Résumé
In 2024, around 13,000 women are expected to die from Ovarian Cancer (OC) in the US. Masked disease progression leads to late-stage diagnosis after the disease has spread to the peritoneal cavity (peritoneal carcinomatosis, PC). Treatments do not show substantial curative benefits, as disease will reoccur in 70-90% of patients. Targeted Radionuclide Therapy (TRT) specifically irradiates tumors sparing the surrounding healthy tissues, offering an attractive therapeutic option for metastatic spread. Here, we investigated the radiosensitizing effects of Gadolinium-based nanoparticles (Gd-NPs) combined with [177Lu]Lu-DOTA-trastuzumab. [177Lu]Lu-DOTA-trastuzumab injected activity (IA) combined or not with Gd-NPs was investigated in athymic female mice bearing intraperitoneal (IP) SKOV3 HER2+ tumor xenografts. The therapeutic efficacy and toxicity of 5 MBq [177Lu]Lu-DOTA-trastuzumab with Gd-NPs administered in different fractionated regimens were evaluated. NaCl, trastuzumab plus Gd-NPs and [177Lu]Lu-DOTA-trastuzumab were used as controls. Biodistribution and dosimetry were determined, and Monte Carlo simulation of energy deposits was performed. Gd-NPs’ subcellular localization and uptake, cytotoxic effects of the combination and underlying radiosensitization mechanisms were investigated in 3 OC cell lines (SKOV3, OVCAR3, A431). Optimal therapeutic response was obtained with 2 injections of 5 mg Gd-NPs at 24 and 72 h after injection of [177Lu]Lu-DOTA-trastuzumab. The combination delayed tumor growth and significantly increased mice's median survival compared to all controls. SPECT/CT imaging on recovered tumor nodules highlighted specific targeting of both compounds after IP injection. In vitro experiments support the preclinical data, showing increased cytotoxicity of the drug combination. Fluorescence and Transmission Electron Microscopy (TEM) imaging showed co-localization of the NPs with the lysosomal compartment. Combination with Gd-NPs increased Reactive Oxygen Species (ROS) production and lipid peroxidation, suggesting a potential role of ferroptosis in the NPs-mediated toxicity. Fewer lysosomes were observed associated with cytoplasmic pH decrease, suggesting lysosomal disruption. Cytoplasmic vacuolization, mitochondrial depolarization, apoptosis, and micronuclei formation were noted and reversed by iron chelation. Dosimetry calculations revealed that exposure of Gd-NPs to 177Lu increased the Auger electron yield, but not the absorbed dose. We provide strong evidence in vivo of Gd-NPs radiosensitizing effect when combined, for the first time, with a radiolabeled antibody. At a cellular level, we report a high dependence on iron-derived hydroxyl radical production, leading to a lysosomal–mediated cell disruption. The radiosensitization effect allows reduction of the IA in mice, keeping a high therapeutic efficacy while decreasing treatment-related toxicities. As Gd-NPs are already combined with EBRT in clinical trials, the present study opens perspectives to optimize and translate this theranostic strategy for the treatment of OC-derived PC. Citation Format: Clara Diaz Garcia-Prada, Lena Carmes, Ali Parach, Alejandro Bertolet, Sophie Poty, Jan Schuemann, Olivier Tillement, François Lux, Julie Constanzo, Jean-Pierre Pouget.Gadolinium-based nanoparticles sensitize ovarian peritoneal carcinomatosis to targeted radionuclide therapy.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P009