Tumor microenvironment (TME) responsive polymeric micelles are promising carriers for drug delivery. In order to meet the needs of various applications, multifarious TME-responsive switches are used to construct smart polymeric micelles, which causes the complexity and corpulence of the polymeric micelle system and increases the difficulty of preparation. In this study, we designed and synthesized an ingenious TME-responsive switch through grafting disulfide bond-modified piperidinepropionic acid (CPA) on copolymer poly(ethylene glycol)-b-poly(aspartate)(PEG-b-PAsp) and built a novel pH/reduction-responsive PEG-b-PAsp-g-CPA polymeric micelle delivery system. The CPA-pendants can reverse the surface charge of the polymeric micelle from negative to positive at pH 6.5 because of the protonation of piperidine groups, thereby enhancing the internalization of cell. Subsequently, more piperidine groups are protonated at pH 5.0 which will increase the hydrophilicity of polymeric micelles and cause the hydrophobic core to swell, thus making the disulfide bonds packed in the core to be more easily broken by GSH. With the synergistic effect of the pH-triggered protonation of piperidine groups and reduction triggered break of disulfide bonds, the polymeric micelles will disintegrate and achieve efficient intracellular drug release. The TME-responsive polymeric micelles exhibited good biological safety, enhanced internalization, and rapid intracellular doxorubicin (DOX) release in vitro. Moreover, the PEG-b-PAsp-g-CPA/DOX polymeric micelles showed excellent antitumor efficacy and low systemic toxicity in lung tumor-bearing BALB/C mice. These results indicated that the novel integrated TME-responsive switch CPA helps the PEG-b-PAsp-g-CPA polymeric micelles to obtain excellent TME-responsiveness and antitumor drug delivery capabilities, while it also makes the preparation of TME-responsive polymeric micelles simpler and more convenient. This work provides a new idea for the architecture of TME-responsive polymeric micelles.

中文翻译：

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用于智能给药和有效药物释放的集成肿瘤微环境响应聚合物胶束

肿瘤微环境 (TME) 响应性聚合物胶束是有前途的药物递送载体。为了满足各种应用的需要，利用多种TME响应开关构建智能聚合物胶束，导致聚合物胶束体系的复杂性和庞大性，增加了制备难度。在这项研究中，我们通过在共聚物聚（乙二醇）-b-聚（天冬氨酸）（PEG- b - PAsp）上接枝二硫键修饰的哌啶丙酸（CPA），设计并合成了一种巧妙的 TME 响应开关，并构建了一种新型的TME 响应开关。pH/还原反应性 PEG- b -PAsp- g-CPA 聚合物胶束输送系统。由于哌啶基团的质子化，CPA 悬垂物可以在 pH 6.5 时将聚合物胶束的表面电荷从负电荷反转为正电荷，从而增强细胞的内化。随后，更多的哌啶基团在 pH 5.0 时质子化，这将增加聚合物胶束的亲水性并导致疏水核膨胀，从而使包裹在核中的二硫键更容易被 GSH 破坏。在pH引发的哌啶基团质子化和还原引发的二硫键断裂的协同作用下，聚合物胶束将崩解并实现有效的细胞内药物释放。TME 响应聚合物胶束表现出良好的生物安全性、增强的内化、和体外快速细胞内多柔比星 (DOX) 释放。此外，PEG-b- PAsp- g- CPA/DOX 聚合物胶束在肺肿瘤荷瘤 BALB/C 小鼠中显示出优异的抗肿瘤功效和低全身毒性。这些结果表明，新型集成的 TME 响应开关 CPA 有助于 PEG- b -PAsp- g -CPA 聚合物胶束获得优异的 TME 响应性和抗肿瘤药物递送能力，同时也使 TME 响应性聚合物胶束的制备更加简单而且更方便。这项工作为 TME 响应聚合物胶束的结构提供了新思路。