Showing papers by "Xiaoyuan Chen published in 2007"

In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice

Abstract: Single-walled carbon nanotubes (SWNTs) exhibit unique size, shape and physical properties1,2,3 that make them promising candidates for biological applications. Here, we investigate the biodistribution of radio-labelled SWNTs in mice by in vivo positron emission tomography (PET), ex vivo biodistribution and Raman spectroscopy. It is found that SWNTs that are functionalized with phospholipids bearing polyethylene-glycol (PEG) are surprisingly stable in vivo. The effect of PEG chain length on the biodistribution and circulation of the SWNTs is studied. Effectively PEGylated SWNTs exhibit relatively long blood circulation times and low uptake by the reticuloendothelial system (RES). Efficient targeting of integrin positive tumour in mice is achieved with SWNTs coated with PEG chains linked to an arginine–glycine–aspartic acid (RGD) peptide. A high tumour accumulation is attributed to the multivalent effect of the SWNTs. The Raman signatures of SWNTs are used to directly probe the presence of nanotubes in mice tissues and confirm the radio-label-based results.

Nanoplatforms for targeted molecular imaging in living subjects.

Abstract: Molecular or personalized medicine is the future of patient management and molecular imaging plays a key role towards this goal. Recently, nanoplatform-based molecular imaging has emerged as an interdisciplinary field, which involves chemistry, engineering, biology, and medicine. Possessing unprecedented potential for early detection, accurate diagnosis, and personalized treatment of diseases, nanoplatforms have been employed in every single biomedical imaging modality, namely, optical imaging, computed tomography, ultrasound, magnetic resonance imaging, single-photon-emission computed tomography, and positron emission tomography. Multifunctionality is the key advantage of nanoplatforms over traditional approaches. Targeting ligands, imaging labels, therapeutic drugs, and many other agents can all be integrated into the nanoplatform to allow for targeted molecular imaging and molecular therapy by encompassing many biological and biophysical barriers. In this Review, we will summarize the current state-of-the-art of nanoplatforms for targeted molecular imaging in living subjects.

Dual-Function Probe for PET and Near-Infrared Fluorescence Imaging of Tumor Vasculature

Abstract: To date, the in vivo imaging of quantum dots (QDs) has been mostly qualitative or semiquantitative. The development of a dual-function PET/near-infrared fluorescence (NIRF) probe can allow for accurate assessment of the pharmacokinetics and tumor-targeting efficacy of QDs. Methods: A QD with an amine-functionalized surface was modified with RGD peptides and 1,4,7,10-tetraazacyclodocecane-N,N′,N″,N‴-tetraacetic acid (DOTA) chelators for integrin αvβ3–targeted PET/NIRF imaging. A cell-binding assay and fluorescence cell staining were performed with U87MG human glioblastoma cells (integrin αvβ3–positive). PET/NIRF imaging, tissue homogenate fluorescence measurement, and immunofluorescence staining were performed with U87MG tumor–bearing mice to quantify the probe uptake in the tumor and major organs. Results: There are about 90 RGD peptides per QD particle, and DOTA–QD–RGD exhibited integrin αvβ3–specific binding in cell cultures. The U87MG tumor uptake of 64Cu-labeled DOTA–QD was less than 1 percentage injected dose per gram (%ID/g), significantly lower than that of 64Cu-labeled DOTA–QD–RGD (2.2 ± 0.3 [mean ± SD] and 4.0 ± 1.0 %ID/g at 5 and 18 h after injection, respectively; n = 3). Taking into account all measurements, the liver-, spleen-, and kidney-to-muscle ratios for 64Cu-labeled DOTA–QD–RGD were about 100:1, 40:1, and 1:1, respectively. On the basis of the PET results, the U87MG tumor-to-muscle ratios for DOTA–QD–RGD and DOTA–QD were about 4:1 and 1:1, respectively. Excellent linear correlation was obtained between the results measured by in vivo PET imaging and those measured by ex vivo NIRF imaging and tissue homogenate fluorescence (r2 = 0.93). Histologic examination revealed that DOTA–QD–RGD targets primarily the tumor vasculature through an RGD–integrin αvβ3 interaction, with little extravasation. Conclusion: We quantitatively evaluated the tumor-targeting efficacy of a dual-function QD-based probe with PET and NIRF imaging. This dual-function probe has significantly reduced potential toxicity and overcomes the tissue penetration limitation of optical imaging, allowing for quantitative targeted imaging in deep tissue.

64Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor αvβ3 integrin expression

Abstract: Integrin αvβ3 plays a critical role in tumor angiogenesis and metastasis. Suitably radiolabeled cyclic arginine-glycine-aspartic (RGD) peptides can be used for noninvasive imaging of αvβ3 expression and targeted radionuclide therapy. In this study, we developed 64Cu-labeled multimeric RGD peptides, E{E[c(RGDyK)]2}2 (RGD tetramer) and E(E{E[c(RGDyK)]2}2)2 (RGD octamer), for PET imaging of tumor integrin αvβ3 expression. Methods: Both RGD tetramer and RGD octamer were synthesized with glutamate as the linker. After conjugation with 1,4,7,10-tetra-azacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA), the peptides were labeled with 64Cu for biodistribution and small-animal PET imaging studies (U87MG human glioblastoma xenograft model and c-neu oncomouse model). A cell adhesion assay, a cell-binding assay, receptor blocking experiments, and immunohistochemistry were also performed to evaluate the αvβ3-binding affinity/specificity of the RGD peptide-based conjugates in vitro and in vivo. Results: RGD octamer had significantly higher integrin αvβ3-binding affinity and specificity than RGD tetramer analog (inhibitory concentration of 50% was 10 nM for octamer vs. 35 nM for tetramer). 64Cu-DOTA-RGD octamer had higher tumor uptake and longer tumor retention than 64Cu-DOTA-RGD tetramer in both tumor models tested. The integrin αvβ3 specificity of both tracers was confirmed by successful receptor-blocking experiments. The high uptake and slow clearance of 64Cu-DOTA-RGD octamer in the kidneys was attributed mainly to the integrin positivity of the kidneys, significantly higher integrin αvβ3-binding affinity, and the larger molecular size of the octamer, as compared with the other RGD analogs. Conclusion: Polyvalency has a profound effect on the receptor-binding affinity and in vivo kinetics of radiolabeled RGD multimers. The information obtained here may guide the future development of RGD peptide-based imaging and internal radiotherapeutic agents targeting integrin αvβ3.

Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody

Abstract: Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab. We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA), labeled with 64Cu, and tested the resulting 64Cu-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated. MicroPET imaging showed that 64Cu-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined (<5%ID/g). There was a good correlation (R 2 = 0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver. The success of EGFR-positive tumor imaging using 64Cu-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents.

microPET-Based Biodistribution of Quantum Dots in Living Mice

Abstract: This study evaluates the quantitative biodistribution of commercially available CdSe quantum dots (QD) in mice. Methods: 64Cu-Labeled 800- or 525-nm emission wavelength QD (21- or 12-nm diameter), with or without 2,000 MW (molecular weight) polyethylene glycol (PEG), were injected intravenously into mice (5.55 MBq/25 pmol QD) and studied using well counting or by serial microPET and region-of-interest analysis. Results: Both methods show rapid uptake by the liver (27.4–38.9 %ID/ g) (%ID/g is percentage injected dose per gram tissue) and spleen (8.0–12.4 %ID/g). Size has no influence on biodistribution within the range tested here. Pegylated QD have slightly slower uptake into liver and spleen (6 vs. 2 min) and show additional low-level bone uptake (6.5–6.9 %ID/g). No evidence of clearance from these organs was observed.Conclusion: Rapid reticuloendothelial system clearance of QD will require modification of QD for optimal utility in imaging living subjects. Formal quantitative biodistribution/imaging studies will be helpful in studying many types of nanoparticles, including quantum dots.

Are quantum dots ready for in vivo imaging in human subjects

Abstract: Nanotechnology has the potential to profoundly transform the nature of cancer diagnosis and cancer patient management in the future. Over the past decade, quantum dots (QDs) have become one of the fastest growing areas of research in nanotechnology. QDs are fluorescent semiconductor nanoparticles suitable for multiplexed in vitro and in vivo imaging. Numerous studies on QDs have resulted in major advancements in QD surface modification, coating, biocompatibility, sensitivity, multiplexing, targeting specificity, as well as important findings regarding toxicity and applicability. For in vitro applications, QDs can be used in place of traditional organic fluorescent dyes in virtually any system, outperforming organic dyes in the majority of cases. In vivo targeted tumor imaging with biocompatible QDs has recently become possible in mouse models. With new advances in QD technology such as bioluminescence resonance energy transfer, synthesis of smaller size non-Cd based QDs, improved surface coating and conjugation, and multifunctional probes for multimodality imaging, it is likely that human applications of QDs will soon be possible in a clinical setting.

microPET of Tumor Integrin αvβ3 Expression Using 18F-Labeled PEGylated Tetrameric RGD Peptide (18F-FPRGD4)

Abstract: In vivo imaging of αvβ3 expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin αvβ3–binding affinity due to the polyvalency effect. Here we report an example of 18F-labeled tetrameric RGD peptide for PET of αvβ3 expression in both xenograft and spontaneous tumor models. Methods: The tetrameric RGD peptide E{E[c(RGDyK)]2}2 was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate α-amino group. NH2-mini-PEG-E{E[c(RGDyK)]2}2 (PRGD4) was labeled with 18F via the N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer 18F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. Results: The decay-corrected radiochemical yield for 18F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from 18F-F−. The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. 18F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of 18F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). Conclusion: The tetrameric RGD peptide tracer 18F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin αvβ3 expression in cancer and other angiogenesis related diseases.

PET Imaging of Colorectal Cancer in Xenograft-Bearing Mice by Use of an 18F-Labeled T84.66 Anti–Carcinoembryonic Antigen Diabody

Abstract: In this study, we investigated the 18F-labeled anti–carcinoembryonic antigen (CEA) T84.66 diabody, a genetically engineered noncovalent dimer of single-chain variable fragments, for small-animal PET imaging of CEA expression in xenograft-bearing mice. Methods:18F labeling of the anti-CEA T84.66 diabody (molecular mass, 55 kDa) was achieved with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB). The biodistribution of the 18F-fluorobenzyl-T84.66 diabody (18F-FB-T84.66 diabody) was evaluated in athymic nude mice bearing subcutaneous LS 174T human colon carcinoma and C6 rat glioma tumors. Serial small-animal PET imaging studies were performed to further evaluate in vivo targeting efficacy and pharmacokinetics. Results: Radiolabeling required 35 ± 5 (mean ± SD) min starting from 18F-SFB, and the tracer 18F-FB-T84.66 diabody was synthesized with a specific activity of 1.83 ± 1.71 TBq/mmol. The decay-corrected radiochemical yield was 1.40% ± 0.16% (n = 4), and the radiochemical purity was greater than 98%. The radioimmunoreactivity was 57.1% ± 2.0%. The 18F-FB-T84.66 diabody showed rapid and high tumor uptake and fast clearance from the circulation in the LS 174T xenograft model, as evidenced by both small-animal PET imaging and biodistribution studies. High-contrast small-animal PET images were obtained as early as 1 h after injection of the 18F-FB-T84.66 diabody, and only a background level of activity accumulation was found in CEA-negative C6 tumors. The tracer exhibited predominantly renal clearance, with some activity in the liver and spleen at early time points. Conclusion: The 18F-labeled diabody represents a new class of tumor-specific probes for PET that are based on targeting cell surface antigen expression. The 18F-FB-T84.66 diabody can be used for high-contrast small-animal PET imaging of CEA-positive tumor xenografts. It may be translated to the clinic for PET of CEA-positive malignancies.

A new PET tracer specific for vascular endothelial growth factor receptor 2.

Abstract: Noninvasive positron emission tomography (PET) imaging of vascular endothelial growth factor receptor 2 (VEGFR-2) expression could be a valuable tool for evaluation of patients with a variety of malignancies, and particularly for monitoring those undergoing antiangiogenic therapies that block VEGF/VEGFR-2 function. The aim of this study was to develop a VEGFR-2-specific PET tracer. The D63AE64AE67A mutant of VEGF121 (VEGFDEE) was generated by recombinant DNA technology. VEGF121 and VEGFDEE were purified and conjugated with DOTA for 64Cu labeling. The DOTA conjugates were tested in vitro for VEGFR-2 specificity and functional activity. In vivo tumor targeting efficacy and pharmacokinetics of 64Cu-labeled VEGF121 and VEGFDEE were compared using an orthotopic 4T1 murine breast tumor model. Blocking experiments, biodistribution studies, and immunofluorescence staining were carried out to confirm the noninvasive imaging results. Cell binding assay demonstrated that VEGFDEE had about 20-fold lower VEGFR-1 binding affinity and only slightly lower VEGFR-2 binding affinity as compared with VEGF121. MicroPET imaging studies revealed that both 64Cu-DOTA-VEGF121 and 64Cu-DOTA-VEGFDEE had rapid and prominent activity accumulation in VEGFR-2-expressing 4T1 tumors. The renal uptake of 64Cu-DOTA-VEGFDEE was significantly lower than that of 64Cu-DOTA-VEGF121 as rodent kidneys expressed high levels of VEGFR-1 based on immunofluorescence staining. Blocking experiments and biodistribution studies confirmed the VEGFR specificity of 64Cu-DOTA-VEGFDEE. We have developed a VEGFR-2-specific PET tracer, 64Cu-DOTA-VEGFDEE. It has comparable tumor targeting efficacy to 64Cu-DOTA-VEGF121 but much reduced renal toxicity. This tracer may be translated into the clinic for imaging tumor angiogenesis and monitoring antiangiogenic treatment efficacy.

18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2): synthesis and microPET imaging of αvβ3 integrin expression

Abstract: Purpose We have previously reported that 18F-FB-E[c(RGDyK)]2 (18F-FRGD2) allows quantitative PET imaging of integrin αvβ3 expression. However, the potential clinical translation was hampered by the relatively low radiochemical yield. The goal of this study was to improve the radiolabeling yield, without compromising the tumor targeting efficiency and in vivo kinetics, by incorporating a hydrophilic bifunctional mini-PEG spacer.

Multimodality Molecular Imaging of Glioblastoma Growth Inhibition with Vasculature-Targeting Fusion Toxin VEGF121/rGel

Abstract: Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF121/rGel) composed of the VEGF-A isoform VEGF121 linked with a G4S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET. Methods: Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with 64Cu-1,4,7,10-tetraazacyclododedane-N,N′,N″,N‴-tetraacetic acid (DOTA)-VEGF121/rGel was performed before VEGF121/rGel treatment. 18F-Fluorothymidine (18F-FLT) scans were obtained before and after treatment to evaluate VEGF121/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses. Results: Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with 64Cu-DOTA-VEGF121/rGel before treatment revealed a tumor accumulation (mean ± SD) of 11.8 ± 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF121. PET with 18F-FLT revealed significant a decrease in tumor proliferation in VEGF121/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF121/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity. Conclusion: The results of this study suggest that future clinical multimodality imaging and therapy with VEGF121/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF121/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.

Multimodality imaging of vascular endothelial growth factor and vascular endothelial growth factor receptor expression.

Abstract: Angiogenesis is a critical process in both physiological development and many pathological processes. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathway plays a pivotal role in regulating angiogenesis. Many therapeutic agents targeting VEGF and VEGFR are currently in preclinical and clinical development. The ability to quantitatively image VEGF/VEGFR expression in a non-invasive manner can aid in lesion detection, patient stratification, new drug development/validation, treatment monitoring, and dose optimization. It can also help in decide when or whether to start anti-angiogenic treatment targeting VEGF/VEGFR. This review summarizes the recent advances in multimodality imaging of VEGF/VEGFR expression using ultrasound, optical fluorescence, optical bioluminescence, SPECT, and PET in many diseases such as cancer, myocardial infarction, and ischemia. Much research effort will be needed in the future to improve the in vivo stability, tumor targeting efficacy, and pharmacokinetics of the imaging probes. With the development of new tracers with better targeting efficacy and desirable pharmacokinetics, clinical translation will be critical for the maximum benefit of VEGF/VEGFR targeted imaging agents.

Quantitative radioimmunoPET imaging of EphA2 in tumor-bearing mice

Abstract: EphA2 receptor tyrosine kinase is significantly overexpressed in a wide variety of cancer types. High EphA2 expression has been correlated with increased metastatic potential and poor patient survival. Although many recent reports have focused on blocking the EphA2 signaling pathway in cancer, the in vivo imaging of EphA2 has not yet been investigated. We labeled 1C1, a humanized monoclonal antibody against both human and murine EphA2, with 64Cu through the chelating agent 1,4,7,10-tetraazacyclododecane N,N′,N″,N″′-tetraacetic acid (DOTA) and carried out positron emission tomography (PET) imaging of eight tumor models with different EphA2 expression levels. Western blotting of tumor tissue lysate was performed to correlate the EphA2 expression level with 64Cu-DOTA-1C1 uptake in the tumors. Immunofluorescence staining and biodistribution studies were also carried out to validate the in vivo results. The radiolabeling yield was 88.9 ± 9.5% (n = 7) and the specific activity of 64Cu-DOTA-1C1 was 1.32 ± 0.14 GBq/mg of 1C1 mAb. The antibody retained antigen-binding affinity/specificity after DOTA conjugation as measured by FACS analysis. The uptake of 64Cu-DOTA-1C1 in CT-26 tumors was as high as 25.1 ± 2.5 %ID/g (n = 3) at 18 h post injection. 64Cu-DOTA-IgG, an isotype-matched control, exhibited minimal non-specific uptake in all eight tumor models. In vivo EphA2 specificity of 64Cu-DOTA-1C1 was confirmed by successful blocking of CT-26 tumor uptake by unlabeled 1C1. Most importantly, the tumor uptake value obtained from PET imaging had excellent linear correlation with the relative tumor tissue EphA2 expression level measured by Western blot, where r 2 equals 0.90 and 0.92 at 18 h and 42 h post injection, respectively. The tumor uptake of 64Cu-DOTA-1C1 measured by microPET imaging reflects tumor EphA2 expression level in vivo. This is, to our knowledge, the first report of quantitative radioimmunoPET imaging of EphA2 in living subjects. Future clinical investigation of 64Cu-DOTA-1C1 is warranted.

Semiconductor quantum dots for in vivo imaging.

Abstract: Quantum dots play an important role in the in vitro, ex vivo, and in vivo optical imaging. Dramatic improvements have been achieved in the aspect of surface modification, biocompatibility, and targeting specificity, which had significant impact on the in vivo applications of quantum dots. This review summarizes the recent advances of quantum dots for in vivo imaging using both non-specific and targeted approaches. The toxicity of cadmium chalcogenide materials and alternative approaches such as the use of doped nanocrystal quantum dots were also discussed. The integration of quantum dots with other imaging techniques is also expected to give rise to a new generation of multifunctional probes for biomedical applications.

Methods for high figure-of-merit in nanostructured thermoelectric materials

Abstract: Thermoelectric materials with high figures of merit, ZT values, are disclosed. In many instances, such materials include nano-sized domains (e.g., nanocrystalline), which are hypothesized to help increase the ZT value of the material (e.g., by increasing phonon scattering due to interfaces at grain boundaries or grain/inclusion boundaries). The ZT value of such materials can be greater than about 1, 1.2, 1.4, 1.5, 1.8, 2 and even higher. Such materials can be manufactured from a thermoelectric starting material by generating nanoparticles therefrom, or mechanically alloyed nanoparticles from elements which can be subsequently consolidated (e.g., via direct current induced hot press) into a new bulk material. Non-limiting examples of starting materials include bismuth, lead, and/or silicon-based materials, which can be alloyed, elemental, and/or doped. Various compositions and methods relating to aspects of nanostructured thermoelectric materials (e.g., modulation doping) are further disclosed.

Small-Animal PET of Melanocortin 1 Receptor Expression Using a 18F-Labeled α-Melanocyte-Stimulating Hormone Analog

Abstract: 18F-Labeled small synthetic peptides have emerged as attractive probes for imaging various molecular targets with PET. The α-melanocyte-stimulating hormone (α-MSH) receptor (melanocortin type 1 receptor [MC1R]) is overexpressed in most murine and human melanomas. It is a promising molecular target for diagnosis and therapy of melanomas. However, 18F compounds have not been successfully developed for imaging the MC1R. Methods: In this study, an α-MSH analog, Ac-Nle-Asp-His-d-Phe-Arg-Trp-Gly-Lys-NH2 (NAPamide), was radiolabeled with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB). The resulting radiopeptide was evaluated as a potential molecular probe for small-animal PET of melanoma and MC1R expression in melanoma xenografted mouse models. Results: The binding affinity of 19F-SFB−conjugated NAPamide, 19F-FB-NAPamide, was determined to be 7.2 ± 1.2 nM (mean ± SD) using B16/F10 cells and 125I-(Tyr2)-[Nle4,d-Phe7]-α-MSH [125I-(Tyr2)-NDP] as a radioligand. The biodistribution of 18F-FB-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16/F10 melanoma tumors with high expression of MC1Rs and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Biodistribution experiments showed that tumor uptake values (percentage injected dose per gram of tumor [%ID/g]) of 18F-FB-NAPamide were 1.19 ± 0.11 %ID/g and 0.46 ± 0.11 %ID/g, in B16/F10 and A375M xenografted melanoma at 1 h after injection, respectively. Furthermore, the B16/F10 tumor uptake was significantly inhibited by coinjection with excess α-MSH peptide (P

Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor Inhibitors as Anti-Angiogenic Agents in Cancer Therapy

Abstract: New blood vessel formation (angiogenesis) is fundamental to the process of tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) family of ligands and receptors are well established as key regulators of these processes. VEGF is a glycoprotein with mitogenic activity on vascular endothelial cells. Specifically, VEGF-receptor pathway activation results in signaling cascades that promote endothelial cell growth, migration, differentiation, and survival from pre-existing vasculature. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Recent identification of seven VEGF ligand variants (VEGF [A-F], PIGF) and three VEGF tyrosine kinase receptors (VEGFR- [1-3]) has led to the development of several novel inhibitory compounds. Clinical trials have shown inhibitors to this pathway (anti-VEGF therapies) are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. Having been first described in the 1980s, VEGF patenting activity since then has focused on anti-cancer therapeutics designed to inhibit tumoral vascular formation. This review will focus on patents which target VEGF-[A-F] and/or VEGFR-[1-3] for use in anti-cancer treatment.

PET imaging of acute and chronic inflammation in living mice

Abstract: Purpose In this study, we evaluated the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced acute and chronic inflammation in living mice by PET imaging of TNF-α and integrin αvβ3 expression.

Integrin alpha v beta 3 antagonists for anti-angiogenic cancer treatment.

Abstract: Direct contact between cellular and extracellular matrix (ECM) proteins is necessary for a diverse array of physiologic processes including cellular activation, migration, proliferation, and differentiation. These direct interactions are modulated by cell adhesion molecules (CAMs) such as integrins, selectins, cadherins, and immunoglobulins. Integrin signaling also plays a key role in tumor growth, angiogenesis, and metastasis. Recent advances in the discovery and characterization of CAMs and their receptors, most notably integrin alpha(v)beta(3), and the clarification of their roles in disease states have laid the groundwork for the development and clinical implementation of novel anti-cancer treatments. Integrin alpha (v)beta(3) is a glycoprotein membrane receptor which recognizes ECM proteins expressing an arginine-glycine-aspartic acid (RGD) peptide sequence. The receptor is highly expressed on activated tumor endothelial cells, but not resting endothelial cells and normal organ systems, thus making alpha(v)beta(3) an appropriate target for anti-angiogenic therapeutics. In addition, alpha(v)beta(3) is also expressed on tumor cells, allowing for both tumor cell and tumor vasculature targeting of anti-integrin therapy. Throughout the past decade, numerous patents have been published and issued using alpha(v)beta(3) antagonists for the prevention and/or treatment of cancer, with many antagonists demonstrating positive pre-clinical anti-angiogenic and anti-tumor results. This review will focus on the key points and distinguishing factors for patents which use antibodies, RGD peptides, non-RGD peptides, peptidomimetics, and amine salts as alpha(v)beta(3) antagonists.

Solar thermoelectric conversion

Abstract: Systems and methods utilizing solar-electrical generators are discussed. Solar- electrical generators are disclosed having a radiation-capture structure and one or more thermoelectric converters. Heat produced in a capture structure via impingement of solar radiation can maintain a portion of a thermoelectric converter at a high temperature, while the use of a low temperature at another portion allows electricity generation. Thus, unlike photovoltaic cells which are generally primarily concerned with optical radiation management, solar thermoelectrics converters are generally concerned with a variety of mechanisms for heat management. Generators can include any number of features including selective radiation surfaces, low emissivity surfaces, flat panel configurations, evacuated environments, and other concepts that can act to provide thermal concentration. Designs utilizing one or more optical concentrators are also disclosed.

In Vivo Bioluminescence Tumor Imaging of RGD Peptide-modified Adenoviral Vector Encoding Firefly Luciferase Reporter Gene

Abstract: Purpose The goal of this study is to demonstrate the feasibility of chemically modified human adenovirus (Ad) vectors for tumor retargeting.

Molecular imaging can accelerate anti-angiogenic drug development and testing

Abstract: Angiogenesis is one of the fundamental processes during tumor growth and disease progression, and is regulated by numerous molecular pathways, including, but not limited to, VEGF, matrix metalloproteinases (MMPs), endoglin (CD105), integrin αvβ3and E-selectin. All these pathways could serve as targets for molecular imaging, as outlined in this Viewpoint.

Computer prediction of cardiovascular and hematological agents by statistical learning methods.

Abstract: Computational methods have been explored for predicting agents that produce therapeutic or adverse effects in cardiovascular and hematological systems. The quantitative structure-activity relationship (QSAR) method is the first statistical learning methods successfully used for predicting various classes of cardiovascular and hematological agents. In recent years, more sophisticated statistical learning methods have been explored for predicting cardiovascular and hematological agents particularly those of diverse structures that might not be straightforwardly modelled by single QSAR models. These methods include partial least squares, multiple linear regressions, linear discriminant analysis, k-nearest neighbour, artificial neural networks and support vector machines. Their application potential has been exhibited in the prediction of various classes of cardiovascular and hematological agents including 1, 4-dihydropyridine calcium channel antagonists, angiotensin converting enzyme inhibitors, thrombin inhibitors, AchE inhibitors, HERG potassium channel inhibitors and blockers, potassium channel openers, platelet aggregation inhibitors, protein kinase inhibitors, dopamine antagonists and torsade de pointes causing agents. This article reviews the strategies, current progresses and problems in using statistical learning methods for predicting cardiovascular and hematological agents. It also evaluates algorithms for properly representing and extracting the structural and physicochemical properties of compounds relevant to the prediction of cardiovascular and hematological agents.

Pet imaging of vascular endothelial growth factor receptor (VEGFR), compositions for VEGF cancer imaging, and methods of VEGF cancer imaging

Abstract: Briefly described, embodiments of this disclosure include polypeptides, in particular a labeled VEGF protein, kits for imaging, methods for imaging tissue, methods of diagnosing the presence in a tissue of one or more of precancerous cells, cancerous cells, tumor cells, and cells related to ischemic or hypoxic related diseases, methods of monitoring the progress in a tissue of the presence of one or more of precancerous cells, cancerous cells, tumor cells, and cells related to ischemic or hypoxic related diseases, and the like