School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, Jiangsu, China.
Department of Pharmacy, Wuxi Higher Health Vocational Technology School, Wuxi 214028, Jiangsu, China.
Acta Biomater. 2022 Mar 1;140:686-699. doi: 10.1016/j.actbio.2021.11.050. Epub 2021 Dec 5.
Multidrug resistance (MDR) is the main challenge faced by cancer chemotherapy. Drug-conjugate offers a promising strategy for breast cancer therapy. In this regard, we developed a DNVM multifunctional drug delivery system by crosslinking doxorubicin (DOX) and vitamin E succinate (VES) with a pH-sensitive hydrazone bond and then encapsulated the DOX-NN-VES prodrug into pH-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine (HOD) micelles. DOX resistant MCF-7/ADR cell were adopted as a model to study the capability and mechanism of MDR reversal. DNVM exhibited much higher cytotoxicity and cell uptake efficiency compared with that of acid-insensitive DOX-VES loaded HOD micelles (DVSM) and DOX loaded HOD micelles (DOXM), indicating the better capacity of DNVM for the reversal of MDR. Moreover, DNVM prevented drug efflux more effectively, inhibited the expression of P-gp, induced excessive production of reactive oxygen species and affected the expression of apoptosis-related proteins. In vivo experiments showed that DNVM significantly inhibited the tumor growth with no obvious changes in the body weight of MCF-7/ADR cells-bearing nude mice. The results suggested that the "double gain" DNVM can synergistically enhance the efficacy of chemotherapeutics for DOX resistant tumor cells and has the potential to overcome tumor MDR. STATEMENT OF SIGNIFICANCE: A dual-functional pH-sensitive doxorubicin - vitamin E succinate prodrug was developed and loaded into tumor microenvironment-sensitive hyaluronic acid-2-(octadecyloxy)-1,3-dioxan-5-amine micelle system (DNVM) for sequencing stimuli-release and overcoming doxorubicin resistance. The "double gain" DNVM can synergistically enhance the efficacy of chemotherapeutics for doxorubicin resistant tumor cells and has the potential to overcome tumor multiple drug resistance.
多药耐药（MDR）是癌症化疗面临的主要挑战。药物偶联物为乳腺癌治疗提供了一种有前途的策略。在这方面，我们通过将阿霉素（DOX）和维生素 E 琥珀酸（VES）与 pH 敏感腙键交联，然后将 DOX-NN-VES 前药包封到 pH 敏感透明质酸-2-（十八烷氧基）-1,3-二氧戊环-5-胺（HOD）胶束中，开发了一种 DNVM 多功能药物递送系统。采用 DOX 耐药 MCF-7/ADR 细胞作为模型，研究 MDR 逆转的能力和机制。与酸不敏感的 DOX-VES 负载 HOD 胶束（DVSM）和 DOX 负载 HOD 胶束（DOXM）相比，DNVM 表现出更高的细胞毒性和细胞摄取效率，表明 DNVM 逆转 MDR 的能力更强。此外，DNVM 更有效地阻止药物外排，抑制 P-gp 的表达，诱导过量产生活性氧并影响凋亡相关蛋白的表达。体内实验表明，DNVM 显著抑制 MCF-7/ADR 荷瘤裸鼠肿瘤生长，裸鼠体重无明显变化。结果表明，“双增益”DNVM 可以协同增强 DOX 耐药肿瘤细胞化疗药物的疗效，并有潜力克服肿瘤多药耐药。
开发了一种双重功能的 pH 敏感阿霉素-维生素 E 琥珀酸前药，并将其装载到肿瘤微环境敏感的透明质酸-2-（十八烷氧基）-1,3-二氧戊环-5-胺胶束系统（DNVM）中，用于顺序刺激释放并克服阿霉素耐药。“双增益”DNVM 可以协同增强 DOX 耐药肿瘤细胞化疗药物的疗效，并有潜力克服肿瘤多药耐药。
