Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences , Anhui University , 111 Jiulong Road , Hefei , Anhui Province 230601 , P. R. China.
ACS Appl Mater Interfaces. 2019 Aug 14;11(32):28597-28609. doi: 10.1021/acsami.9b05855. Epub 2019 Jul 30.
An ortho-ester-linked indomethacin (IND) dimer-based nanodrug delivery system was prepared to improve the therapeutic effect of doxorubicin (DOX) by reversing the multidrug resistance. The synthesized dimer (IND-OE) could form stable nanoparticles (IND-OE/DOX) loaded with DOX via the single-emulsion method. Compare to insensitive nanoparticles (IND-C12/DOX), IND-OE/DOX showed a rapid degradation behavior and accelerated drug release at mildly acidic environments. In vitro cell experiments verified that IND-OE nanoparticles could increase DOX concentration due to the efficient intracellular drug release by the degradation of the ortho ester as well as reduced DOX efflux by IND-mediated P-gp downregulation. In vivo studies further demonstrated that IND-OE/DOX displayed the maximized synergetic antitumor efficacy than free DOX or IND-C12/DOX, and the tumor inhibition rates versus saline were 46.78% (free DOX), 60.23% (IND-C12/DOX), and 80.62% (IND-OE/DOX). Overall, this strategy of combination with chemosensitizers and ortho ester linkage has great potential to serve as an amplifying chemotherapy platform against various drug-resistant tumors.
一种基于正交酯键连接的吲哚美辛（IND）二聚体的纳米药物递送系统被制备出来，以通过逆转多药耐药性来提高阿霉素（DOX）的治疗效果。合成的二聚体（IND-OE）可以通过单乳液法形成稳定的载有 DOX 的纳米颗粒（IND-OE/DOX）。与不敏感的纳米颗粒（IND-C12/DOX）相比，IND-OE/DOX 在轻度酸性环境下表现出快速降解行为和加速药物释放。体外细胞实验验证，IND-OE 纳米颗粒可以通过正交酯的降解增加 DOX 浓度，以及通过 IND 介导的 P-糖蛋白下调减少 DOX 外排，从而实现有效的细胞内药物释放。体内研究进一步表明，与游离 DOX 或 IND-C12/DOX 相比，IND-OE/DOX 显示出最大化的协同抗肿瘤疗效，并且与生理盐水相比，肿瘤抑制率分别为 46.78%（游离 DOX）、60.23%（IND-C12/DOX）和 80.62%（IND-OE/DOX）。总的来说，这种与化疗增敏剂和正交酯键结合的策略具有作为针对各种耐药肿瘤的放大化疗平台的巨大潜力。
