Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.

中文翻译：

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双pH敏感电荷逆转纳米复合物，用于靶向肿瘤的药物递送，具有增强的抗癌活性

聚（β-L-苹果酸）（PMLA）是一种天然脂族聚酯，已被证明是抗癌药物的有前途的载体。尽管具有优异的生物相容性，但由于PMLA的细胞摄取效率低，因此限制了PMLA作为癌症治疗药物载体的应用。由于静电排斥，PMLA的强负电荷阻碍了癌细胞的摄取。在这项研究中，开发了一种双重pH敏感的电荷逆转基于PMLA的纳米复合物（PMLA-PEI-DOX-TAT @ PEG-DMMA），用于有效靶向肿瘤的药物递送，增强的细胞吸收和细胞内药物释放。所制备的纳米复合物在生理pH下具有负表面电荷，可以保护纳米复合物免受血浆蛋白的攻击和网状内皮系统的识别，从而延长其循环时间。在肿瘤细胞外pH值为6.8时，DMMA水解，导致电荷逆转和TAT在聚合物胶束上的暴露，从而增强了细胞的内在化。然后，响应于肿瘤细胞的溶酶/内膜区室中的酸性pH，聚合物胶束经历解离和药物释放。两个都体外和体内功效研究表明，纳米复合物可显着抑制肿瘤生长，而治疗显示出可忽略的全身毒性，这表明开发的基于pH敏感的双重基于PMLA的纳米复合物将成为一种有前景的药物靶向系统，可用于肿瘤靶向药物的递送。增强抗癌活性。