WRCBB, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India.
Cancer Lett. 2013 Jul 1;334(2):274-83. doi: 10.1016/j.canlet.2012.08.022. Epub 2012 Aug 27.
Hexadecylphosphocholine (HePC) or miltefosine based proapoptotic lipid nanovesicles encapsulating paclitaxel for synergistic anticancer effect of paclitaxel and miltefosine in chemoresistant human glioblastoma multiforme (U-87 MG) overexpressing multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp), were developed in this study. The nanovesicles had 100-200nm size and a negative zeta potential (∼-25mV) and optimized for miltefosine content based on their physiochemical properties. With a high encapsulation efficiency of 94%, the nanovesicles showed sustained release of paclitaxel in nasal fluid and triggered release in the cerebrospinal fluid. Synergistic action of paclitaxel and miltefosine was observed with a low IC50 of 162±5nM. The nanovesicle also overcame drug resistance and showed ATP dependent uptake via clathrin mediated pathway in glioblastoma cells. An improved therapeutic efficacy in comparison to Taxol®, the current clinical formulation of paclitaxel was observed. Efficient brain uptake of the nanovesicles upon intranasal administration was observed in vivo and the nanovesicles were also found to be able to cross blood brain barrier. These studies therefore suggest the therapeutic potential of proapoptotic lipid nanovesicles and their feasibility for intranasal administration in the treatment of chemoresistant glioblastoma.
本研究中，为了增强对过度表达多药耐药基因产物 P-糖蛋白（P-gp）的化疗耐药人多形性成胶质细胞瘤（U-87 MG）的紫杉醇和米替福新的协同抗癌效果，开发了十六烷基磷酸胆碱（HePC）或米替福新为基础的促凋亡脂质纳米囊泡，包载紫杉醇。这些纳米囊泡具有 100-200nm 的大小和负的 ζ 电位（约-25mV），并基于其物理化学性质优化了米替福新的含量。纳米囊泡具有 94%的高包封效率，在鼻液中表现出紫杉醇的持续释放，并在脑脊液中呈现触发释放。紫杉醇和米替福新表现出协同作用，IC50 低至 162±5nM。纳米囊泡还克服了耐药性，并通过网格蛋白介导的途径显示出对 ATP 依赖性摄取作用。与紫杉醇的现有临床制剂 Taxol®相比，观察到纳米囊泡具有更好的治疗效果。经鼻腔给予后，体内观察到纳米囊泡的脑内摄取效率提高，并且还发现纳米囊泡能够穿过血脑屏障。因此，这些研究表明促凋亡脂质纳米囊泡具有治疗潜力，并可通过鼻腔给药用于治疗化疗耐药性胶质细胞瘤。
