Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation
Co-delivery of silybin and paclitaxel by dextran-based nanoparticles for effective anti-tumor treatment through chemotherapy sensitization and microenvironment modulation
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基于葡聚糖的纳米颗粒共同递送水飞蓟宾和紫杉醇，通过化疗增敏和微环境调节进行有效的抗肿瘤治疗
DOI：
10.1016/j.jconrel.2020.02.017
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发表时间：
2020-05-10
影响因子：
10.8
通讯作者：
Yin, Tingjie
中科院分区：
文献类型：
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作者：
Huo, Meirong;Wang, Honglan;Yin, Tingjie
调节肿瘤微环境（TME）已被指示为提高癌症治疗功效的方法。在这里，我们提出了一种基于纳米共递送的紫杉醇（PTX）和水飞蓟宾（SB）的联合治疗，其可以通过化疗增敏和微环境调节来发挥协同效应。基于葡聚糖的两亲性聚合物（Dex-DOCA）被成功地开发用于体内共递送，从而“同步”PTX和SB的生物分布、转运和释放。结果，Dex-DOCA对PTX和SB表现出优异的包封效率，并且具有可调节的负载比以获得最佳协同抗肿瘤活性。此外，共同加载的纳米颗粒有效地排出两种药物在预期的剂量比，特别是在酸性内/溶酶体模拟环境。体外细胞毒性和细胞凋亡试验结果进一步证实了SB致敏PTX的效力。最后，体内研究表明，共负载的纳米颗粒可以通过被动靶向有效地在肿瘤部位积聚，并通过增强的肿瘤内渗透（由基质成分根除和肿瘤血管正常化相关的TME调节引起）以及SB对PTX细胞毒性化疗的增敏作用来抑制肿瘤生长。
Modulation of tumor microenvironment (TME) has been indicated as an approach to improve efficacy of cancer therapy. Here, we proposed a nano co-delivery based combination therapy of paclitaxel (PTX) and silybin (SB) which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. A dextran-based amphiphilic polymer (Dex-DOCA) was successfully developed for in vivo co-delivery and thus "synchronizing" the biodistribution, transport and release of PTX and SB. Resultantly, Dex-DOCA exhibited an excellent encapsulating efficiency for both PTX and SB with adjustable loading ratio for an optimal synergistic antitumor activity. Moreover, the co-loaded nanoparticles efficiently discharged the two drugs at the prospective dosage ratio specifically in acid endo/lysosome mimic environments. The results of in vitro cytotoxicity and cell apoptosis assays further confirmed the SB sensitized PTX potency. Finally, in vivo investigation demonstrated that the co-loaded nanoparticles could effectively accumulate in tumor sites by passive targeting, and inhibit tumor growth through an enhanced intratumoral penetration (resulted from stromal components eradication and tumor vessels normalization associated TME modulation), as well as a sensitization effect of SB on PTX cytotoxic chemotherapy.