Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin 14195, Germany.
Research Center of Electron Microscopy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Fabeckstrasse 36a, Berlin 14195, Germany.
J Control Release. 2015 May 10;205:15-24. doi: 10.1016/j.jconrel.2014.11.012. Epub 2014 Nov 20.
Charge-conversional and reduction-sensitive polyvinyl alcohol (PVA) nanogels were developed for efficient cancer treatment by enhanced cell uptake and intracellular triggered doxorubicin (DOX) release. These PVA nanogels were prepared in a straightforward manner by inverse nanoprecipitation via "click" reaction with an average diameter of 118nm. The introduction of COOH into the PVA nanogels efficiently improved the DOX encapsulation due to the electrostatic interaction. The in vitro release result showed that the decrease of electrostatic interaction between COOH and DOX under a mimicking endosomal pH, in combination with the cleavage of the intervening disulfide bonds in response to a high glutathione (GSH) concentration led to a fast and complete release of DOX. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the ultra pH-sensitive terminal groups allowed nanogels to reverse their surface charge from negative to positive under a tumor extracellular pH (6.5-6.8) which facilitated cell internalization. MTT assays and real time cell analysis (RTCA) showed that these DOX-loaded charge-conversional and reducible PVA nanogels had much better cell toxicity than DOX-loaded non-charge-conversional or reduction-insensitive PVA nanogels following 48h of incubation. These novel charge-conversional and stimuli-responsive PVA nanogels are highly promising for targeted intracellular anticancer drug release.
制备了一种具有载药转换和还原敏感性的聚乙烯醇（PVA）纳米凝胶，通过增强细胞摄取和细胞内触发阿霉素（DOX）释放，实现高效癌症治疗。这些 PVA 纳米凝胶通过“点击”反应以简单的方式通过反向纳米沉淀制备，平均直径为 118nm。在 PVA 纳米凝胶中引入 COOH 由于静电相互作用，有效地提高了 DOX 的包封效率。体外释放结果表明，在模拟内涵体 pH 下，COOH 与 DOX 之间的静电相互作用降低，同时响应高谷胱甘肽（GSH）浓度下的中间二硫键断裂，导致 DOX 的快速完全释放。此外，共聚焦激光扫描显微镜（CLSM）显示，超 pH 敏感末端基团使纳米凝胶在肿瘤细胞外 pH（6.5-6.8）下能够从负电荷转变为正电荷，从而促进细胞内化。MTT 测定和实时细胞分析（RTCA）表明，与负载 DOX 的非载药转换或还原不敏感的 PVA 纳米凝胶相比，这些负载 DOX 的载药转换和还原敏感 PVA 纳米凝胶在孵育 48 小时后具有更好的细胞毒性。这些新型的载药转换和刺激响应性 PVA 纳米凝胶非常有希望用于靶向细胞内抗癌药物释放。
