Pulmonary-Affinity Paclitaxel Polymer Micelles in Response to Biological Functions of Ambroxol Enhance Therapeutic Effect on Lung Cancer
Pulmonary-Affinity Paclitaxel Polymer Micelles in Response to Biological Functions of Ambroxol Enhance Therapeutic Effect on Lung Cancer
复制标题
肺亲和紫杉醇聚合物胶束响应氨溴索的生物学功能增强对肺癌的治疗效果
DOI：
10.2147/ijn.s229576
复制
发表时间：
2020-01-01
影响因子：
8
通讯作者：
Sha, Xianyi
中科院分区：
文献类型：
--
作者：
He, Wenxiu;Xiao, Wenze;Sha, Xianyi
目的：肿瘤化疗的效果在很大程度上受到细胞自噬和作用部位药物蓄积不足的限制。在此，我们设计了一种智能策略，涉及紫杉醇（PTX）聚合物胶束响应氨溴索（Ax）的生物功能。以两亲性聚合物聚乙二醇-聚乳酸（PEG-PLA）和Pluronic P105为纳米载体，将紫杉醇（PTX）包封于PEG-PLA/P105/PTX胶束中，形成肺亲和性胶束。方法：通过对胶束的大小、形态、临界胶束浓度（CMC）及体外释药行为等理化性质进行表征，并结合药物释放动力学模型，研究其在肺组织中的作用。通过体内外实验，对联合用药方案的疗效进行了研究，包括对Ax促进肺表面活性物质分泌、体外细胞毒性、细胞摄取、Western blotting、体内生物分布、体内药代动力学和体内抗肿瘤疗效的研究。PEG-PLA/P105/PTX胶束的粒径为16.7 ± 0.5nm，呈近似圆形，CMC小，具有药物缓释性能。体外实验结果表明，Ax能增加PS和LC 3蛋白的分泌，增强PEG-PLA/P105/PTX胶束对A549细胞的细胞毒性。体内实验结果表明，该联合治疗方案可促进胶束在肺内的分布，增强对肺癌的治疗效果。结论：这种通过调节肿瘤微环境来增强作用部位药物转运和细胞杀伤敏感性的多功能途径可能为肺癌的有效治疗提供新的途径。
Purpose: Cancer chemotherapy effect has been largely limited by cell autophagy and little drug accumulation at the action sites. Herein, we designed an intelligent strategy involving paclitaxel (PTX) polymer micelles in response to biological functions of ambroxol (Ax). The amphiphilic polymers polyethyleneglycol-polylactic acid (PEG-PLA) and Pluronic P105 were selected as nanocarriers to encapsulate PTX to form into lung affinity PEG-PLA/P105/PTX micelles. Ax which can up-regulate the secretion of pulmonary surfactant (PS) and inhibit autophagy was hired to change the microenvironment of the lung, thereby promoting the lung accumulation and increasing cell-killing sensitivity of the micelles.Methods: The physical and chemical properties of the micelles were characterized including size, morphology, critical micellar concentration (CMC) and in vitro drug release behavior. The therapeutic effects of the combination regimen were characterized both in vitro and in vivo including study on Ax in promoting the secretion of pulmonary surfactant, in vitro cytotoxicity, cellular uptake, Western blotting, in vivo biodistribution, in vivo pharmacokinetics and in vivo antitumor efficacy.Results: The PEG-PLA/P105/PTX micelles showed a particle size of 16.7 +/- 0.5 nm, a nearly round shape, small CMC and sustained drug release property. Moreover, the in vitro results indicated that Ax could increase PS and LC3 protein secretion and enhance the cytotoxicity of PEG-PLA/P105/PTX micelles toward A549 cells. The in vivo results indicated that the combination therapeutic regimen could promote the micelles to distribute in lung and enhance the therapeutic effect on lung cancer.Conclusion: This multifunctional approach of modulating the tumor microenvironment to enhance drug transportation and cell-killing sensitivity in the action sites might offer a new avenue for effective lung cancer treatment.