A novel micelle-encapsulated platinum(II) anticancer agent

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• 作者：Vithal B. Jadhav ; Yong Joo Jun ; Ju Hee Song ; Min Kyoung Park ; Ji Hyun Oh ; Song Wha Chae ; In-Sun Kim ; Soo-Jin Choi ; Hwa Jeong Lee ; Youn Soo Sohn
• 关键词：cis-bis(cyclohexylamine)dinitratoplatinum ; Cyclotriphosphazene ; Micelle ; Anticancer drug ; Platinum drug
• 刊名：Journal of Controlled Release
• 出版年：2010
• 出版时间：1 October 2010
• 年：2010
• 卷：147
• 期：1
• 页码：144-150
• 全文大小：518 K

文摘

A hydrophobic and water-insoluble platinum(II) compound, cis-(cha)₂Pt(NO₃)₂ was encapsulated by macromolecular micelles self-assembled from an amphiphilic cyclotriphosphazene [NP(MPEG750)(GlyPheLeu)₂Et]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 μg h/ml) compared with the free carboplatin (AUC = 4.32 μg h/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 2 h post injection and 4.67 at 24 h 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 LD₅₀ values of free and the micellar cis-(cha)₂Pt(NO₃)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.