Radiosensitization by intratumoral administration of cisplatin in a sustained-release drug delivery system

Abstract

Purpose: Effects of combining local irradiation and intratumoral (i.t.) administration of cisplatin (CDDP) in a sustained-release drug delivery system (epi gel) were studied in a murine SCCVII squamous cell carcinoma model in mice. Materials and methods: The epinephrine injectable gel was used as a drug delivery system. Intratumoral pharmacokinetics of CDDP was studied by using 195mPt-CDDP. The tumor volume quadrupling time (TVQT) and tumor growth delay (TGD) time were used to evaluate the antitumor efficacy of treatment regimens. Results: The concentration and residence of 195mPt-CDDP was significantly higher in tumors treated with 195mPt-CDDP/epi gel than in tumors treated with 195mPt CDDP gel or 195mPt-CDDP suspension. Intratumoral administration of CDDP/epi gel (4 mg/kg) produced an average TGD time of 15.5±2.8 days, which was 5.2 – 7.4 times longer than CDDP suspension i.t. or i.p. When combined with a single dose of radiation (10 Gy), i.t. administration of CDDP/epi gel was 2.0 – 3.6-fold as effective as administered i.t. in suspension (39.2±4.1 vs. 19.8±3.9 days of TGD, P<0.05) or i.p. in solution (39.2±4.1 vs. 11.0±1.6 days, P<0.001) in inhibiting tumor growth and produced 20–60% complete remission of tumors. When combined with fractionated irradiation, pre-irradiation CDDP administration was more effective than post-radiation administration (26.7 vs. 12.1 days of TGD, P<0.05). Mice treated with CDDP/epi gel i.t. alone or in combination with irradiation, had little systemic toxicity. Conclusions: Intratumoral administration of CDDP using the sustained-release drug delivery system is an efficient and safe method to maximize the drug concentration in tumor, minimize the systemic toxicity and enhance antitumor efficacy of irradiation.