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Showing papers by "Xiaoyuan Chen published in 2009"


Journal ArticleDOI
TL;DR: In this article, several approaches, including delivery using liposomes (DOXIL), have been developed to reduce the toxicity and enhance the clinical utility of this highly active antineoplastic agent.
Abstract: Doxorubicin (DOX) is a member of the anthracycline class of chemotherapeutic agents that are used for the treatment of many common human cancers, including aggressive non-Hodgkin’s lymphoma.[1,2] However, DOX is highly toxic in humans and can result in severe suppression of hematopoiesis, gastrointestinal toxicity,[3] and cardiac toxicity.[4] To date, several approaches, including delivery using liposomes (DOXIL),[5] have been developed to reduce the toxicity and enhance the clinical utility of this highly active antineoplastic agent.

496 citations


Journal ArticleDOI
01 Jan 2009-Small
TL;DR: In this paper, the influence of particle size, PEGylation, and surface coating on the quantitative biodistribution of near-infrared-emitting quantum dots (QDs) in mice was evaluated.
Abstract: This study evaluates the influence of particle size, PEGylation, and surface coating on the quantitative biodistribution of near-infrared-emitting quantum dots (QDs) in mice. Polymer- or peptide-coated 64Cu-labeled QDs 2 or 12 nm in diameter, with or without polyethylene glycol (PEG) of molecular weight 2000, are studied by serial micropositron emission tomography imaging and region-of-interest analysis, as well as transmission electron microscopy and inductively coupled plasma mass spectrometry. PEGylation and peptide coating slow QD uptake into the organs of the reticuloendothelial system (RES), liver and spleen, by a factor of 6-9 and 2-3, respectively. Small particles are in part renally excreted. Peptide-coated particles are cleared from liver faster than physical decay alone would suggest. Renal excretion of small QDs and slowing of RES clearance by PEGylation or peptide surface coating are encouraging steps toward the use of modified QDs for imaging living subjects.

426 citations


Journal ArticleDOI
TL;DR: The MSCs‐R can selectively localize, survive, and proliferate in both subcutaneous tumor and lung metastasis as evidenced by noninvasive bioluminescence imaging and ex vivo validation.
Abstract: The objective of the study was to track the distribution and differentiation of mesenchymal stem cells (MSCs) in tumor-bearing mice. The 4T1 murine breast cancer cells were labeled with renilla luciferase-monomeric red fluorescence protein (rLuc-mRFP) reporter gene. The MSCs labeled with firefly luciferase-enhanced green fluorescence protein (fLuc-eGFP) reporter gene (MSCs-R) were isolated from L2G85 transgenic mice that constitutively express fLuc-eGFP reporter gene. To study the tumor tropism of MSCs, we established both subcutaneous and lung metastasis models. In lung metastasis tumor mice, we injected MSCs-R intravenously either on the same day or 4 days after 4T1 tumor cell injection. In subcutaneous tumor mice, we injected MSCs-R intravenously 7 days after subcutaneous 4T1 tumor inoculation. The tumor growth was monitored by rLuc bioluminescence imaging (BLI). The fate of MSCs-R was monitored by fLuc BLI. The localization of MSCs-R in tumors was examined histologically. The osteogenic and adipogenic differentiation of MSCs-R was investigated by alizarin red S and oil red O staining, respectively. The mechanism of the dissimilar differentiation potential of MSCs-R under different tumor microenvironments was investigated. We found that the 4T1 cells were successfully labeled with rLuc-mRFP. The MSCs-R isolated from L2G85 transgenic mice constitutively express fLuc-eGFP reporter gene. When injected intravenously, MSCs-R survived, proliferated, and differentiated in tumor sites but not elsewhere. The localization of GFP(+) MSCs-R in tumor lesions was confirmed ex vivo. In conclusion, the MSCs-R can selectively localize, survive, and proliferate in both subcutaneous tumor and lung metastasis as evidenced by noninvasive bioluminescence imaging and ex vivo validation. The MSCs-R migrated to lung tumor differentiated into osteoblasts, whereas the MSCs-R targeting subcutaneous tumor differentiated into adipocytes.

204 citations


Journal ArticleDOI
TL;DR: A new protease activatable strategy based on a polymer nanoparticle platform that delivers chemically labeled matrix metalloproteinase (MMP)-activatable fluorogenic peptides to the specific MMPs of interest in vivo is reported.
Abstract: We report here a new protease activatable strategy based on a polymer nanoparticle platform. This nanosensor delivers chemically labeled matrix metalloproteinase (MMP)-activatable fluorogenic peptides to the specific MMPs of interest in vivo. Intravenous administration of the nanosensor in an MMP-positive SCC-7 xenograft tumor and a colon cancer mouse model verified the enzyme specificity of the nanosensor in vivo. The design platform of the nanosensor is flexible and can be fine-tuned for a wide array of applications such as the detection of biomarkers, early diagnosis of disease, and monitoring therapeutic efficacy.

161 citations


Journal ArticleDOI
Chuancheng Ren1, Zhimin Yan1, Dingtai Wei1, Xuwen Gao1, Xiaoyuan Chen1, Heng Zhao1 
TL;DR: Results showed that rapid RIP performed immediately after CCA release reduced infarction by 67% measured at 2 days after stroke, suggesting that RIP blocks ischemic injury by modulating protein synthesis and nerve activity.

149 citations


Journal ArticleDOI
TL;DR: Two novel RGD dimers with high affinity, high specificity and excellent pharmacokinetic properties are developed and investigated in integrin αvβ3-positive tumor xenografts and exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than 68Ga-NOTA-RGD2.
Abstract: Radiolabeled cyclic RGD (Arg-Gly-Asp) peptides have great potential for the early tumor detection and noninvasive monitoring of tumor metastasis and therapeutic response. 18F-labeled RGD analogs ([18F]-AH111585 and [18F]Galacto-RGD) have been investigated in clinical trials for positron emission tomography (PET) imaging of integrin expression in cancer patients. To develop new RGD radiotracers with higher tumor accumulation, improved in vivo kinetics, easy availability and low cost, we developed two new RGD peptides and labeled them with generator-eluted 68Ga (t1/2 = 68 min) for PET imaging of integrin αvβ3 expression in tumor xenograft models. The two new cyclic RGD dimers, E[PEG4-c(RGDfK)]2 (P4-RGD2, PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) and E[Gly3-c(RGDfK)]2 (G3-RGD2, G3 = Gly-Gly-Gly) were designed, synthesized and conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) for 68Ga labeling. The microPET imaging and biodistribution of the 68Ga labeled RGD tracers were investigated in integrin αvβ3-positive tumor xenografts. The new RGD dimers with the Gly3 and PEG4 linkers showed higher integrin αvβ3 binding affinity than no-linker RGD dimer (RGD2). NOTA-G3-RGD2 and NOTA-P4-RGD2 could be labeled with 68Ga within 30 min with higher purity (>98%) and specific activity (8.88–11.84 MBq/nmol). Both 68Ga-NOTA-P4-RGD2 and 68Ga-NOTA-G3-RGD2 exhibited significantly higher tumor uptake and tumor-to-normal tissue ratios than 68Ga-NOTA-RGD2. Because of their high affinity, high specificity and excellent pharmacokinetic properties, further investigation of the two novel RGD dimers for clinical PET imaging of integrin αvβ3 expression in cancer patients is warranted.

144 citations


Journal ArticleDOI
TL;DR: A novel RGD-IONP conjugate is developed with excellent tumor integrin targeting efficiency and specificity as well as limited RES uptake for molecular MRI.

138 citations


Journal ArticleDOI
Zhaofei Liu1, Yongjun Yan1, Shuanglong Liu1, Fan Wang1, Xiaoyuan Chen1 
TL;DR: The prosthetic labeling groups, chelators, and isotopes all have a profound effect on the tumor targeting efficacy and in vivo kinetics of the RGD-BBN tracers for dual integrin and GRPR recognition.

135 citations


Journal ArticleDOI
TL;DR: This review discusses the advantages and challenges in developing dual-modality imaging probes and summarizes the current state-of-the-art systems with respect to their unique design strategies and applications.
Abstract: Various imaging modalities have been exploited and are successfully employed to investigate the anatomic or functional dissemination of tissues in the body. However, no single imaging modality allo...

123 citations


Journal ArticleDOI
TL;DR: The results from this study provide a possible explanation for the lack of an observed correlation between therapeutic efficacy of cetuximab and panitumumab and EGFR expression level as determined by immunohistochemistry or fluorescent in situ hybridization and may shed new light on the complications of anti-EGFR mAb therapy for HNSCC and other malignancies.
Abstract: Epidermal growth factor receptor (EGFR) is a well-characterized protooncogene that has been shown to promote tumor progression in solid cancers. Clinical results for EGFR targeting with specific monoclonal antibodies (mAbs) such as cetuximab and panitumumab are promising; however, most studies indicate that only a subgroup of patients receiving the mAbs benefit from the immunotherapy, independent of EGFR expression level. To understand the in vivo kinetics of antibody delivery and localization, we performed small-animal PET studies with 64 Cu-labeled panitumumab in xenografts derived from 3 cell lines of human head and neck squamous cell carcinoma (HNSCC). Methods: Nude mice bearing HNSCC tumors with different levels of EGFR expression were imaged with

117 citations


Journal ArticleDOI
TL;DR: The focus is on how to utilize the knowledge gained from fundamental studies to fabricate functional MTB nanoparticles (MTB-NPs) that are capable of tackling real biomedical problems.
Abstract: Magnetotactic bacteria (MTB) were first discovered by Richard P. Blakemore in 1975, and this led to the discovery of a wide collection of microorganisms with similar features i.e., the ability to internalize Fe and convert it into magnetic nanoparticles, in the form of either magnetite (Fe3O4) or greigite (Fe3S4). Studies showed that these particles are highly crystalline, monodisperse, bioengineerable and have high magnetism that is comparable to those made by advanced synthetic methods, making them candidate materials for a broad range of bio-applications. In this review article, the history of the discovery of MTB and subsequent efforts to elucidate the mechanisms behind the magnetosome formation are briefly covered. The focus is on how to utilize the knowledge gained from fundamental studies to fabricate functional MTB nanoparticles (MTB-NPs) that are capable of tackling real biomedical problems.

Journal ArticleDOI
TL;DR: Compared with other tracers, 64Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications.
Abstract: The overexpression of gastrin-releasing peptide receptor (GRPR) in various tumor types suggests that GRPR is an attractive target for cancer imaging and therapy with radiolabeled bombesin analogs. We recently reported the ability of 18F-labeled RGD-bombesin heterodimer to be used for dual integrin αvβ3– and GRPR-targeted imaging. To further investigate the synergistic effect of the dual-receptor targeting of peptide heterodimers, we evaluated 64Cu-labeled RGD-bombesin for PET imaging of tumors. Methods: RGD-bombesin was coupled with 1,4,7,10-tetraazacyclododecane-N, N′, N′′, N′′′-tetraacetic acid (DOTA) and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), and the conjugates were labeled with 64Cu. The in vitro and in vivo characteristics of 64Cu-NOTA-RGD-bombesin were compared with those of 64Cu-NOTA-RGD, 64Cu-NOTA-bombesin, and 64Cu-DOTA-RGD-bombesin. Results:64Cu-NOTA-RGD-bombesin and 64Cu-DOTA-RGD-bombesin had comparable dual integrin αvβ3– and GRPR-binding affinities in vitro, both of which were slightly lower than RGD for integrin binding and bombesin for GRPR binding. 64Cu-NOTA-RGD-bombesin possessed significantly higher tumor uptake than did 64Cu-NOTA-RGD, 64Cu-NOTA-bombesin, the mixture of 64Cu-NOTA-RGD and 64Cu-NOTA-bombesin, or 64Cu-DOTA-RGD-bombesin in PC-3 prostate cancer. 64Cu-NOTA-RGD-bombesin also showed improved in vivo kinetics such as lower liver and intestinal activity accumulation than did the bombesin tracers. 64Cu-NOTA-RGD-bombesin also outperformed 64Cu-NOTA-RGD in a 4T1 murine mammary carcinoma model that expresses integrin on tumor vasculature but no GRPR in tumor tissue, which had no uptake of 64Cu-NOTA-bombesin. Conclusion: Compared with other tracers, 64Cu-NOTA-RGD-bombesin showed favorable in vivo kinetics and enhanced tumor uptake, which warrants its further investigation for targeting tumors that express integrin or GRPR or that coexpress integrin and GRPR for imaging and therapeutic applications. The synergistic effect of RGD-bombesin heterodimers observed in this study also encourages further investigations of novel heterodimers recognizing other cell surface receptors for tumor targeting.

Journal ArticleDOI
TL;DR: The favorable characterizations of 68Ga-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging.
Abstract: Radiolabeled Arg-Gly-Asp (RGD) and bombesin (BBN) peptide analogs have been extensively investigated for the imaging of tumor integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) expression, respectively. Recently, we designed and synthesized a RGD-BBN heterodimeric peptide from c(RGDyK) and BBN(7–14) through a glutamate linker. The goal of this study was to investigate the dual receptor-targeting property and tumor diagnostic value of RGD-BBN heterodimeric peptide labeled with generator-eluted 68Ga (t1/2 68 min, β+ 89% and EC 11%), 68Ga-NOTA-RGD-BBN. RGD-BBN heterodimer was conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with 68Ga. The dual receptor binding affinity was investigated by a radioligand competition binding assay. The in vitro and in vivo dual receptor targeting of 68Ga-NOTA-RGD-BBN was evaluated and compared with that of 68Ga-NOTA-RGD and 68Ga-NOTA-BBN. NOTA-RGD-BBN had integrin αvβ3 and GRPR binding affinities comparable to those of the monomeric RGD and BBN, respectively. The dual receptor targeting property of 68Ga-NOTA-RGD-BBN was validated by blocking studies in a PC-3 tumor model. 68Ga-NOTA-RGD-BBN showed higher tumor uptake than 68Ga-NOTA-RGD and 68Ga-NOTA-BBN. 68Ga-NOTA-RGD-BBN can also image tumors with either integrin or GRPR expression. 68Ga-NOTA-RGD-BBN exhibited dual receptor targeting properties both in vitro and in vivo. The favorable characterizations of 68Ga-NOTA-RGD-BBN such as convenient synthesis, high specific activity, and high tumor uptake, warrant its further investigation for clinical cancer imaging.

Journal ArticleDOI
Zhaofei Liu1, Yongjun Yan1, Frederic T Chin1, Fan Wang1, Xiaoyuan Chen1 
TL;DR: (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging.
Abstract: Radiolabeled RGD and bombesin peptides have been extensively investigated for tumor integrin alpha(v)beta(3) and GRPR imaging, respectively. Due to the fact that many tumors are both integrin and GRPR positive, we designed and synthesized a heterodimeric peptide Glu-RGD-BBN, which is expected to be advantageous over the monomeric peptides for dual-receptor targeting. A PEG(3) spacer was attached to the glutamate alpha-amino group of Glu-RGD-BBN to enhance the (18)F labeling yield and to improve the in vivo kinetics. PEG(3)-Glu-RGD-BBN possesses the comparable GRPR and integrin alpha(v)beta(3) receptor-binding affinities as the corresponding monomers, respectively. The dual-receptor targeting properties of (18)F-FB-PEG(3)-Glu-RGD-BBN were observed in PC-3 tumor model. (18)F-FB-PEG(3)-Glu-RGD-BBN with high tumor contrast and favorable pharmacokinetics is a promising PET tracer for dual integrin and GRPR positive tumor imaging. This heterodimer strategy may also be an applicable method to develop other molecules with improved in vitro and in vivo characterizations for tumor diagnosis and therapy.

Journal ArticleDOI
TL;DR: In this paper, the authors designed a new RGD homodimeric peptide with two PEG4 spacers (PEG4 = 15amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG 4 linker on the glutamate α-amino group.
Abstract: Various radiolabeled Arg-Gly-Asp (RGD) peptides have been previously investigated for tumor integrin αvβ3 imaging. To further develop RGD radiotracers with enhanced tumor-targeting efficacy and improved in vivo pharmacokinetics, we designed a new RGD homodimeric peptide with two PEG4 spacers (PEG4 = 15-amino-4,7,10,13-tetraoxapentadecanoic acid) between the two monomeric RGD motifs and one PEG4 linker on the glutamate α-amino group (18F-labeled PEG4-E[PEG4-c(RGDfK)]2, P-PRGD2), as a promising agent for noninvasive imaging of integrin expression in mouse models. P-PRGD2 was labeled with 18F via 4-nitrophenyl 2-18F-fluoropropionate (18F-FP) prosthetic group. In vitro and in vivo characteristics of the new dimeric RGD peptide tracer 18F-FP-P-PRGD2 were investigated and compared with those of 18F-FP-P-RGD2 (18F-labeled RGD dimer without two PEG4 spacers between the two RGD motifs). The ability of 18F-FP-P-PRGD2 to image tumor vascular integrin expression was evaluated in a 4T1 murine breast tumor model. With the insertion of two PEG4 spacers between the two RGD motifs, 18F-FP-P-PRGD2 showed enhanced integrin αvβ3-binding affinity, increased tumor uptake and tumor-to-nontumor background ratios compared with 18F-FP-P-RGD2 in U87MG tumors. MicroPET imaging with 18F-FP-P-PRGD2 revealed high tumor contrast and low background in tumor-bearing nude mice. Biodistribution studies confirmed the in vivo integrin αvβ3-binding specificity of 18F-FP-P-RGD2. 18F-FP-P-PRGD2 can specifically image integrin αvβ3 on the activated endothelial cells of tumor neovasculature. 18F-FP-P-PRGD2 can provide important information on integrin expression on the tumor vasculature. The high integrin binding affinity and specificity, excellent pharmacokinetic properties and metabolic stability make the new RGD dimeric tracer 18F-FP-P-PRGD2 a promising agent for PET imaging of tumor angiogenesis and for monitoring the efficacy of antiangiogenic treatment.

Journal ArticleDOI
TL;DR: In this paper, the authors summarize the recent measurements of radiative transfer between two parallel silica surfaces and between a silica microsphere and a flat silica surface that show unambiguous evidence of enhancement due to near-field effects above the Planck limit.
Abstract: The Planck theory of blackbody radiation imposes a limit on the maximum radiative transfer between two objects at given temperatures. When the two objects are close enough, near-field effects due to tunneling of evanescent waves lead to enhancement of radiative transfer above the Planck limit. When the objects can support electromagnetic surface polaritons, the enhancement can be a few orders-of-magnitude larger than the blackbody limit. In this paper, we summarize our recent measurements of radiative transfer between two parallel silica surfaces and between a silica microsphere and a flat silica surface that show unambiguous evidence of enhancement of radiative transfer due to near-field effects above the Planck limit.

Journal ArticleDOI
TL;DR: The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab and this approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.
Abstract: 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat-shock protein 90 (Hsp90) inhibitor, has been intensively investigated for cancer therapy and is undergoing clinical trials. Human epidermal growth factor receptor 2 (HER-2) is one of the client proteins of Hsp90 and its expression is decreased upon 17-DMAG treatment. In this study, we aimed to noninvasively monitor the HER-2 response to 17-DMAG treatment in xenografted mice. The sensitivity of human ovarian cancer SKOV-3 cells to 17-DMAG in vitro was measured by MTT assay. HER-2 expression in SKOV-3 cells was determined by flow cytometry. Nude mice bearing SKOV-3 tumors were treated with 17-DMAG and the therapeutic efficacy was evaluated by tumor size measurement. Both treated and control mice were imaged with microPET using 64Cu-DOTA-trastuzumab and 18F-FDG. Biodistribution studies and immunofluorescence staining were performed to validate the microPET results. SKOV-3 cells are sensitive to 17-DMAG treatment, in a dose-dependent manner, with an IC50 value of 24.72 nM after 72 h incubation. The tumor growth curve supported the inhibition effect of 17-DMAG on SKOV-3 tumors. Quantitative microPET imaging showed that 64Cu-DOTA-trastuzumab had prominent tumor accumulation in untreated SKOV-3 tumors, which was significantly reduced in 17-DMAG-treated tumors. There was no uptake difference detected by FDG PET. Immunofluorescence staining confirmed the significant reduction in tumor HER-2 level upon 17-DMAG treatment. The early response to anti-Hsp90 therapy was successfully monitored by quantitative PET using 64Cu-DOTA-trastuzumab. This approach may be valuable in monitoring the therapeutic response in HER-2-positive cancer patients under 17-DMAG treatment.

Journal ArticleDOI
Kai Chen1, Weibo Cai1, Zibo Li1, Hui Wang1, Xiaoyuan Chen1 
TL;DR: The tumor uptake value obtained from PET imaging had good linear correlation with the relative tumor tissue VEGFR-2 expression as measured by Western blot, where r2 equals 0.68 based on the PET uptake at 4 h post-injection.
Abstract: Purpose Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling pathway plays pivotal roles in regulating tumor angiogenesis. Quantitative positron emission tomography (PET) imaging of VEGFR will facilitate the planning of whether, and when, to start anti-angiogenic treatment and enable more robust and effective monitoring of such treatment.

Journal ArticleDOI
TL;DR: By targeting alpha(v)beta(3) integrin, the ability of (64)Cu-DOTA-RGD4 to noninvasively visualize teratoma formation in vivo for the first time is shown.
Abstract: Teratoma formation can be a serious drawback after the therapeutic transplantation of human embryonic stem (hES) cells. Therefore, noninvasive imaging of teratomas could be a valuable tool for monitoring patients undergoing hES cell treatment. Here, we investigated the angiogenic process within teratomas derived from hES cells and now report the first example of using 64Cu-labeled RGD tetramer (64Cu-DOTA-RGD4) for positron emission tomography imaging of teratoma formation by targeting αvβ3 integrin. H9 hES cells (2 × 106), stably expressing firefly luciferase, and enhanced green fluorescence protein (Fluc-eGFP) were injected into adult nude mice ( n = 12) s.c. Eight weeks after transplantation, these hES cell grafts evolved into teratomas as confirmed by longitudinal bioluminescence imaging. Under micropositron emission tomography imaging, 2-deoxy-2-[18F]fluoro-D-glucose and 3′-deoxy-3′-[18F]-fluorothymidine both failed to detect hES cell–derived teratomas (0.8 ± 0.5 versus 1.1 ± 0.4 %ID/g, respectively; P = not significant versus background signals). By contrast, 64Cu-DOTA-RGD4 revealed specific and prominent uptake in vascularized teratoma and significantly lower uptake in control tumors (human ovarian carcinoma 2008 cell line), which had low intergrin expression (10.1 ± 3.4 versus 1.4 ± 1.2 %ID/g; P < 0.01). Immunofluorescence staining of CD31 and β3 integrin also supported our in vivo imaging results ( P < 0.05). Moreover, we found that the cells dissociated from teratomas showed higher αvβ3 integrin expression than the 2008 cells. In conclusion, by targeting αvβ3 integrin, we successfully showed the ability of 64Cu-DOTA-RGD4 to noninvasively visualize teratoma formation in vivo for the first time. [Cancer Res 2009;69(7):2709–13]

Journal ArticleDOI
TL;DR: An RGD-based protein conjugate with prolonged circulation half-life for NIRF imaging of tumor integrin αvβ3 expression is developed and may be generalizable for other peptide-based probes to be conjugated with HSA for prolonged tumor contrast and improved pharmacokinetics.
Abstract: Cyclic arginine-glycine-aspartate (RGD) peptides and their derivatives have been intensively studied as tumor targeting probes. One major drawback, however, is their short blood circulation half-lives, which greatly compromises their targeting efficacy. To address this issue, a cyclic peptide, c(RGDyK), and an organic dye (IRDye800 or Cy5.5) were covalently conjugated onto human serum albumin (HSA). The conjugates were subjected to in vitro cell staining, in vivo near-infrared fluorescence (NIRF) imaging, ex vivo NIRF imaging, and histologic studies to evaluate their feasibility as tumor imaging probes. As a control, RAD peptide was also coupled with HSA and labeled with IRDye800 for in vivo imaging. The HSA-RGDIRDye800 exhibited integrin α v β 3 ‐specific binding in cell staining experiment. In vivo NIRF imaging showed higher tumor accumulation and tumor to background contrast of HSA-RGD-IRDye800 over RGD-IRDye800. The integrin specificity of HSA-RGD-IRDye800 is confirmed by both successful inhibition of tumor uptake in the presence of c(RGDyK) and the inability to accumulate in integrin-positive tumors by RAD-HSA-IRDye800. Histologic examination revealed initial tumor vascular binding and eventually both tumor vasculature and tumor cell integrin binding in vivo. In summary, we successfully developed an RGD-based protein conjugate with prolonged circulation half-life for NIRF imaging of tumor integrin α v β 3 expression. The success of this study may be generalizable for other peptide-based probes to be conjugated with HSA for prolonged tumor contrast and improved pharmacokinetics.

Journal ArticleDOI
01 Jan 2009-Stroke
TL;DR: In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis in a rat stroke model for the first time.
Abstract: Background and Purpose— Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis. Methods— Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, 18F-FDG PET, and 64Cu-DOTA-VEGF121 PET scans. Several control experiments were performed to confirm the VEGFR specificity of 64Cu-DOTA-VEGF121 uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and 125I-VEGF165 autoradiography on stroke brain tissue slices were performed to validate the in vivo findings. Results— T2-weighed MRI correlated with the “cold spot” on 18F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The 64Cu-DOTA-VEGF121 uptake in the stroke border zone peaked at ≈10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-...

Journal ArticleDOI
TL;DR: In vivo NIR imaging results indicated specific uptake in EGFR-positive tumors, and Erbitux-Cy5.5 may be used as a specific NIR contrast agent for the noninvasive characterization of EGFR expression level in breast cancer xenografts.
Abstract: Background: Epidermal growth factor receptor (EGFR) overexpression is associated with several key features of cancer development and growth. Therefore, EGFR is a very promising biological target for tumor diagnosis and anticancer therapy. Characterization of EGFR expression is important for clinicians to select patients for EGFR-targeted therapy and evaluate therapeutic effects.Purpose: To investigate whether near-infrared (NIR) fluorescent dye Cy5.5-labeled anti-EGFR monoclonal antibody Erbitux can characterize EGFR expression level in MDA-MB-231 and MCF-7 breast cancer xenografts using an in vivo NIR imaging method.Material and Methods: A fluorochrome probe was designed by coupling Cy5.5 to Erbitux through acidylation, and the fluorescence property of the Erbitux-Cy5.5 conjugate was characterized by fluorospectroscopy. Flow cytometry and laser confocal microscopy were used to test the EGFR specificity of the antibody probe in vitro. Erbitux-Cy5.5 was also injected intravenously into immune-deficient mic...

Journal ArticleDOI
TL;DR: The nanothermometers made of nanospheres with a nanometer scaled spatial resolution can record the highest temperature in the event and be read at a later time after the event is over, and are demonstrated to measure temperature based on temperature-dependent size distribution and areal density of metal nanosphere.
Abstract: Conventional thermometers have been widely employed in scientific researches and industrial applications. Thermometers with nanometer scaled spatial resolution attract more and more attentions recently with the rapid development of nanotechnology and nanoengineering. Many kinds of nanothermometers have been designed by duplicating the conventional thermometers at nanoscale through decreasing the geometrical size of the conventional thermometers. For example, nanoscale thermocouples are fabricated from nano-junctions based on Seebeck effect, liquid-in-tube nanothermometers from nanotubes based on temperature-dependent thermal expansion of liquid, nanosized fluorescence thermometers from nanoparticles based on temperature-dependent photoluminescence, nanoscale infrared thermometers from metal nanoparticles based on blackbody radiation, Coulomb Blockade nanothermometers from nanosized superconductor-insulator-metal tunnel junctions based on the Coulomb blockade of tunneling, and complex structured nanothermometers from MicroElectro-Mechanical-Systems based on temperature-dependent resonator quality factor or Fermi-level shift, etc. In all of these nanothermometers, the physical properties such as the voltage in nanoscale thermocouples, volume of liquid in liquid-in-tube nanothermometers, or photoluminescence spectrum in nanosized fluorescence thermometers are restored to their original state at room temperature after the temperature drops from high temperature. These nanothermometers are usually employed in real-time and in situ temperature detection, but not for recording and readout later, which is not useful for the situation where real-time readout is not possible like in the case of explosion, but the open-ended gallium-filled carbon nanotube thermometers can in principle also be a readout device after the event. Here another kind of nanothermometers, ex situ nanothermometers, which can record the temperature they were exposed to and be read later when the event is over, are demonstrated to measure temperature based on temperature-dependent size distribution and areal density of metal nanospheres. Compared with the reported nanothermometers, the nanothermometers made of nanospheres with a nanometer scaled spatial resolution, described in this paper, can record the highest temperature in the event and be read at a later time after the event is over. Figure 1a shows the deposited silver nanoparticles before being heated. Silver nanoparticles aggregate on the carbon supporting film coated on TEM grid. The shape of the nanoparticles is irregular and the size varies from 10nm to 100 nm. After heating to a certain temperature, smaller silver nanoparticles nucleate and grow on the whole carbon film (Fig. 1b). It is speculated that the surface diffusion causes the nucleation and growth of the new nanoparticles. Statistical analysis shows that all the nucleated nanoparticles are spherical with an average circularity M1⁄4 0.82–0.85. So these nucleated nanoparticles are named as nanospheres. The spherical morphology of the nanospheres should come from the surface melting because of melting point depression. The inset in Figure 1c shows a high-resolution TEM (HRTEM) image of a nanosphere with diameter of 16 nm observed at 500 8C. The surface of the silver nanosphere melts at 500 8Cwhile the melting point of bulk silver is 961 8C, a direct observation of the significant melting point reduction of nanosized silver particles. Themelting liquid layer covers the nanospheres, conceals the lowest-energy growth facets, and forms perfect spheres because of surface tension. When the surface-melted nanospheres cool down quickly from heating temperature, the main spherical shape is kept. High magnification TEM images (Fig. 1c) show that the nucleated nanospheres distribute uniformly on the carbon film and the size distribution of the nanospheres is narrow. HRTEM image of the nanospheres (Fig. 1d) indicates that the nanospheres are single crystalline at room temperature. EDS spectrum (Fig. 1e) and selected area electron diffraction of the nanospheres (Fig. 1f) confirm that the nucleated nanospheres are silver with face-centered cubic structure. Figure 2 shows the room temperature TEM images, size distribution, and the average diameter of the nanospheres after heating at different annealing temperatures and cooling down. Each sample was heated at a certain heating temperature for 5min and then cooled down to room temperature for TEM examination. TEM images (Fig. 2a) show that the nucleated nanospheres are smaller with heating at 300 8C than those at 500 8C. Histogram of the nanospheres (Fig. 2b) indicates that the diameter of most nanospheres is 4 nm after heating at 300 8C and 14 nm at 700 8C. The average diameter is systematically larger with higher heating temperature (Fig. 2c) because of coalescence.

Journal ArticleDOI
Zibo Li1, Kai Chen1, Zhanhong Wu1, Hui Wang1, Gang Niu1, Xiaoyuan Chen1 
TL;DR: 64Cu-labeled polyethylenimine can be used for both cell trafficking and tumor imaging and PEGylation reduces the toxicity of 64Cu-PEI and improves the tumor imaging ability.
Abstract: Purpose In this study, we exploited the potential of 64Cu-labeled polyethylenimine (PEI) for cell trafficking and tumor imaging as compared to copper-64-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (64Cu-PTSM).

Journal ArticleDOI
TL;DR: This review article summarizes the synthesis and characterization of various biomaterials that carry targeting motifs, imaging tags and therapeutic agents as theragnostics for imaging guided drug delivery.
Abstract: Molecular imaging allows non-invasive characterization and quantification of biological processes at cellular and molecular level. Such technologies make it possible to enhance our understanding of drug activity and pharmokinetic properties, and therefore aid decisions to select candidates that are most likely to benefit from targeted drug therapy. Targeted DDSs are nanometer-sized carrier materials designed for improving the biodistribution of systemically applied (chemo-)therapeutics by strictly localizing its pharmacological activity to the site or organ of action. The parallel development of molecular imaging and targeted drug delivery offers great challenges and opportunities for a single multifunctional platform technology, combining targeted motif, therapeutic agents and imaging agents for imaging guided drug delivery. This review article summarizes the synthesis and characterization of various biomaterials that carry targeting motifs, imaging tags and therapeutic agents as theragnostics.

Journal ArticleDOI
TL;DR: An Avi-tagged VEGF(121) protein is developed, which is site-specifically biotinylated in the presence of bacterial BirA biotin ligase, which retains high affinity for VEGFR in vitro and allows receptor specific targeting in vivo in a 67NR murine xenograft model.
Abstract: The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway is considered to be one of the most important regulators of angiogenesis and a key target in anticancer treatment. Imaging VEGFR expression can serve as a new paradigm for assessing the efficacy of antiangiogenic cancer therapy, improving cancer management, and elucidating the role and modulation of VEGF/VEGFR signaling during cancer development and intervention. In this study we developed an Avi-tagged VEGF(121) protein, which is site-specifically biotinylated in the presence of bacterial BirA biotin ligase. BirA biotinylated VEGF(121)-Avi (VEGF(121)-Avib) forms a stable complex with streptavidin-IRDye800 (SA800) that retains high affinity for VEGFR in vitro and allows receptor specific targeting in vivo in a 67NR murine xenograft model. In contrast, chemical coupling of IRDye800 abrogated the VEGFR binding ability of the modified protein both in vitro and in vivo. The VEGF(121)-Avib/SA800 complex (VEGF-Avib/SA800) may be used for quantitative and repetitive near-infrared fluorescence imaging of VEGFR expression and translated into clinic for evaluating cancer and other angiogenesis related diseases.

Patent
02 Dec 2009
TL;DR: In this article, a radiation absorbing structure consisting of a metallic layer and a plurality of protuberances formed in the metallic layer is proposed to selectively enhance radiation absorptance at wavelengths less than a cut-off wavelength.
Abstract: In one aspect, the present invention provides a radiation-absorbing structure, which includes a metallic layer and a plurality of protuberances formed in the metallic layer. The protuberances are configured to selectively enhance radiation absorptance at wavelengths less than a cut-off wavelength, for example, for incident radiation wavelengths less than about 2500 nm (2.5 microns), hi some cases, the cut-off wavelength below which the protuberance provide enhanced radiation absorptance can be about 2000 nm or 1800 nm. For example, the protuberances can enhance radiation absorptance for wavelengths in a range of about 300 nm to about 2500 nm, or in a range of about 300 nm to about 2000 nm, or in a range of about 300 nm to about 1800 nm. Further, in many embodiments the radiation absorbing structure exhibits a low emissivity at longer wavelengths, e.g., at wavelengths greater than about 3000 nm.

Proceedings ArticleDOI
12 Feb 2009
TL;DR: The utility of single walled carbon nanotubes (SWNTs) as targeted imaging agents in living mice bearing tumor xenografts is demonstrated for the first time.
Abstract: Photoacoustic molecular imaging is an emerging technology offering non-invasive high resolution imaging of the molecular expressions of a disease using a photoacoustic imaging agent. Here we demonstrate for the first time the utility of single walled carbon nanotubes (SWNTs) as targeted imaging agents in living mice bearing tumor xenografts. SWNTs were conjugated with polyethylene-glycol-5000 connected to Arg-Gly-Asp (RGD) peptide to target the αvβ3 integrin that is associated with tumor angiogenesis. In-vitro, we characterized the photoacoustic spectra of the particles, their signal linearity and tested their uptake by αvβ3-expressing cells (U87MG). The photoacoustic signal of SWNTs was found not to be affected by the RGD conjugation to the SWNTs and was also found to be highly linear with concentration (R2 = 0.9997 for 25-400nM). The cell uptake studies showed that RGD-targeted SWNTs gave 75% higher photoacoustic signal than non-targeted SWNTs when incubated with U87MG cells. In-vivo, we measured the minimal detectable concentration of SWNTs in living mice by subcutaneously injecting SWNTs at increasing concentrations. The lowest detectable concentration of SWNTs in living mice was found to be 50nM. Finally, we administered RGDtargeted and non-targeted SWNTs via the tail-vein to U87MG tumor-bearing mice (n=4 for each group) and measured the signal from the tumor before and up to 4 hours post-injection. At 4 hours post-injection, tumors of mice injected with RGD-targeted SWNTs showed 8 times higher photoacoustic signal compared with mice injected with non-targeted SWNTs. These results were verified ex-vivo using a Raman microscope that is sensitive to the SWNTs Raman signal.

Journal ArticleDOI
19 Feb 2009-PLOS ONE
TL;DR: The figure titles and legends are not affected and are correct as they appear.
Abstract: Figures 1 and 2 do not appear correctly. Figure 2 should be considered Figure 1, and the correct file for Figure 2 can be viewed here: The figure titles and legends are not affected and are correct as they appear.