Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China.
Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg, 194064, Russia.
Biomaterials. 2021 Aug;275:120891. doi: 10.1016/j.biomaterials.2021.120891. Epub 2021 May 21.
Insufficient drug accumulation and chemoresistance remain two major challenges in cancer chemotherapy. Herein, we designed a furin-responsive aggregated nanoplatform loaded with doxorubicin (DOX) and hydroxychloroquine (HCQ) (AuNPs-D&H-R&C) to combine chemotherapy, autophagy inhibition and macrophage polarization. AuNPs-D&H-R&C could passively target breast tumor via enhanced permeability and retention (EPR) effect after systemic administration and further aggregate together triggered by furin overexpressed in breast cancer. The in situ aggregations hindered the back-flow of NPs to the bloodstream and exocytosis of tumor cells, leading to enhanced drug accumulation within tumors. Moreover, upon exposure to acidic pH in the endosomes/lysosomes, HCQ was efficiently released and it inhibited autophagy and thus restored the sensitivity of tumor cell to DOX. Meanwhile, autophagy inhibition could reprogram tumor-promoting M2-like TAMs to anti-tumor M1 phenotype, exerting a synergistic effect in overcoming chemoresistance. In vitro studies demonstrated the superiority of furin-triggered aggregated AuNPs delivery system in enhancing drug accumulation in breast tumor, compared with PEGlyated AuNPs. The co-delivery of DOX and HCQ showed much improved chemotherapeutic efficiency to chemoresistant MCF-7/ADR breast tumor, in large part due to macrophage polarization. In conclusion, we developed a stimulus-responsive delivery system and proposed a potential combination strategy to overcome chemoresistance in cancer chemotherapy.
药物蓄积不足和化疗耐药仍然是癌症化疗的两大挑战。在此，我们设计了一种溶酶体蛋白酶（furin）响应性聚集纳米平台，负载多柔比星（DOX）和羟氯喹（HCQ）（AuNPs-D&H-R&C），以结合化疗、自噬抑制和巨噬细胞极化。AuNPs-D&H-R&C 可以通过系统给药后增强的渗透性和保留（EPR）效应被动靶向乳腺癌，并在乳腺癌中过度表达的 furin 触发下进一步聚集。原位聚集阻碍了 NPs 回流到血液中以及肿瘤细胞的胞吐作用，导致肿瘤内药物蓄积增加。此外，在内涵体/溶酶体中的酸性 pH 下，HCQ 被有效地释放出来，它抑制自噬，从而恢复肿瘤细胞对 DOX 的敏感性。同时，自噬抑制可以将促进肿瘤的 M2 样 TAMs 重新编程为抗肿瘤 M1 表型，在克服化疗耐药方面发挥协同作用。体外研究表明，与聚乙二醇化 AuNPs 相比，溶酶体蛋白酶触发的聚集 AuNPs 递送系统在增强乳腺癌中药物蓄积方面具有优势。DOX 和 HCQ 的共递送显示出对化疗耐药 MCF-7/ADR 乳腺癌的化疗效率有了很大提高，这在很大程度上是由于巨噬细胞极化。总之，我们开发了一种刺激响应性递药系统，并提出了一种潜在的联合策略来克服癌症化疗中的耐药性。
