Dual-targeted Contrast Agent for US Assessment of Tumor Angiogenesis in Vivo

Willmann, Jürgen K.; Lutz, A.M.; Paulmurugan, Ramasamy; Patel, Manishkumar; Chu, Pauline; Rosenberg, Jarrett; Gambhir, Sanjiv S.

doi:10.1148/radiol.2483072231

Cited by 194 publications

(157 citation statements)

References 23 publications

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“…Accurate knowledge of the blood clearance time of targeted MBs is of practical value when planning targeted contrast-enhanced US experiments, since repeated injections of targeted MBs may be needed in the same animal in a single imaging session (3)(4)(5)(6)18). Our study showed that 50% of targeted MBs cleared after 3.5 minutes and about 95% were cleared from the blood circulation after 30 minutes.…”

Section: Molecular Imaging: Tumor Angiogenesis Assessment With Microbmentioning

confidence: 70%

Targeted Microbubbles for Imaging Tumor Angiogenesis: Assessment of Whole-Body Biodistribution with Dynamic Micro-PET in Mice

Willmann¹,

Cheng²,

Davis³

et al. 2008

Radiology

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163

138

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Purpose:To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice. Materials and Methods:Animal protocols were approved by the Institutional Administrative Panel on Laboratory Animal Care. Lipid-shell perfluorocarbon-filled MBs, targeted to VEGFR2 via anti-VEGFR2 antibodies, were radiolabeled by conjugating the radiofluorination agent N-succinimidyl-4-[ 18 F]fluorobenzoate (SFB) to the anti-VEGFR2 antibodies. These MBs were then injected intravenously into nude mice (n ϭ 4) bearing angiosarcomas, and the whole-body biodistribution of these probes was assessed for 60 minutes by using dynamic micro-PET. Results were compared with ex vivo gamma counting (n ϭ 6) and immunofluorescence staining (n ϭ 6). Control studies in angiosarcoma-bearing mice were performed with injection of the radiolabeled antibodies alone (n ϭ 3) or free SFB (n ϭ 3). A mixed-effects regression of MB accumulation on fixed effects of time and tissue type (tumor or muscle) and random effect of animal was performed. Results:VEGFR2-targeted MBs rapidly cleared from the blood circulation (50% blood clearance after approximately 3.5 minutes) and accumulated in the liver (mean, 33.4% injected dose [ID]/g Ϯ 13.7 [standard deviation] at 60 minutes) and spleen (mean, 9.3% ID/g Ϯ 6.5 at 60 minutes) on the basis of micro-PET imaging. These findings were confirmed with ex vivo gamma counting. Uptake of targeted MBs was significantly higher (P Ͻ .0001) in tumor than in adjacent skeletal muscle tissue. Immunofluorescence staining demonstrated accumulation of the targeted MBs within hepatic Kupffer cells and splenic macrophages. Biodistribution of the radiolabeled antibodies and free SFB differed from the distribution of the targeted MBs.

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Section: Molecular Imaging: Tumor Angiogenesis Assessment With Microbmentioning

confidence: 70%

Targeted Microbubbles for Imaging Tumor Angiogenesis: Assessment of Whole-Body Biodistribution with Dynamic Micro-PET in Mice

Willmann¹,

Cheng²,

Davis³

et al. 2008

Radiology

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163

138

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“…Interaction between VEGFR2 and a v b 3 integrin is necessary for VEGF to signal stress-activated protein kinase-2/p38 in normal endothelial cells undergoing angiogenesis. 39 Expression of VEGFR2 and a v b 3 was detected in endothelial cells in SKOV-3 EOC xenografts, 40 but to our knowledge, this is the first report of a relationship between VEGFR2 and integrin expression in EOC cells themselves. Our shRNAKDR OVCAR-3 cells showed altered survival in suspension, which was reflected in their ability to form ascites and subcutaneous cystic tumors in vivo.…”

Section: Vegfr2 Rnai Knockdown Increases Eoc Malignancy Sai Adham Et Almentioning

confidence: 73%

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

Adham

Sher

Coomber

2010

Laboratory Investigation

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Human epithelial ovarian cancer (EOC) is the most lethal neoplasm affecting the female genital tract, and is characterized by overexpression of vascular endothelial growth factor (VEGF) and growth as ascites. Anti-VEGF strategies are currently used in EOC therapy with promising results; however, molecular targeting of specific VEGF receptors on the cancer cells themselves has not been explored to date. We previously showed that activation of a VEGF/VEGFR2 signaling loop in EOC cells supports their survival in suspension, and short-term pharmacological inhibition of this loop increased EOC cell apoptosis in vitro. In this study, we stably knocked down VEGFR2 in OVCAR-3 and SKOV-3 EOC cells using short hairpin RNA (shRNA), an RNA interference strategy that could potentially overcome chemoresistance arising with angiogenic inhibitors. Unexpectedly, we observed an induction of more aggressive cellular behavior in transfected cells, leading to increased growth in mouse xenografts, enhanced accumulation of ascites, increased VEGF and neuropilin-1 (NRP-1) expression, and decreased expression of adhesion proteins, notably cadherins and integrins. Sonic hedgehog (SHH) pathways do not seem to be involved in the upregulation of NRP-1 message in VEGFR2 knockdown cells. Supporting our mouse model, we also found a significant increase in the ratio between NRP-1 and VEGFR2 with increasing tumor grade in 80 cases of human EOC. The change in EOC behavior that we report in this study occurred independent of the angiogenic response and shows the direct effect of VEGF blockade on the cancer cells themselves. Our findings highlight the possible confounding events that may affect the usefulness of RNAi in a therapeutic setting for disrupting EOC cell survival in ascites.

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“…Imaging results demonstrated a significantly higher average intensity in images from studies using targeted microbubbles compared with studies using only control microbubbles (461) (see FIGURE 7B). Following these results, Willmann et al (460) investigated the use of a dual-targeted microbubble for visualization of angiogenesis by conjugating two different antibodies known to bind different markers of angiogenesis, VEGFR2 and ␣v␤3 integrin, to the shell of perfluorocarbon-filled microbubbles. Results from these US imaging studies, using human ovarian cancer xenograft tumor model in mice, showed that dual-targeted microbubbles provided superior images compared with that of microbubbles targeted at one or the other angiogenic marker (either VEGFR2 and ␣v␤3 integrin) (460).…”

Section: )mentioning

confidence: 99%

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

James

Gambhir

2012

Physiological Reviews

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923

935

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Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.

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Dual-targeted Contrast Agent for US Assessment of Tumor Angiogenesis in Vivo

Cited by 194 publications

References 23 publications

Targeted Microbubbles for Imaging Tumor Angiogenesis: Assessment of Whole-Body Biodistribution with Dynamic Micro-PET in Mice

Targeted Microbubbles for Imaging Tumor Angiogenesis: Assessment of Whole-Body Biodistribution with Dynamic Micro-PET in Mice

Molecular blockade of VEGFR2 in human epithelial ovarian carcinoma cells

A Molecular Imaging Primer: Modalities, Imaging Agents, and Applications

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