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...

KRN5500 is a highly active new semi-synthetic water-insoluble anticancer agent. The only mechanism of anticancer activity of KRN5500 described so far is an inhibitory effect on protein synthesis. At the time of writing, a phase I clinical trial is under way at the National Cancer Center Hospital, Tokyo, and at the National Cancer Institute in the USA. Although preclinical data did not indicate lung toxicity, some cases of severe pulmonary disorder were reported in the phase I clinical trials. This study has been conducted to examine whether incorporation of KRN5500 into polymeric micelles (KRN/m) could reduce the toxic effects caused by the current formulation of KRN5500. The in vitro and in vivo antitumor activities of KRN5500 and KRN/m were compared. Pulmonary toxicity of KRN5500 and KRN/m was studied using a bleomycin (BLM)-induced lung injury rat model. In BLM-rats, extensive pulmonary hemorrhage with diapedesis was observed with KRN5500 i.v. bolus injection at the dose of 3 mg/kg, which is equivalent to 21.0 mg/m 2 (level 5) of the Japanese phase I trial. However, toxicity was not observed when rats were administered KRN/ m at the equivalent dose to KRN5500 in potency. Electron microscopy of the lung treated with KRN5500 showed disruption of the alveolar type II membrane with release of lamellar debris. Furthermore, in vivo, KRN/m showed similar antitumor activity to KRN5500. These results indicate that KRN/m may be useful for reducing the pulmonary toxicity associated with the current formulation of KRN5500, while fully maintaining its antitumor activity.