Shell cross-linked (SCL) polymeric prodrug micelles have the advantages of good blood circulation stability and high drug content. Herein, we report on a new kind of pH/redox responsive dynamic covalent SCL micelle, which was fabricated by self-assembly of a multifunctional polymeric prodrug. At first, a macroinitiator PBYP-ss-iBuBr was prepared via ring-opening polymerization (ROP), wherein PBYP represents poly[2-(but-3-yn-1-yloxy)-2-oxo-1,3,2-dioxaphospholane]. Subsequently, PBYP-hyd-DOX-ss-P(DMAEMA-co-FBEMA) prodrug was synthesized by a one-pot method with a combination of atom transfer radical polymerization (ATRP) and a Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reaction using a doxorubicin (DOX) derivative containing an azide group to react with the alkynyl group of the side chain in the PBYP block, while DMAEMA and FBEMA are the abbriviations of N,N-(2-dimethylamino)ethyl methacrylate and 2-(4-formylbenzoyloxy)ethyl methacrylate, respectively. The chemical structures of the polymer precursors and the prodrugs have been fully characterized. The SCL prodrug micelles were obtained by self-assembly of the prodrug and adding cross-linker dithiol bis(propanoic dihydrazide) (DTP). Compared with the shell un-cross-linked prodrug micelles, the SCL prodrug micelles can enhance the stability and prevent the drug from leaking in the body during blood circulation. The average size and morphology of the SCL prodrug micelles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM), respectively. The SCL micelles can be dissociated under a moderately acidic and/or reductive microenvironment, that is, endosomal/lysosomal pH medium or high GSH level in the tumorous cytosol. The results of DOX release also confirmed that the SCL prodrug micelles possessed pH/reduction responsive properties. Cytotoxicity and cellular uptake analyses further revealed that the SCL prodrug micelles could be rapidly internalized into tumor cells through endocytosis and efficiently release DOX into the HeLa and HepG2 cells, which could efficiently inhibit the cell proliferation. This study provides a fast and precise synthesis method for preparing multifunctional polymer prodrugs, which hold great potential for optimal antitumor therapy.

中文翻译：

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pH /氧化还原响应性高分子前药的一锅法合成和壳交联前药胶束的制备，用于抗肿瘤药物的运输。

壳交联（SCL）聚合物前药胶束具有良好的血液循环稳定性和高药物含量的优点。在本文中，我们报告了一种新型的pH /氧化还原响应动态共价SCL胶束，它是通过自组装多功能聚合物前药制成的。起初，大分子引发剂PBYP- SS -我BuBr经由开环聚合（ROP），其中PBYP表示聚[2-（丁-3-炔-1-基氧基）制备-2-氧代- 1,3,2 -二氧戊环]。随后，PBYP- hyd -DOX- ss -P（DMAEMA- co-FBEMA）前药通过一锅法结合原子转移自由基聚合（ATRP）和Cu（I）催化的叠氮化物-炔烃环加成反应（CuAAC）结合使用含有叠氮化物基团的阿霉素（DOX）衍生物合成与PBYP嵌段中侧链的炔基反应，而DMAEMA和FBEMA是N，N的衍生分别为甲基丙烯酸-（2-二甲基氨基）乙酯和甲基丙烯酸2-（4-甲酰基苯甲酰氧基）乙酯。聚合物前体和前药的化学结构已得到充分表征。通过自组装前药并添加交联剂二硫醇双（丙二酰肼）（DTP），可获得SCL前药胶束。与外壳未交联的前药胶束相比，SCL前药胶束可增强稳定性并防止药物在血液循环中渗入人体。SCL前药胶束的平均大小和形态分别通过动态光散射（DLS）和透射电子显微镜（TEM）进行测量。SCL胶束可在中等酸性和/或还原性微环境（即内质/溶酶体pH中等或肿瘤细胞质中的GSH含量高）下解离。DOX释放的结果还证实了SCL前药胶束具有pH /还原响应特性。细胞毒性和细胞摄取分析进一步表明，SCL前药胶束可以通过内吞作用迅速内化到肿瘤细胞中，并有效地将DOX释放到HeLa和HepG2细胞中，从而可以有效抑制细胞增殖。这项研究提供了一种快速，精确的合成方法来制备多功能聚合物前药，这些药物具有最佳的抗肿瘤治疗潜力。细胞毒性和细胞摄取分析进一步表明，SCL前药胶束可以通过内吞作用迅速内化到肿瘤细胞中，并有效地将DOX释放到HeLa和HepG2细胞中，从而可以有效抑制细胞增殖。这项研究提供了一种快速，精确的合成方法来制备多功能聚合物前药，这些药物具有最佳的抗肿瘤治疗潜力。细胞毒性和细胞摄取分析进一步表明，SCL前药胶束可以通过内吞作用迅速内化到肿瘤细胞中，并有效地将DOX释放到HeLa和HepG2细胞中，从而可以有效抑制细胞增殖。这项研究提供了一种快速，精确的合成方法来制备多功能聚合物前药，这些药物具有最佳的抗肿瘤治疗潜力。