Yi Qiangying, Ma Jin, Kang Ke, Gu Zhongwei
National Engineering Research Center for Biomaterials, Sichuan University, 29 Wangjiang Road, Chengdu 610064, China.
J Mater Chem B. 2016 Jul 28;4(28):4922-4933. doi: 10.1039/c6tb00651e. Epub 2016 Jul 4.
In this work, we report dual cellular environmental stimuli-responsive hydrogel nanocapsules (HA-NCs) for delivery of an anticancer drug (doxorubicin, DOX). This nanocapsule drug delivery system was specially designed to be triggered by stimuli in intra-cellular environments, specifically high glutathione (GSH) concentration and low pH. Biocompatible hyaluronan was used as the basic nanocapsule shell building material. Chemical modifications were conducted in order to functionalize it; specifically, GSH cleavable crosslinking sites and pH responsive expansion sites were introduced. After passive delivery to tumor sites via an enhanced permeation and retention (EPR) effect and cellular uptake, the nanocapsule shells underwent a swelling/disassembly process due to high GSH concentration (e.g., 10 mM), which induced cleavage of disulfide (S-S) bonds, and low pH (e.g., pH 5), which caused water influx associated with deprotection of the acetal groups. This process enabled rupture of the hydrogel nanocapsules and therefore resulted in release of the encapsulated payloads. This hydrogel nanocapsule system exhibited a great ability to release the vast majority of the encapsulated DOX in tumor cells, as proven by the remarkably (4.7-fold) accelerated drug release rate within tumor cells (pH 5.0, GSH 10 mM), in sharp contrast to the drug release rate under physiological conditions (pH 7.4, GSH 0). In vitro bio-evaluation showed the good biocompatibility of the nanocapsule carriers and their efficient cancer cell growth inhibition activity after drug encapsulation. In vivo studies confirmed that the DOX containing nanocapsules (DOX/HA-NCs) had comparable antitumor efficiency and greatly reduced side effects as compared with free DOX (DOX·HCl).
在本研究中，我们报道了用于递送抗癌药物（阿霉素，DOX）的双细胞环境刺激响应水凝胶纳米胶囊（HA-NCs）。该纳米胶囊药物递送系统经专门设计，可由细胞内环境中的刺激因素触发，特别是高浓度谷胱甘肽（GSH）和低pH值。生物相容性透明质酸被用作纳米胶囊外壳的基本构建材料。为使其功能化进行了化学修饰；具体而言，引入了GSH可裂解交联位点和pH响应性膨胀位点。通过增强渗透与滞留（EPR）效应被动递送至肿瘤部位并被细胞摄取后，由于高浓度GSH（例如10 mM）诱导二硫键（S-S）断裂以及低pH值（例如pH 5）导致与缩醛基团去保护相关的水流入，纳米胶囊外壳经历了溶胀/解体过程。这一过程使水凝胶纳米胶囊破裂，从而导致封装的药物释放。该水凝胶纳米胶囊系统在肿瘤细胞中展现出释放绝大多数封装DOX的强大能力，肿瘤细胞内（pH 5.0，GSH 10 mM）药物释放速率显著加快（4.7倍）就是证明，这与生理条件下（pH 7.4，GSH 0）的药物释放速率形成鲜明对比。体外生物评估表明纳米胶囊载体具有良好的生物相容性，且在封装药物后具有高效的癌细胞生长抑制活性。体内研究证实，与游离DOX（DOX·HCl）相比，含DOX的纳米胶囊（DOX/HA-NCs）具有相当的抗肿瘤效果且副作用大大降低。
