Nitric oxide (NO), as a bioeffector to improve chemosensitivity by reversing multidrug resistance (MDR), is highly attractive for developing combinational delivery systems to deal with MDR tumors, while it is highly challenged by the stability and controlled release of NO during the pathway. Here we design and synthesize a cyclic nitrate trimethylene carbonate monomer (NTC), followed by ring-opening polymerization to prepare amphiphilic biodegradable polycarbonate-based copolymers as polymeric NO donors with tailored contents. The copolymer with desirable molecular weight is readily self-assembled to biodegradable micelles (NO-M) with a uniform size of 130 nm for highly stabilizing NO donors at the physiological conditions, while triggered NO release from micelles is performed at the intracellular reduction conditions. More importantly, NO-M shows superior inhibition of P-gP expression to enhance the chemosensitivity of multidrug-resistant MCF7 cells (MCF7/DOX^R). DOX-loaded NO-M (NO-M@DOX) realizes fast DOX release at the intracellular conditions, resulting in more intracellular DOX accumulation and higher antitumor activity mediated by the reduction-triggered NO/DOX release and NO-induced MDR reversal. Furthermore, the in vivo results show that NO-M@DOX effectively suppresses the MCF7/DOX^R tumor growth by a combination of directly NO-induced therapy and NO-mediated enhanced chemotherapy; meanwhile, the treatment with NO-M systems have much fewer side effects.

中文翻译：

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用于还原触发的药物释放和克服多药耐药性的功能性可生物降解一氧化氮供体含聚碳酸酯基胶束

一氧化氮 (NO) 作为一种通过逆转多药耐药 (MDR) 来提高化学敏感性的生物效应物，对于开发用于治疗 MDR 肿瘤的组合递送系统非常有吸引力，但它在通路过程中受到 NO 的稳定性和可控释放的高度挑战. 在这里，我们设计并合成了环状硝酸盐三亚甲基碳酸酯单体 (NTC)，然后通过开环聚合制备两亲性可生物降解聚碳酸酯基共聚物，作为具有定制含量的聚合 NO 供体。具有理想分子量的共聚物很容易自组装成可生物降解的胶束（NO-M），尺寸均匀为 130 nm，用于在生理条件下高度稳定 NO 供体，而在细胞内还原条件下从胶束中触发 NO 释放。更重要的是，⁾。负载 DOX 的 NO-M (NO-M@DOX) 可在细胞内条件下实现 DOX 的快速释放，从而导致更多的细胞内 DOX 积累和由还原触发的 NO/DOX 释放和 NO 诱导的 MDR 逆转介导的更高的抗肿瘤活性。此外，体内结果表明，NO-M@DOX通过直接 NO 诱导治疗和 NO 介导的增强化疗相结合，有效抑制 MCF7/DOX ^{R肿瘤生长；}同时，使用 NO-M 系统进行治疗的副作用要少得多。