyed by US pulses to locally release the entrapped agent. Recent studies show that US CAs are also valuable tools in hyperthermia-induced ablation therapy of tumors, or can increase cellular uptake of locally released drugs by enhancing membrane permeability. This review summarizes important steps in the development of US CAs and introduces the current clinical applications of contrast-enhanced US. Additionally, an overview of the recent developments in US probe design for functional and molecular diagnosis as well as for drug delivery is given. PMID:26441654

  2. Simple method for quantification of gadolinium magnetic resonance imaging contrast agents using ESR spectroscopy.

    PubMed

    Takeshita, Keizo; Kinoshita, Shota; Okazaki, Shoko

    2012-01-01

    To develop an estimation method of gadolinium magnetic resonance imaging (MRI) contrast agents, the effect of concentration of Gd compounds on the ESR spectrum of nitroxyl radical was examined. A solution of either 4-oxo-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPONE) or 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) was mixed with a solution of Gd compound and the ESR spectrum was recorded. Increased concentration of gadolinium-diethylenetriamine pentaacetic acid chelate (Gd-DTPA), an MRI contrast agent, increased the peak-to-peak line widths of ESR spectra of the nitroxyl radicals, in accordance with a decrease of their signal heights. A linear relationship was observed between concentration of Gd-DTPA and line width of ESR signal, up to approximately 50 mmol/L Gd-DTPA, with a high correlation coefficient. Response of TEMPONE was 1.4-times higher than that of TEMPOL as evaluated from the slopes of the lines. The response was slightly different among Gd compounds; the slopes of calibration curves for acua[N,N-bis[2-[(carboxymethyl)[(methylcarbamoyl)methyl]amino]ethyl]glycinato(3-)]gadolinium hydrate (Gd-DTPA-BMA) (6.22 μT·L/mmol) and gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelate (Gd-DOTA) (6.62 μT·L/mmol) were steeper than the slope for Gd-DTPA (5.45 μT·L/mmol), whereas the slope for gadolinium chloride (4.94 μT·L/mmol) was less steep than that for Gd-DTPA. This method is simple to apply. The results indicate that this method is useful for rough estimation of the concentration of Gd contrast agents if calibration is carried out with each standard compound. It was also found that the plot of the reciprocal square root of signal height against concentrations of contrast agents could be useful for the estimation if a constant volume of sample solution is taken and measured at the same position in the ESR cavity every time. PMID:22223372

  3. Iodinated α-tocopherol nano-emulsions as non-toxic contrast agents for preclinical X-ray imaging.

    PubMed

    Li, Xiang; Anton, Nicolas; Zuber, Guy; Zhao, Minjie; Messaddeq, Nadia; Hallouard, François; Fessi, Hatem; Vandamme, Thierry F

    2013-01-01

    Micro-computed tomography (micro-CT) is an emerging imaging modality, due to the low cost of the imagers as well as their efficiency in establishing high-resolution (1-100 μm) three-dimensional images of small laboratory animals and facilitating rapid, structural and functional in vivo visualization. However use of a contrast agent is absolutely necessary when imaging soft tissues. The main limitation of micro-CT is the low efficiency and toxicity of the commercially available blood pool contrast agents. This study proposes new, efficient and non-toxic contrast agents for micro-CT imaging. This formulation consists of iodinated vitamin E (α-tocopheryl 2,3,5-triiodobenzoate) as an oily phase, formulated as liquid nano-emulsion droplets (by low-energy nano-emulsification), surrounded by a hairy PEG layer to confer stealth properties. The originality and strength of these new contrast agents lie not only in their outstanding contrasting properties, biocompatibility and low toxicity, but also in the simplicity of their fabrication: one-step synthesis of highly iodinated oil (iodine constitutes 41.7% of the oil molecule weight) and its spontaneous emulsification. After i.v. administration in mice (8.5% of blood volume), the product shows stealth properties towards the immune system and thus acts as an efficient blood pool contrast agent (t(1/2) = 9.0 h), exhibiting blood clearance following mono-exponential decay. A gradual accumulation predominantly due to hepatocyte uptake is observed and measured in the liver, establishing a strong hepatic contrast, persistent for more than four months. To summarize, in the current range of available or developed contrast agents for preclinical X-ray imaging, this agent appears to be one of the most efficient. PMID:23083930

  4. Advances in molecular imaging: targeted optical contrast agents for cancer diagnostics

    PubMed Central

    Hellebust, Anne; Richards-Kortum, Rebecca

    2012-01-01

    Over the last three decades, our understanding of the molecular changes associated with cancer development and progression has advanced greatly. This has led to new cancer therapeutics targeted against specific molecular pathways; such therapies show great promise to reduce mortality, in part by enabling physicians to tailor therapy for patients based on a molecular profile of their tumor. Unfortunately, the tools for definitive cancer diagnosis – light microscopic examination of biopsied tissue stained with nonspecific dyes – remain focused on the analysis of tissue ex vivo. There is an important need for new clinical tools to support the molecular diagnosis of cancer. Optical molecular imaging is emerging as a technique to help meet this need. Targeted, optically active contrast agents can specifically label extra-and intracellular biomarkers of cancer. Optical images can be acquired in real time with high spatial resolution to image-specific molecular targets, while still providing morphologic context. This article reviews recent advances in optical molecular imaging, highlighting the advances in technology required to improve early cancer detection, guide selection of targeted therapy and rapidly evaluate therapeutic efficacy. PMID:22385200

  5. Aptamer-Modified Temperature-Sensitive Liposomal Contrast Agent for Magnetic Resonance Imaging.

    PubMed

    Zhang, Kunchi; Liu, Min; Tong, Xiaoyan; Sun, Na; Zhou, Lu; Cao, Yi; Wang, Jine; Zhang, Hailu; Pei, Renjun

    2015-09-14

    A novel aptamer modified thermosensitive liposome was designed as an efficient magnetic resonance imaging probe. In this paper, Gd-DTPA was encapsulated into an optimized thermosensitive liposome (TSL) formulation, followed by conjugation with AS1411 for specific targeting against tumor cells that overexpress nucleolin receptors. The resulting liposomes were extensively characterized in vitro as a contrast agent. As-prepared TSLs-AS1411 had a diameter about 136.1 nm. No obvious cytotoxicity was observed from MTT assay, which illustrated that the liposomes exhibited excellent biocompatibility. Compared to the control incubation at 37 °C, the liposomes modified with AS1411 exhibited much higher T1 relaxivity in MCF-7 cells incubated at 42 °C. These data indicate that the Gd-encapsulated TSLs-AS1411 may be a promising tool in early cancer diagnosis. PMID:26212580

  6. Demonstration of a Sucrose-derived Contrast Agent for Magnetic Resonance Imaging of the GI Tract

    PubMed Central

    Martinez, Gary V.; Navath, Suryakiran; Sewda, Kamini; Rao, Venkataramanarao; Foroutan, Parastou; Alleti, Ramesh; Moberg, Valerie E.; Ahad, Ali M.; Coppola, Domenico; Lloyd, Mark C.; Gillies, Robert J.; Morse, David L.; Mash, Eugene A.

    2013-01-01

    A scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd-DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting contrast agent (CA) was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal (GI) tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 47 hours, by which time the CA had exited the GI tract. No evidence for leakage of the CA from the GI tract was observed. Thus, a new, orally administered CA for MRI of the GI tract has been developed and successfully demonstrated. PMID:23481651

  7. Demonstration of a sucrose-derived contrast agent for magnetic resonance imaging of the GI tract.

    PubMed

    Martinez, Gary V; Navath, Suryakiran; Sewda, Kamini; Rao, Venkataramanarao; Foroutan, Parastou; Alleti, Ramesh; Moberg, Valerie E; Ahad, Ali M; Coppola, Domenico; Lloyd, Mark C; Gillies, Robert J; Morse, David L; Mash, Eugene A

    2013-04-01

    A scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd-DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting contrast agent (CA) was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal (GI) tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 47h, by which time the CA had exited the GI tract. No evidence for leakage of the CA from the GI tract was observed. Thus, a new, orally administered CA for MRI of the GI tract has been developed and successfully demonstrated. PMID:23481651

  8. Stimulus-responsive ultrasound contrast agents for clinical imaging: motivations, demonstrations, and future directions.

    PubMed

    Goodwin, Andrew P; Nakatsuka, Matthew A; Mattrey, Robert F

    2015-01-01

    Microbubble ultrasound contrast agents allow imaging of the vasculature with excellent resolution and signal-to-noise ratios. Contrast in microbubbles derives from their interaction with an ultrasound wave to generate signal at harmonic frequencies of the stimulating pulse; subtracting the elastic echo caused by the surrounding tissue can enhance the specificity of these harmonic signals significantly. The nonlinear acoustic emission is caused by pressure-driven microbubble size fluctuations, which in both theoretical descriptions and empirical measurements was found to depend on the mechanical properties of the shell that encapsulates the microbubble as well as stabilizes it against the surrounding aqueous environment. Thus biochemically induced switching between a rigid 'off' state and a flexible 'on' state provides a mechanism for sensing chemical markers for disease. In our research, we coupled DNA oligonucleotides to a stabilizing lipid monolayer to modulate stiffness of the shell and thereby induce stimulus-responsive behavior. In initial proof-of-principle studies, it was found that signal modulation came primarily from DNA crosslinks preventing the microbubble size oscillations rather than merely damping the signal. Next, these microbubbles were redesigned to include an aptamer sequence in the crosslinking strand, which not only allowed the sensing of the clotting enzyme thrombin but also provided a general strategy for sensing other soluble biomarkers in the bloodstream. Finally, the thrombin-sensitive microbubbles were validated in a rabbit model, presenting the first example of an ultrasound contrast agent that could differentiate between active and inactive clots for the diagnosis of deep venous thrombosis. PMID:25195785

  9. Intravenous ultrasound contrast agents versus other imaging methods in pediatric patients with neoplastic diseases – a comparison

    PubMed Central

    Kosiak, Wojciech; Batko, Tomasz; Adamkiewicz-Drożyńska, Elżbieta; Szarmach, Arkadiusz

    2013-01-01

    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. PMID:26675552

  10. Time-resolved spectroscopy and near infrared imaging enhanced by receptor-targeted contrast agents for prostate cancer detection

    NASA Astrophysics Data System (ADS)

    Pu, Y.; Wang, W. B.; Tang, G. C.; Achilefu, S.; Alfano, R. R.

    2011-03-01

    Time-resolved spectroscopy and near infrared imaging enhanced by receptor-targeted contrast agents for prostate cancer detection will be presented. Two contrast agents, Cybesin and Cytate, were investigated using time-resolved spectroscopy in aqueous solution and cancerous and normal prostate tissues. The time evolution of the fluorescent dipole in solution was studied using a system of first-order linear differential equations containing two main parameters: the decay rate of emission and the rate of one orthogonal emission component transferring to another. An analytical polarization model was developed and used to extract rotational times and fluorescence anisotropies of the contrast agents in prostate tissues. The differences of rotational times and polarization anisotropies were observed for Cybesin (Cytate) in cancerous and normal prostate tissue, which reflect preferred bond of contrast agents and cancerous tissue cells. The conjugation of Cybesin (Cytate) to prostate cancerous cells offers high contrast between normal and cancerous tissues.

  11. Iron oxide nanorods as high-performance magnetic resonance imaging contrast agents

    NASA Astrophysics Data System (ADS)

    Mohapatra, Jeotikanta; Mitra, Arijit; Tyagi, Himanshu; Bahadur, D.; Aslam, M.

    2015-05-01

    An efficient magnetic resonance imaging (MRI) contrast agent with a high R2 relaxivity value is achieved by controlling the shape of iron oxide to rod like morphology with a length of 30-70 nm and diameter of 4-12 nm. Fe3O4 nanorods of 70 nm length, encapsulated with polyethyleneimine show a very high R2 relaxivity value of 608 mM-1 s-1. The enhanced MRI contrast of nanorods is attributed to their higher surface area and anisotropic morphology. The higher surface area induces a stronger magnetic field perturbation over a larger volume more effectively for the outer sphere protons. The shape anisotropy contribution is understood by calculating the local magnetic field of nanorods and spherical nanoparticles under an applied magnetic field (3 Tesla). As compared to spherical geometry, the induced magnetic field of a rod is stronger and hence the stronger magnetic field over a large volume leads to a higher R2 relaxivity of nanorods.An efficient magnetic resonance imaging (MRI) contrast agent with a high R2 relaxivity value is achieved by controlling the shape of iron oxide to rod like morphology with a length of 30-70 nm and diameter of 4-12 nm. Fe3O4 nanorods of 70 nm length, encapsulated with polyethyleneimine show a very high R2 relaxivity value of 608 mM-1 s-1. The enhanced MRI contrast of nanorods is attributed to their higher surface area and anisotropic morphology. The higher surface area induces a stronger magnetic field perturbation over a larger volume more effectively for the outer sphere protons. The shape anisotropy contribution is understood by calculating the local magnetic field of nanorods and spherical nanoparticles under an applied magnetic field (3 Tesla). As compared to spherical geometry, the induced magnetic field of a rod is stronger and hence the stronger magnetic field over a large volume leads to a higher R2 relaxivity of nanorods. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr00055f

  12. The preliminary evaluation of Mn DTPA as a potential contrast agent for nuclear magnetic resonance imaging.

    PubMed

    Boudreau, R J; Frick, M P; Levey, R M; Lund, G; Sirr, S A; Loken, M K

    1986-01-01

    The pharmacokinetics of 54Mn administered as Mn-diethylenetriamine pentaacetic acid (DTPA) are being investigated to determine if tissue-specific uptake of manganese could be observed while increasing urinary excretion. This chelation and increased excretion should reduce toxicity. In order to obviate the need for repetitive quantitative nuclear magnetic resonance imaging (NMR) we have substituted tracer amounts of a radioisotope of manganese, Mn-54, for the stable ion. By 6 hours, 58 +/- 7% of the injected dose had been excreted in the urine. Peak liver accumulation occurred within 30 minutes (0.50 +/- 0.14% injected dose/g X kg body weight). The pancreas also showed a relatively high accumulation of tracer (0.25 +/- 0.04%/g X kg body weight), reaching a peak at 4 hours. The pancreas to liver ratios were highest at 6 hours (0.7). There was also a substantial accumulation of the manganese in bile. The blood concentration fell very rapidly with little tracer remaining in the blood at 1 hour. Based on these pharmacokinetics, imaging experiments were conducted before, immediately after, and 9 or 24 hours postinjection. These images showed enhanced kidneys and, later (at 9 hours), an excellent parenchymal-collecting system differentiation. The gallbladder was negatively enhanced. The liver showed either increased or decreased signal strength relative to skeletal muscle depending on the pulse sequence used. We conclude that Mn++, administered as Mn-DTPA, merits further investigation as an NMR contrast agent. PMID:3451753

  13. Antibiofouling polymer coated gold nanoparticles as a dual modal contrast agent for X-ray and photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Huang, Guojia; Yuan, Yi; Xing, Da

    2011-01-01

    X-ray is one of the most useful diagnostic tools in hospitals in terms of frequency of use and cost, while photoacoustic (PA) imaging is a rapidly emerging non-invasive imaging technology that integrates the merits of high optical contrast with high ultrasound resolution. In this study, for the first time, we used gold nanoparticles (GNPs) as a dual modal contrast agent for X-ray and PA imaging. Soft gelatin phantoms with embedded tumor simulators of GNPs in various concentrations are clearly shown in both X-ray and PA imaging. With GNPs as a dual modal contrast agent, X-ray can fast detect the position of tumor and provide morphological information, whereas PA imaging has important potential applications in the image guided therapy of superficial tumors such as breast cancer, melanoma and Merkel cell carcinoma.

  14. Carbon-Based Nanostructures as Advanced Contrast Agents for Magnetic Resonance Imaging

    NASA Astrophysics Data System (ADS)

    Ananta Narayanan, Jeyarama S.

    2011-12-01

    Superparamagnetic carbon-based nanostructures are presented as contrast agents (CAs) for advanced imaging applications such as cellular and molecular imaging using magnetic resonance imaging (MRI). Gadolinium-loaded, ultra-short single-walled carbon nanotubes (gadonanotubes; GNTs) are shown to have extremely high r1 relaxivities (contrast enhancement efficacy), especially at low-magnetic field strengths. The inherent lipophilicity of GNTs provides them the ability to image cells at low magnetic field strength. A carboxylated dextran-coated GNT (GadoDex) has been synthesized and proposed as a new biocompatible high-performance MRI CA. The r1 relaxivity is ca. 20 times greater than for other paramagnetic Gd-based CAs. This enhanced relaxivity for GadoDex is due to the synergistic effects of an increased molecular tumbling time (tauR) and a faster proton exchange rate (taum). GNTs also exhibit very large transverse relaxivities (r2) at high magnetic fields (≥ 3 T). The dependence of the transverse relaxation rates (especially R2*) of labeled cells on GNT concentration offers the possibility to quantify cell population in vivo using R2* mapping. The cell-labeling efficiency and high transverse relaxivities of GNTs has enabled the first non-iron oxide-based single-cell imaging using MRI. The residual metal catalyst particles of SWNT materials also have transverse relaxation properties. All of the SWNT materials exhibit superior transverse relaxation properties. However, purified SWNTs and US-tubes with less residual metal content exhibit better transverse relaxivities (r2), demonstrating the importance of the SWNT structure for enhanced MRI CA performance. A strategy to improve the r1 relaxivity of Gd-CAs by geometrically confining them within porous silicon particles (SiMPs) has been investigated. The enhancement in relaxivity is attributed to the slow diffusion of water molecules through the pores and the increase in the molecular tumbling time of the nanoconstruct

  15. Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging.

    PubMed

    Mitchell, Nick; Kalber, Tammy L; Cooper, Margaret S; Sunassee, Kavitha; Chalker, Samantha L; Shaw, Karen P; Ordidge, Katherine L; Badar, Adam; Janes, Samuel M; Blower, Philip J; Lythgoe, Mark F; Hailes, Helen C; Tabor, Alethea B

    2013-01-01

    A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd(3+), (64)Cu(2+), or (111)In(3+), and also incorporating fluorescent lipids, have been prepared, and their application in optical, magnetic resonance (MR) and single-photon emission tomography (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumour cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)(2000)] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent. PMID:23131536

  16. Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging

    PubMed Central

    Mitchell, Nick; Kalber, Tammy L.; Cooper, Margaret S.; Sunassee, Kavitha; Chalker, Samantha L.; Shaw, Karen P.; Ordidge, Katherine L.; Badar, Adam; Janes, Samuel M.; Blower, Philip J.; Lythgoe, Mark F.; Hailes, Helen C.; Tabor, Alethea B.

    2013-01-01

    A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd3+, 64Cu2+, or 111In3+, and also incorporating fluorescent lipids, have been prepared, and their application in optical, magnetic resonance (MR) and single-photon emission tomography (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumour cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)2000] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent. PMID:23131536

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

    PubMed

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

    2016-04-01

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

  18. Quasi-Cubic Magnetite/Silica Core-Shell Nanoparticles as Enhanced MRI Contrast Agents for Cancer Imaging

    PubMed Central

    Cowell, Simon F.; Garg, Ashish; Eu, Peter; Bhargava, Suresh K.; Bansal, Vipul

    2011-01-01

    Development of magnetic resonance imaging (MRI) contrast agents that can be readily applied for imaging of biological tissues under clinical settings is a challenging task. This is predominantly due to the expectation of an ideal MR agent being able to be synthesized in large quantities, possessing longer shelf life, reasonable biocompatibility, tolerance against its aggregation in biological fluids, and high relaxivity, resulting in better contrast during biological imaging. Although a repertoire of reports address various aforementioned issues, the previously reported results are far from optimal, which necessitates further efforts in this area. In this study, we demonstrate facile large-scale synthesis of sub-100 nm quasi-cubic magnetite and magnetite/silica core-shell (Mag@SiO2) nanoparticles and their applicability as a biocompatible T2 contrast agent for MRI of biological tissues. Our study suggests that silica-coated magnetite nanoparticles reported in this study can potentially act as improved MR contrast agents by addressing a number of aforementioned issues, including longer shelf life and stability in biological fluids. Additionally, our in vitro and in vivo studies clearly demonstrate the importance of silica coating towards improved applicability of T2 contrast agents for cancer imaging. PMID:21747962

  19. Self-assembled polyelectrolyte nanoparticles as fluorophore-free contrast agents for multicolor optical imaging.

    PubMed

    Shin, Da Hye; Heo, Min Beom; Lim, Yong Taik

    2015-01-01

    In this work, we describe the fabrication of self-assembled polyelectrolyte nanoparticles that provide a multicolor optical imaging modality. Poly(γ-glutamic acid)(γ-PGA) formed self-assembled nanoparticles through electrostatic interactions with two different cationic polymers: poly(L-lysine)(PLL) and chitosan. The self-assembled γ-PGA/PLL and γ-PGA/chitosan nanoparticles were crosslinked by glutaraldehyde. Crosslinking of the ionic self-assembled nanoparticles with glutaraldehyde not only stabilized the nanoparticles but also generated a strong autofluorescence signal. Fluorescent Schiff base bonds (C=N) and double bonds (C=C) were generated simultaneously by crosslinking of the amine moiety of the cationic polyelectrolytes with monomeric glutaraldehyde or with polymeric glutaraldehyde. The unique optical properties of the nanoparticles that resulted from the crosslinking by glutaraldehyde were analyzed using UV/Vis and fluorescence spectroscopy. We observed that the fluorescence intensity of the nanoparticles could be regulated by adjusting the crosslinker concentration and the reaction time. The nanoparticles also exhibited high performance in the labeling and monitoring of therapeutic immune cells (macrophages and dendritic cells). These self-assembled nanoparticles are expected to be a promising multicolor optical imaging contrast agent for the labeling, detection, and monitoring of cells. PMID:25759954

  20. Dual-energy subtraction imaging utilizing indium as a contrast agent

    SciTech Connect

    Le Duc, G.; Zhong, Z.; Warkentien, L.; Laster, B.; Thomlinson, W.

    1997-10-01

    The purpose of our current work is to establish the minimum detection, of indium contrast agent using dual-energy subtraction imaging above and below indium K-edge. Experiments were performed on the X12 and X17B2 beamlines at the National Synchrotron Light Source using the same method but with two different set-ups. Experiments were first carried out on InCl{sub 3} solutions, then on V79 Chinese hamster cells and on BALB/c mice excised tumors, labeled with indium. For each experiment, several layers of Lucite were placed in front of the phantom to ensure a 43 mm thickness, dose to that of a mammography examination. Results were the same on X12 and X17B2. As expected, indium-free materials disappeared on subtracted images (water, steel reference and screw). Indium samples were easily distinguishable for the following concentrations: 10-5-2-1 mg/cm{sup 2}. Smaller concentrations were not clearly distinguishable and we were unable to see cell samples and tumors. To conclude, the lowest concentration we can image is around 1 mg/cm{sup 2}. These results agree with theoretical results. Such results also suggest that indium concentration in both cells and tumors is lower than 0.5 mg/cm{sup 2}. Since the current detection is dose to optimum, we conclude that dual energy subtraction imaging using indium to label tumors cells and tumors is not possible unless the indium uptake is increased by more than an order of magnitude.

  1. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status

    PubMed Central

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors’ ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  2. Estrogen Receptor-Targeted Contrast Agents for Molecular Magnetic Resonance Imaging of Breast Cancer Hormonal Status.

    PubMed

    Pais, Adi; Degani, Hadassa

    2016-01-01

    The estrogen receptor (ER) α is overexpressed in most breast cancers, and its level serves as a major prognostic factor. It is important to develop quantitative molecular imaging methods that specifically detect ER in vivo and assess its function throughout the entire primary breast cancer and in metastatic breast cancer lesions. This study presents the biochemical and molecular features, as well as the magnetic resonance imaging (MRI) effects of two novel ER-targeted contrast agents (CAs), based on pyridine-tetra-acetate-Gd(III) chelate conjugated to 17β-estradiol (EPTA-Gd) or to tamoxifen (TPTA-Gd). The experiments were conducted in solution, in human breast cancer cells, and in severe combined immunodeficient mice implanted with transfected ER-positive and ER-negative MDA-MB-231 human breast cancer xenografts. Binding studies with ER in solution and in human breast cancer cells indicated affinities in the micromolar range of both CAs. Biochemical and molecular studies in breast cancer cell cultures showed that both CAs exhibit estrogen-like agonistic activity, enhancing cell proliferation, as well as upregulating cMyc oncogene and downregulating ER expression levels. The MRI longitudinal relaxivity was significantly augmented by EPTA-Gd in ER-positive cells as compared to ER-negative cells. Dynamic contrast-enhanced studies with EPTA-Gd in vivo indicated specific augmentation of the MRI water signal in the ER-positive versus ER-negative xenografts, confirming EPTA-Gd-specific interaction with ER. In contrast, TPTA-Gd did not show increased enhancement in ER-positive tumors and did not appear to interact in vivo with the tumors' ER. However, TPTA-Gd was found to interact strongly with muscle tissue, enhancing muscle signal intensity in a mechanism independent of the presence of ER. The specificity of EPTA-Gd interaction with ER in vivo was further verified by acute and chronic competition with tamoxifen. The chronic tamoxifen treatment also revealed that this

  3. 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. PMID:19763751

  4. Imaging In Vivo Extracellular pH with a Single Paramagnetic Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agent

    PubMed Central

    Liu, Guanshu; Li, Yuguo; Sheth, Vipul R.; Pagel, Mark D.

    2016-01-01

    The measurement of extracellular pH (pHe) has potential utility for cancer diagnoses and for assessing the therapeutic effects of pH-dependent therapies. A single magnetic resonance imaging (MRI) contrast agent that is detected through paramagnetic chemical exchange saturation transfer (PARACEST) was designed to measure tumor pHe throughout the range of physiologic pH and with magnetic resonance saturation powers that are not harmful to a mouse model of cancer. The chemical characterization and modeling of the contrast agent Yb3+-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,10-o-aminoanilide (Yb-DO3A-oAA) suggested that the aryl amine of the agent forms an intramolecular hydrogen bond with a proximal carboxylate ligand, which was essential for generating a practical chemical exchange saturation transfer (CEST) effect from an amine. A ratio of CEST effects from the aryl amine and amide was linearly correlated with pH throughout the physiologic pH range. The pH calibration was used to produce a parametric pH map of a subcutaneous flank tumor on a mouse model of MCF-7 mammary carcinoma. Although refinements in the in vivo CEST MRI methodology may improve the accuracy of pHe measurements, this study demonstrated that the PARACEST contrast agent can be used to generate parametric pH maps of in vivo tumors with saturation power levels that are not harmful to a mouse model of cancer. PMID:22418027

  5. New oil-in-water magnetic emulsion as contrast agent for in vivo magnetic resonance imaging (MRI).

    PubMed

    Ahmed, Naveed; Jaafar-Maalej, Chiraz; Eissa, Mohamed Mahmoud; Fessi, Hatem; Elaissari, Abdelhamid

    2013-09-01

    Nowadays, bio-imaging techniques are widely applied for the diagnosis of various diseased/tumoral tissues in the body using different contrast agents. Accordingly, the advancement in bionanotechnology research is enhanced in this regard. Among contrast agents used, superparamagnetic iron oxide nanoparticles were developed by many researchers and applied for in vive magnetic resonance imaging (MRI). In this study, a new oil-in-water magnetic emulsion was used as contrast agent in MRI, after being characterized in terms of particle size, iron oxide content, magnetic properties and colloidal stability using dynamic light scattering (DLS), thermal gravimetric analysis (TGA), vibrating sample magnetometer (VSM) and zeta potential measurement techniques, respectively. The hydrodynamic size and magnetic content of the magnetic colloidal particles were found to be 250 nm and 75 wt%, respectively. In addition, the used magnetic emulsion possesses superparamagentic properties and high colloidal stability in aqueous medium. Then, the magnetic emulsion was highly diluted and administered intravenously to the Sprague dawley rats to be tested as contrast agent for in vivo MRI. In this preliminary study, MRI images showed significant enhancement in contrast, especially for T2 (relaxation time) contrast enhancement, indicating the distribution of magnetic colloidal nanoparticles within organs, like liver, spleen and kidneys of the Sprague dawley rats. In addition, it was found that 500 microL of the highly diluted magnetic emulsion (0.05 wt%) was found adequate for MRI analysis. This seems to be useful for further investigations especially in theranostic applications of magnetic emulsion. PMID:23980505

  6. Comparison of Folate Receptor Targeted Optical Contrast Agents for Intraoperative Molecular Imaging.

    PubMed

    De Jesus, Elizabeth; Keating, Jane J; Kularatne, Sumith A; Jiang, Jack; Judy, Ryan; Predina, Jarrod; Nie, Shuming; Low, Philip; Singhal, Sunil

    2015-01-01

    Background. Intraoperative imaging can identify cancer cells in order to improve resection; thus fluorescent contrast agents have emerged. Our objective was to do a preclinical comparison of two fluorescent dyes, EC17 and OTL38, which both target folate receptor but have different fluorochromes. Materials. HeLa and KB cells lines were used for in vitro and in vivo comparisons of EC17 and OTL38 brightness, sensitivity, pharmacokinetics, and biodistribution. In vivo experiments were then performed in mice. Results. The peak excitation and emission wavelengths of EC17 and OTL38 were 470/520 nm and 774/794 nm, respectively. In vitro, OTL38 required increased incubation time compared to EC17 for maximum fluorescence; however, peak signal-to-background ratio (SBR) was 1.4-fold higher compared to EC17 within 60 minutes (p < 0.001). Additionally, the SBR for detecting smaller quantity of cells was improved with OTL38. In vivo, the mean improvement in SBR of tumors visualized using OTL38 compared to EC17 was 3.3 fold (range 1.48-5.43). Neither dye caused noticeable toxicity in animal studies. Conclusions. In preclinical testing, OTL38 appears to have superior sensitivity and brightness compared to EC17. This coincides with the accepted belief that near infrared (NIR) dyes tend to have less autofluorescence and scattering issues than visible wavelength fluorochromes. PMID:26491562

  7. Physicochemical characterization of a novel graphene-based magnetic resonance imaging contrast agent

    PubMed Central

    Kanakia, Shruti; Toussaint, Jimmy D; Chowdhury, Sayan Mullick; Lalwani, Gaurav; Tembulkar, Tanuf; Button, Terry; Shroyer, Kenneth R; Moore, William; Sitharaman, Balaji

    2013-01-01

    We report the synthesis and characterization of a novel carbon nanostructure-based magnetic resonance imaging contrast agent (MRI CA); graphene nanoplatelets intercalated with manganese (Mn2+) ions, functionalized with dextran (GNP-Dex); and the in vitro assessment of its essential preclinical physicochemical properties: osmolality, viscosity, partition coefficient, protein binding, thermostability, histamine release, and relaxivity. The results indicate that, at concentrations between 0.1 and 100.0 mg/mL, the GNP-Dex formulations are hydrophilic, highly soluble, and stable in deionized water, as well as iso-osmolar (upon addition of mannitol) and iso-viscous to blood. At potential steady-state equilibrium concentrations in blood (0.1–10.0 mg/mL), the thermostability, protein-binding, and histamine-release studies indicate that the GNP-Dex formulations are thermally stable (with no Mn2+ ion dissociation), do not allow non-specific protein adsorption, and elicit negligible allergic response. The r1 relaxivity of GNP-Dex was 92 mM−1s−1 (per-Mn2+ ion, 22 MHz proton Larmor frequency); ~20- to 30-fold greater than that of clinical gadolinium (Gd3+)- and Mn2+-based MRI CAs. The results open avenues for preclinical in vivo safety and efficacy studies with GNP-Dex toward its development as a clinical MRI CA. PMID:23946653

  8. Functional Hyperbranched Polylysine as Potential Contrast Agent Probes for Magnetic Resonance Imaging.

    PubMed

    Zu, Guangyue; Liu, Min; Zhang, Kunchi; Hong, Shanni; Dong, Jingjin; Cao, Yi; Jiang, Bin; Luo, Liqiang; Pei, Renjun

    2016-06-13

    Researchers have never stopped questing contrast agents with high resolution and safety to overcome the drawbacks of small-molecule contrast agents in clinic. Herein, we reported the synthesis of gadolinium-based hyperbranched polylysine (HBPLL-DTPA-Gd), which was prepared by thermal polymerization of l-lysine via one-step polycondensation. After conjugating with folic acid, its potential application as MRI contrast agent was then evaluated. This contrast agent had no obvious cytotoxicity as verified by WST assay and H&E analysis. Compared to Gd(III)-diethylenetriaminepentaacetic acid (Gd-DTPA) (r1 = 4.3 mM(-1) s(-1)), the FA-HBPLL-DTPA-Gd exhibited much higher longitudinal relaxivity value (r1 = 13.44 mM(-1) s(-1)), up to 3 times higher than Gd-DTPA. The FA-HBPLL-DTPA-Gd showed significant signal intensity enhancement in the tumor region at various time points and provided a long time window for MR examination. The results illustrate that FA-HBPLL-DTPA-Gd will be a potential candidate for tumor-targeted MRI. PMID:27187578

  9. Dual-modal MRI contrast agent with aggregation-induced emission characteristic for liver specific imaging with long circulation lifetime.

    PubMed

    Chen, Yilong; Li, Min; Hong, Yuning; Lam, Jacky W Y; Zheng, Qichang; Tang, Ben Zhong

    2014-07-01

    We herein report a novel dual-modal MRI contrast agent, TPE-2Gd, for both magnetic and fluorescence imaging. TPE-2Gd consists of a hydrophobic tetraphenylethene (TPE) fluorophore and two hydrophilic gadolinium (Gd) diethylenetriaminepentaacetic acid moieties. As an amphiphilic molecule, TPE-2Gd aggregates into micelles at a high concentration in aqueous medium. These aggregates are highly emissive, showing an aggregation-induced emission (AIE) characteristic. TPE-2Gd is used as a fluorescent agent for cell imaging, which demonstrates negligible cytotoxicity and excellent photostability owing to its AIE property. As a magnetic resonance imaging (MRI) contrast agent, TPE-2Gd exhibits similar longitudinal relaxivity in water (R1,TPE-2Gd = 3.36 ± 0.10 s(-1) per mM of Gd(3+)) as those commercial agents (e.g., Magnevist, R1,magnevist = 3.70 ± 0.02 s(-1) per mM of Gd(3+)). Compared with Magnevist, the circulation lifetime of TPE-2Gd nanoaggregates in living rats is extended from 10 min to 1 h. With relatively high specificity to the liver, the MR imaging could remain hyperintense in liver even after 150 min post injection. These TPE-2Gd nanoparticles can be excreted gradually via renal filtration due to the disassembly of the nanoparticles into small molecules during circulation. TPE-2Gd could thus potentially be used as a liver specific MRI contrast agent for clinical diagnosis. PMID:24942209

  10. Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents

    PubMed Central

    Qiao, Jingjuan; Xue, Shenghui; Pu, Fan; White, Natalie; Jiang, Jie; Liu, Zhi-Ren

    2014-01-01

    Epidermal growth factor receptor (EGFR) and HER2 are major prognosis biomarkers and drug targets overexpressed in various types of cancer cells. There is a pressing need to develop MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, capable of targeting tumors, and with high intratumoral distribution and minimal toxicity. In this review, we first discuss EGFR signaling and its role in tumor progression as a major drug target. We then report our progress in the development of protein contrast agents with significant improvement of both r1 and r2 relaxivities, pharmacokinetics, in vivo retention time, and in vivo dose efficiency. Finally, we report our effort in the development of EGFR-targeted protein contrast agents with the capability to cross the endothelial boundary and with good tissue distribution across the entire tumor mass. The noninvasive capability of MRI to visualize spatially and temporally the intratumoral distribution as well as quantify the levels of EGFR and HER2 would greatly improve our ability to track changes of the biomarkers during tumor progression, monitor treatment efficacy, aid in patient selection, and further develop novel targeted therapies for clinical application. PMID:24366655

  11. Time-domain imaging with quench-based fluorescent contrast agents

    NASA Astrophysics Data System (ADS)

    Akers, Walter J.; Solomon, Metasebya; Sudlow, Gail P.; Berezin, Mikhail; Achilefu, Samuel

    2012-03-01

    Quench-based probes utilize unique characteristics of fluorescence resonance energy transfer (FRET) to enhance contrast upon de-quenching. This mechanism has been used in a variety of molecular probes for imaging of cancer related enzyme activity such as matrix metalloproteinases, cathepsins and caspases. While non-fluorescent upon administration, fluorescence can be restored by separation of donor and acceptor, resulting in higher intensity in the presence of activator. Along with decreased quantum yield, FRET also results in altered fluorescence lifetime. Time-domain imaging can further enhance contrast and information yield from quench-based probes. We present in vivo time-domain imaging for detecting activation of quench-based probes. Quench-based probes utilize unique characteristics of fluorescence resonance energy transfer (FRET) to enhance contrast upon de-quenching. This mechanism has been used in a variety of molecular probes for imaging of cancer related enzyme activity such as matrix metalloproteinases, cathepsins and caspases. While non-fluorescent upon administration, fluorescence can be restored by separation of donor and acceptor, resulting in higher intensity in the presence of activator. Along with decreased quantum yield, FRET also results in altered fluorescence lifetime. Time-domain imaging can further enhance contrast and information yield from quench-based probes. We present in vivo time-domain imaging for detecting activation of quench-based probes. Time-domain diffuse optical imaging was performed to assess the FRET and quenching in living mice with orthotopic breast cancer. Tumor contrast enhancement was accompanied by increased fluorescence lifetime after administration of quenched probes selective for matrix metalloproteinases while no significant change was observed for non-quenched probes for integrin receptors. These results demonstrate the utility of timedomain imaging for detection of cancer-related enzyme activity in vivo.

  12. Integrating Anatomic and Functional Dual-Mode Magnetic Resonance Imaging: Design and Applicability of a Bifunctional Contrast Agent.

    PubMed

    Ni, Dalong; Shen, Zhiwei; Zhang, Jiawen; Zhang, Chen; Wu, Renhua; Liu, Jianan; Yi, Meizhi; Wang, Jing; Yao, Zhenwei; Bu, Wenbo; Shi, Jianlin

    2016-03-22

    In recent decades, extensive attention has been paid to developing anatomic and functional imaging contrast agents that could provide a wealth of complementary bioimaging information. Among them, dual-mode nanoprobes that combine anatomic magnetic resonance imaging (MRI) with functional fluorescent imaging have been mostly used for separated imaging. However, the lack of a machine for simultaneous dual-mode imaging greatly limits further clinical application. One effective strategy is to rationally design MRI contrast agents that own both anatomic and functional MR imaging capability on a single MRI machine, which is highly attractive but remains a great challenge. Herein, ultrasmall NaGdF4@PLL nanodots (NDs) were developed as a novel class of MR contrast agent, which offers a high longitude relaxivity (6.42 mM(-1) s(-1)) for T1-weighted MRI and an excellent sensitive chemical exchange saturation transfer (CEST) effect for pH mapping (at +3.7 ppm). Further in vivo animal experiments show the feasibility of NaGdF4@PLL NDs as contrast agents for efficient kidney and brain tumor diagnosis and pH mapping, which will undoubtedly enhance the diagnosis accuracy and is beneficial for disease precaution and prognosis. Different from other complex dual-mode nanoprobes, the as-constructed NaGdF4@PLL NDs enable both anatomic and functional imaging on a single MR machine, which is a simple and cost-effective new approach to realize dual-mode MR imaging and holds great potential for future clinical application. PMID:26910513

  13. Crimson Carrier, A Long-Acting Contrast Agent for In Vivo Near-Infrared Imaging of Injured and Diseased Muscle

    PubMed Central

    Prajapati, Suresh I.; Martinez, Carlo O.; Abraham, Jinu; McCleish, Amanda T.; Michalek, Joel E.; McManus, Linda M.; Rubin, Brian P.; Shireman, Paula K.; Keller, Charles

    2010-01-01

    Introduction The near-infrared wavelengths (700nm–900nm) are the most suitable optical window for light penetration and deep tissue imaging in small animals. Herein we report a near-infrared fluorescent contrast agent, crimson carrier, which acts as a blood pool contrast agent to detect and quantify injury and disease in live animals. Methods After determining the excitation-emission spectra and pharmacokinetics, crimson carrier was injected into myoinjured mice to monitor their recovery. Crimson carrier was also used to image transgenic mice with spontaneous tumors. Results Crimson carrier has maximal excitation and emission wavelengths of 745 nm and 820 nm, respectively. Elimination occurs predominantly via urinary excretion. Discussion We demonstrate the utility of this contrast agent for serial imaging of traumatized muscle as well as muscle tumors. The unique long-acting pharmacokinetics and urinary excretion route characteristics make crimson carrier a contrast agent of choice for the visualization of tumors and injured muscle or other tissues in live animal studies. PMID:20544935

  14. Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging.

    PubMed

    Ray, Aniruddha; Mukundan, Ananya; Xie, Zhixing; Karamchand, Leshern; Wang, Xueding; Kopelman, Raoul

    2014-11-01

    Here, we present a new optical contrast agent based on silver nanoplate clusters embedded inside of a polymer nano matrix. Unlike nanosphere clusters, which have been well studied, nanoplate clusters have unique properties due to the different possible orientations of interaction between the individual plates, resulting in a significant broadening of the absorption spectra. These nanoclusters were immobilized inside of a polymer cladding so as to maintain their stability and optical properties under in vivo conditions. The polymer-coated silver nanoplate clusters show a lower toxicity compared to the uncoated nanoparticles. At high nanoparticle concentrations, cell death occurs mostly due to apoptosis. These nanoparticles were used for targeted fluorescence imaging in a rat glioma cell line by incorporating a fluorescent dye into the matrix, followed by conjugation of a tumor targeting an F3 peptide. We further used these nanoparticles as photoacoustic contrast agents in vivo to enhance the contrast of the vasculature structures in a rat ear model. We observed a contrast enhancement of over 90% following the nanoparticle injection. It is also shown that these NPs can serve as efficient contrast agents, with specific targeting abilities for broadband multimodal imaging that are usable for diagnostic applications and that extend into use as therapeutic agents as well. PMID:25325364

  15. Highly stable polymer coated nano-clustered silver plates: a multimodal optical contrast agent for biomedical imaging

    NASA Astrophysics Data System (ADS)

    Ray, Aniruddha; Mukundan, Ananya; Xie, Zhixing; Karamchand, Leshern; Wang, Xueding; Kopelman, Raoul

    2014-11-01

    Here, we present a new optical contrast agent based on silver nanoplate clusters embedded inside of a polymer nano matrix. Unlike nanosphere clusters, which have been well studied, nanoplate clusters have unique properties due to the different possible orientations of interaction between the individual plates, resulting in a significant broadening of the absorption spectra. These nanoclusters were immobilized inside of a polymer cladding so as to maintain their stability and optical properties under in vivo conditions. The polymer-coated silver nanoplate clusters show a lower toxicity compared to the uncoated nanoparticles. At high nanoparticle concentrations, cell death occurs mostly due to apoptosis. These nanoparticles were used for targeted fluorescence imaging in a rat glioma cell line by incorporating a fluorescent dye into the matrix, followed by conjugation of a tumor targeting an F3 peptide. We further used these nanoparticles as photoacoustic contrast agents in vivo to enhance the contrast of the vasculature structures in a rat ear model. We observed a contrast enhancement of over 90% following the nanoparticle injection. It is also shown that these NPs can serve as efficient contrast agents, with specific targeting abilities for broadband multimodal imaging that are usable for diagnostic applications and that extend into use as therapeutic agents as well.

  16. Highly stable polymer coated nano-clustered silver plates: A multimodal optical contrast agent for biomedical imaging

    PubMed Central

    Ray, Aniruddha; Mukundan, Ananya; Xie, Zhixing; Karamchand, Leshern; Wang, Xueding; Kopelman, Raoul

    2014-01-01

    Here we present a new optical contrast agent, based on silver nanoplate clusters embedded inside a polymer nano matrix. Unlike nanosphere clusters, which have been well studied, nanoplate clusters have unique properties due to the different possible orientations of interaction between the individual plates, resulting in a significant broadening of the absorption spectra. These nanoclusters were immobilized inside a polymer cladding, so as to maintain their stability and optical properties under in vivo conditions. The polymer coated silver nanoplate clusters show a lower toxicity, compared to the uncoated nanoparticles. At high nanoparticle concentrations, cell death occurs mostly due to apoptosis. These nanoparticles were used for targeted fluorescence imaging in a rat glioma cell line by incorporating a fluorescent dye into the matrix, followed by conjugation of a tumor targeting F3 peptide. We further used these nanoparticles as photoacoustic contrast agents in vivo, to enhance the contrast of the vasculature structures in a rat ear model. We observed a contrast enhancement of over 90%, following nanoparticle injection. It is also shown that these NP’s can serve as efficient contrast agents, with specific targeting abilities, for broadband multimodal imaging, usable for diagnostic applications and extendable into use as therapeutic agents as well. PMID:25325364

  17. Optimization of multi-pulse sequences for nonlinear contrast agent imaging using a cMUT array

    NASA Astrophysics Data System (ADS)

    Novell, Anthony; Arena, Christopher B.; Kasoji, Sandeep; Dayton, Paul A.

    2015-04-01

    Capacitive micromachined ultrasonic transducer (cMUT) technology provides advantages such as wide frequency bandwidth, which can be exploited for contrast agent imaging. Nevertheless, the efficiency of traditional multi-pulse imaging schemes, such as pulse inversion (PI), remains limited because of the intrinsic nonlinear character of cMUTs. Recently, a new contrast imaging sequence, called bias voltage modulation sequence (BVM), has been specifically developed for cMUTs to suppress their unwanted nonlinear behavior. In this study, we propose to optimize contrast agent detection by combining the BVM sequence with PI and/or chirp reversal (CR). An aqueous dispersion of lipid encapsulated microbubbles was exposed to several combinations of multi-pulse imaging sequences. Approaches were evaluated in vitro using 9 inter-connected elements of a cMUT linear array (excitation frequency of 4 MHz peak negative pressure of 100 kPa). For sequences using chirp excitations, a specific compression filter was designed to compress and extract several nonlinear components from the received microbubble responses. A satisfactory cancellation of the nonlinear signal from the source is achieved when BVM is combined with PI and CR. In comparison with PI and CR imaging modes alone, using sequences incorporating BVM increases the contrast-to-tissue ratio by 10.0 dB and 4.6 dB, respectively. Furthermore, the combination of BVM with CR and PI results in a significant increase of the contrast-to-noise ratio (+29 dB). This enhancement is attributed to the use of chirps as excitation signals and the improved preservation of several nonlinear components contained within the contrast agent response.

  18. Optimization of Multi-Pulse Sequences For Nonlinear Contrast Agent Imaging Using a cMUT Array

    PubMed Central

    Novell, Anthony; Arena, Christopher B.; Kasoji, Sandeep; Dayton, Paul A.

    2015-01-01

    Capacitive micromachined ultrasonic transducer (cMUT) technology provides advantages such as wide frequency bandwidth, which can be exploited for contrast agent imaging. Nevertheless, the efficiency of traditional multi-pulse imaging schemes, such as pulse inversion (PI), remains limited because of the intrinsic nonlinear character of cMUTs. Recently, a new contrast imaging sequence, called bias voltage modulation sequence (BVM), had been specifically developed for cMUTs to suppress their unwanted nonlinear behavior. In this study, we propose to optimize contrast agent detection by combining the BVM sequence with PI and/or chirp reversal (CR). An aqueous dispersion of lipid encapsulated microbubbles was exposed to several combinations of multi-pulse imaging sequences. Approaches were evaluated in vitro using 9 inter-connected elements of a cMUT linear array (excitation frequency of 4 MHz; peak negative pressure of 100 kPa). For sequences using chirp excitations, a specific compression filter was designed to compress and extract several nonlinear components from the received microbubble responses. A satisfactory cancellation of the nonlinear signal from the source is achieved when BVM is combined with PI and CR. In comparison with PI and CR imaging modes alone, using sequences incorporating BVM increases the contrast-to-tissue ratio by 10.0 dB and 4.6 dB, respectively. Furthermore, the combination of BVM with CR and PI results in a significant increase of the contrast-to-noise ratio (+29 dB). This enhancement is attributed to the use of chirps as excitation signals and the improved preservation of several nonlinear components contained within the contrast agent response. PMID:25803232

  19. Advances in functional X-ray imaging techniques and contrast agents

    PubMed Central

    Chen, Hongyu; Rogalski, Melissa M.

    2012-01-01

    X-rays have been used for non-invasive high-resolution imaging of thick biological specimens since their discovery in 1895. They are widely used for structural imaging of bone, metal implants, and cavities in soft tissue. Recently, a number of new contrast methodologies have emerged which are expanding X-ray’s biomedical applications to functional as well as structural imaging. These techniques are promising to dramatically improve our ability to study in situ biochemistry and disease pathology. In this review, we discuss how X-ray absorption, X-ray fluorescence, and X-ray excited optical luminescence can be used for physiological, elemental, and molecular imaging of vasculature, tumours, pharmaceutical distribution, and the surface of implants. Imaging of endogenous elements, exogenous labels, and analytes detected with optical indicators will be discussed. PMID:22962667

  20. Gentamicin-gold nanoparticles conjugate: a contrast agent for X-ray imaging of infectious foci due to Staphylococcus aureus.

    PubMed

    Ahangari, Azam; Salouti, Mojtaba; Saghatchi, Faranak

    2016-08-01

    There is no optimal imaging method for the detection of unknown infectious foci in some diseases. This study introduces a novel method in X-ray imaging of infection foci due to Staphylococcus aureus by developing a contrast agent based on gold nanoparticles (GNPs). GNPs in spherical shape were synthesised by the reduction of tetrachloroauric acid with sodium citrate. Then gentamicin was bound directly to citrate functionalised GNPs and the complex was stabilised by polyethylene glycol. The interaction of gentamicin with GNPs was confirmed by ultraviolet-visible and Fourier transform infrared spectroscopies. The stability of complex was studied in human blood up to 6 h. The stability of conjugate was found to be high in human blood with no aggregation. The biodistribution study showed localisation of gentamicin-GNPs conjugate at the site of Staphylococcal infection. The infection site was properly visualised in X-ray images in mouse model using the gentamicin-GNPs conjugate as a contrast agent. The results demonstrated that one may consider the potential of new nanodrug as a contrast agent for X-ray imaging of infection foci in human beings which needs more investigations. PMID:27463788

  1. Gold nano-rods as a targeting contrast agent for photoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Agarwal, A.; Huang, S.-W.; Day, K. C.; O'Donnell, M.; Day, M.; Kotov, N.; Ashkenazi, S.

    2007-02-01

    We have studied the potential of gold nanorods to target cancer cells and provide contrast for photoacoustic imaging. The elongated "rod" shape of these nanoparticles provides a mechanism to tune their plasmon peak absorption wavelength. The absorption peak is shifted to longer wavelengths by increasing the aspect ratio of the rods. Particles 15 nm in diameter and 45 nm long were prepared using a seed mediated growth method. Their plasmon absorption peak was designed to be at 800 nm for increased penetration depth into biological tissue. They were conjugated with a specific antibody to target prostate cancer cells. We have applied photoacoustics to image a prostate cell culture targeted by conjugated gold particles. Images confirm the efficiency of conjugated particle binding to the targeted cell membranes. Photoacoustic detection of a single cell layer is demonstrated. To evaluate the applicability of the technique to clinical prostate cancer detection, we have imaged phantom objects mimicking a real tissue with small (2 mm size) inclusions of nanoparticle gel solution. Our photoacoustic imaging setup is based on a modified commercial ultrasonic scanner which makes it attractive for fast implementation in cancer diagnosis in clinical application. In addition, the setup allows for dual mode operation where a photoacoustic image is superimposed on a conventional B-mode ultrasound image. Dual mode operation is demonstrated by imaging a mouse with gold nanorod gel solution implanted in its hind limb.

  2. Contrast enhancement of laser speckle skin image: use of optical clearing agent in conjunction with micro-needling

    NASA Astrophysics Data System (ADS)

    Son, Taeyoon; Yoon, Jinhee; Ko, Chang-Yong; Lee, Yong-Heum; Kwon, Kiwoon; Kim, Han Sung; Lee, Kyoung Joung; Jung, Byungjo

    2008-02-01

    Laser speckle imaging modality is one of widely used methods to evaluate blood flow because of its simplicity. However, laser speckle image has a limitation in the evaluation of subcutaneous blood flow due to its low contrast perfusion image. Various methods have been tried to enhance the perfusion image contrast. Such methods presented positive results in some degree. However, it could not be fundamental solutions due to low penetration depth of lasers restricted by optical tissue scattering property. This study suggests a method to enhance the perfusion image contrast of laser speckle imaging modality by increasing the penetration depth of lasers. An optical clearing agent (glycerol) was topically applied on skin treated with micro-needle roller in order to reduce the time period of optical tissue clearing and therefore, enhance the penetration depth of laser. In this study, we investigated the effect of glycerol and micro-needling methods in the contrast enhancement of laser speckle perfusion skin image and presented the results of in-vitro and in-vivo animal experiment.

  3. In vivo 3D PIXE-micron-CT imaging of Drosophila melanogaster using a contrast agent

    NASA Astrophysics Data System (ADS)

    Matsuyama, Shigeo; Hamada, Naoki; Ishii, Keizo; Nozawa, Yuichiro; Ohkura, Satoru; Terakawa, Atsuki; Hatori, Yoshinobu; Fujiki, Kota; Fujiwara, Mitsuhiro; Toyama, Sho

    2015-04-01

    In this study, we developed a three-dimensional (3D) computed tomography (CT) in vivo imaging system for imaging small insects with micrometer resolution. The 3D CT imaging system, referred to as 3D PIXE-micron-CT (PIXEμCT), uses characteristic X-rays produced by ion microbeam bombardment of a metal target. PIXEμCT was used to observe the body organs and internal structure of a living Drosophila melanogaster. Although the organs of the thorax were clearly imaged, the digestive organs in the abdominal cavity could not be clearly discerned initially, with the exception of the rectum and the Malpighian tubule. To enhance the abdominal images, a barium sulfate powder radiocontrast agent was added. For the first time, 3D images of the ventriculus of a living D. melanogaster were obtained. Our results showed that PIXEμCT can provide in vivo 3D-CT images that reflect correctly the structure of individual living organs, which is expected to be very useful in biological research.

  4. A Functional CT Contrast Agent for In Vivo Imaging of Tumor Hypoxia.

    PubMed

    Shi, Hongyuan; Wang, Zhiming; Huang, Chusen; Gu, Xiaoli; Jia, Ti; Zhang, Amin; Wu, Zhiyuan; Zhu, Lan; Luo, Xianfu; Zhao, Xuesong; Jia, Nengqin; Miao, Fei

    2016-08-01

    Hypoxia, which has been well established as a key feature of the tumor microenvironment, significantly influences tumor behavior and treatment response. Therefore, imaging for tumor hypoxia in vivo is warranted. Although some imaging modalities for detecting tumor hypoxia have been developed, such as magnetic resonance imaging, positron emission tomography, and optical imaging, these technologies still have their own specific limitations. As computed tomography (CT) is one of the most useful imaging tools in terms of availability, efficiency, and convenience, the feasibility of using a hypoxia-sensitive nanoprobe (Au@BSA-NHA) for CT imaging of tumor hypoxia is investigated, with emphasis on identifying different levels of hypoxia in two xenografts. The nanoprobe is composed of Au nanoparticles and nitroimidazole moiety which can be electively reduced by nitroreductase under hypoxic condition. In vitro, Au@BSA-NHA attain the higher cellular uptake under hypoxic condition. Attractively, after in vivo administration, Au@BSA-NHA can not only monitor the tumor hypoxic environment with CT enhancement but also detect the hypoxic status by the degree of enhancement in two xenograft tumors with different hypoxic levels. The results demonstrate that Au@BSA-NHA may potentially be used as a sensitive CT imaging agent for detecting tumor hypoxia. PMID:27345304

  5. Vascular imaging with contrast agent in hard and soft tissues using microcomputed-tomography.

    PubMed

    Blery, P; Pilet, P; Bossche, A Vanden-; Thery, A; Guicheux, J; Amouriq, Y; Espitalier, F; Mathieu, N; Weiss, P

    2016-04-01

    Vascularization is essential for many tissues and is a main requisite for various tissue-engineering strategies. Different techniques are used for highlighting vasculature, in vivo and ex vivo, in 2-D or 3-D including histological staining, immunohistochemistry, radiography, angiography, microscopy, computed tomography (CT) or micro-CT, both stand-alone and synchrotron system. Vascularization can be studied with or without a contrast agent. This paper presents the results obtained with the latest Skyscan micro-CT (Skyscan 1272, Bruker, Belgium) following barium sulphate injection replacing the bloodstream in comparison with results obtained with a Skyscan In Vivo 1076. Different hard and soft tissues were perfused with contrast agent and were harvested. Samples were analysed using both forms of micro-CT, and improved results were shown using this new micro-CT. This study highlights the vasculature using micro-CT methods. The results obtained with the Skyscan 1272 are clearly defined compared to results obtained with Skyscan 1076. In particular, this instrument highlights the high number of small vessels, which were not seen before at lower resolution. This new micro-CT opens broader possibilities in detection and characterization of the 3-D vascular tree to assess vascular tissue engineering strategies. PMID:27002484

  6. GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI

    PubMed Central

    Pu, Fan; Qiao, Jingjuan; Xue, Shenghui; Yang, Hua; Patel, Anvi; Wei, Lixia; Hekmatyar, Khan; Salarian, Mani; Grossniklaus, Hans E.; Liu, Zhi-Ren; Yang, Jenny J.

    2015-01-01

    Gastrin-releasing peptide receptor (GRPR) is differentially expressed on the surfaces of various diseased cells, including prostate and lung cancer. However, monitoring temporal and spatial expression of GRPR in vivo by clinical MRI is severely hampered by the lack of contrast agents with high relaxivity, targeting capability and tumor penetration. Here, we report the development of a GRPR-targeted MRI contrast agent by grafting the GRPR targeting moiety into a scaffold protein with a designed Gd3+ binding site (ProCA1.GRPR). In addition to its strong binding affinity for GRPR (Kd = 2.7 nM), ProCA1.GRPR has high relaxivity (r1 = 42.0 mM−1s−1 at 1.5 T and 25 °C) and strong Gd3+ selectivity over physiological metal ions. ProCA1.GRPR enables in vivo detection of GRPR expression and spatial distribution in both PC3 and H441 tumors in mice using MRI. ProCA1.GRPR is expected to have important preclinical and clinical implications for the early detection of cancer and for monitoring treatment effects. PMID:26577829

  7. Near-infrared absorbing polymer nano-particle as a sensitive contrast agent for photo-acoustic imaging.

    PubMed

    Aoki, Hiroyuki; Nojiri, Mayumi; Mukai, Rieko; Ito, Shinzaburo

    2015-01-01

    Polymer nano-particles (PNPs) with a near-infrared (NIR) light absorption were prepared by the nano-emulsion method to develop contrast agents for photo-acoustic (PA) imaging. The PNP containing silicon naphthalocyanine showed a high absorption coefficient up to 10(10) M(-1) cm(-1). This is comparable to plasmonic gold nano-particles, which have been studied as PA contrast agents. For the PNP larger than 100 nm, the enhancement of the PA signal was observed compared to the gold nano-particle with a similar absorption coefficient and size. In the case of the PNP, the heat by the light absorption is confined in the particle due to the low thermal diffusivity of polymer materials. We showed that the strong thermal confinement effect of PNP results in the enhancement of the efficiency of the PA signal generation and that the PA intensity can be enhanced by the increase of the Grüneisen parameter of the matrix polymer of PNP. The PA signal from the PNP of poly(methyl methacrylate) was 9-fold larger than that of gold nano-particles with the same absorption coefficient. We demonstrated that in the in vivo PA imaging the detection limit of PNP was of the order of 10(-13) M. The NIR absorbing PNP will be a promising candidate of a sensitive contrast agent for PA imaging. PMID:25407911

  8. Multifunctional polyelectrolyte microcapsules as a contrast agent for photoacoustic imaging in blood.

    PubMed

    Yashchenok, Alexey M; Jose, Jithin; Trochet, Philippe; Sukhorukov, Gleb B; Gorin, Dmitry A

    2016-08-01

    The polyelectrolyte microcapsules that can be accurate either visualized in biological media or in tissue would enhance their further in vivo application both as a carrier of active payloads and as a specific sensor. The immobilization of active species, for instance fluorescent dyes, quantum dots, metal nanoparticles, in polymeric shell enables visualization of capsules by optical imaging techniques in aqueous solution. However, for visualization of capsules in complex media an instrument with high contrast modality requires. Herein, we show for the first time photoacoustic imaging (PAI) of multifunctional microcapsules in water and in blood. The microcapsules exhibit greater photoacoustic intensity compare to microparticles with the same composition of polymeric shell presumably their higher thermal expansion. Photoacoustic intensity form microcapsules dispersed in blood displays an enhancement (2-fold) of signal compare to blood. Photoacoustic imaging of microcapsules might contribute to non-invasive carrier visualization and further their in vivo distribution. PMID:26913984

  9. Anti-biofouling conducting polymer nanoparticles as a label-free optical contrast agent for high resolution subsurface biomedical imaging.

    PubMed

    Au, Kin Man; Lu, Zenghai; Matcher, Stephen J; Armes, Steven P

    2013-11-01

    Optical coherence tomography (OCT) is a modern high resolution subsurface medical imaging technique. Herein we describe: (i) the synthesis of a thiophene-functionalized oligo(ethylene glycol) methacrylate (OEGMA)-based statistical copolymer, denoted poly(2TMOI-OEGMA); (ii) the preparation of sterically-stabilized polypyrrole (PPy) nanoparticles of approximately 60 nm diameter; (iii) the evaluation of these nanoparticles as a NIR-absorbing optical contrast agent for high-resolution OCT imaging. We show that poly(2TMOI-OEGMA)-stabilized PPy nanoparticles exhibit similar optical properties to poly(vinyl alcohol) (PVA)-stabilized PPy nanoparticles of comparable size prepared using commercially available PVA. Spectroscopic measurements and Mie calculations indicate that both types of PPy nanoparticles strongly absorb NIR radiation above 1000 nm, suggesting their potential use as OCT contrast agents. In vitro OCT studies indicate that both types of PPy nanoparticles reduce NIR backscattering within homogeneous intralipid tissue phantoms, offering almost identical contrast performance in this medium. However, PVA-stabilized PPy nanoparticles became colloidally unstable when dispersed in physiological buffer and immersed in a solid biotissue phantom and hence failed to generate a strong contrast effect. In contrast, the poly(2TMOI-OEGMA)-stabilized PPy nanoparticles remained well-dispersed and hence exhibited a strong rapid onset contrast effect within the biotissue phantom under identical physiological conditions. Ex vivo studies performed on excised chicken and porcine skin tissue demonstrated that topical administration of a low concentration of poly(2TMOI-OEGMA)-stabilized PPy nanoparticles rapidly enhances OCT image contrast in both cases, allowing key tissue features to be readily identified. PMID:23968854

  10. Line-scanning confocal microscopy for high-resolution imaging of upconverting rare-earth-based contrast agents.

    PubMed

    Higgins, Laura M; Zevon, Margot; Ganapathy, Vidya; Sheng, Yang; Tan, Mei Chee; Riman, Richard E; Roth, Charles M; Moghe, Prabhas V; Pierce, Mark C

    2015-11-01

    Rare-earth (RE) doped nanocomposites emit visible luminescence when illuminated with continuous wave near-infrared light, making them appealing candidates for use as contrast agents in biomedical imaging. However, the emission lifetime of these materials is much longer than the pixel dwell times used in scanning intravital microscopy. To overcome this limitation, we have developed a line-scanning confocal microscope for high-resolution, optically sectioned imaging of samples labeled with RE-based nanomaterials. Instrument performance is quantified using calibrated test objects. NaYF4 : Er,Yb nanocomposites are imaged in vitro, and in ex vivo tissue specimens, with direct comparison to point-scanning confocal microscopy. We demonstrate that the extended pixel dwell time of line-scanning confocal microscopy enables subcellular-level imaging of these nanomaterials while maintaining optical sectioning. The line-scanning approach thus enables microscopic imaging of this emerging class of contrast agents for preclinical studies, with the potential to be adapted for real-time in vivo imaging in the clinic. PMID:26603495

  11. Line-scanning confocal microscopy for high-resolution imaging of upconverting rare-earth-based contrast agents

    NASA Astrophysics Data System (ADS)

    Higgins, Laura M.; Zevon, Margot; Ganapathy, Vidya; Sheng, Yang; Tan, Mei Chee; Riman, Richard E.; Roth, Charles M.; Moghe, Prabhas V.; Pierce, Mark C.

    2015-11-01

    Rare-earth (RE) doped nanocomposites emit visible luminescence when illuminated with continuous wave near-infrared light, making them appealing candidates for use as contrast agents in biomedical imaging. However, the emission lifetime of these materials is much longer than the pixel dwell times used in scanning intravital microscopy. To overcome this limitation, we have developed a line-scanning confocal microscope for high-resolution, optically sectioned imaging of samples labeled with RE-based nanomaterials. Instrument performance is quantified using calibrated test objects. NaYF4:Er,Yb nanocomposites are imaged in vitro, and in ex vivo tissue specimens, with direct comparison to point-scanning confocal microscopy. We demonstrate that the extended pixel dwell time of line-scanning confocal microscopy enables subcellular-level imaging of these nanomaterials while maintaining optical sectioning. The line-scanning approach thus enables microscopic imaging of this emerging class of contrast agents for preclinical studies, with the potential to be adapted for real-time in vivo imaging in the clinic.

  12. High-resolution three-dimensional scanning optical image system for intrinsic and extrinsic contrast agents in tissue

    NASA Astrophysics Data System (ADS)

    Gu, Yueqing; Qian, Zhiyu; Chen, Jinxian; Blessington, Dana; Ramanujam, Nimmi; Chance, Britton

    2002-01-01

    This article presents the theory and development of a three-dimensional (3D) imaging instrument capable of determining the biochemical properties of tissue by measuring the absorption or fluorescence of different intrinsic and extrinsic agents simultaneously. A bifurcated optical fiber bundle, serving to deliver the excitation light and collect the emission or reflection light, scans over the flat tissue surface retrieving optical signals in each pixel. Two-dimensional (2D) images of a series of subsequent sections are obtained after signal conversion and processing to yield a 3D image. Manipulation of the scanning step and diameter size of the fibers within the bundle, the spatial resolution of the instrument attains a maximum of 40 × 40 × 10 μm3. The wavelength range is extended from ultraviolet to the near infrared (NIR) through specialized optical design, typically employed for the NIR extrinsic contrast agents study. The instrument is most applicable in situations involving the measurement of fluorescence or absorption at any specific wavelength within the spectrum range. Flavoprotein and nicotinamide adeine dinucleotide are the two typical intrinsic agents indicating the oxidization and reduction status of the tissue sample, with their fluorescence detected at wavelengths of 540 and 440 nm, respectively. Oxy and deoxy hemoglobin are two other significant intrinsic agents for evaluating the blood oxygenation saturation by recording their absorptions at two different wavelengths of 577 and 546 nm. These intrinsic agents were measured in this study for comparison of biochemical properties of rat liver in different gas inhalation treatments. Indocyanine green, a NIR extrinsic contrast agent measured at wavelengths of 780 nm/830 nm as excitation/emission can indicate blood pooling by displaying the distribution of blood vessels within a 9 L tumor. The advantage of high sensitivity, spatial resolution, and broad applied potentiality were demonstrated by the

  13. Ex Vivo Perfusion-Simulation Measurements of Microbubbles as a Scattering Contrast Agent for Grating-Based X-Ray Dark-Field Imaging

    PubMed Central

    Velroyen, Astrid; Bech, Martin; Tapfer, Arne; Yaroshenko, Andre; Müller, Mark; Paprottka, Philipp; Ingrisch, Michael; Cyran, Clemens C.; Auweter, Sigrid D.; Nikolaou, Konstantin; Reiser, Maximilian F.; Pfeiffer, Franz

    2015-01-01

    The investigation of dedicated contrast agents for x-ray dark-field imaging, which exploits small-angle scattering at microstructures for contrast generation, is of strong interest in analogy to the common clinical use of high-atomic number contrast media in conventional attenuation-based imaging, since dark-field imaging has proven to provide complementary information. Therefore, agents consisting of gas bubbles, as used in ultrasound imaging for example, are of particular interest. In this work, we investigate an experimental contrast agent based on microbubbles consisting of a polyvinyl-alcohol shell with an iron oxide coating, which was originally developed for multimodal imaging and drug delivery. Its performance as a possible contrast medium for small-animal angiography was examined using a mouse carcass to realistically consider attenuating and scattering background signal. Subtraction images of dark field, phase contrast and attenuation were acquired for a concentration series of 100%, 10% and 1.3% to mimic different stages of dilution in the contrast agent in the blood vessel system. The images were compared to the gold-standard iodine-based contrast agent Solutrast, showing a good contrast improvement by microbubbles in dark-field imaging. This study proves the feasibility of microbubble-based dark-field contrast-enhancement in presence of scattering and attenuating mouse body structures like bone and fur. Therefore, it suggests a strong potential of the use of polymer-based microbubbles for small-animal dark-field angiography. PMID:26134130

  14. Ex Vivo Perfusion-Simulation Measurements of Microbubbles as a Scattering Contrast Agent for Grating-Based X-Ray Dark-Field Imaging.

    PubMed

    Velroyen, Astrid; Bech, Martin; Tapfer, Arne; Yaroshenko, Andre; Müller, Mark; Paprottka, Philipp; Ingrisch, Michael; Cyran, Clemens C; Auweter, Sigrid D; Nikolaou, Konstantin; Reiser, Maximilian F; Pfeiffer, Franz

    2015-01-01

    The investigation of dedicated contrast agents for x-ray dark-field imaging, which exploits small-angle scattering at microstructures for contrast generation, is of strong interest in analogy to the common clinical use of high-atomic number contrast media in conventional attenuation-based imaging, since dark-field imaging has proven to provide complementary information. Therefore, agents consisting of gas bubbles, as used in ultrasound imaging for example, are of particular interest. In this work, we investigate an experimental contrast agent based on microbubbles consisting of a polyvinyl-alcohol shell with an iron oxide coating, which was originally developed for multimodal imaging and drug delivery. Its performance as a possible contrast medium for small-animal angiography was examined using a mouse carcass to realistically consider attenuating and scattering background signal. Subtraction images of dark field, phase contrast and attenuation were acquired for a concentration series of 100%, 10% and 1.3% to mimic different stages of dilution in the contrast agent in the blood vessel system. The images were compared to the gold-standard iodine-based contrast agent Solutrast, showing a good contrast improvement by microbubbles in dark-field imaging. This study proves the feasibility of microbubble-based dark-field contrast-enhancement in presence of scattering and attenuating mouse body structures like bone and fur. Therefore, it suggests a strong potential of the use of polymer-based microbubbles for small-animal dark-field angiography. PMID:26134130

  15. Preservation of imaging capability in sensitive ultrasound contrast agents after indirect plasma sterilization.

    PubMed

    Albala, Lorenzo; Ercan, Utku K; Joshi, Suresh G; Eisenbrey, John R; Teraphongphom, Nutte; Wheatley, Margaret A

    2015-10-15

    Many injectables are not amenable to standard sterilization methods, which destroy sensitive materials. This is particularly true for ultrasound contrast agents (UCA) consisting of gas bubbles stabilized by a surfactant or polymer shell. We investigated a new method to achieve safe and effective sterilization in production by introducing dielectric-barrier discharge non-thermal plasma. A dielectric-barrier discharge was generated to first produce plasma-treated phosphate-buffered saline (PTPBS), which was used as a sterilant solution for our UCA SE61, avoiding direct heat, pressure, chemicals, or radiation. Treated samples were tested for acoustic properties in vitro and in a flow phantom, and for sterility by standard methods. Three minutes plasma treatment of phosphate-buffered saline (PBS) proved effective. The samples showed significant inactivation of inoculated bacteria upon PTPBS treatment as compared to un-treated-PBS (p=0.0022). The treated and untreated samples showed no statistical significance (p>0.05) in acoustic response or bubble diameter (mean±SEM: 2.52±0.31 μm). Nile Red was used to model intercalation of drug in the hydrophobic shell, intercalated successfully into SE61, and was unaffected by plasma treatment. The PTPBS completely sterilized suspensions of UCA, and it did not compromise the acoustic properties of the agent or its ability to retain a hydrophobic compound. PMID:26241754

  16. "Basic MR Relaxation Mechanisms & Contrast Agent Design"

    PubMed Central

    De León-Rodríguez, Luis M.; Martins, André F.; Pinho, Marco; Rofsky, Neil; Sherry, A. Dean

    2015-01-01

    The diagnostic capabilities of magnetic resonance imaging (MRI) have undergone continuous and substantial evolution by virtue of hardware and software innovations and the development and implementation of exogenous contrast media. Thirty years since the first MRI contrast agent was approved for clinical use, a reliance on MR contrast media persists largely to improve image quality with higher contrast resolution and to provide additional functional characterization of normal and abnormal tissues. Further development of MR contrast media is an important component in the quest for continued augmentation of diagnostic capabilities. In this review we will detail the many important considerations when pursuing the design and use of MR contrast media. We will offer a perspective on the importance of chemical stability, particularly kinetic stability, and how this influences one's thinking about the safety of metal-ligand based contrast agents. We will discuss the mechanisms involved in magnetic resonance relaxation in the context of probe design strategies. A brief description of currently available contrast agents will be accompanied by an in-depth discussion that highlights promising MRI contrast agents in development for future clinical and research applications. Our intention is to give a diverse audience an improved understanding of the factors involved in developing new types of safe and highly efficient MR contrast agents and, at the same time, provide an appreciation of the insights into physiology and disease that newer types of responsive agents can provide. PMID:25975847

  17. Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI.

    PubMed

    Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing; Yang, Jenny J

    2016-07-01

    Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd(3+) contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd(3+) binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 ± 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 ± 0.1 × 10(-22) M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM(-1) s(-1) and r2 of 37.9 mM(-1) s(-1) per Gd (55.2 and 75.8 mM(-1) s(-1) per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM(-1) s(-1) per Gd (188.0 mM(-1) s(-1) per molecule) and r1 of 18.6 mM(-1) s(-1) per Gd (37.2 mM(-1) s(-1) per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI. PMID:26961235

  18. Magnetomotive imaging of iron oxide nanoparticles as cellular contrast agents for optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Cimalla, Peter; Werner, Theresa; Gaertner, Maria; Mueller, Claudia; Walther, Julia; Wittig, Dierk; Ader, Marius; Karl, Mike; Koch, Edmund

    2013-06-01

    Recent studies in animal models provided proof-of-principle evidence for cell transplantation as a potential future therapeutic approach for retinal pathologies in humans such as Retinitis pigmentosa or age-related macular degeneration. In this case, donor cells are injected into the eye in order to protect or replace degenerating photoreceptors or retinal pigment epithelium. However, currently there is no three-dimensional imaging technique available that allows tracking of cell migration and integration into the host tissue under in vivo conditions. Therefore, we investigate about magnetomotive optical coherence tomography (OCT) of substances labeled with iron oxide nanoparticles as a potential method for noninvasive, three-dimensional cell tracking in the retina. We use a self-developed spectral domain OCT system for high-resolution imaging in the 800 nm-wavelength region. A suitable AC magnetic field for magnetomotive imaging was generated using two different setups, which consist of an electrically driven solenoid in combination with a permanent magnet, and a mechanically driven all-permanent magnet configuration. In the sample region the maximum magnetic flux density was 100 mT for both setups, with a field gradient of 9 T/m and 13 T/m for the solenoid and the allpermanent magnet setup, respectively. Magnetomotive OCT imaging was performed in elastic tissue phantoms and single cells labeled with iron oxide nanoparticles. Particle-induced sub-resolution movement of the elastic samples and the single cells could successfully be detected and visualized by means of phase-resolved Doppler OCT analysis. Therefore, this method is a potential technique to enhance image contrast of specific cells in OCT.

  19. Anti-biofouling polymer-decorated lutetium-based nanoparticulate contrast agents for in vivo high-resolution trimodal imaging.

    PubMed

    Liu, Zhen; Dong, Kai; Liu, Jianhua; Han, Xueli; Ren, Jinsong; Qu, Xiaogang

    2014-06-25

    Nanomaterials have gained considerable attention and interest in the development of novel and high-resolution contrast agents for medical diagnosis and prognosis in clinic. A classical urea-based homogeneous precipitation route that combines the merits of in situ thermal decomposition and surface modification is introduced to construct polyethylene glycol molecule (PEG)-decorated hybrid lutetium oxide nanoparticles (PEG-UCNPs). By utilizing the admirable optical and magnetic properties of the yielded PEG-UCNPs, in vivo up-conversion luminescence and T1 -enhanced magnetic resonance imaging of small animals are conducted, revealing obvious signals after subcutaneous and intravenous injection, respectively. Due to the strong X-ray absorption and high atomic number of lanthanide elements, X-ray computed-tomography imaging based on PEG-UCNPs is then designed and carried out, achieving excellent imaging outcome in animal experiments. This is the first example of the usage of hybrid lutetium oxide nanoparticles as effective nanoprobes. Furthermore, biodistribution, clearance route, as well as long-term toxicity are investigated in detail after intravenous injection in a murine model, indicating the overall safety of PEG-UCNPs. Compared with previous lanthanide fluorides, our nanoprobes exhibit more advantages, such as facile construction process and nearly total excretion from the animal body within a month. Taken together, these results promise the use of PEG-UCNPs as a safe and efficient nanoparticulate contrast agent for potential application in multimodal imaging. PMID:24610806

  20. In vivo imaging of inflammatory responses by photoacoustics using cell-targeted gold nanorods (GNR) as contrast agent

    NASA Astrophysics Data System (ADS)

    Kim, K.; Agarwal, A.; Mcdonald, A. M.; Moore, R. M.; Myers, D. D., Jr.; Witte, R. S.; Huang, S.-W.; Ashkenazi, S.; Kaplan, M. J.; Wakefield, T. W.; O'Donnell, M.; Kotov, N. A.

    2008-02-01

    Cardiovascular inflammatory activity was imaged in vivo. Inflammation is known to be a major cause of cardiovascular disease. Photoacoustic (PA) imaging was employed using bio-conjugated gold nanorods (GNR) as a contrast agent. A mouse model based on vascular endothelium injury by a photochemical reaction of Rose Bengal (RB) dye to green light laser was used. Following a mid-line laparotomy under an approved animal protocol, anti-ICAM-1 conjugated GNR was injected through the dorsal penile vein followed by RB injection through the same vein. The inferior vena cava immediately distal to the renal veins of a C57BL/6 mouse was exposed to the green light laser for 10 minutes. The peak absorption of GNR was tuned to be 700 nm to minimize possible background absorption by blood and RB. The stability of GNR in the blood plasma was tested in vitro. Photoacoustic images were obtained through an ultrasound gel pouch in the mouse abdomen using a commercial ultrasound probe to evaluate inflammatory changes to the vascular endothelium, confirmed by histology. Preliminary results demonstrate the feasibility of in vivo photoacoustic imaging by a commercial ultrasound scanner of inflammation using GNR as a contrast agent.

  1. Targeted Aucore-Agshell nanorods as a dual-functional contrast agent for photoacoustic imaging and photothermal therapy

    PubMed Central

    Shi, Yiwen; Peng, Dong; Wang, Kun; Chai, Xinyu; Ren, Qiushi; Tian, Jie; Zhou, Chuanqing

    2016-01-01

    Optimizing contrast enhancement is essential for producing specific signals in biomedical imaging and therapy. The potential of using Aucore-Agshell nanorods (Au@Ag NRs) as a dual-functional theranostic contrast agent is demonstrated for effective cancer imaging and treatments. Due to its strong NIR absorption and high efficiency of photothermal conversion, effects of both photoacoustic tomography (PAT) and photothermal therapy (PTT) are enhanced significantly. The PAT signal grows by 45.3% and 82% in the phantom and in vivo experiments, respectively, when compared to those using Au NRs. In PTT, The maximum increase of tissue temperature treated with Au@Ag NRs is 22.8 °C, twice that with Au NRs. Results of the current study show the feasibility of using Au@Ag NRs for synergetic PAT with PTT. And it will enhance the potential application on real-time PAT guided PTT, which will greatly benefit the customized PTT treatment of cancer. PMID:27231624

  2. Prostate-specific membrane antigen targeted protein contrast agents for molecular imaging of prostate cancer by MRI

    NASA Astrophysics Data System (ADS)

    Pu, Fan; Salarian, Mani; Xue, Shenghui; Qiao, Jingjuan; Feng, Jie; Tan, Shanshan; Patel, Anvi; Li, Xin; Mamouni, Kenza; Hekmatyar, Khan; Zou, Juan; Wu, Daqing; Yang, Jenny J.

    2016-06-01

    Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high resolution has yet to be achieved due to the lack of contrast agents with significantly improved relaxivity for sensitivity, targeting capabilities and metal selectivity. We have previously reported our creation of a novel class of protein Gd3+ contrast agents, ProCA32, which displayed significantly improved relaxivity while exhibiting strong Gd3+ binding selectivity over physiological metal ions. In this study, we report our effort in further developing biomarker-targeted protein MRI contrast agents for molecular imaging of PSMA. Among three PSMA targeted contrast agents engineered with addition of different molecular recognition sequences, ProCA32.PSMA exhibits a binding affinity of 1.1 +/- 0.1 μM for PSMA while the metal binding affinity is maintained at 0.9 +/- 0.1 × 10-22 M. In addition, ProCA32.PSMA exhibits r1 of 27.6 mM-1 s-1 and r2 of 37.9 mM-1 s-1 per Gd (55.2 and 75.8 mM-1 s-1 per molecule r1 and r2, respectively) at 1.4 T. At 7 T, ProCA32.PSMA also has r2 of 94.0 mM-1 s-1 per Gd (188.0 mM-1 s-1 per molecule) and r1 of 18.6 mM-1 s-1 per Gd (37.2 mM-1 s-1 per molecule). This contrast capability enables the first MRI enhancement dependent on PSMA expression levels in tumor bearing mice using both T1 and T2-weighted MRI at 7 T. Further development of these PSMA-targeted contrast agents are expected to be used for the precision imaging of prostate cancer at an early stage and to monitor disease progression and staging, as well as determine the effect of therapeutic treatment by non-invasive evaluation of the PSMA level using MRI.Prostate-specific membrane antigen (PSMA) is one of the most specific cell surface markers for prostate cancer diagnosis and targeted treatment. However, achieving molecular imaging using non-invasive MRI with high

  3. Ultrasound-Triggered Phase Transition Sensitive Magnetic Fluorescent Nanodroplets as a Multimodal Imaging Contrast Agent in Rat and Mouse Model

    PubMed Central

    Chen, Yunchao; Luo, Binhua; Liu, Xuhan; Liu, Wei; Xu, Haibo; Yang, Xiangliang

    2013-01-01

    Ultrasound-triggered phase transition sensitive nanodroplets with multimodal imaging functionality were prepared via premix Shirasu porous glass (SPG) membrane emulsification method. The nanodroplets with fluorescence dye DiR and SPIO nanoparticles (DiR-SPIO-NDs) had a polymer shell and a liquid perfluoropentane (PFP) core. The as-formed DiR-SPIO-NDs have a uniform size of 385±5.0 nm with PDI of 0.169±0.011. The TEM and microscopy imaging showed that the DiR-SPIO-NDs existed as core-shell spheres, and DiR and SPIO nanoparticles dispersed in the shell or core. The MTT and hemolysis studies demonstrated that the nanodroplets were biocompatible and safe. Moreover, the proposed nanodroplets exhibited significant ultrasound-triggered phase transition property under clinical diagnostic ultrasound irradiation due to the vaporization of PFP inside. Meanwhile, the high stability and R2 relaxivity of the DiR-SPIO-NDs suggested its applicability in MRI. The in vivo T2-weighted images of MRI and fluorescence images both showed that the image contrast in liver and spleen of rats and mice model were enhanced after the intravenous injection of DiR-SPIO-NDs. Furthermore, the ultrasound imaging (US) in mice tumor as well as MRI and fluorescence imaging in liver of rats and mice showed that the DiR-SPIO-NDs had long-lasting contrast ability in vivo. These in vitro and in vivo findings suggested that DiR-SPIO-NDs could potentially be a great MRI/US/fluorescence multimodal imaging contrast agent in the diagnosis of liver tissue diseases. PMID:24391983

  4. Computed Tomography Imaging of Solid Tumors Using a Liposomal-Iodine Contrast Agent in Companion Dogs with Naturally Occurring Cancer

    PubMed Central

    Ghaghada, Ketan B.; Sato, Amy F.; Starosolski, Zbigniew A.; Berg, John; Vail, David M.

    2016-01-01

    Objectives Companion dogs with naturally occurring cancer serve as an important large animal model in translational research because they share strong similarities with human cancers. In this study, we investigated a long circulating liposomal-iodine contrast agent (Liposomal-I) for computed tomography (CT) imaging of solid tumors in companion dogs with naturally occurring cancer. Materials and Methods The institutional animal ethics committees approved the study and written informed consent was obtained from all owners. Thirteen dogs (mean age 10.1 years) with a variety of masses including primary and metastatic liver tumors, sarcomas, mammary carcinoma and lung tumors, were enrolled in the study. CT imaging was performed pre-contrast and at 15 minutes and 24 hours after intravenous administration of Liposomal-I (275 mg/kg iodine dose). Conventional contrast-enhanced CT imaging was performed in a subset of dogs, 90 minutes prior to administration of Liposomal-I. Histologic or cytologic diagnosis was obtained for each dog prior to admission into the study. Results Liposomal-I resulted in significant (p < 0.05) enhancement and uniform opacification of the vascular compartment. Non-renal, reticulo-endothelial systemic clearance of the contrast agent was demonstrated. Liposomal-I enabled visualization of primary and metastatic liver tumors. Sub-cm sized liver lesions grossly appeared as hypo-enhanced compared to the surrounding normal parenchyma with improved lesion conspicuity in the post-24 hour scan. Large liver tumors (> 1 cm) demonstrated a heterogeneous pattern of intra-tumoral signal with visibly higher signal enhancement at the post-24 hour time point. Extra-hepatic, extra-splenic tumors, including histiocytic sarcoma, anaplastic sarcoma, mammary carcinoma and lung tumors, were visualized with a heterogeneous enhancement pattern in the post-24 hour scan. Conclusions The long circulating liposomal-iodine contrast agent enabled prolonged visualization of small

  5. Self-assembled polymeric nanoparticles as new, smart contrast agents for cancer early detection using magnetic resonance imaging

    PubMed Central

    Mouffouk, Fouzi; Simão, Teresa; Dornelles, Daniel F; Lopes, André D; Sau, Pablo; Martins, Jorge; Abu-Salah, Khalid M; Alrokayan, Salman A; Rosa da Costa, Ana M; dos Santos, Nuno R

    2015-01-01

    Early cancer detection is a major factor in the reduction of mortality and cancer management cost. Here we developed a smart and targeted micelle-based contrast agent for magnetic resonance imaging (MRI), able to turn on its imaging capability in the presence of acidic cancer tissues. This smart contrast agent consists of pH-sensitive polymeric micelles formed by self-assembly of a diblock copolymer (poly(ethyleneglycol-b-trimethylsilyl methacrylate)), loaded with a gadolinium hydrophobic complex (tBuBipyGd) and exploits the acidic pH in cancer tissues. In vitro MRI experiments showed that tBuBipyGd-loaded micelles were pH-sensitive, as they turned on their imaging capability only in an acidic microenvironment. The micelle-targeting ability toward cancer cells was enhanced by conjugation with an antibody against the MUC1 protein. The ability of our antibody-decorated micelles to be switched on in acidic microenvironments and to target cancer cells expressing specific antigens, together with its high Gd(III) content and its small size (35–40 nm) reveals their potential use for early cancer detection by MRI. PMID:25565804

  6. Quantitation of Epidermal and Mucosal Tissue Injury Using Contrasts Agents and Imaging Techniques

    PubMed Central

    Visscher, Marty O.; Sullivan, David; Sullivan, Steven; Barford, Brian; Dock, Murray; Sommers, Marilyn S.

    2011-01-01

    Background/Purpose Epidermal injury is common but the accuracy of visual methods is significantly impacted by the inherent skin pigmentation. We examined imaging and fluorescence techniques to quantify tissue injury as a function of skin color. Methods Epidermal and mucosal scratches were created in 20 light (L* 68.2 ±2.3) and 20 dark skinned (L* 46.4 ± 5.2) females. Injured and uninjured sites were treated with toluidine blue (TB), fluorescein (FL) and a TB/FL mixture and photographed under conditions of white and fluorescent light. Area and intensity parameters were determined. Results Injured sites with TB and TB/FL had higher areas than the control for both light and dark subjects (ANOVA, p < 0.05). The intensity of the injured TB site was higher than the control for light skin only. The areas of injured sites with FL and TB/FL were higher than the control for both groups as were the intensities of the injured sites with FL. The findings were similar for the lip skin. Conclusions Application of TB and FL contrasts under white and fluorescent light can be used to quantify tissue injuries for L* values > 35 and is a promising approach for the quantitation across a range of skin pigmentation. PMID:19622128

  7. 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

  8. Efficient labeling in vitro with non-ionic gadolinium magnetic resonance imaging contrast agent and fluorescent transfection agent in bone marrow stromal cells of neonatal rats.

    PubMed

    Li, Ying-Qin; Tang, Ying; Fu, Rao; Meng, Qiu-Hua; Zhou, Xue; Ling, Ze-Min; Cheng, Xiao; Tian, Su-Wei; Wang, Guo-Jie; Liu, Xue-Guo; Zhou, Li-Hua

    2015-07-01

    Although studies have been undertaken on gadolinium labeling-based molecular imaging in magnetic resonance imaging (MRI), the use of non-ionic gadolinium in the tracking of stem cells remains uncommon. To investigate the efficiency in tracking of stem cells with non-ionic gadolinium as an MRI contrast agent, a rhodamine-conjugated fluorescent reagent was used to label bone marrow stromal cells (BMSCs) of neonatal rats in vitro, and MRI scanning was undertaken. The fluorescent-conjugated cell uptake reagents were able to deliver gadodiamide into BMSCs, and cell uptake was verified using flow cytometry. In addition, the labeled stem cells with paramagnetic contrast medium remained detectable by an MRI monitor for a minimum of 28 days. The present study suggested that this method can be applied efficiently and safely for the labeling and tracking of bone marrow stromal cells in neonatal rats. PMID:25816076

  9. Efficient labeling in vitro with non-ionic gadolinium magnetic resonance imaging contrast agent and fluorescent transfection agent in bone marrow stromal cells of neonatal rats

    PubMed Central

    LI, YING-QIN; TANG, YING; FU, RAO; MENG, QIU-HUA; ZHOU, XUE; LING, ZE-MIN; CHENG, XIAO; TIAN, SU-WEI; WANG, GUO-JIE; LIU, XUE-GUO; ZHOU, LI-HUA

    2015-01-01

    Although studies have been undertaken on gadolinium labeling-based molecular imaging in magnetic resonance imaging (MRI), the use of non-ionic gadolinium in the tracking of stem cells remains uncommon. To investigate the efficiency in tracking of stem cells with non-ionic gadolinium as an MRI contrast agent, a rhodamine-conjugated fluorescent reagent was used to label bone marrow stromal cells (BMSCs) of neonatal rats in vitro, and MRI scanning was undertaken. The fluorescent-conjugated cell uptake reagents were able to deliver gadodiamide into BMSCs, and cell uptake was verified using flow cytometry. In addition, the labeled stem cells with paramagnetic contrast medium remained detectable by an MRI monitor for a minimum of 28 days. The present study suggested that this method can be applied efficiently and safely for the labeling and tracking of bone marrow stromal cells in neonatal rats. PMID:25816076

  10. Anatomical and functional imaging of myocardial infarction in mice using micro-CT and eXIA 160 contrast agent

    PubMed Central

    Ashton, Jeffrey R.; Befera, Nicholas; Clark, Darin; Qi, Yi; Mao, Lan; Rockman, Howard A.; Johnson, G. Allan; Badea, Cristian T.

    2014-01-01

    Non-invasive small animal imaging techniques are essential for evaluation of cardiac disease and potential therapeutics. A novel preclinical iodinated contrast agent called eXIA 160 has recently been developed, which has been evaluated for micro-CT cardiac imaging. eXIA 160 creates strong contrast between blood and tissue immediately after its injection and is subsequently taken up by the myocardium and other metabolically active tissues over time. We focus on these properties of eXIA and show its use in imaging myocardial infarction in mice. Five C57BL/6 mice were imaged ~ 2 weeks after LAD coronary artery ligation. Six C57BL/6 mice were used as controls. Immediately after injection of eXIA 160, an enhancement difference between blood and myocardium of ~340 HU enabled cardiac function estimation via 4D micro-CT scanning with retrospective gating. Four hours post-injection, the healthy perfused myocardium had a contrast difference of ~140 HU relative to blood while the infarcted myocardium showed no enhancement. These differences allowed quantification of infarct size via dual energy micro-CT. In vivo micro-SPECT imaging and ex vivo TTC staining provided validation for the micro-CT findings. Root mean squared error of infarct measurements was 2.7% between micro-CT and SPECT, and 4.7% between micro-CT and TTC. Thus, micro-CT with eXIA 160 can be used to provide both morphological and functional data for preclinical studies evaluating myocardial infarction and potential therapies. Further studies are warranted to study the potential use of eXIA 160 as a CT molecular imaging tool for other metabolically active tissues in the mouse. PMID:24523061

  11. Study of anti-angiogenic drugs by fluorescence imaging and spectroscopy of a contrast agent in mice

    NASA Astrophysics Data System (ADS)

    Valentini, G.; D'Andrea, C.; Ferrari, R.; Pifferi, A.; Cubeddu, R.; Caronia, D.; Martinelli, M.; Giavazzi, R.

    2007-07-01

    We used two fluorescence techniques based on the Indocyanine Green contrast agent to study the effectiveness of antiangionenic drugs in mice. To this purpose, the volume of the active vasculature in different tumor models implanted in mice was assessed by means of a low noise fluorescence imaging setup and by a photon counting system working in transmittance geometry. Using a first tumor model (carcinoma MDA-MB-435) we observed that mice treated with a Vascular Disrupting Agent (ZD6126) showed a reduction in fluorescence emission of the contrast agent with respect to control mice. This was a clear indication of the vascular shutdown that took place in tumors. The effectiveness of the treatment was also confirmed by histological sections. Then, in a second experiment we considered a second tumor model (carcinoma 1A9-VS1) overexpressing the Vascular Endotelial Growth Factor (VEGF121), which is used by tumor cells to promote angiogenesis. We measured the Indocyanine Green fluorescence in mice treated with an antioangiogenic drug (Avastin TM) and in control mice. In tumors of treated mice we observed an ICG emission lower than the one detected in control mice. This demonstrated that VEGF activity was effectively blocked by the treatment with Avastin. In conclusion, ICG fluorescence provides a simple and reliable way to assess the effectiveness of vascular targeting therapies. Measurements of the fluorescence signal can be repeated every 24 hours, thus allowing oncologists to perform longitudinal studies on the same animals.

  12. Biodegradable human serum albumin nanoparticles as contrast agents for the detection of hepatocellular carcinoma by magnetic resonance imaging.

    PubMed

    Watcharin, Waralee; Schmithals, Christian; Pleli, Thomas; Köberle, Verena; Korkusuz, Hüdayi; Huebner, Frank; Zeuzem, Stefan; Korf, Hans W; Vogl, Thomas J; Rittmeyer, Claudia; Terfort, Andreas; Piiper, Albrecht; Gelperina, Svetlana; Kreuter, Jörg

    2014-05-01

    Tumor visualization by magnetic resonance imaging (MRI) and nanoparticle-based contrast agents may improve the imaging of solid tumors such as hepatocellular carcinoma (HCC). In particular, human serum albumin (HSA) nanoparticles appear to be a suitable carrier due to their safety and feasibility of functionalization. In the present study HSA nanoparticles were conjugated with gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) using carbodiimide chemistry. The nanoparticles had a uniform spherical shape and a diameter of 235±19nm. For better optical visualization in vitro and in vivo, the HSA-Gd nanoparticles were additionally labeled with rhodamine 123. As shown by confocal microscopy and flow cytometry analysis, the fluorescent nanoparticles were readily taken up by Huh-7 hepatocellular carcinoma cells. After 24h incubation in blood serum, less than 5% of the Gd(III) was released from the particles, which suggests that this nanoparticulate system may be stable in vivo and, therefore, may serve as potentially safe T1 MRI contrast agent for MRI of hepatocellular carcinoma. PMID:24365328

  13. Study of Tissue Phantoms, Tissues, and Contrast Agent with the Biophotoacoustic Radar and Comparison to Ultrasound Imaging for Deep Subsurface Imaging

    NASA Astrophysics Data System (ADS)

    Alwi, R.; Telenkov, S.; Mandelis, A.; Gu, F.

    2012-11-01

    In this study, the imaging capability of our wide-spectrum frequency-domain photoacoustic (FD-PA) imaging alias "photoacoustic radar" methodology for imaging of soft tissues is explored. A practical application of the mathematical correlation processing method with relatively long (1 ms) frequency-modulated optical excitation is demonstrated for reconstruction of the spatial location of the PA sources. Image comparison with ultrasound (US) modality was investigated to see the complementarity between the two techniques. The obtained results with a phased array probe on tissue phantoms and their comparison to US images demonstrated that the FD-PA technique has strong potential for deep subsurface imaging with excellent contrast and high signal-to-noise ratio. FD-PA images of blood vessels in a human wrist and an in vivo subcutaneous tumor in a rat model are presented. As in other imaging modalities, the employment of contrast agents is desirable to improve the capability of medical diagnostics. Therefore, this study also evaluated and characterized the use of Food and Drug Administration (FDA)-approved superparamagnetic iron oxide nanoparticles (SPION) as PA contrast agents.

  14. Quantum dots decorated gold nanorod as fluorescent-plasmonic dual-modal contrasts agent for cancer imaging.

    PubMed

    Wu, Qiong; Chen, Lu; Huang, Liang; Wang, Jing; Liu, Jiawei; Hu, Chao; Han, Heyou

    2015-12-15

    Constructing integrative optical bioprobe with both fluorophores and plasmonic functional groups is of particular interest in precise co-localized bio-imaging probe development. Herein, we fabricated a novel hierarchical complex nanoparticle with fluorescent and plasmonic components spatially separated, which is composed of highly brilliant CdSe/CdS/ZnS QDs decorated gold nanorod (AuNR) with silicon coating. This complex structure served as an efficient dual-modality imaging contrast agent, where the potential fluorescence resonance energy transfer (FRET) between QDs and AuNR was avoided by the intermediate silica layer as well as minimized spectral overlap between QDs and AuNRs. The high-density loading of QDs was achieved by thiol-metal affinity driven assembly of hydrophobic QDs with thiolated AuNR@SiO2 substrate, which is able to show a strong fluorescence emission. After amphiphilic organosilica-mediated phase transferring and functionalization with transferrin (Tf), these nanoparticles entered A549 cells and exhibited high contrasting fluorescent and dark-field signals for co-localized cancer cells imaging. The results demonstrate that these nanoparticles are potential candidates as dual modal probes for fluorescence and dark-field image. PMID:26093124

  15. Contrast agent choice for intravenous coronary angiography

    SciTech Connect

    Zeman, H.D.; Siddons, D.P.

    1989-01-01

    The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation x-rays and an iodine containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic x-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the x-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation x-rays is visualizing a coronary artery through the left ventricle or aorta which also contains a contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth.

  16. Multifunctional nanoparticles as coupled contrast agents

    PubMed Central

    Jin, Yongdong; Jia, Congxian; Huang, Sheng-Wen; O’Donnell, Matthew; Gao, Xiaohu

    2011-01-01

    Engineering compact imaging probes with highly integrated modalities is a key focus in bionanotechnology and will have profound impact on molecular diagnostics, imaging, and therapeutics. However, combining multiple components on a nanometer scale to create new imaging modalities unavailable from individual components has proven challenging. Here, we demonstrate iron oxide and gold coupled core-shell nanoparticles with well defined structural characteristics (e.g., size, shell thickness, and core-shell separation) and physical properties (e.g., electronic, magnetic, optical, thermal, and acoustic). The resulting multifunctional nanoprobes not only offer contrast for electron microscopy, magnetic resonance imaging, and scattering-based imaging, but more importantly, enable a new imaging mode, magnetomotive photoacoustic (mmPA) imaging, with remarkable contrast enhancement compared to PA images using conventional nanoparticle contrast agents. PMID:20975706

  17. MR Molecular Imaging of Prostate Cancer with a Peptide Targeted Contrast Agent in a Mouse Orthotopic Prostate Cancer Model

    PubMed Central

    Tan, Mingqian; Burden-Gulley, Susan M.; Li, Wen; Wu, Xueming; Lindner, Daniel; Brady-Kalnay, Susann M.; Gulani, Vikas; Lu, Zheng-Rong

    2014-01-01

    Purpose To study the effectiveness of a peptide targeted nanoglobular Gd-DOTA complexes for MR molecular imaging of prostate cancer in a mouse orthotopic PC-3 prostate cancer model. Methods A CLT1 (CGLIIQKNEC) peptide targeted generation 2 nanoglobular Gd-DOTA monoamide conjugate [CLT1-G2-(Gd-DOTA)] was used for imaging fibrin-fibronectin complexes in prostate tumor using a non-specific peptide KAREC modified conjugate, KAREC-G2-(Gd-DOTA) as a control. Cy5 conjugates of CLT1 and KAREC were synthesized for binding studies. Orthotopic PC-3 prostate tumors were established in the prostate of athymic male nude mice. MRI study was performed on a Bruker 7T animal scanner. Results CLT1 peptide showed specific binding in the prostate tumor with no binding in normal tissues. The control peptide had little binding in both normal and tumor tissues. CLT1-G2-(Gd-DOTA) resulted in stronger contrast enhancement in the tumor tissue than the KAREC-G2-(Gd-DOTA). CLT1-G2-(Gd-DOTA) generated approximately 100% increase in contrast-to-noise ratio (CNR) in the tumor as compared to precontrast CNR at 1 minute post-injection, while the control agent KAREC-G2-(Gd-DOTA) only resulted in 8% CNR increase. Conclusion CLT1-G2-(Gd-DOTA) is a promising molecular MRI contrast agent for fibrin-fibronectin complexes in the tumor stroma. It has a potential for the diagnosis and assessing prognosis of malignant tumors with MRI. PMID:22139536

  18. Synchrotron- and laboratory-based X-ray phase-contrast imaging for imaging mouse articular cartilage in the absence of radiopaque contrast agents

    PubMed Central

    Marenzana, Massimo; Hagen, Charlotte K.; Borges, Patricia Das Neves; Endrizzi, Marco; Szafraniec, Magdalena B.; Vincent, Tonia L.; Rigon, Luigi; Arfelli, Fulvia; Menk, Ralf-Hendrik; Olivo, Alessandro

    2014-01-01

    The mouse model of osteoarthritis (OA) has been recognized as the most promising research tool for the identification of new OA therapeutic targets. However, this model is currently limited by poor throughput, dependent on the extremely time-consuming histopathology assessment of the articular cartilage (AC). We have recently shown that AC in the rat tibia can be imaged both in air and in saline solution using a laboratory system based on coded-aperture X-ray phase-contrast imaging (CAXPCi). Here, we explore ways to extend the methodology for imaging the much thinner AC of the mouse, by means of gold-standard synchrotron-based phase-contrast methods. Specifically, we have used analyser-based phase-contrast micro-computed tomography (micro-CT) for its high sensitivity to faint phase changes, coupled with a high-resolution (4.5 μm pixel) detector. Healthy, diseased (four weeks post induction of OA) and artificially damaged mouse AC was imaged at the Elettra synchrotron in Trieste, Italy, using the above method. For validation, we used conventional micro-CT combined with radiopaque soft-tissue staining and standard histomorphometry. We show that mouse cartilage can be visualized correctly by means of the synchrotron method. This suggests that: (i) further developments of the laboratory-based CAXPCi system, especially in terms of pushing the resolution limits, might have the potential to resolve mouse AC ex vivo and (ii) additional improvements may lead to a new generation of CAXPCi micro-CT scanners which could be used for in vivo longitudinal pre-clinical imaging of soft tissue at resolutions impossible to achieve by current MRI technology. PMID:24470419

  19. Development of a magnetic resonance imaging protocol to visualize encapsulated contrast agent markers in prostate brachytherapy recipients: initial patient experience

    PubMed Central

    Lim, Tze Yee; Wang, Jihong; Bathala, Tharakeswara; Szklaruk, Janio; Pugh, Thomas J.; Mahmood, Usama; Ibbott, Geoffrey S.; Frank, Steven J.

    2016-01-01

    Purpose Computed tomography (CT)-based prostate post-implant dosimetry allows for definitive seed localization but is associated with high interobserver variation in prostate contouring. Currently, magnetic resonance imaging (MRI)-based post-implant dosimetry allows for accurate anatomical delineation but is limited due to inconsistent seed localization. Encapsulated contrast agent markers were previously proposed to overcome the seed localization limitation on MRI images by placing hyperintense markers adjacent to hypointense seeds. The aim of this study was to assess the appearance of these markers in prostatic tissue, and develop an MRI protocol to enable marker visualization. Material and methods We acquired MRI scans in prostate implant patients (n = 10) on day 0 (day of implant) and day 30 (month after implant). Before implantation of the markers, the routine post-implant MRI protocol included a 3D T2-weighted fast-spin-echo (FSE) sequence with which markers and seeds could not be clearly visualized. To visualize the MRI markers, a 3D fast radiofrequency-spoiled gradient-recalled echo (FSPGR) sequence was evaluated for marker and seed visibility, as well as prostate boundary definitions. Results The 3D FSPGR sequence allowed for the visualization of markers in the prostate, enabling the distinction of signal voids as seeds versus needle tracks. The updated post-implant MRI protocol consists of this 3D FSPGR scan and an optional 3D T2-weighted FSE scan. The optional 3D T2-weighted FSE sequence may be employed to better visualize intraprostatic detail. We also described the observed image artifacts, including seed susceptibility, marker chemical shift, partial volume averaging, motion, and wraparound artifacts. Conclusions We have demonstrated an MRI protocol for use with hyperintense encapsulated contrast agent markers to assist in the identification of hypointense seeds. PMID:27504133

  20. Monte Carlo simulations of dose enhancement around gold nanoparticles used as X-ray imaging contrast agents and radiosensitizers

    NASA Astrophysics Data System (ADS)

    Li, W. B.; Müllner, M.; Greiter, M. B.; Bissardon, C.; Xie, W. Z.; Schlatll, H.; Oeh, U.; Li, J. L.; Hoeschen, C.

    2014-03-01

    Gold nanoparticles (GNPs) were demonstrated as X-ray imaging contrast agents and radiosensitizers in mice. However, the translational medical applications of GNPs in to the clinical practice need further detailed information on the biological effects related to the enhanced doses in malignant and healthy cells. The idea of improving radiotherapy with high atomic number materials, especially gold foils, was initiated in our research unit in the 1980s. Recently, experimental and theoretical efforts were made to investigate the potential improvement of imaging and radiotherapy with GNPs. Initially, the present work attempts to validate the dose enhancement effects of GNPs to cancer cells; secondly, it intends to examine the possible side effects on healthy cells when using GNPs as X-ray contrast agent. In this study, three Monte Carlo simulation programs, namely PENELOPE-2011, GEANT4 and EGSnrc were used to simulate the local energy deposition and the resulting dose enhancement of GNPs. Diameters of the GNPs were assumed to be 2 nm, 15 nm, 50 nm, 100 nm and 200 nm. The X-ray energy spectra for irradiation were 60 kVp, 80 kVp, 100 kVp, 150 kVp with a filtering of 2.7 mm Al for projectional radiography, and 8 mm Al for 100 kVp and 150 kVp for computed tomography. Additional peak energy of 200 kVp was simulated for radiotherapy purpose. The information of energy deposition and dose enhancement can help understanding the physical processes of medical imaging and the implication of nanoparticles in radiotherapy.

  1. Method for nuclear magnetic resonance imaging using deuterum as a contrast agent

    DOEpatents

    Kehayias, Joseph J.; Joel, Darrel D.; Adams, William H.; Stein, Harry L.

    1990-01-01

    A method for in vivo NMR imaging of the blood vessels and organs of a patient characterized by using a dark dye-like imaging substance consisting essentially of a stable, high-purity concentration of D.sub.2 O in a solution with water.

  2. The study of photoacoustic imaging without nanoparticles as a contrast agent for anti-body drug monitoring

    NASA Astrophysics Data System (ADS)

    Han, Seung Hee; Kang, Jeeun; Wilson, Brian; Song, Tai-Kyong; Kim, Young Il

    2015-03-01

    As an emerging hybrid Imaging, Photoacoustic became a powerful tool that can scan disease at the deeper site in tissue and monitor of drug delivery in vivo. PAI system used nano-particle as contrast agent to enhance the PA signal in deeper site in tissue. So this makes that PAI's application have some limitation for monitoring of all kinds of anti-body drug, because of various anti-body's absorption excitation. In this study, we designed a PAI system with a tunable pulse OPO laser (from 450~700nm excitation wavelength) to show the optimal wavelength for monitoring of the antibody drug; doxorubicin having peak absorption at near 500nm excitation without any nano-particle combine. We made a gelatin phantoms having 4 different concentration doxorubicin as an anti-body drug; Doxorubicin concentration were in- 0mg/ml, 0.5mg/ml, 1mg/ml, and 2mg/ml. We found that 500nm is optimization wavelength to produce PA peak signal and PAI can be tool to monitor of anti-body drug without contrast agent.

  3. Susceptibility Contrast Magnetic Resonance Imaging Determination of Fractional Tumor Blood Volume: A Noninvasive Imaging Biomarker of Response to the Vascular Disrupting Agent ZD6126

    SciTech Connect

    Robinson, Simon P. Howe, Franklyn A.; Griffiths, John R.; Ryan, Anderson J.; Waterton, John C.

    2007-11-01

    Purpose: To assess tumor fractional blood volume ({xi}), determined in vivo by susceptibility contrast magnetic resonance imaging (MRI) as a noninvasive imaging biomarker of tumor response to the vascular disrupting agent ZD6126. Methods and Materials: The transverse MRI relaxation rate R{sub 2}* of rat GH3 prolactinomas was quantified prior to and following injection of 2.5 mgFe/kg feruglose, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, and {xi} (%) was determined from the change in R{sub 2}*. The rats were then treated with either saline or 50 mg/kg ZD6126, and {xi} measured again 24 hours later. Following posttreatment MRI, Hoechst 33342 (15 mg/kg) was administered to the rats and histological correlates from composite images of tumor perfusion and necrosis sought. Results: Irrespective of treatment, tumor volume significantly increased over 24 hours. Saline-treated tumors showed no statistically significant change in {xi}, whereas a significant (p = 0.002) 70% reduction in {xi} of the ZD6126-treated cohort was determined. Hoechst 33342 uptake was associated with viable tumor tissue and was significantly (p = 0.004) reduced and restricted to the rim of the ZD6126-treated tumors. A significant positive correlation between posttreatment {xi} and Hoechst 33342 uptake was obtained (r = 0.83, p = 0.002), providing validation of the MRI-derived measurements of fractional tumor blood volume. Conclusions: These data clearly highlight the potential of susceptibility contrast MRI with ultrasmall superparamagnetic iron oxide contrast agents to provide quantitative imaging biomarkers of fractional tumor blood volume at high spatial resolution to assess tumor vascular status and response to vascular disrupting agents.

  4. J-aggregate Nanoparticles as Photoacoustic Contrast Agents for Prostate Cancer Imaging

    NASA Astrophysics Data System (ADS)

    Shakiba, Mojdeh

    Management of early stage prostate cancer (PCa) is plagued with the dilemma between active surveillance that risks progression, and aggressive treatments of potentially indolent disease that significantly reduces quality of life. This results from the inability of current diagnostic techniques to accurately distinguish between indolent and aggressive disease, which has resulted in overtreatment of PCa. Photoacoutic imaging allows for imaging of specific molecular constituents in tissue. To enable for its use in PCa imaging, we designed a novel organic nanoparticle that combines the unique spectral properties and efficient photon capture of nature's photosynthetic apparatus with the stable and specific delivery offered by nanoparticles. These Jaggregate nanoparticles are shown to produce an intense, narrow photo acoustic signal and to have nanoparticle-dependent photonic properties that enable for assessment of the state of the particle. Preliminary assessment of their use in an orthotopic PCa model showed accumulation in and delineation of the tumor boundary.

  5. In vivo multimodal magnetic particle imaging (MPI) with tailored magneto/optical contrast agents

    PubMed Central

    Arami, Hamed; Khandhar, Amit; Tomitaka, Asahi; Yu, Elaine; Goodwill, Patrick; Conolly, Steven; Krishnan, Kannan M.

    2015-01-01

    Magnetic Particle Imaging (MPI) is a novel non-invasive biomedical imaging modality that uses safe magnetite nanoparticles as tracers. Controlled synthesis of iron oxide nanoparticles (NPs) with tuned size-dependent magnetic relaxation properties is critical for the development of MPI. Additional functionalization of these NPs for other imaging modalities (e.g. MRI and fluorescent imaging) would accelerate screening of the MPI tracers based on their in vitro and in vivo performance in pre-clinical trials. Here, we conjugated two different types of poly-ethylene-glycols (NH2-PEG-NH2 and NH2-PEG FMOC) to monodisperse carboxylated 19.7nm NPs by amide bonding. Further, we labeled these NPs with Cy5.5 near infra-red fluorescent (NIRF) molecules. Bi-functional PEG (NH2-PEG-NH2) resulted in larger hydrodynamic size (~98nm vs. ~43nm) of the tracers, due to interparticle crosslinking. Formation of such clusters impacted the multimodal imaging performance and pharmacokinetics of these tracers. We found that MPI signal intensity of the tracers in blood depends on their plasmatic clearance pharmacokinetics. Whole body mice MPI/MRI/NIRF, used to study the biodistribution of the injected NPs, showed primary distribution in liver and spleen. Biodistribution of tracers and their clearance pathway was further confirmed by MPI and NIRF signals from the excised organs where the Cy5.5 labeling enabled detailed anatomical mapping of the tracers.in tissue sections. These multimodal MPI tracers, combining the strengths of each imaging modality (e.g. resolution, tracer sensitivity and clinical use feasibility) pave the way for various in vitro and in vivo MPI applications. PMID:25818431

  6. Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging

    PubMed Central

    2012-01-01

    The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT. PMID:22429280

  7. Highly biocompatible TiO2:Gd3+ nano-contrast agent with enhanced longitudinal relaxivity for targeted cancer imaging

    NASA Astrophysics Data System (ADS)

    Chandran, Parwathy; Sasidharan, Abhilash; Ashokan, Anusha; Menon, Deepthy; Nair, Shantikumar; Koyakutty, Manzoor

    2011-10-01

    We report the development of a novel magnetic nano-contrast agent (nano-CA) based on Gd3+ doped amorphous TiO2 of size ~25 nm, exhibiting enhanced longitudinal relaxivity (r1) and magnetic resonance (MR) contrasting together with excellent biocompatibility. Quantitative T1 mapping of phantom samples using a 1.5 T clinical MR imaging system revealed that the amorphous phase of doped titania has the highest r1 relaxivity which is ~2.5 fold higher than the commercially used CA Magnevist™. The crystalline (anatase) samples formed by air annealing at 250 °C and 500 °C showed significant reduction in r1 values and MR contrast, which is attributed to the loss of proton-exchange contribution from the adsorbed water and atomic re-arrangement of Gd3+ ions in the crystalline host lattice. Nanotoxicity studies including cell viability, plasma membrane integrity, reactive oxygen stress and expression of pro-inflammatory cytokines, performed on human primary endothelial cells (HUVEC), human blood derived peripheral blood mononuclear cells (PBMC) and nasopharyngeal epidermoid carcinoma (KB) cell line showed excellent biocompatibility up to relatively higher doses of 200 μg ml-1. The potential of this nano-CA to cause hemolysis, platelet aggregation and plasma coagulation were studied using human peripheral blood samples and found no adverse effects, illustrating the possibility of the safe intravenous administration of these agents for human applications. Furthermore, the ability of these agents to specifically detect cancer cells by targeting molecular receptors on the cell membrane was demonstrated on folate receptor (FR) positive oral carcinoma (KB) cells, where the folic acid conjugated nano-CA showed receptor specific accumulation on cell membrane while leaving the normal fibroblast cells (L929) unstained. This study reveals that the Gd3+ doped amorphous TiO2 nanoparticles having enhanced magnetic resonance contrast and high biocompatibility is a promising candidate for

  8. Contrast agent choice for intravenous coronary angiography

    NASA Astrophysics Data System (ADS)

    Zeman, H. D.; Siddons, D. P.

    1990-05-01

    The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation X-rays and an iodine-containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic X-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron radiation source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the X-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation X-rays is visualizing a coronary artery through the left ventricle or aorta which also contain contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth. The X-ray energy spectrum of the X-17 superconduction wiggler beam line at the National Synchrotron Light Source at Brookhaven National Laboratory has been used for these calculations. Both perfect Si crystals and Si crystals with a small mosaic spread are considered as monochromators. Contrast agents containing Gd or Yb seem to have about the optimal calculated signal to noise ratio. Gd-DTPA is already approved for use as a contrast agent for

  9. Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo

    PubMed Central

    Cui, Wenjin; Tavri, Sidhartha; Benchimol, Michael J.; Itani, Malak; Olson, Emilia S.; Zhang, Hong; Decyk, Marika; Ramirez, Rosemarie G.; Barback, Christopher V.; Kono, Yuko; Mattrey, Robert F.

    2013-01-01

    Tracking neuroprogenitor cells (NPCs) that are used to target tumors, infarction or inflammation, is paramount for cell-based therapy. We employed ultrasound imaging that can detect a single microbubble because it can distinguish its unique signal from those of surrounding tissues. NPCs efficiently internalized positively charged microbubbles allowing a clinical ultrasound system to detect a single cell at 7 MHz. When injected intravenously, labeled NPCs traversed the lungs to be imaged in the left ventricle and the liver where they accumulated. Internalized microbubbles were not only less sensitive to destruction by ultrasound, but remained visible in vivo for days as compared to minutes when given free. The extended longevity provides ample time to allow cells to reach their intended target. We were also able to transfect NPCs in vitro when microbubbles were preloaded with GFP plasmid only when cells were insonated. Transfection efficiency and cell viability were both greater than 90%. PMID:23578557

  10. The Optimized Fabrication of Nanobubbles as Ultrasound Contrast Agents for Tumor Imaging

    PubMed Central

    Cai, Wen Bin; Yang, Heng Li; Zhang, Jian; Yin, Ji Kai; Yang, Yi Lin; Yuan, Li Jun; Zhang, Li; Duan, Yun You

    2015-01-01

    Nanobubbles, which have the potential for ultrasonic targeted imaging and treatment in tumors, have been a research focus in recent years. With the current methods, however, the prepared uniformly sized nanobubbles either undergo post-formulation manipulation, such as centrifugation, after the mixture of microbubbles and nanobubbles, or require the addition of amphiphilic surfactants. These processes influence the nanobubble stability, possibly create material waste, and complicate the preparation process. In the present work, we directly prepared uniformly sized nanobubbles by modulating the thickness of a phospholipid film without the purification processes or the addition of amphiphilic surfactants. The fabricated nanobubbles from the optimal phospholipid film thickness exhibited optimal physical characteristics, such as uniform bubble size, good stability, and low toxicity. We also evaluated the enhanced imaging ability of the nanobubbles both in vitro and in vivo. The in vivo enhancement intensity in the tumor was stronger than that of SonoVue after injection (UCA; 2 min: 162.47 ± 8.94 dB vs. 132.11 ± 5.16 dB, P < 0.01; 5 min: 128.38.47 ± 5.06 dB vs. 68.24 ± 2.07 dB, P < 0.01). Thus, the optimal phospholipid film thickness can lead to nanobubbles that are effective for tumor imaging. PMID:26333917

  11. The Optimized Fabrication of Nanobubbles as Ultrasound Contrast Agents for Tumor Imaging.

    PubMed

    Cai, Wen Bin; Yang, Heng Li; Zhang, Jian; Yin, Ji Kai; Yang, Yi Lin; Yuan, Li Jun; Zhang, Li; Duan, Yun You

    2015-01-01

    Nanobubbles, which have the potential for ultrasonic targeted imaging and treatment in tumors, have been a research focus in recent years. With the current methods, however, the prepared uniformly sized nanobubbles either undergo post-formulation manipulation, such as centrifugation, after the mixture of microbubbles and nanobubbles, or require the addition of amphiphilic surfactants. These processes influence the nanobubble stability, possibly create material waste, and complicate the preparation process. In the present work, we directly prepared uniformly sized nanobubbles by modulating the thickness of a phospholipid film without the purification processes or the addition of amphiphilic surfactants. The fabricated nanobubbles from the optimal phospholipid film thickness exhibited optimal physical characteristics, such as uniform bubble size, good stability, and low toxicity. We also evaluated the enhanced imaging ability of the nanobubbles both in vitro and in vivo. The in vivo enhancement intensity in the tumor was stronger than that of SonoVue after injection (UCA; 2 min: 162.47 ± 8.94 dB vs. 132.11 ± 5.16 dB, P < 0.01; 5 min: 128.38.47 ± 5.06 dB vs. 68.24 ± 2.07 dB, P < 0.01). Thus, the optimal phospholipid film thickness can lead to nanobubbles that are effective for tumor imaging. PMID:26333917

  12. 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

  13. MR imaging of stem cell apoptosis in arthritic joints with a caspase-activatable contrast agent

    PubMed Central

    Nejadnik, Hossein; Ye, Deju; Lenkov, Olga D.; Donig, Jessica; Martin, John E.; Castillo, Rostislav; Derugin, Nikita; Sennino, Barbara; Rao, Jianghong; Daldrup-Link, Heike E.

    2015-01-01

    About 43 million individuals in the U.S. encounter cartilage injuries due to trauma or osteoarthritis, leading to joint pain and functional disability. Matrix associated stem cell implants (MASI) represent a promising approach for repair of cartilage defects. However, limited survival of MASI creates a significant bottleneck for successful cartilage regeneration outcomes and functional reconstitution. We report a new approach for non-invasive detection of stem cell apoptosis with MR imaging, based on a caspase-3 sensitive nano-aggregation MRI probe (C-SNAM). C-SNAM self-assembles into nanoparticles after hydrolysis by caspase-3, leading to 90% amplification of 1H MR and prolonged in vivo retention. Following intra-articular injection, C-SNAM causes significant MR signal enhancement in apoptotic MASI compared to viable MASI. Our results indicate that C-SNAM functions as an imaging biomarker for stem cell apoptosis in MASI. This concept could be applied to a broad range of cell transplants and target sites. PMID:25597243

  14. Magnetic resonance imaging of organic contrast agents in mice: capturing the whole-body redox landscape

    PubMed Central

    Davis, Ryan M.; Matsumoto, Shingo; Bernardo, Marcelino; Sowers, Anastasia; Matsumoto, Ken-Ichiro; Krishna, Murali C.; Mitchell, James B.

    2010-01-01

    Nitroxides are a class of stable free radicals that have several biomedical applications including radioprotection and non-invasive assessment of tissue redox status. For both of these applications, it is necessary to understand the in vivo biodistribution and reduction of nitroxides. In this study, magnetic resonance imaging was used to compare tissue accumulation (concentration) and reduction of two commonly studied nitroxides: the piperidine nitroxide Tempol and the pyrrolidine nitroxide 3-CP. It was found that 3-CP is reduced three to eleven times slower (depending on the tissue) than Tempol in vivo, and that maximum tissue concentration varies substantially between tissues (0.6 mM – 7.2 mM.) For a given tissue, the maximum concentration usually did not vary between the two nitroxides. Furthermore, using electron paramagnetic resonance (EPR) spectroscopy, it was shown that the nitroxide reduction rate depends only weakly on cellular pO2 in the oxygen range expected in vivo. These observations, taken with the marked variation in nitroxide reduction rates observed between tissues, suggest that tissue pO2 is not a major determinant of the nitroxide reduction rate in vivo. For the purpose of redox imaging, 3-CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo. PMID:21130158

  15. In Vitro Longitudinal Relaxivity Profile of Gd(ABE-DTTA), an Investigational Magnetic Resonance Imaging Contrast Agent

    PubMed Central

    Varga-Szemes, Akos; Kiss, Pal; Rab, Andras; Suranyi, Pal; Lenkey, Zsofia; Simor, Tamas; Bryant, Robert G.; Elgavish, Gabriel A.

    2016-01-01

    Purpose MRI contrast agents (CA) whose contrast enhancement remains relatively high even at the higher end of the magnetic field strength range would be desirable. The purpose of this work was to demonstrate such a desired magnetic field dependency of the longitudinal relaxivity for an experimental MRI CA, Gd(ABE-DTTA). Materials and Methods The relaxivity of 0.5mM and 1mM Gd(ABE-DTTA) was measured by Nuclear Magnetic Relaxation Dispersion (NMRD) in the range of 0.0002 to 1T. Two MRI and five NMR instruments were used to cover the range between 1.5 to 20T. Parallel measurement of a Gd-DTPA sample was performed throughout as reference. All measurements were carried out at 37°C and pH 7.4. Results The relaxivity values of 0.5mM and 1mM Gd(ABE-DTTA) measured at 1.5, 3, and 7T, within the presently clinically relevant magnetic field range, were 15.3, 11.8, 12.4 s-1mM-1 and 18.1, 16.7, and 13.5 s-1mM-1, respectively. The control 4 mM Gd-DTPA relaxivities at the same magnetic fields were 3.6, 3.3, and 3.0 s-1mM-1, respectively. Conclusions The longitudinal relaxivity of Gd(ABE-DTTA) measured within the presently clinically relevant field range is three to five times higher than that of most commercially available agents. Thus, Gd(ABE-DTTA) could be a practical choice at any field strength currently used in clinical imaging including those at the higher end. PMID:26872055

  16. Dual-Energy Computed Tomography Arthrography of the Shoulder Joint Using Virtual Monochromatic Spectral Imaging: Optimal Dose of Contrast Agent and Monochromatic Energy Level

    PubMed Central

    An, Chansik; Chun, Yong-Min; Kim, Sungjun; Lee, Young Han; Yun, Min Jeong; Suh, Jin-Suck

    2014-01-01

    Objective To optimize the dose of contrast agent and the level of energy for dual-energy computed tomography (DECT) arthrography of the shoulder joint and to evaluate the benefits of the optimized imaging protocol. Materials and Methods Dual-energy scans with monochromatic spectral imaging mode and conventional single energy scans were performed on a shoulder phantom with 10 concentrations from 0 to 210 mg/mL of iodinated contrast medium at intervals of 15 or 30 mg/mL. Image noise, tissue contrast, and beam hardening artifacts were assessed to determine the optimum dose of contrast agent and the level of monochromatic energy for DECT shoulder arthrography in terms of the lowest image noise and the least beam hardening artifacts while good tissue contrast was maintained. Material decomposition (MD) imaging for bone-iodine differentiation was qualitatively assessed. The optimized protocol was applied and evaluated in 23 patients. Results The optimal contrast dose and energy level were determined by the phantom study at 60 mg/mL and 72 keV, respectively. This optimized protocol for human study reduced the image noise and the beam-hardening artifacts by 35.9% and 44.5%, respectively. Bone-iodine differentiation by MD imaging was not affected by the iodine concentration or level of energy. Conclusion Dual-energy scan with monochromatic spectral imaging mode results in reduced image noise and beam hardening artifacts. PMID:25469086

  17. Poly(acrylic acid) Bridged Gadolinium Metal-Organic Framework-Gold Nanoparticle Composites as Contrast Agents for Computed Tomography and Magnetic Resonance Bimodal Imaging

    PubMed Central

    Tian, Chixia; Zhu, Liping; Lin, Feng; Boyes, Stephen G.

    2015-01-01

    Imaging contrast agents for magnetic resonance imaging (MRI) and computed tomography (CT) have received significant attention in the development of techniques for early-stage cancer diagnosis. Gadolinium (Gd) (III), which has seven unpaired electrons and a large magnetic moment, can dramatically influence the water proton relaxation and hence exhibits excellent MRI contrast. On the other hand, gold (Au), which has a high atomic number and high x-ray attenuation coefficient, is an ideal contrast agent candidate for x-ray based CT imaging. Gd metal organic framework (MOF) nanoparticles with tunable size, high Gd (III) loading and multivalency can potentially overcome the limitations of clinically utilized Gd chelate contrast agents. In this work, we report for the first time the integration of GdMOF nanoparticles with gold nanoparticles (AuNPs) for the preparation of a MRI/CT bimodal imaging agent. Highly stable hybrid GdMOF/AuNPs composites have been prepared by using poly(acrylic acid) as a bridge between the GdMOF nanoparticles and AuNPs. The hybrid nanocomposites were then evaluated in MRI and CT imaging. The results revealed high longitudinal relaxivity in MRI and excellent CT imaging performance. Therefore, these GdMOF/AuNPs hybrid nanocomposites potentially provide a new platform for the development of multi-modal imaging probes. PMID:26147906

  18. PLGA/PFC particles loaded with gold nanoparticles as dual contrast agents for photoacoustic and ultrasound imaging

    NASA Astrophysics Data System (ADS)

    Wang, Yan J.; Strohm, Eric M.; Sun, Yang; Niu, Chengcheng; Zheng, Yuanyi; Wang, Zhigang; Kolios, Michael C.

    2014-03-01

    Phase-change contrast agents consisting of a perfluorocarbon (PFC) liquid core stabilized by a lipid, protein, or polymer shell have been proposed for a variety of clinical applications. Previous work has demonstrated that vaporization can be induced by laser irradiation through optical absorbers incorporated inside the droplet. In this study, Poly-lactide-coglycolic acid (PLGA) particles loaded with PFC liquid and silica-coated gold nanoparticles (GNPs) were developed and characterized using photoacoustic (PA) methods. Microsized PLGA particles were loaded with PFC liquid and GNPs (14, 35, 55nm each with a 20nm silica shell) using a double emulsion method. The PA signal intensity and optical vaporization threshold were investigated using a 375 MHz transducer and a focused 532-nm laser (up to 450-nJ per pulse). The laser-induced vaporization threshold energy decreased with increasing GNP size. The vaporization threshold was 850, 690 and 420 mJ/cm2 for 5μm-sized PLGA particles loaded with 14, 35 and 55 nm GNPs, respectively. The PA signal intensity increased as the laser fluence increased prior to the vaporization event. This trend was observed for all particles sizes. PLGA particles were then incubated with MDA-MB-231 breast cancer cells for 6 hours to investigate passive targeting, and the vaporization of the PLGA particles that were internalized within cells. The PLGA particles passively internalized by MDA cells were visualized via confocal fluorescence imaging. Upon PLGA particle vaporization, bubbles formed inside the cells resulting in cell destruction. This work demonstrates that GNPs-loaded PLGA/PFC particles have potential as PA theranostic agents in PA imaging and optically-triggered drug delivery systems.

  19. Targeting and in vivo imaging of non-small-cell lung cancer using nebulized multimodal contrast agents.

    PubMed

    Bianchi, Andrea; Dufort, Sandrine; Lux, François; Fortin, Pierre-Yves; Tassali, Nawal; Tillement, Olivier; Coll, Jean-Luc; Crémillieux, Yannick

    2014-06-24

    One of the main reasons for the dismal prognosis of lung cancer is related to the late diagnosis of this pathology. In this work, we evaluated the potential of optimized lung MRI techniques and nebulized ultrasmall multimodal gadolinium-based contrast agents [ultrasmall rigid platforms (USRPs)] as a completely noninvasive approach for non-small-cell lung cancer (NSCLC) in vivo detection. A mouse model of NSCLC expressing the luciferase gene was developed. Ultrashort echo-time free-breathing MRI acquisitions were performed before and after i.v. or intrapulmonary administration of the nanoparticles to identify and segment the tumor. After orotracheal or i.v. administration of USRPs, an excellent colocalization of the position the tumor with MRI, bioluminescence and fluorescence reflectance imaging, and histology was observed in all mice. Significantly higher signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using lower doses, reducing the toxicity issues and the interobserver variability in tumor detection. The observations suggested the existence of an unknown original mechanism (different from the enhanced permeability and retention effect) responsible for this phenomenon. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify, and longitudinally monitor the development of submillimetric NSCLCs. The absence of ionizing radiation and high resolution MRI, along with the complete noninvasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge this is the first time that the advantages of an orotracheal administration route are demonstrated for the investigation of the pathomorphological changes due to NSCLCs. PMID:24927562

  20. PEGylated NaHoF4 nanoparticles as contrast agents for both X-ray computed tomography and ultra-high field magnetic resonance imaging.

    PubMed

    Ni, Dalong; Zhang, Jiawen; Bu, Wenbo; Zhang, Chen; Yao, Zhenwei; Xing, Huaiyong; Wang, Jing; Duan, Fei; Liu, Yanyan; Fan, Wenpei; Feng, Xiaoyuan; Shi, Jianlin

    2016-01-01

    It is well-known that multimodal imaging can integrate the advantages of different imaging modalities by overcoming their individual limitations. As ultra-high field magnetic resonance imaging (MRI) will be inevitably used in future MRI/X-ray computed tomography (CT) scanner, it is highly expected to develop high-performance nano-contrast agents for ultra-high field MR and CT dual-modality imaging, which has not been reported yet. Moreover, specific behavior of nano-contrast agents for ultra-high field MRI is a challenging work and still remains unknown. Herein, a novel type of NaHoF4 nanoparticles (NPs) with varied particle sizes were synthesized and explored as high-performance dual-modality contrast agents for ultra-high field MR and CT imaging. The specific X-ray absorption and MR relaxivity enhancements with varied nanoparticle diameters (3 nm, 7 nm, 13 nm and 29 nm) under different magnetic field (1.5/3.0/7.0 T) are investigated. Based on experimental results and theoretical analysis, the Curie and dipolar relaxation mechanisms of NaHoF4 NPs are firstly separated. Our results will greatly promote the future medical translational development of the NaHoF4 nano-contrast agents for ultra-high field MR/CT dual-modality imaging applications. PMID:26546914

  1. Self-assembled dual-modality contrast agents for non-invasive stem cell tracking via near-infrared fluorescence and magnetic resonance imaging.

    PubMed

    Liu, Hong; Tan, Yan; Xie, Lisi; Yang, Lei; Zhao, Jing; Bai, Jingxuan; Huang, Ping; Zhan, Wugen; Wan, Qian; Zou, Chao; Han, Yali; Wang, Zhiyong

    2016-09-15

    Stem cells hold great promise for treating various diseases. However, one of the main drawbacks of stem cell therapy is the lack of non-invasive image-tracking technologies. Although magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging have been employed to analyse cellular and subcellular events via the assistance of contrast agents, the sensitivity and temporal resolution of MRI and the spatial resolution of NIRF are still shortcomings. In this study, superparamagnetic iron oxide nanocrystals and IR-780 dyes were co-encapsulated in stearic acid-modified polyethylenimine to form a dual-modality contrast agent with nano-size and positive charge. These resulting agents efficiently labelled stem cells and did not influence the cellular viability and differentiation. Moreover, the labelled cells showed the advantages of dual-modality imaging in vivo. PMID:27299677

  2. Lanthanide Oleates: Chelation, Self-assembly, and Exemplification of Ordered Nanostructured Colloidal Contrast Agents for Medical Imaging

    SciTech Connect

    Liu, Guozhen; Conn, Charlotte E.; Drummond, Calum J.

    2010-01-12

    Eight lanthanide(III) oleates have been prepared and characterized. The chelation and self-assembly structures of these rare-earth oleates have been studied by elemental analysis, Fourier transfer infrared spectroscopy (FTIR), and X-ray powder diffraction (XRD) analysis. Elemental analysis and FTIR results indicate that three oleate anions are complexed with one lanthanide cation and, with the exception of anhydrous cerium(III) oleate, form either a mono- or a hemihydrate. The X-ray analysis showed that the neat lanthanide soaps have a lamellar bilayer structure at room temperature. The thermal behavior has been investigated by cross-polarized optical microscopy (POM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). POM scans showed that all the lanthanide oleates form a lamellar phase in the presence of excess water. Small-angle X-ray scattering (SAXS) and XRD were used to investigate the internal structure of the bulk lanthanide oleates in excess water, and these X-ray results confirmed that the lanthanide oleates do not swell in water. Select lanthanide oleates were dispersed in water to form nonswelling lamellar submicrometer particles, confirmed by dynamic light scattering (DLS) and synchrotron SAXS measurements. NMR results indicated that colloidal dispersions of lanthanide oleates containing paramagnetic ions, such as gadolinium(III), terbium(III), and dysprosium(III), have a significant effect on the longitudinal (T{sub 1}) and transverse (T{sub 2}) relaxation times of protons in water. Time-resolved fluorescence measurements have demonstrated that colloidal dispersions of europium(III) oleate exhibit strong luminescence. The rare earth metal soaps exemplify the potential of self-assembled chelating amphiphiles as contrast agents in medical imaging modalities such as magnetic resonance imaging (MRI) and fluorescence imaging.

  3. Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS)

    PubMed Central

    Huang, Yuegao; Coman, Daniel; Hyder, Fahmeed; Ali, Meser M.

    2016-01-01

    Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA4−) complexed with thulium ion (Tm3+). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA−)x (where n = 1–4, x = 6–39) were comparable to that of prominent signals in TmDOTA−. Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA−)x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA−. A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors. PMID:26497087

  4. Dendrimer-Based Responsive MRI Contrast Agents (G1-G4) for Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

    PubMed

    Huang, Yuegao; Coman, Daniel; Hyder, Fahmeed; Ali, Meser M

    2015-12-16

    Biosensor imaging of redundant deviation in shifts (BIRDS) is a molecular imaging platform for magnetic resonance that utilizes unique properties of low molecular weight paramagnetic monomers by detecting hyperfine-shifted nonexchangeable protons and transforming the chemical shift information to reflect its microenvironment (e.g., via temperature, pH, etc.). To optimize translational biosensing potential of BIRDS we examined if this detection scheme observed with monomers can be extended onto dendrimers, which are versatile and biocompatible macromolecules with modifiable surface for molecular imaging and drug delivery. Here we report on feasibility of paramagnetic dendrimers for BIRDS. The results show that BIRDS is resilient with paramagnetic dendrimers up to the fourth generation (i.e., G1-G4), where the model dendrimer and chelate were based on poly(amido amine) (PAMAM) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(4-)) complexed with thulium ion (Tm(3+)). Temperature sensitivities of two prominent signals of Gn-PAMAM-(TmDOTA(-))x (where n = 1-4, x = 6-39) were comparable to that of prominent signals in TmDOTA(-). Transverse relaxation times of the coalesced nonexchangeable protons on Gn-PAMAM-(TmDOTA(-))x were relatively short to provide signal-to-noise ratio that was comparable to or better than that of TmDOTA(-). A fluorescent dye, rhodamine, was conjugated to a G2-PAMAM-(TmDOTA)12 to create a dual-modality nanosized contrast agent. BIRDS properties of the dendrimer were unaltered with rhodamine conjugation. Purposely designed paramagnetic dendrimers for BIRDS in conjunction with novel macromolecular surface modification for functional ligands/drugs could potentially be used for biologically compatible theranostic sensors. PMID:26497087

  5. Lanthanide oleates: chelation, self-assembly, and exemplification of ordered nanostructured colloidal contrast agents for medical imaging.

    PubMed

    Liu, Guozhen; Conn, Charlotte E; Drummond, Calum J

    2009-12-10

    Eight lanthanide(III) oleates have been prepared and characterized. The chelation and self-assembly structures of these rare-earth oleates have been studied by elemental analysis, Fourier transfer infrared spectroscopy (FTIR), and X-ray powder diffraction (XRD) analysis. Elemental analysis and FTIR results indicate that three oleate anions are complexed with one lanthanide cation and, with the exception of anhydrous cerium(III) oleate, form either a mono- or a hemihydrate. The X-ray analysis showed that the neat lanthanide soaps have a lamellar bilayer structure at room temperature. The thermal behavior has been investigated by cross-polarized optical microscopy (POM), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). POM scans showed that all the lanthanide oleates form a lamellar phase in the presence of excess water. Small-angle X-ray scattering (SAXS) and XRD were used to investigate the internal structure of the bulk lanthanide oleates in excess water, and these X-ray results confirmed that the lanthanide oleates do not swell in water. Select lanthanide oleates were dispersed in water to form nonswelling lamellar submicrometer particles, confirmed by dynamic light scattering (DLS) and synchrotron SAXS measurements. NMR results indicated that colloidal dispersions of lanthanide oleates containing paramagnetic ions, such as gadolinium(III), terbium(III), and dysprosium(III), have a significant effect on the longitudinal (T(1)) and transverse (T(2)) relaxation times of protons in water. Time-resolved fluorescence measurements have demonstrated that colloidal dispersions of europium(III) oleate exhibit strong luminescence. The rare earth metal soaps exemplify the potential of self-assembled chelating amphiphiles as contrast agents in medical imaging modalities such as magnetic resonance imaging (MRI) and fluorescence imaging. PMID:19904961

  6. Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle

    PubMed Central

    Hindel, Stefan; Sauerbrey, Anika; Maaß, Marc; Maderwald, Stefan; Schlamann, Marc; Lüdemann, Lutz

    2015-01-01

    The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the

  7. Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle.

    PubMed

    Hindel, Stefan; Sauerbrey, Anika; Maaß, Marc; Maderwald, Stefan; Schlamann, Marc; Lüdemann, Lutz

    2015-01-01

    The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the

  8. Dual-mode T1 and T2 magnetic resonance imaging contrast agent based on ultrasmall mixed gadolinium-dysprosium oxide nanoparticles: synthesis, characterization, and in vivo application.

    PubMed

    Tegafaw, Tirusew; Xu, Wenlong; Ahmad, Md Wasi; Baeck, Jong Su; Chang, Yongmin; Bae, Ji Eun; Chae, Kwon Seok; Kim, Tae Jeong; Lee, Gang Ho

    2015-09-11

    A new type of dual-mode T1 and T2 magnetic resonance imaging (MRI) contrast agent based on mixed lanthanide oxide nanoparticles was synthesized. Gd(3+) ((8)S7/2) plays an important role in T1 MRI contrast agents because of its large electron spin magnetic moment resulting from its seven unpaired 4f-electrons, and Dy(3+) ((6)H15/2) has the potential to be used in T2 MRI contrast agents because of its very large total electron magnetic moment: among lanthanide oxide nanoparticles, Dy2O3 nanoparticles have the largest magnetic moments at room temperature. Using these properties of Gd(3+) and Dy(3+) and their oxide nanoparticles, ultrasmall mixed gadolinium-dysprosium oxide (GDO) nanoparticles were synthesized and their potential to act as a dual-mode T1 and T2 MRI contrast agent was investigated in vitro and in vivo. The D-glucuronic acid coated GDO nanoparticles (davg = 1.0 nm) showed large r1 and r2 values (r2/r1 ≈ 6.6) and as a result clear dose-dependent contrast enhancements in R1 and R2 map images. Finally, the dual-mode imaging capability of the nanoparticles was confirmed by obtaining in vivo T1 and T2 MR images. PMID:26291827

  9. Rare-Earth Doped Particles as Dual-Modality Contrast Agent for Minimally-Invasive Luminescence and Dual-Wavelength Photoacoustic Imaging

    NASA Astrophysics Data System (ADS)

    Sheng, Yang; Liao, Lun-De; Thakor, Nitish; Tan, Mei Chee

    2014-10-01

    Multi-modal imaging is an emerging area that integrates multiple imaging modalities to simultaneously capture visual information over many spatial scales. Complementary contrast agents need to be co-developed in order to achieve high resolution and contrast. In this work, we demonstrated that rare-earth doped particles (REDPs) can be employed as dual-modal imaging agents for both luminescence and photoacoustic (PA) imaging to achieve intrinsic high contrast, temporal and spatial resolution, reaching deeper depth. REDPs synthesized with different surfactants (citric acid, polyacrylic acid, ethylenediaminetetraacetic acid and sodium citrate) exhibit tunable emission properties and PA signal amplitudes. Amongst these samples, sodium citrate-modified REDPs showed the strongest PA signals. Furthermore, since REDPs have multiple absorption peaks, they offer a unique opportunity for multi-wavelength PA imaging (e.g. PA signals were measured using 520 and 975 nm excitations). The in vivo PA images around the cortical superior sagittal sinus (SSS) blood vessel captured with enhanced signal arising from REDPs demonstrated that in addition to be excellent luminescent probes, REDPs can also be used as successful PA contrast agents. Anisotropic polyacrylic acid-modified REDPs were found to be the best candidates for dual-modal luminescence and PA imaging due to their strong luminescence and PA signal intensities.

  10. Rare-Earth Doped Particles as Dual-Modality Contrast Agent for Minimally-Invasive Luminescence and Dual-Wavelength Photoacoustic Imaging

    PubMed Central

    Sheng, Yang; Liao, Lun-De; Thakor, Nitish; Tan, Mei Chee

    2014-01-01

    Multi-modal imaging is an emerging area that integrates multiple imaging modalities to simultaneously capture visual information over many spatial scales. Complementary contrast agents need to be co-developed in order to achieve high resolution and contrast. In this work, we demonstrated that rare-earth doped particles (REDPs) can be employed as dual-modal imaging agents for both luminescence and photoacoustic (PA) imaging to achieve intrinsic high contrast, temporal and spatial resolution, reaching deeper depth. REDPs synthesized with different surfactants (citric acid, polyacrylic acid, ethylenediaminetetraacetic acid and sodium citrate) exhibit tunable emission properties and PA signal amplitudes. Amongst these samples, sodium citrate-modified REDPs showed the strongest PA signals. Furthermore, since REDPs have multiple absorption peaks, they offer a unique opportunity for multi-wavelength PA imaging (e.g. PA signals were measured using 520 and 975 nm excitations). The in vivo PA images around the cortical superior sagittal sinus (SSS) blood vessel captured with enhanced signal arising from REDPs demonstrated that in addition to be excellent luminescent probes, REDPs can also be used as successful PA contrast agents. Anisotropic polyacrylic acid-modified REDPs were found to be the best candidates for dual-modal luminescence and PA imaging due to their strong luminescence and PA signal intensities. PMID:25297843