Cisplatin‐incorporated Polymeric Micelles Eliminate Nephrotoxicity, While Maintaining Antitumor Activity

Abstract

cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), a potent anticancer agent, was bound to the aspartic acid residues of poly(ethylene glycol)-poly(aspartic acid) (PEG-P(ASP)) block copolymer by ligand substitution reaction at the platinum atom of CDDP. The polymeric drug thus obtained was observed to form a micelle structure in aqueous medium, showing excellent water solubility. In the present study, in vitro and in vivo antitumor activity against several human tumor cell lines, toxicity and pharmacokinetic characteristics in rodents of CDDP-incorporated polymeric micelles (CDDP/m) were evaluated in comparison with those of CDDP. In vitro, CDDP/m exhibited 10-17% of the cytotoxicity of CDDP against human tumor cell lines. CDDP/m given by intravenous (i.v.) injection yielded higher and more sustained serum levels than CDDP. In vivo CDDP/m treatment resulted in higher and more sustained levels in tumor tissue than CDDP, and showed similar antitumor activity to CDDP against MKN 45 human gastric cancer xenograft. CDDP/m treatment caused much less renal damage than CDDP. These results indicate that CDDP/m treatment can reduce CDDP-induced nephrotoxicity without compromising the anticancer cytotoxicity of CDDP.Key words: Polymeric micelles -Cisplatin -Nephrotoxicity -EPR effect -DDS cis-Diamminedichloroplatinum (II) (cisplatin, CDDP), the most commonly used anticancer agent, consists of a central platinum atom surrounded by four ligands, two ammonias and two chlorides.1) A high antitumor activity results when the two chloride ligands in CDDP are bi-aquated in aqueous physiological environments; CDDP can then interact directly with DNA and display cytotoxic activity.2, 3) The clinical utility of CDDP is limited by significant general organ toxicity including myelosuppression, 4) ototoxicity, 5) gastrointestinal disturbance, 5, 6) and especially acute nephrotoxicity.7) CDDP, a low-molecularweight compound, is distributed readily into almost all tissues and intracellular compartments. CDDP traverses plasma membranes rapidly via passive diffusion or active transport, and is also rapidly cleared from blood by glomerular excretion, limiting its therapeutic availability. Injection of the maximum permissible amount of this lowmolecular-weight drug to raise its therapeutic concentration and AUC (area under the curve) results in severe toxicity without significantly greater antitumor efficacy. Therefore, several novel forms of controlled release drug delivery have been designed to improve distribution and to prolong the exposure of the tumor to an effective drug concentration.It is known that solid tumors generally possess the following pathophysiological characteristics: hypervascularity, incomplete vascular architecture, secretion of vascular permeability factors, and also the absence of effective lymphatic drainage, preventing the efficient clearance of accumulated macromolecules. These characteristics, unique to solid tumors, are believed to be the basis of the so-called EPR effect (enhanced permeability and retention ef...

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