Biodegradable polymer-mediated intratumoral delivery of cisplatin for treatment of human head and neck squamous cell carcinoma in a chimeric mouse model.

Abstract

The effectiveness of chemotherapeutic agents is proportional to the dose of the agents at their targets; however, the dose is limited by systemic toxicity. Attempts have been made to improve therapeutic effectiveness by increasing maximum tolerated dose (MTD) of chemotherapeutic agents using various local and regional drug delivery systems. Herein we report the use of an injectable biodegradable polymer to deliver cisplatin for intratumoral treatment of human head and neck squamous cell carcinoma (HNSCC) in a chimeric mouse model. The objectives of this research project were (1) to determine the release kinetics of cisplatin from the polymer delivery system, (2) to identify the MTD of polymer-delivered cisplatin, and (3) to evaluate its therapeutic efficacy. To determine the in vivo release kinetics, cisplatin-loaded polymer was injected subcutaneously into rats. Implants were removed and analyzed for remaining cisplatin by a high-performance liquid chromatography technique. Sera from these rats were assayed for platinum by atomic absorption spectrophotometry. For MTD determination, SCID mice were engrafted subcutaneously with fresh biopsy specimens of HNSCC. Various doses of free or polymer-loaded cisplatin were injected intratumorally. MTD was estimated based on the threshold at which all mice survived. The antitumor efficacy of free and polymer-loaded cisplatin at their respective MTD was assayed on the same chimeric mouse model. The polymer delivery system released 80% of the loaded cisplatin in vivo over a 7-day period. The polymer-delivered cisplatin exhibited higher MTD (36 mg/kg) than free cisplatin (18 mg/kg) and had a statistically significant tumor suppression effect compared with free cisplatin when used at their respective MTD. The polymer delivery system can sustain cisplatin release for a period of 7 days. It can increase MTD and potentially enhance the antitumor efficacy of cisplatin against human head and neck cancers.