Wang Kaiyuan, Ye Hao, Zhang Xuanbo, Wang Xia, Yang Bin, Luo Cong, Zhao Zhiqiang, Zhao Jian, Lu Qi, Zhang Haotian, Kan Qiming, Wang Yongjun, He Zhonggui, Sun Jin
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China.
Biomaterials. 2020 Oct;257:120224. doi: 10.1016/j.biomaterials.2020.120224. Epub 2020 Jul 15.
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.
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，但抗转移效率仍远不尽人意，主要原因是对血液中循环肿瘤细胞（CTC）的识别较差。在此，我们开发了一种类外泌体顺序生物激活前药纳米平台（EMPCs）来克服这一障碍。具体而言，将活性氧（ROS）响应性硫醚连接的紫杉醇 - 亚油酸共轭物（PTX - S - LA）和葫芦素B（CuB）共包封到聚合物胶束中，并且纳米颗粒进一步用外泌体膜（EM）修饰。所得的EMPCs能够在血液循环过程中通过癌细胞膜与同型EM之间的高亲和力相互作用特异性捕获并中和CTC。细胞摄取后，EMPCs首先释放CuB，通过下调FAK/MMP信号通路显著阻断肿瘤转移。此外，CuB明显提高细胞内氧化水平以诱导ROS响应性PTX - S - LA的顺序生物激活。体外和体内结果表明，EMPCs不仅表现出放大的前药生物激活、延长的血液循环、对同型肿瘤细胞的选择性靶向和增强的肿瘤渗透，而且还通过清除CTC和调节FAK/MMP信号通路来抑制肿瘤转移。本研究提出了一种基于机制抑制肿瘤转移的综合方法，并展示了可编程生物激活前药纳米平台在抑制癌症转移方面的广阔前景。
