Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer

Zhao-Hui Jin (1) , Atsushi Tsuji (1) , Mélissa Degardin (2) , Aya Sugyo (1) , Satoshi Obara (1) , Hidekatsu Wakizaka (1) , Kotaro Nagatsu (1) , Kuan Hu (1) , Ming-Rong Zhang (1) , Pascal Dumy (3) , Didier Boturyn (2) , Tatsuya Higashi (1)

1 QST - National Institutes for Quantum and Radiological Science and Technology
2 DCM - Département de Chimie Moléculaire
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

Purpose: 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-positiveOCPM 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. Experimental Design: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. Results: Intraperitoneal administration was an efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescent 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; 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. Conclusions: 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. Based on 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.

Mots clés: Positron emission tomography; Tumor hypoxia; Ttargeted radionuclide therapy; 64Cu-labeled multimeric RGD peptide; Radiopeptide; Theranostics; Tumor angiogenesis; αVβ3 integrin; Ovarian cancer peritoneal metastases; Intra- and intertumoral heterogeneity

Domaines: Chimie thérapeutique; Cancer; Médecine nucléaire; Gynécologie et obstétrique

Zhao-Hui Jin, Atsushi Tsuji, Mélissa Degardin, Aya Sugyo, Satoshi Obara, et al.. Radiotheranostic Agent 64Cu-cyclam-RAFT-c(-RGDfK-)4 for Management of Peritoneal Metastasis in Ovarian Cancer. Clinical Cancer Research, 2020, 26 (23), pp.6230-6241. ⟨10.1158/1078-0432.CCR-20-1205⟩. ⟨hal-02943140⟩