A novel liposomal irinotecan formulation with significant anti-tumour activity: Use of the divalent cation ionophore A23187 and copper-containing liposomes to improve drug retention

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• 作者：Euan Ramsay ; Jehan Alnajim ; Malathi Anantha ; Jason Zastre ; Hong Yan ; Murray Webb ; Dawn Waterhouse ; Marcel Bally
• 关键词：Copper ; Liposome ; Irinotecan ; A23187 ; In vivo
• 刊名：European Journal of Pharmaceutics and Biopharmaceutics
• 出版年：2008
• 出版时间：March 2008
• 年：2008
• 卷：68
• 期：3
• 页码：607-617
• 全文大小：548 K

文摘

We determined whether the method used to encapsulate irinotecan into 1,2-distearoyl-sn-glycero-phosphocholine/cholesterol (DSPC/Chol; 55:45 mol % ) liposomes influenced: (i) irinotecan release rate and (ii) therapeutic efficacy. DSPC/Chol (55:45 mol % ) liposomes were prepared with: (i) unbuffered CuSO₄; (ii) buffered (pH 7.5) CuSO₄; (iii) unbuffered MnSO₄ and the ionophore A23187 (exchanges internal metal²⁺ with external 2H⁺ to establish and maintain a transmembrane pH gradient); and (iv) unbuffered CuSO₄ and ionophore A23187. All formulations exhibited >98 % irinotecan encapsulation (0.2 drug-to-lipid molar ratio; 10 min incubation at 50 °C). Following a single intravenous injection (100 mg/kg irinotecan) into Balb/c mice, the unbuffered CuSO₄ plus A23187 formulation mediated a half-life of irinotecan release of 44.4 h; a 4-fold increase compared to the other liposome formulations. This surprising observation demonstrated that the CuSO₄ plus A23187 formulation enhanced irinotecan retention compared to the MnSO₄ plus A23187 formulation, indicating the importance of the divalent metal. A single dose of the CuSO₄ plus A23187 formulation (50 mg/kg irinotecan) mediated an 18-fold increase in median T − C (the difference in days for treated and control subcutaneous human LS 180 adenocarcinoma xenografts to increase their initial volume by 400 % ) when compared to a comparable dose of Camptosar^®. Improved irinotecan retention was associated with increased therapeutic activity.