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.