Key Laboratory of Smart Drug Delivery, Ministry of Education, Center for Medical Research and Innovation, Shanghai Pudong Hospital, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, People's Republic of China.
Int J Nanomedicine. 2020 Feb 4;15:779-793. doi: 10.2147/IJN.S229576. eCollection 2020.
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.
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.
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.
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.
癌症化疗效果在很大程度上受到细胞自噬和作用部位药物积累少的限制。在此，我们设计了一种智能策略，涉及紫杉醇（PTX）聚合物胶束，以响应氨溴索（Ax）的生物学功能。两亲性聚合物聚乙二醇-聚乳酸（PEG-PLA）和 Pluronic P105 被选为纳米载体，以封装 PTX 形成具有肺亲和力的 PEG-PLA/P105/PTX 胶束。Ax 可以上调肺表面活性剂（PS）的分泌并抑制自噬，从而改变肺部的微环境，从而促进肺部积累并增加胶束的细胞杀伤敏感性。
对胶束的物理化学性质进行了表征，包括粒径、形态、临界胶束浓度（CMC）和体外药物释放行为。在体外和体内对联合方案的治疗效果进行了表征，包括 Ax 促进肺表面活性剂分泌的研究、体外细胞毒性、细胞摄取、Western blot、体内分布、体内药代动力学和体内抗肿瘤功效。
PEG-PLA/P105/PTX 胶束粒径为 16.7±0.5nm，呈近圆形，CMC 较小，具有持续的药物释放特性。此外，体外结果表明，Ax 可以增加 PS 和 LC3 蛋白的分泌，并增强 PEG-PLA/P105/PTX 胶束对 A549 细胞的细胞毒性。体内结果表明，联合治疗方案可以促进胶束在肺部的分布，并增强对肺癌的治疗效果。
这种调节肿瘤微环境以增强作用部位药物运输和细胞杀伤敏感性的多功能方法可能为有效治疗肺癌提供新途径。
