Preclinical evaluation of a novel cathepsin-activated fluorescent probe VGT-309 for identification of ovarian cancer in a mouse model (248)

Abstract

<b>Objectives:</b> Cathepsin activity is upregulated in many solid cancers. VGT-309 is a novel near-infrared cathepsin-activated fluorescent probe that covalently binds to cysteine cathepsins, localizing the fluorescent signal to sites of high cathepsin activity. The goal was to determine the utility of VGT-309 in a mouse model of ovarian cancer. <b>Methods:</b> NCG mice with luciferase-labeled ovarian cancer cell lines (OVCAR3-ffLuc, OVCAR8-ffLuc), implanted subcutaneously (SQ) (<i>n</i>=6) or intraperitoneally (IP) (<i>n</i>=6), were injected with intravenous VGT-309 (2 mg/kg) and sacrificed after 24 hours for fluorescence imaging and anatomical dissection. Near-infrared (NIR) and luciferase imaging were performed on tumors and internal organs with the Pearl Imaging system. Image Studio Lite was used to quantitate fluorescence signals. Background muscle signal was compared with specimen signal from various sized tumors and organs to establish signal-to-background ratio (SBR) and an average was taken. <b>Results:</b> Twenty-four hours after mice were injected with VGT-309, we were able to visualize NIR fluorescence signal in SQ mouse models for OVCAR3 and OVCAR8 <i>in situ</i>. After dissecting tumors and organs, we compared NIR fluorescence activity with luciferase activity. The fluorescence signal from VGT-309 overlapped with the luciferase signal, indicating that VGT-309 was able to specifically image cancerous tissue in both SQ and IP models. There was high SBR noted for the tumors from the SQ tumor models (SBR 14 for OVCAR8 and 14.3 for OVCAR3), as compared to the peritoneum (SBR 0.7 for OVCAR8 and 0.6 for OVCAR3). Similar findings were also noted for the IP tumors (SBR 10.1 for OVCAR8 and 12.6 for OVCAR3) as compared to the peritoneum (SBR 1.4 for OVCAR8 and 0.6 for OVCAR3). <b>Conclusions:</b> VGT-309 is a cathepsin-based activatable fluorescence probe that can visualize ovarian cancer cells in an animal model with a high signal-to-background ratio as compared to the peritoneum. VGT-309 is currently in early phase clinical trials for lung cancer. These data would encourage clinical testing of VGT-309 as a tool for the intraoperative identification of ovarian cancers.