An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition
An exosome-like programmable-bioactivating paclitaxel prodrug nanoplatform for enhanced breast cancer metastasis inhibition
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一种类似外泌体的可编程生物激活紫杉醇前药纳米平台，用于增强乳腺癌转移抑制
DOI：
10.1016/j.biomaterials.2020.120224
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发表时间：
2020-10-01
期刊：
影响因子：
14
通讯作者：
Sun, Jin
中科院分区：
文献类型：
--
作者：
Wang, Kaiyuan;Ye, Hao;Sun, Jin
转移与乳腺癌的高死亡率密切相关。尽管基于纳米技术的抗转移治疗发展迅速，但抗转移效果仍不尽如人意，这主要是由于血液中循环肿瘤细胞(CTCs)识别能力差所致。在此，我们开发了一种类似外显子的序贯生物激活前药纳米平台(EMPC)来克服这一障碍。具体地说，反应性氧物种(ROS)反应的硫醚连接紫杉醇亚油酸偶合物(Ptx-S-LA)和葫芦素B(CUB)被共包裹到聚合物胶束中，并进一步用外切体膜(EM)修饰纳米粒子。通过癌细胞膜与同型EM之间的高亲和力相互作用，产生的EMPC可以在血液循环中特异性地捕获和中和CTCs。细胞摄取后，内皮祖细胞首先释放CUB，通过下调FAK/基质金属蛋白酶信号通路显著阻断肿瘤转移。此外，CUB明显提高细胞内的氧化水平，诱导ROS反应的PTX-S-LA的一系列生物激活。体内外实验结果表明，EMPC不仅具有增强前药生物活性、延长血液循环、选择性靶向同型肿瘤细胞、增强肿瘤穿透性的作用，而且通过CTCs清除和FAK/MMPs信号通路调节抑制肿瘤转移。本研究提出了一种基于机制抑制肿瘤转移的综合方法，展示了可编程生物激活前药纳米平台抑制肿瘤转移的前景。
Metastasis is closely associated with high breast cancer mortality. Although nanotechnology-based anti-metastatic treatments have developed rapidly, the anti-metastasis efficiency is still far from satisfactory, mainly due to the poor recognition of circulating tumor cells (CTCs) in blood. Herein, we developed an exosome-like sequential-bioactivating prodrug nanoplatform (EMPCs) to overcome the obstacle. Specifically, the reactive oxygen species (ROS)-responsive thioether-linked paclitaxel-linoleic acid conjugates (PTX-S-LA) and cucurbitacin B (CuB) are co-encapsulated into polymeric micelles, and the nanoparticles are further decorated with exosome membrane (EM). The resulting EMPCs could specifically capture and neutralize CTCs during blood circulation through the high-affinity interaction between cancer cell membrane and homotypic EM. Following cellular uptake, EMPCs first release CuB, remarkably blocking tumor metastasis via downregulation of the FAK/MMP signaling pathway. Moreover, CuB obviously elevates the intracellular oxidative level to induce a sequential bioactivation of ROS-responsive PTX-S-LA. In vitro and in vivo results demonstrate that EMPCs not only exhibit amplified prodrug bioactivation, prolonged blood circulation, selective targeting of homotypic tumor cells, and enhanced tumor penetration, but also suppress tumor metastasis through CTCs clearance and FAK/MMP signaling pathway regulation. This study proposes an integrated approach for mechanism-based inhibition of tumor metastasis and manifests a promising potential of programmable-bioactivating prodrug nanoplatform for cancer metastasis inhibition.