Imaging of Vx‐2 rabbit tumors with α_νβ₃‐integrin‐targeted ¹¹¹In nanoparticles

Abstract

Earlier tumor detection can improve 5-year survival of patients, particularly among those presenting with cancers less than 1 cm in diameter. a m b 3 - Targeted 111 In nanoparticles (NP) were developed and studied for detection of tumor angiogenesis. Studies were conducted in New Zealand white rabbits implanted 12 days earlier with Vx-2 tumor. a m b 3 - Targeted 111 In/NP bearing 10 111In/NP vs. 1 111In/NP nuclide payloads were compared to nontargeted radiolabeled control particles. In vivo competitive binding studies were used to assess ligand-targeting specificity. a m b 3 -Integrin-targeted NP with 10 111In/NP provided better (p < 0.05) tumor-to-muscle ratio contrast (6.3 6 0.2) than 1 111In/NP (5.1 6 0.1) or nontargeted particles with 10 111In/NP (3.7 6 0.1) over the initial 2-hr postinjection. At 18 hr, mean tumor activity in rabbits receiving a m b 3 -integrin-targeted NP was 4-fold higher than the nontargeted control. Specificity of the NP for the tumor neovasculature was supported by in vivo competition studies and by fluorescence microscopy of a m b 3 -targeted fluorescent-labeled NP. Biodistribution studies revealed that the primary clearance organ in rabbits as a %ID/g tissue was the spleen. Circulatory half-life (t 1/2b ) was estimated to be 5 hr using a 2-compartment model. a m b 3 - Targeted 111 In perfluorocarbon NP may provide a clinically useful tool for sensitively detecting angiogenesis in nascent tumors, particularly in combination with secondary highresolution imaging modalities, such as MRI. ' 2007 Wiley-Liss, Inc.Key words: indium; angiogenesis; integrin; nanoparticles; Vx2; cancer Data accumulated over the last 25 years in the surveillance, epidemiology and end results cancer registry support the principle that earlier tumor detection improves 5-year survival of patients with either localized or regional invasive breast carcinoma. 1 Improvements in survival were correlated with an overall downward shift in tumor size distribution, with particular advantage noted among patients presenting with cancers less than 1 cm. A widespread desire to detect and treat cancer earlier has spawned interest in molecular imaging and genomic-proteomic technologies, which in combination with new strategies to treat cancer may further improve cancer survival.One approach to identifying small solid tumors has involved early detection of angiogenesis by targeting unique biosignatures of neovascular endothelium, such as a v b 3 -integrin. We have previously demonstrated that paramagnetic perfluorocarbon emulsions targeted to the a v b 3 -integrin can be used to detect the neovasculature of tumors 30 mm 3 at clinical field strengths (1.5 T). Because perfluorocarbon nanoparticles (NP) have a nominal particle size of 250 nm and are constrained within the vasculature, access to a v b 3 -integrin expressed on extravascular macrophages, smooth muscle and other cells is sterically precluded. MRI provides outstanding high-resolution images of even minute tumors enhanced by the bound paramagnetic NP; however, the ...

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