Data from Radiotheranostic Agent <sup>64</sup>Cu-cyclam-RAFT-c(-RGDfK-)<sub>4</sub> for Management of Peritoneal Metastasis in Ovarian Cancer

Abstract

<div>AbstractPurpose:<p>Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. α<sub>V</sub>β<sub>3</sub> integrin (α<sub>V</sub>β<sub>3</sub>) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant α<sub>V</sub>β<sub>3</sub>-positive OCPM mouse models, we studied the theranostic potential of an α<sub>V</sub>β<sub>3</sub>-specific radiopeptide, <sup>64</sup>Cu-cyclam-RAFT-c(-RGDfK-)<sub>4</sub> (<sup>64</sup>Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.</p>Experimental Design:<p>α<sub>V</sub>β<sub>3</sub>-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. <sup>64</sup>Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.</p>Results:<p>Intraperitoneal administration was an efficient route for targeting <sup>64</sup>Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of <sup>64</sup>Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. <sup>64</sup>Cu-RaftRGD–based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2–17.2 mm). <sup>64</sup>Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.</p>Conclusions:<p>Collectively, these results demonstrate the all-in-one potential of <sup>64</sup>Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing α<sub>V</sub>β<sub>3</sub>- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.</p></div>