Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, Berlin, 14195, Germany.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, P. R. China.
Small. 2017 Feb;13(6). doi: 10.1002/smll.201601997. Epub 2016 Nov 16.
Cyclo(Arg-Gly-Asp) peptide (cRGD) decorated disulfide (SS) containing poly(vinyl alcohol) nanogels (cRGD-SS-NGs) with an average diameter of 142 nm prepared by inverse nanoprecipitation, "click" reaction, and cRGD conjugation are developed for targeted treatment of integrin overexpressing human glioblastoma in vivo. Doxorubicin (DOX) release from cRGD-SS-NGs is highly inhibited under physiological conditions, while accelerated at endosomal pH and in response to cytoplasmic concentration of glutathione. Confocal microscopy shows that cRGD-SS-NGs facilitate the cellular uptake and intracellular DOX release in α β integrin overexpressing human glioblastoma U87-MG cells. DOX-loaded cRGD-SS-NGs present much better killing activity toward U87-MG cells than that for nontargeted nanogels determined by MTT assay. The in vivo imaging and biodistribution studies reveal that DOX-loaded cRGD-SS-NGs have a much better tumor targetability toward human U87-MG glioblastoma xenograft in nude mice. Also the tumor growth is effectively inhibited by treatment with DOX-loaded cRGD-SS-NGs, while continuous tumor growth is observed for mice treated with nondecorated nanogels as well as free DOX. Furthermore, the treatment with DOX-loaded cRGD-SS-NGs has much fewer side effects, rendering these nanogels as a new platform for cancer chemotherapy in vivo.
环（精氨酸-甘氨酸-天冬氨酸）肽（cRGD）修饰的二硫键（SS）含有平均直径为 142nm 的聚（乙烯醇）纳米凝胶（cRGD-SS-NGs），通过反相纳米沉淀、“点击”反应和 cRGD 缀合制备，用于体内靶向治疗整合素过表达的人胶质母细胞瘤。cRGD-SS-NGs 在生理条件下对阿霉素（DOX）的释放受到高度抑制，而在内涵体 pH 下和细胞质谷胱甘肽浓度响应下加速释放。共聚焦显微镜显示，cRGD-SS-NGs 促进了αβ整合素过表达的人胶质母细胞瘤 U87-MG 细胞的细胞内摄取和细胞内 DOX 释放。载 DOX 的 cRGD-SS-NGs 对 U87-MG 细胞的杀伤活性明显优于非靶向纳米凝胶，这是通过 MTT 测定确定的。体内成像和生物分布研究表明，载 DOX 的 cRGD-SS-NGs 对裸鼠人 U87-MG 胶质母细胞瘤异种移植物具有更好的肿瘤靶向性。此外，用载 DOX 的 cRGD-SS-NGs 治疗可有效抑制肿瘤生长，而用未修饰的纳米凝胶和游离 DOX 治疗的小鼠则持续肿瘤生长。此外，用载 DOX 的 cRGD-SS-NGs 治疗的副作用要少得多，这使得这些纳米凝胶成为体内癌症化疗的新平台。
