Cisplatin-loaded polymer-metal complex micelle with time-modulated decaying property as a novel drug delivery system.
OBJECTIVE
The pharmacological activity and pharmacokinetics of cisplatin (CDDP)-loaded polymeric micelles were examined to reveal their usefulness as a novel tumor-directed drug carrier system of CDDP.


METHODS
In biodistribution assay, free CDDP or CDDP-loaded micelles were administered intravenously to Lewis lung carcinoma-bearing mice. Antitumor activity and nephrotoxicity were respectively evaluated by the measurement of tumor size and plasma blood urea nitrogen (BUN) after single bolus i.v. administration of each drug.


RESULTS
The time profile of the plasma Pt level after the injection of the micelles exhibited a time-modulated disappearance as observed in saline in vitro. The micelles exhibited 5.2- and 4.6-fold higher AUC of Pt in the plasma and tumor, respectively, with minimal change in the kidney, in comparison with free CDDP, suggesting that prolonged circulation of Pt in circulation and specific accumulation in the tumor were achieved utilizing the micellar drug carrier system. Administration of the micelles at the dose exhibiting antitumor activity similar to free CDDP did not increase the plasma BUN, whereas free CDDP induced its remarkable increase.


CONCLUSIONS
CDDP-loaded micelles restrained nephrotoxicity, which is the dose-limiting factor of CDDP, while exhibiting tumor-specific accumulation. Thus, CDDP-loaded micelles are expected to be a novel formulation of CDDP for clinical use.
Nishiyama
N
N
Department of Materials Science, Graduate School of Engineering, University of Tokyo, Japan.
Kato
Y
Y
Sugiyama
Y
Y
Kataoka
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009368:Neoplasm Transplantation; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D008823:Micelles; D011108:Polymers; D002945:Cisplatin