Proapoptotic lipid nanovesicles: Synergism with paclitaxel in human lung adenocarcinoma A549 cells
Proapoptotic lipid nanovesicles: Synergism with paclitaxel in human lung adenocarcinoma A549 cells
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DOI：
10.1016/j.jconrel.2011.07.025
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发表时间：
2011-12-20
影响因子：
10.8
通讯作者：
Banerjee, Rinti
中科院分区：
文献类型：
--
作者：
Joshi, Nitin;Shanmugam, Thanigaivel;Banerjee, Rinti
本研究主要研究基于磷脂酰丝氨酸的促凋亡脂质纳米囊泡（PSN-PTX）作为气溶胶与紫杉醇协同抗肺癌的活性。PSN-PTX的颗粒尺寸呈单峰分布（100-200 nm），表面负电荷为-29 mV，紫杉醇包封效率高达82%，其中19%的紫杉醇在48 h内释放。与紫杉醇上市制剂紫杉醇(R)相比，PSN-PTX具有较高的表面活性，而紫杉醇的表面活性对肺力学是有害的。与紫杉醇(R)不同，PSN-PTX在毛细管表面计中也显示出较高的气道通畅度，表明其具有模拟肺表面活性物质功能的能力。雾化后双撞击器下撞击腔内PSN-PTX的高沉积提示其能够到达肺末梢区域。纳米囊泡在A549细胞中表现出促进和ATP依赖的活性摄取。磷脂酰丝氨酸纳米囊泡与紫杉醇联合作为PSN-PTX对A549细胞株的细胞毒性增强，其IC50值为18 nM，比空白磷脂酰丝氨酸纳米囊泡和紫杉醇单独作用的IC50值低10-50倍。此外，发现组合指数小于1，这表明两个成分的协同作用。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，因此在联合治疗中具有促凋亡纳米囊泡的作用。总之，这些研究表明促凋亡脂质纳米囊泡与包封紫杉醇联合化疗的治疗潜力和优势，以及雾化给药治疗肺癌的可行性。(C) 2011 Elsevier B.V.版权所有
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 (R), 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 (R), 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 IC50 of 18 nM which is 10-50 folds less than the IC50 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. (C) 2011 Elsevier B.V. All rights reserved.