Abstract The surface chemistry of stimulus-responsive nanoparticles plays an important role in mediating nano-bio interactions in cancer nanomedicine by targeting the unique features of the tumor microenvironment, such as low extracellular pH. To develop therapeutic nanoparticles with high sensitivity and instant response to slight pH differences in the systemic circulation, we produced a novel polyzwitterion with acylsulfonamide-based betaine structure by one-step modification of polycarboxybetaine (PCB) with benzene sulfonamide. The zwitterionic micellar shells show high antifouling in the blood circulation and acutely convert into positive charge via acylsulfonamide protonation, thereby improving cell affinity at tumor sites. Moreover, a disulfide bond between the shell and poly-e-caprolactone (PCL) core allows for reductive-responsive release of doxorubicin (DOX) after internalization of the polymeric micelles. Finally, in vitro and in vivo competition assays demonstrated that dual responsive drug-loaded micelles have better anticancer efficiency than free DOX or micelles without zwitterionic pH-responsive properties. Thus, we have developed a simple and valuable strategy to enhance pH sensitivity of micellar carriers for cancer treatment.

中文翻译：

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具有基于酰基磺酰胺的甜菜碱结构的工程聚两性离子，用于肿瘤pH下表面化学的质子化转换和聚合物胶束的还原反应性药物释放

摘要 刺激响应性纳米颗粒的表面化学通过靶向肿瘤微环境的独特特征，如低细胞外 pH 值，在介导癌症纳米医学中的纳米生物相互作用中发挥重要作用。为了开发对体循环中轻微 pH 差异具有高灵敏度和即时响应的治疗性纳米粒子，我们通过用苯磺酰胺一步改性聚羧基甜菜碱 (PCB)，制备了一种具有基于酰基磺酰胺的甜菜碱结构的新型聚两性离子。两性离子胶束壳在血液循环中显示出高抗污性，并通过酰基磺酰胺质子化迅速转化为正电荷，从而提高肿瘤部位的细胞亲和力。而且，外壳和聚ε-己内酯 (PCL) 核之间的二硫键允许在聚合物胶束内化后还原反应性释放多柔比星 (DOX)。最后，体外和体内竞争试验表明，双响应载药胶束比游离 DOX 或没有两性离子 pH 响应特性的胶束具有更好的抗癌效率。因此，我们开发了一种简单而有价值的策略来提高胶束载体对癌症治疗的 pH 敏感性。