Chen Wei-Liang, Li Fang, Tang Yan, Yang Shu-di, Li Ji-Zhao, Yuan Zhi-Qiang, Liu Yang, Zhou Xiao-Feng, Liu Chun, Zhang Xue-Nong
Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou.
Department of Ultrasound, Changshu Hospital of Traditional Chinese Medicine, Changshu.
Int J Nanomedicine. 2017 Jun 6;12:4241-4256. doi: 10.2147/IJN.S129748. eCollection 2017.
Physicochemical properties, including particle size, zeta potential, and drug release behavior, affect targeting efficiency, cellular uptake, and antitumor effect of nanocarriers in a formulated drug-delivery system. In this study, a novel stepwise pH-responsive nanodrug delivery system was developed to efficiently deliver and significantly promote the therapeutic effect of doxorubicin (DOX). The system comprised dimethylmaleic acid-chitosan-urocanic acid and elicited stepwise responses to extracellular and intracellular pH. The nanoparticles (NPs), which possessed negative surface charge under physiological conditions and an appropriate nanosize, exhibited advantageous stability during blood circulation and enhanced accumulation in tumor sites via enhanced permeability and retention effect. The tumor cellular uptake of DOX-loaded NPs was significantly promoted by the first-step pH response, wherein surface charge reversion of NPs from negative to positive was triggered by the slightly acidic tumor extracellular environment. After internalization into tumor cells, the second-step pH response in endo/lysosome acidic environment elicited the on-demand intracellular release of DOX from NPs, thereby increasing cytotoxicity against tumor cells. Furthermore, stepwise pH-responsive NPs showed enhanced antiproliferation effect and reduced systemic side effect in vivo. Hence, the stepwise pH-responsive NPs provide a promising strategy for efficient delivery of antitumor agents.
物理化学性质，包括粒径、zeta电位和药物释放行为，会影响纳米载体在制剂药物递送系统中的靶向效率、细胞摄取和抗肿瘤效果。在本研究中，开发了一种新型的逐步pH响应纳米药物递送系统，以有效递送并显著提高阿霉素（DOX）的治疗效果。该系统由二甲基马来酸-壳聚糖-尿刊酸组成，并对细胞外和细胞内pH产生逐步响应。纳米颗粒（NPs）在生理条件下具有负表面电荷且尺寸合适，在血液循环过程中表现出良好的稳定性，并通过增强的渗透和滞留效应在肿瘤部位实现了增强的积累。第一步pH响应显著促进了载DOX的NPs的肿瘤细胞摄取，其中肿瘤细胞外微酸性环境触发了NPs表面电荷从负向正的转变。内化进入肿瘤细胞后，内吞/溶酶体酸性环境中的第二步pH响应引发了DOX从NPs中按需在细胞内释放，从而增加了对肿瘤细胞的细胞毒性。此外，逐步pH响应的NPs在体内显示出增强的抗增殖作用和降低的全身副作用。因此，逐步pH响应的NPs为高效递送抗肿瘤药物提供了一种有前景的策略。
