Department of Biomedical Engineering, School of Engineering, Sun Yat-sen University , Guangzhou, Guangdong 510006, China.
Department of Neurosurgery and Department of Biomedical Engineering, Yale University , New Haven, Connecticut 06511, United States.
ACS Appl Mater Interfaces. 2017 Sep 13;9(36):30519-30535. doi: 10.1021/acsami.7b10148. Epub 2017 Sep 1.
We have designed and constructed novel multifunctional nanoparticle drug-delivery systems that are stable under physiological conditions and responsive to tumor-relevant pH and intracellular reduction potential. The nanoparticles were fabricated from enzymatically synthesized poly(ethylene glycol) (PEG)-poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PPMD) and PEG-poly(ε-caprolactone-co-N-methyldiethyleneamine-co-3,3'-dithiodipropionate) (PEG-PCMD) block copolymers via self-assembly processes in aqueous solution. At acidic pH and in the presence of a reductant (e.g., d,l-dithiothreitol or glutathione), the nanosized micelle particles rapidly swell and disintegrate due to the protonation of amino groups and reductive cleavage of disulfide bonds in the micelle cores. Consistently, docetaxel (DTX)-loaded PEG-PPMD and PEG-PCMD micelles can be triggered synergistically by acidic endosomal pH and a high intracellular reduction potential to rapidly release the drug for efficient killing of cancer cells. The drug formulations based on PEG-PPMD and PEG-PCMD copolymers exhibited a substantially higher potency than free DTX in inhibiting tumor growth in mice, whereas their therapeutic effects on important organ tissues were minimal. These results demonstrate that PEG-PPMD and PEG-PCMD nanoparticles have a great potential to serve as site-specific, controlled drug-delivery vehicles for safe and efficient antitumor treatment.
我们设计并构建了新型多功能纳米粒子药物递送系统，该系统在生理条件下稳定，并对肿瘤相关的 pH 值和细胞内还原电势具有响应性。这些纳米粒子是通过酶合成的聚乙二醇（PEG）-聚（ω-十五内酯-co-N-甲基二亚乙基胺-co-3,3'-二硫代二丙酸盐）（PEG-PPMD）和 PEG-聚（ε-己内酯-co-N-甲基二亚乙基胺-co-3,3'-二硫代二丙酸盐）（PEG-PCMD）嵌段共聚物在水溶液中通过自组装过程制备的。在酸性 pH 值和还原剂（如 d,l-二硫苏糖醇或谷胱甘肽）存在下，由于纳米胶束核中的氨基质子化和二硫键的还原断裂，纳米胶束颗粒迅速溶胀和崩解。一致地，载多西紫杉醇（DTX）的 PEG-PPMD 和 PEG-PCMD 胶束可以通过酸性内涵体 pH 值和高细胞内还原电势协同触发，迅速释放药物，从而有效地杀死癌细胞。基于 PEG-PPMD 和 PEG-PCMD 共聚物的药物制剂在抑制小鼠肿瘤生长方面表现出比游离 DTX 更高的效力，而它们对重要器官组织的治疗效果则最小。这些结果表明，PEG-PPMD 和 PEG-PCMD 纳米粒子具有作为靶向、控制药物递送载体的巨大潜力，可用于安全有效的抗肿瘤治疗。
