Preclinical evaluation of local prolonged release of paclitaxel from gelatin microspheres for the prevention of recurrence of peritoneal carcinomatosis in advanced ovarian cancer

Abstract

Patients with advanced ovarian cancer develop recurrence despite initial treatment response to standard treatment of surgery and intravenous/intraperitoneal (IP) chemotherapy, partly due to a limited peritoneal exposure time of chemotherapeutics. Paclitaxel-loaded genipin-crosslinked gelatin microspheres (PTX-GP-MS) are evaluated for the treatment of microscopic peritoneal carcinomatosis and prevention of recurrent disease. The highest drug load (39.2 µg PTX/mg MS) was obtained by immersion of GP-MS in aqueous PTX nanosuspension (PTX_nano-GP-MS) instead of ethanolic PTX solution (PTX_EtOH-GP-MS). PTX release from PTX-GP-MS was prolonged. PTX_nano-GP-MS displayed a more controlled release compared to a biphasic release from PTX_EtOH-GP-MS. Anticancer efficacy of IP PTX-GP-MS (PTX_EtOH-GP-MS, D = 7.5 mg PTX/kg; PTX_nano-GP-MS D = 7.5 and 35 mg PTX/kg), IP nanoparticular albumin-bound PTX (D = 35 mg PTX/kg) and controls (0.9% NaCl, blank GP-MS) was evaluated in a microscopic peritoneal carcinomatosis xenograft mouse model. PTX_nano-GP-MS showed superior anticancer efficacy with significant increased survival time, decreased peritoneal carcinomatosis index score and ascites incidence. However, prolonged PTX release over 14 days from PTX_nano-GP-MS caused drug-related toxicity in 27% of high-dosed PTX_nano-GP-MS-treated mice. Dose simulations for PTX_nano-GP-MS demonstrated an optimal survival without drug-induced toxicity in a range of 7.5-15 mg PTX/kg. Low-dosed PTX_nano-GP-MS can be a promising IP drug delivery system to prevent recurrent ovarian cancer.