Chemotherapeutic drugs have been shown to be promising for the treatment of tumors, however, they are associated with several disadvantages including low aqueous solubility, non-specificity, and poor plasma stability. Hence, they accumulate in the health organs and create several adverse effects. Drug encapsulated stimuli-responsive nanoparticles bearing redox-responsive disulfide linkages have emerged as promising delivery vehicle to address these limitations. A glutathione (GSH) responsive disulfide-based drug delivery system based on a polyethylene glycol methyl ether (PEGME) and a polydisulfide (PDS) diblock copolymer has been developed. The cyclic lactone containing a disulfide link, 1,4,5-oxadithiepan-2-one, was prepared using a thiol-free method utilizing the reaction of 2-bromoethyl bromoacetate with sodium disulfide. Ring-opening polymerization (ROP) of 1,4,5-oxadithiepan-2-one using 1-butanol in the presence of Sn(oct) generated the homopolymer PDS whereas the diblock copolymer PEGME--PDS was obtained when PEGME was used as a macroinitiator. In aqueous solution, PEGME--PDS self-assembled into spherical-shaped micelles with a hydrodynamic radius of 146 and 116 nm as measured by Field-emission Scanning Electron Microscopy (FESEM) and Dynamic Light Scattering (DLS), respectively. At pH = 7.4, a Doxorubicin (DOX) loaded PEGME--PDS micelle showed a cumulative release of ∼98.2, ∼9.9, and ∼1.9 % in presence of 2 mM, 2 μM DTT and in absence of DTT, respectively clearly demonstrating the redox responsiveness of the PDS block. The best fit of kinetic data using with the Korsmeyer-Peppas model suggests a Fickian diffusion as well as chain-relaxation controlled drug release process. DOX loaded micelles and free DOX displayed similar cytotoxicity towards both 4T1 and MCF-7 cells indicating that the encapsulation inside the micelle did not affect the anticancer efficacy of the drug. The drug loaded micelle showed higher cellular uptake than free DOX in both 4T1 and MCF-7 lines and lower cellular uptake than free DOX in 3T3-L1 cell lines. This polymeric micellar nanoparticle may be further exploited for encapsulation of other hydrophobic drugs.

中文翻译：

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1,4,5-oxadithiepan-2-one 的简便合成和聚合用于基于二硫化物的氧化还原响应药物递送

化疗药物已被证明有望用于治疗肿瘤，但它们也存在一些缺点，包括水溶性低、非特异性和血浆稳定性差。因此，它们会积聚在健康器官中并产生多种不利影响。带有氧化还原响应二硫键的药物封装的刺激响应纳米颗粒已成为解决这些限制的有前途的递送载体。开发了一种基于聚乙二醇甲醚（PEGME）和聚二硫醚（PDS）二嵌段共聚物的谷胱甘肽（GSH）响应性二硫键药物递送系统。含有二硫键的环内酯，1,4,5-oxadithiepan-2-one，是利用溴乙酸2-溴乙酯与二硫化钠的反应，采用无硫醇方法制备的。在 Sn(oct) 存在下使用 1-丁醇对 1,4,5-oxadithiepan-2-one 进行开环聚合 (ROP) 生成均聚物 PDS，而当使用 PEGME 时则获得二嵌段共聚物 PEGME--PDS宏观引发剂。在水溶液中，PEGME--PDS 自组装成球形胶束，通过场发射扫描电子显微镜 (FESEM) 和动态光散射 (DLS) 测量，流体动力学半径分别为 146 和 116 nm。在 pH = 7.4 时，负载阿霉素 (DOX) 的 PEGME--PDS 胶束在存在 2 mM、2 μM DTT 和不存在 DTT 的情况下分别显示出 ∼98.2、∼9.9 和 ∼1.9% 的累积释放量，分别清楚地证明了PDS 块的氧化还原反应性。使用 Korsmeyer-Peppas 模型的动力学数据的最佳拟合表明存在 Fickian 扩散以及链松弛控制的药物释放过程。负载 DOX 的胶束和游离 DOX 对 4T1 和 MCF-7 细胞表现出相似的细胞毒性，表明胶束内的封装不会影响药物的抗癌功效。载药胶束在 4T1 和 MCF-7 细胞系中显示出比游离 DOX 更高的细胞摄取，在 3T3-L1 细胞系中显示出比游离 DOX 更低的细胞摄取。这种聚合物胶束纳米颗粒可进一步用于封装其他疏水性药物。