Abstract 5402: Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery

Attempted surgical removal of advanced stage peritoneal cancers is mostly insufficient and often fails in areas affected by disseminated disease. But the successful elimination of peritoneal surface spread is known to have a significant impact on patient survival. However, standard therapies such as surgical cytoreduction and systemic chemotherapy combined with radiation have only shown limited-efficacy, accessibility, and nonspecific toxicity as well as frequent development of multidrug resistance (MDR). To overcome those limitations, we previously reported about the development of a mucoadhesive, chitosan-hybrid gel (CS(BCDDP)) embedded with cisplatin (CDDP) containing alginate beads for intraperitoneal administration (# 1948, AACR 2012). Here we report additional results illustrating CDDP release from CS(BCDDP) at different pH in vitro, CDDP accumulation to genomic DNA (gDNA) isolated from tissues as well as toxicity data in vivo. To determine the amount of CDDP released from CS (BCDDP) in vitro, B50μgCDDP, CDDP-chitosan (CS50μgCDDP) and CS (B50μgCDDP) pellets (8 mm o, 1.5 mm thickness) were prepared and placed into a 6 well plate containing 2 ml/well PBS (pH 6, 7, 7.4 and 8). Multiple samples were collected during the 24 h incubation (37°C, 100rpm) period. The majority (75%) of CDDP was successfully released from CS(BCDDP) within the first 2 h at pH 7.4 showing the rate of drug release to be inversely correlated with pH yielding a more rapid release under acidic pH conditions. To assess CDDP accumulation to gDNA, inductively coupled plasma mass spectrometry (ICP-MS) was performed with tissue samples obtained from the left peritoneal sidewall of female nu/nu mice 24 hours after treatment with CS50μgCDDP, CS(B50μgCDDP), intravenously (i.v.) CDDP(IV50μgCDDP) and intraperitoneal (i.p) CDDP (IP50μgCDDP), respectively. The results demonstrated a greater than three-time enhancement of CDDP-accumulation to the gDNA from CS(B50μgCDDP) when compared to CS50μgCDDP and IV50μgCDDP administration. In addition, CS(B50μgCDDP) showed similar levels of CDDP adduction compared to direct IP50μgCDDP administration. Moreover, assessment of CDDP accumulation in kidneys and blood 24 h following treatment with either IP50μgCDDP or CS(B50μgCDDP), demonstrated significantly decreased kidney toxicity from CS(B50μgCDDP) when compared to IP50μgCDDP. Our results, therefore strongly suggest that administration of this hybrid gel directly to mucosal surfaces such as the peritoneal cavity is feasible making it an advantageous, safe and non-toxic intraperitoneal drug delivery system for the treatment of disseminated peritoneal cancers such as advanced or recurrent ovarian cancer. Currently ongoing experiments are evaluating the efficacy and safety of our hybrid gel/CDDP in an orthotopic peritoneal cancer animal model. Citation Format: Sungpil Cho, Yongen Sun, Elke A. Jarboe, Andrew P. Soisson, Mark K. Dodson, David K. Gaffney, C.Mattew Peterson, Margit M. Janat-Amsbury. Tissue accumulation and toxicity of platinum released from a novel chitosan hybrid gel for intraperitoneal drug delivery. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5402. doi:10.1158/1538-7445.AM2014-5402