Preclinical development of a docetaxel nanocarrier to enhance prostate cancer radiosensitivity.

Abstract

41 Background: From 30% to 50% of high risk prostate cancer patients who undergo radiation therapy (RT) will have a biochemical failure. Combining chemotherapy, such as Docetaxel (DXL), with RT can enhance its efficiency. Multidrug resistance mechanisms often limit drug efficacy by decreasing tumor cell intracellular concentration of drugs. There is interest to develop nanocarrier of DXL to maintain drug inside cancer cells by improving its efficacy. The purpose of this study was to develop a titanate-nanotube (TiONt)-DXL nanocarrier (nanohybrid) and to evaluate its in vivobiodistribution as well as its radiosensitizing efficacy in association with RT on a hormone-independent prostate cancer model. Methods: DXL molecules were grafted on TiONts using PEG-3000 molecules to generate the nanohybrid. In vitrocytotoxic activity of the nanohybrid was evaluated on PC-3 cell line using MTS assay. After intratumoral injection, biodistribution analysis was performed by SPEC-CT imaging of mice bearing subcutaneous PC-3 human prostate tumors. To evaluate the benefit of nanohybrid and RT association, tumors were irradiated using 3 fractions of 4Gy administrated after the injection of nanohybrids. Nine groups of 7 mice were used to evaluate nanohybrid and RT association efficacy : untreated, control with buffer IT injection, +/- RT, free DXL, +/- RT, TiONt +/- RT and TiONt-DXL +/- RT. Mice behavior, health status and tumor volume were monitored twice a week until tumor growth recovery. Results: Biodistribution kinetics showed that more than 70% of nanohybrids were localized into the tumor 96 hours after injection. Mice receiving nanohybrid-RT exhibited a significant tumor growth delay to reach a volume of 1,000mm3compared to mice receiving free DXL-RT: 73.7 days (median, [58.9-89]) vs 56 days (median, [31.5-74]) (p=0.0127). Conclusions: TiONt-DXL improves RT efficacy compared to free DXL. These results suggest that local control might be enhanced by TiONt-DXL. TiONt-DXL can be injected as a radiosensitizer in men harboring high risk localized prostate cancer with needles during prostate brachytherapy procedure.