Poly(γ,l-glutamic acid)–cisplatin conjugate effectively inhibits human breast tumor xenografted in nude mice

Abstract

An easily administered cis-dichlorodiammineplatinum (II) (CDDP) formulation with less toxicity and greater antitumor effect would be extremely valuable. We describe PGA-CDDP, a water-soluble CDDP derivative. The hydrolyzed gamma-PGA has a molecular weight between 45 and 60 kDa, and is a water-soluble, biodegradable, and nontoxic polymer produced by microbial fermentation. CDDP can be released from the resulting conjugate in PBS: there was initially a burst release during the first 6h, followed by sustained release. In vitro, PGA-CDDP was less potent than free CDDP at inhibiting cell growth in the Bcap-37 cell line. PGA-CDDP was given as 3 doses at an equivalent CDDP dose of 4 or 12 mg/kg with 2-day intervals between injections to Bcap-37-grafted mice. This treatment showed stronger antitumor activity and was less toxic than CDDP in vivo. Antitumor activity assays demonstrated that the PGA-CDDP conjugate treatment had significantly higher antitumor activity than control PBS treatment (P<0.01). PGA-CDDP also increased the survival of mice bearing Bcap-37 cells with reference to PBS treatment or free CDDP treatment. Furthermore, mice treated with PGA-CDDP (4 mg/kg, administered on day 0 and 5) showed no body weight loss (P>0.05 with respect to PBS treatment), whereas free CDDP treatment at the same dose caused a body weight loss of 20-30% (P<0.001). These findings suggest that PGA produced by microbial fermentation may be used as an effective drug carrier for CDDP and that PGA-CDDP may have potential applications in the treatment of human breast cancer.