A Novel Formulation Of Cisplatin With Gamma-Polyglutamic Acid And Chitosan Reduces Its Adverse Renal Effects: An In Vitro And In Vivo Animal Study

Cisplatin (cis-diamminedichloroplatinum (II); CDDP) is a key chemotherapeutic agent but causes renal damage and other off-target effects. Here, we describe the pharmacological and biochemical characteristics of a novel formulation of CDDP complexed with gamma-polyglutamic acid (gamma-PGA) and chitosan (CS), gamma-PGA/CDDP-CS, developed by complexing CDDP with gamma-PGA, then adding CS (15 kDa; 10 mol%/gamma-PGA). We analyzed tumor cytotoxicity in vitro, as well as blood kinetics, acute toxicity, and antitumor efficacy in vivo in BALB/cAJcl mice. gamma-PGA/CDDP-CS showed pH-dependent release in vitro over 12 days (9.1% CDDP released at pH 7.4; 49.9% at pH 5.5). It showed in vitro cytotoxicity in a dose-dependent manner similar to that of uncomplexed CDDP. In a mesothelioma-bearing mouse model, a 15 mg/kg dose of CDDP inhibited tumor growth regardless of the type of formulation, complexed or uncomplexed; however, all mice in the uncomplexed CDDP group died within 13 days. gamma-PGA/CDDP-CS was as effective as free CDDP in vivo but much less toxic.