WRCBB, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai-400076, India.
J Control Release. 2011 Dec 20;156(3):413-20. doi: 10.1016/j.jconrel.2011.07.025. Epub 2011 Jul 23.
The present study focuses on the development and evaluation of phosphatidylserine based proapoptotic lipid nanovesicles (PSN-PTX) as aerosols for synergistic activity with paclitaxel against lung cancer. PSN-PTX showed a unimodal size distribution of the particles (100-200 nm), negative surface charge of -29 mV and high encapsulation efficiency of paclitaxel (82%) with 19% of it releasing in 48 h. PSN-PTX was found to be highly surface active as compared to Taxol®, marketed formulation of paclitaxel, whose surface activity was found to be detrimental for pulmonary mechanics. PSN-PTX also showed high airway patency in capillary surfactometer unlike Taxol®, suggesting its ability to mimic pulmonary surfactant functions. High deposition of PSN-PTX in lower impingement chamber of twin impinger upon nebulization suggested it to be capable of reaching the terminal regions of the lungs. Nanovesicles showed facilitated and ATP dependent active uptake by A549 cells. The combination of phosphatidylserine nanovesicles and paclitaxel as PSN-PTX enhanced cytotoxicity in A549 cell line showing an IC(50) of 18 nM which is10-50 folds less than the IC(50) values observed for blank phosphtidylserine nanovesicles and paclitaxel alone. Further, the combination index was found to be less than one which indicates a synergism of the two components. DNA fragmentation study showed that blank phosphatidylserine nanovesicles induce apoptosis in A549 cells and hence behave as proapoptotic nanovesicles in the combination therapy. Overall, these studies suggest the therapeutic potential and advantages of combination chemotherapy of proapoptotic lipid nanovesicles with encapsulated paclitaxel and their feasibility for aerosol administration in the treatment of lung cancer.
本研究专注于开发和评估基于磷脂酰丝氨酸的促凋亡脂质纳米囊泡（PSN-PTX）作为与紫杉醇联合治疗肺癌的气溶胶。PSN-PTX 显示出粒子的单峰尺寸分布（100-200nm）、负表面电荷-29mV 和紫杉醇的高包封效率（82%），其中 19%在 48 小时内释放。与市售紫杉醇制剂 Taxol®相比，PSN-PTX 的表面活性更高，Taxol®的表面活性被发现对肺力学有害。PSN-PTX 也在毛细表面张力计中显示出高气道通畅性，与 Taxol®不同，表明其模拟肺表面活性剂功能的能力。PSN-PTX 在雾化后双冲击器的下撞击室中高度沉积表明其能够到达肺部的末端区域。纳米囊泡显示通过 A549 细胞进行促进和 ATP 依赖性主动摄取。PSN-PTX 与紫杉醇的组合增强了 A549 细胞系中的细胞毒性，显示出 IC（50）为 18 nM，比空白 PSN-PTX 和紫杉醇单独使用时观察到的 IC（50）值低 10-50 倍。此外，组合指数小于一，表明两种成分具有协同作用。DNA 片段化研究表明，空白磷脂酰丝氨酸纳米囊泡诱导 A549 细胞凋亡，因此在联合治疗中表现为促凋亡纳米囊泡。总的来说，这些研究表明了载紫杉醇的促凋亡脂质纳米囊泡联合化疗的治疗潜力和优势，以及其作为肺癌治疗气溶胶给药的可行性。
