Improved i.p. drug delivery with bioadhesive nanoparticles

Significance

Resistance to platinum-based chemotherapies and paclitaxel is common in recurrence of both high-grade ovarian and endometrial cancers. Paclitaxel resistance has been correlated with overexpression of class III β-tubulin, the preferential target of the epothilones, microtubule-stabilizing agents. Epothilone B (EB) is manifold more effective than paclitaxel, but clinical use is limited by side effects. To reduce side effects, we encapsulated EB into bioadhesive nanoparticles (BNPs), reasoning that bioadhesive nanoparticles loaded with epothilone B (EB/BNPs) would interact with abdominal tissues and gradually release EB in proximity of peritoneal cancer implants, thus maintaining EB concentration at the site of action and limiting systemic exposure and toxicity. Our experiments show the higher therapeutic activity and limited toxicity of EB/BNPs compared with nonadhesive nanoparticles loaded with EB or carrier-free EB.

Abstract

The i.p. administration of chemotherapy in ovarian and uterine serous carcinoma patients by biodegradable nanoparticles may represent a highly effective way to suppress peritoneal carcinomatosis. However, the efficacy of nanoparticles loaded with chemotherapeutic agents is currently hampered by their fast clearance by lymphatic drainage. Here, we show that a unique formulation of bioadhesive nanoparticles (BNPs) can interact with mesothelial cells in the abdominal cavity and significantly extend the retention of the nanoparticles in the peritoneal space. BNPs loaded with a potent chemotherapeutic agent [epothilone B (EB)] showed significantly lower systemic toxicity and higher therapeutic efficacy against i.p. chemotherapy-resistant uterine serous carcinoma-derived xenografts compared with free EB and non-BNPs loaded with EB.