Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40506, USA.
J Control Release. 2012 Sep 10;162(2):330-9. doi: 10.1016/j.jconrel.2012.07.001. Epub 2012 Jul 16.
Nanoparticulate drug carriers such as liposomal drug delivery systems are of considerable interest in cancer therapy because of their ability to passively accumulate in solid tumors. For liposomes to have practical utility for antitumor therapy in patients, however, optimization of drug loading, retention, and release kinetics are necessary. Active loading is the preferred method for optimizing loading of ionizable drugs in liposomes as measured by drug-to-lipid ratios, but the extremely low aqueous solubilities of many anticancer drug candidates may limit the external driving force, thus slowing liposomal uptake during active loading. This report demonstrates the advantages of maintaining drug supersaturation during active loading. A novel method was developed for creating and maintaining supersaturation of a poorly soluble camptothecin analogue, AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin), using a low concentration of a cyclodextrin (sulfobutylether-β-cyclodextrin) to inhibit crystallization over a 48 h period. Active loading into liposomes containing high concentrations of entrapped sodium or calcium acetate was monitored using drug solutions at varying degrees of supersaturation. Liposomal uptake rates increased linearly with the degree of supersaturation of drug in the external loading solution. A mathematical model was developed to predict the rate and extent of drug loading versus time, taking into account the chemical equilibria inside and outside of the vesicles and the transport kinetics of various permeable species across the lipid bilayer and the dialysis membrane. Intraliposomal sink conditions were maintained by the high internal pH caused by the efflux of acetic acid and exchange with AR-67, which undergoes lactone ring-opening, ionization, and membrane binding in the interior of the vesicles. The highest drug to lipid ratio achieved was 0.17 from a supersaturated solution at a total drug concentration of 0.6 mg/ml. The rate and extent of loading was similar when a different intraliposomal metal cation (sodium) was used instead of calcium. The proposed method may have general application in overcoming the formulation challenges associated with the liposomal delivery of poorly soluble, ionizable anticancer agents.
纳米颗粒药物载体，如脂质体药物传递系统，因其能够被动地在实体瘤中积累而在癌症治疗中受到极大关注。然而，为了使脂质体在患者的抗肿瘤治疗中具有实际应用价值，有必要优化药物的装载、保留和释放动力学。主动载药是优化可离子化药物在脂质体中载药量的首选方法，可通过药物与脂质的比例来衡量，但许多抗癌候选药物的水溶解度极低可能会限制外部驱动力，从而在主动载药过程中减缓脂质体的摄取。本报告展示了在主动载药过程中保持药物过饱和度的优势。开发了一种新方法，使用低浓度的环糊精（磺丁基醚-β-环糊精）在 48 小时内抑制结晶，以保持较差溶解度的喜树碱类似物 AR-67（7-t-丁基二甲基硅基-10-羟基喜树碱）的过饱和度。通过在不同过饱和度的药物溶液中监测含有高浓度包封的醋酸钠或醋酸钙的脂质体的主动载药，来监测脂质体的摄取率。脂质体的摄取率随外部载药溶液中药物的过饱和度线性增加。开发了一个数学模型来预测药物载药率和载药量随时间的变化，考虑到囊泡内外的化学平衡以及各种可渗透物质穿过脂质双层和透析膜的转运动力学。内部的高 pH 值由醋酸的流出和 AR-67 的交换维持，在囊泡内部，AR-67 经历内酯环的打开、离子化和膜结合，从而产生内部的亲脂性条件。从总药物浓度为 0.6mg/ml 的过饱和溶液中实现的最高药物与脂质比为 0.17。当使用不同的内部脂质体金属阳离子（钠）代替钙时，载药的速率和程度相似。所提出的方法可能具有普遍适用性，可克服与疏水性、可离子化抗癌药物的脂质体递送相关的制剂挑战。
