College of Chemical and Environment Protection, Southwest Minzu University, First Ring Road, 4th Section No. 16, Chengdu, Sichuan 610041, China.
School of Biomedical Sciences and Technology, Chengdu Medical College, Xindu Road No. 783, Chengdu, Sichuan 610500, China.
J Mater Chem B. 2019 Dec 7;7(45):7129-7140. doi: 10.1039/c9tb01773a. Epub 2019 Oct 30.
The systemic toxicity, reduced cellular internalization, and uncontrollable intracellular drug release of smart nanoparticles (NPs) still need to be overcome for effective cancer therapy. Herein, a series of stepwise dual pH and redox responsive cross-linked polypeptides based on poly(l-lysine-co-N,N-bis(acryloyl)cystamine-co-γ-glutamic acid) (PLBG), were prepared for enhanced cellular uptake and effective cancer therapy. The prepared cross-linked PLBG nanoparticles (PLBG-NPs) exhibit negatively charged surfaces under physiological conditions, and the surface charge of the PLBG-NPs was observed to switch from negative to positive in a slightly acidic tumor extracellular environment at a pH level of ∼6.5. Finally, the endosome escape of the PLBG-NPs was facilitated via a "proton-sponge" effect via protonation of the polymer chain in the endo/lysosome environment of the tumor cell at a pH level of ∼5.0. Moreover, rapid drug release was triggered by a high concentration of reducing glutathione (GSH) in tumor cells via destruction of the disulfide linkages in the PLBG-NPs. Cytotoxicity assays demonstrated that no noticeable cytotoxicity was observed for the PLBG-NPs. However, DOX-loaded PLBG-NPs (PLBG-NPs-DOX) demonstrated remarkable tumor cell killing effects. In HeLa tumor-bearing mice, PLBG-NPs-DOX showed sustained tumor accumulation and enhanced inhibitory effects on tumor growth and angiogenesis. In conclusion, it is suggested that the as-designed novel charge-conversion PLBG-NPs with stepwise pH-responsivity and biodegradability could be used as a potential drug carrier for effective cancer therapy with less systemic toxicity.
智能纳米颗粒（NPs）的全身毒性、减少的细胞内化和不可控的细胞内药物释放仍然需要克服，以实现有效的癌症治疗。在此，我们基于聚（L-赖氨酸-co-N，N-双（丙烯酰基）半胱氨酸-co-γ-谷氨酸）（PLBG）制备了一系列逐步双 pH 和还原响应交联多肽，以增强细胞摄取并有效治疗癌症。所制备的交联 PLBG 纳米颗粒（PLBG-NPs）在生理条件下具有带负电荷的表面，并且在 pH 值约为 6.5 的略酸性肿瘤细胞外环境中观察到 PLBG-NPs 的表面电荷从负变为正。最后，通过肿瘤细胞内体/溶酶体环境中聚合物链的质子化，通过“质子海绵”效应促进了 PLBG-NPs 的内体逃逸，在 pH 值约为 5.0 的情况下。此外，通过肿瘤细胞中高浓度的还原型谷胱甘肽（GSH）破坏 PLBG-NPs 中的二硫键，触发快速药物释放。细胞毒性试验表明，PLBG-NPs 没有明显的细胞毒性。然而，载 DOX 的 PLBG-NPs（PLBG-NPs-DOX）表现出显著的肿瘤细胞杀伤作用。在 HeLa 荷瘤小鼠中，PLBG-NPs-DOX 表现出持续的肿瘤积累和增强的抑制肿瘤生长和血管生成的作用。总之，建议设计的新型具有逐步 pH 响应性和生物降解性的新型电荷转换 PLBG-NPs 可作为一种有效的癌症治疗潜在药物载体，具有较低的全身毒性。
