Abstract
Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVβ3 integrin (αVβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVβ3-positive OCPM mouse models, we studied the theranostic potential of an αVβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment. αVβ3-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64Cu-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. Intraperitoneal administration was an efficient route for targeting 64Cu-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 64Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. 64Cu-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). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity. Collectively, these results demonstrate the all-in-one potential of 64Cu-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 αVβ3- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.
Highlights
Epithelial ovarian cancer (OC) accounts for over 90% of ovarian malignancies, typically occurs in postmenopausal women, and remains the leading cause of death from gynecological malignancies [1]
Using the fluorescent surrogate Cy5.5-RaftRGD in our unique high-resolution multifluorescence analysis, we found that the intratumoral distribution (ITD) of 64Cu-RaftRGD was spatially distinct from but complementary to that of hypoxia. 64Cu-RaftRGD–based positron emission tomography (PET) enabled clear visualization of multiple ovarian cancer peritoneal metastasis (OCPM) deposits and ascites; biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2–17.2 mm). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, and negligible toxicity
Based on the ITD finding, we propose that pairing V 3and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments
Summary
Epithelial ovarian cancer (OC) accounts for over 90% of ovarian malignancies, typically occurs in postmenopausal women, and remains the leading cause of death from gynecological malignancies [1]. OC is a highly metastatic disease characterized by widely disseminated tumor depositions throughout the peritoneal cavity together with malignant ascites [2]. Because of the lack of clear symptoms or an effective screening method in the early stage of the disease, over 70% of OC patients are diagnosed with peritoneal metastases (PMs) and have a 5-year survival rate of
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