Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, PR China.
J Control Release. 2013 Dec 10;172(2):444-55. doi: 10.1016/j.jconrel.2013.05.029. Epub 2013 Jun 3.
The pH and reduction dual-responsive polypeptide nanogels with self-reinforced endocytoses were prepared through ring-opening polymerization of l-glutamate N-carboxyanhydrides, deprotection of benzyl group and subsequent quaternization reaction between γ-2-chloroethyl-l-glutamate unit in polypeptide block and 2,2'-dithiobis(N,N-dimethylethylamine). The nanogels were revealed to exhibit smart pH and reduction dual-responsiveness, and excellent biocompatibilities, which expressed great potential as antitumor drug nanocarriers. Doxorubicin (DOX) as a model antitumor drug was loaded into nanogels through dispersion. DOX-loaded nanogels displayed a stable core-cross-linked structure under normal physiological condition (pH7.4), while rapidly releasing the payloads in the mimicking endosomal (pH5.3), tumor tissular (pH6.8) or intracellular reductive microenvironments (10.0mM glutathione). Confocal fluorescence microscopy demonstrated that DOX-loaded nanogels could deliver DOX into HepG2 cells (a human hepatoma cell line) more efficiently than the parent DOX-loaded micelle and free DOX. The enhanced cellular internalizations of DOX-loaded nanogels were more significant under tumor tissular acidic condition (pH6.8) ascribed to the quaternary ammonium groups in the cores. In addition, DOX-loaded nanogels exhibited improved in vitro and in vivo antitumor activities, and in vivo securities compared with DOX-loaded micelle and free DOX. These excellent features of the smart nanogels with quaternary ammonium groups were endowed with a bright prospect for intracellular targeting antitumor drug delivery.
通过开环聚合 L-谷氨酸 N-羧酸酐、脱保护苄基以及γ-2-氯乙基-L-谷氨酸单元与多肽嵌段中的 2,2'-二硫代双（N,N-二甲乙基胺）之间的季铵化反应，制备了具有自增强内吞作用的 pH 和还原双重响应的多肽纳米凝胶。纳米凝胶表现出智能的 pH 和还原双重响应性和优异的生物相容性，作为抗肿瘤药物纳米载体具有很大的潜力。阿霉素（DOX）作为一种模型抗肿瘤药物通过分散作用被载入纳米凝胶中。在正常生理条件下（pH7.4），载 DOX 的纳米凝胶显示出稳定的核交联结构，而在模拟内体（pH5.3）、肿瘤组织（pH6.8）或细胞内还原微环境（10.0mM 谷胱甘肽）中则迅速释放药物。共聚焦荧光显微镜表明，与载 DOX 的胶束和游离 DOX 相比，载 DOX 的纳米凝胶能更有效地将 DOX 递送到 HepG2 细胞（人肝癌细胞系）中。由于核心中的季铵基团，在肿瘤组织酸性条件（pH6.8）下，载 DOX 的纳米凝胶的细胞内化增强更为显著。此外，与载 DOX 的胶束和游离 DOX 相比，载 DOX 的纳米凝胶表现出改善的体外和体内抗肿瘤活性和体内安全性。这些具有季铵基团的智能纳米凝胶的优异特性为细胞内靶向抗肿瘤药物递送提供了广阔的前景。
