Poly(gamma,L-glutamic acid)-cisplatin conjugate effectively inhibits human breast tumor xenografted in nude mice.
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.
Ye
Haifeng
H
Laboratory of Molecular Biology, School of Life Science, East China Normal University, 3663 Zhongshan North Road, Shanghai, 200062, PR China.
Jin
Li
L
Hu
Rongzhang
R
Yi
Zhengfang
Z
Li
Jing
J
Wu
Yelin
Y
Xi
Xuguang
X
Wu
Zirong
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002945:Cisplatin / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011099:Polyglutamic Acid / Q000737:chemistry*
D000970:Antineoplastic Agents; D011099:Polyglutamic Acid; D002945:Cisplatin