Size-adjustable micelles co-loaded with a chemotherapeutic agent and an autophagy inhibitor for enhancing cancer treatment via increased tumor retention
Size-adjustable micelles co-loaded with a chemotherapeutic agent and an autophagy inhibitor for enhancing cancer treatment via increased tumor retention
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大小可调的胶束共同负载化疗剂和自噬抑制剂，通过增加肿瘤保留来增强癌症治疗
DOI：
10.1016/j.actbio.2019.03.022
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发表时间：
2019-04-15
影响因子：
9.7
通讯作者：
He, Qin
中科院分区：
文献类型：
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作者：
Rao, Jingdong;Mei, Ling;He, Qin
自噬在肿瘤细胞的应激反应中起着关键作用，它通过降解细胞质蛋白来提供能量和清除有害物质，从而促进肿瘤细胞的存活和对化疗的抵抗力。因此，化疗药物和自噬抑制剂的联合治疗被认为可以获得理想的抗肿瘤效果。纳米粒具有更强的渗透性和滞留性，在肿瘤靶向给药方面显示出巨大的潜力。然而，固定粒径的纳米颗粒并不能达到最佳的输送效果。为此，开发了一种基于铜(I)催化点击化学触发的叠氮化物/炔修饰胶束聚集的策略，用于化疗药物阿霉素(Dox)和自噬抑制剂Wortmannin(WtMN)的共传递。体外实验表明，胶束的大小随时间的增加而增大，这促进了胶束在B16F10和4T1细胞中的积累。荧光共振能量转移(FRET)实验和生物分布研究进一步证明，通过点击环加成的胶束聚集显着改善了载药胶束在肿瘤区域的蓄积。此外，透射电子显微镜观察到自噬小体数量减少，免疫印迹和免疫组织化学检测显示LC3-II表达降低，p62表达增加，证实Dox/WtMn共负载大小可调胶束对自噬有明显的抑制作用，具有协同抑制肿瘤的作用。此外，共负载的大小可调的胶束具有良好的细胞毒性和抗肿瘤作用。因此，这一策略有效地抑制了小鼠的黑色素瘤和乳腺癌。意义陈述化疗的治疗效果可以受到自噬的限制，因此，自噬抑制剂与化疗药物的联合使用可以达到理想的抗癌效果。在本研究中，我们通过修饰胶束表面的点击反应底物叠氮基和炔基来设计尺寸可调的胶束，并随后将自噬抑制剂Wortmannin和化疗药物阿霉素共负载。当将催化剂注入肿瘤内时，胶束可以通过点击反应在肿瘤部位聚集。结果表明，大小可调的胶束在肿瘤中实现了高效的药物传递、渗透和滞留；通过Wortmannin介导的自噬抑制和阿霉素介导的细胞毒的联合作用，该策略在黑色素瘤和乳腺癌的治疗中发挥了显著的抗癌作用。(C)2019 Acta Materialia Inc.由Elsevier Ltd.出版。保留所有权利。
Autophagy plays a key role in the stress response of tumor cells, which contributes to cancer cell survival and resistance to chemotherapy by degrading cytoplasmic proteins to provide energy and clear the hazardous substances. Therefore, combined treatment of chemotherapeutics and autophagy inhibitors is thought to obtain a desirable antitumor effect. Nanoparticles (NPs) show potential in tumor-targeting drug delivery because of the enhanced permeability and retention (EPR) effect. However, NPs with fixed particle size cannot achieve optimal delivery effect. Herein, a strategy based on Cu (I)-catalyzed click chemistry-triggered aggregation of azide/alkyne-modified micelles was developed for the co-delivery of the chemotherapeutic drug doxorubicin (Dox) and the autophagy inhibitor wortmannin (Wtmn). In vitro experiments showed that the size of micelles increased in a time-dependent manner, which enhanced micelle accumulation in both B16F10 and 4 T1 cells. The fluorescence resonance energy transfer (FRET) experiment and biodistribution study further demonstrated that the aggregation of micelles through click cycloaddition significantly improved the accumulation of drug-loading micelles at the tumor region. Furthermore, the decreased amount of autophagosomes observed by transmission electron microscopy (TEM), the declined expression of LC3-II, and the increased level of p62 by western blotting and immunohistochemistry (IHC) confirmed the obvious inhibition of autophagy induced by Dox/Wtmn co-loaded size-adjustable micelles, which had a synergistic effect in cancer suppression. In addition, the co-loaded size-adjustable micelles showed outstanding cytotoxicity and antitumor effect. Therefore, this strategy effectively suppressed melanoma and breast cancer in mice.Statement of SignificanceThe therapeutic effects of chemotherapy can be limited by autophagy; hence, combined use of autophagy inhibitors with chemotherapeutics achieves desirable anticancer efficacy. In the present study, we designed size-adjustable micelles by modifying the click reaction substrate azide group and the alkyne group on the surface of micelles, and subsequently, the autophagy inhibitor wortmannin and the chemotherapeutic drug doxorubicin were co-loaded. The micelles could aggregate by click reaction at the tumor site when the catalysts were intratumorally injected. The results showed that the size adjustable micelles achieved efficient drug delivery, penetration, and retention in tumors; through the combined effect of wortmannin-mediated autophagy inhibition and doxorubicin-mediated cytotoxicity, this strategy exerted significant anticancer effect in melanoma and breast cancer treatment. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.