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Novel Cisplatin-Incorporated Polymeric Micelles Can Eradicate Solid Tumors in Mice

¹ Department of Materials Science and Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo;
² NanoCarrier Co., Ltd., Chiba;
³ Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo;
⁴ Pharmacology Division, National Cancer Center Research Institute, Tokyo; and
⁵ Investigative Treatment Division, National Cancer Center Research Institute East, Chiba, Japan

Polymeric micelles incorporating cisplatin (CDDP) were prepared through the polymer-metal complex formation between CDDP and poly(ethylene glycol)-poly(glutamic acid) block copolymers, and their utility as a tumor-targeted drug delivery system was investigated. CDDP-incorporated micelles (CDDP/m) had a size of 28 nm with remarkably narrow distribution. CDDP/m were very stable in distilled water even in long-time storage, but exhibited a sustained drug release accompanied with the decay of the carrier itself in physiological saline. These micelles showed remarkably prolonged blood circulation and effectively accumulated in solid tumors (Lewis lung carcinoma cells) according to the passive targeting manner (20-fold higher than free CDDP). Reduced accumulation of the micelles in normal organs provided high selectivity to the tumor. In vivo antitumor activity assay demonstrated that both free CDDP and the CDDP/m had significant antitumor activity in C 26-bearing mice compared with nontreatment (P < 0.05 for free CDDP; P < 0.01 for CDDP/m), but complete tumor regression was observed only for the treatment with CDDP/m. Four of 10 mice treated with CDDP/m (4 mg/kg; five times administration at 2-day intervals) showed complete tumor regression with no significant body weight loss, whereas free CDDP treatment at the same drug dose and regime resulted in tumor survivals and 20% of body weight loss. These data suggest that CDDP/m could be a promising formulation of CDDP for the targeted therapy of solid tumors.

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