title: A novel micelle-encapsulated platinum(II) anticancer agent.
abstract: A hydrophobic and water-insoluble platinum(II) compound, cis-(cha)(2)Pt(NO(3))(2) was encapsulated by macromolecular micelles self-assembled from an amphiphilic cyclotriphosphazene [NP(MPEG750)(GlyPheLeu)(2)Et](3) (CP750). The micelle-encapsulated platinum(II) compound exhibited outstanding pharmacokinetics in rats by showing long blood circulation and much larger systemic exposure (AUC=43.5 μgh/ml) compared with the free carboplatin (AUC=4.32 μgh/ml). Biodistribution study of the micellar platinum(II) compound using male Sprague-Dawley rats has shown excellent tumor to tissue ratios of 4.03 at 2h post injection and 4.67 at 24h post injection. Furthermore, the micellar platinum(II) compound exhibited more than 6 times higher cellular uptake in human cervical (HeLa) and lung (A549) tumor cells compared with the free platinum compound. Also it is surprising that the micellar platinum(II) compound displayed specifically high cytotoxicity against the stomach tumor cells (SNU638), which are one of the least responsive to chemotherapeutic agents currently in clinical use. The acute toxicity study has shown that the LD(50) values of free and the micellar cis-(cha)(2)Pt(NO(3))(2) are approximately 70 mg/kg and 90 mg/kg, respectively. Thus the platinum compound encapsulated by cyclotriphosphazene micelles is a promising candidate for preclinical studies.
authors.affiliation: Center for Intelligent Nano-Bio Materials, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemun-Ku, Seoul 120-750, Republic of Korea.
authors.forename: Vithal B
authors.initials: VB
authors.lastname: Jadhav
authors.forename: Yong Joo
authors.initials: YJ
authors.lastname: Jun
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Song
authors.forename: Min Kyoung
authors.initials: MK
authors.lastname: Park
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Oh
authors.forename: Song Wha
authors.initials: SW
authors.lastname: Chae
authors.forename: In-Sun
authors.initials: IS
authors.lastname: Kim
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Choi
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Sohn
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007928:Lethal Dose 50; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D009944:Organoplatinum Compounds; C012936:1,2-cyclohexanediamine dinitratoplatinum