Yang Hao, Wang Qin, Huang Shan, Xiao Ai, Li Fuying, Gan Lu, Yang Xiangliang
National Engineering Research Center for Nanomedicine, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, and §School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology , Wuhan 430074, China.
ACS Appl Mater Interfaces. 2016 Mar;8(12):7729-38. doi: 10.1021/acsami.6b01602. Epub 2016 Mar 18.
Efficient accumulation and intracellular drug release in cancer cells remain a crucial challenge in developing ideal anticancer drug delivery systems. Here, poly(N-isopropylacrylamide)-ss-acrylic acid (P(NIPAM-ss-AA)) nanogels based on NIPAM and AA cross-linked by N,N'-bis(acryloyl)cystamine (BAC) were constructed by precipitation polymerization. The nanogels exhibited pH/redox dual responsive doxorubicin (DOX) release behavior in vitro and in tumor cells, in which DOX release from nanogels was accelerated in lysosomal pH (pH 4.5) and cytosolic reduction (10 mM GSH) conditions. Moreover, intracellular tracking of DOX-loaded nanogels confirmed that after the nanogels and the loaded DOX entered the cells simultaneously mainly via lipid raft/caveolae-mediated endocytosis, DOX-loaded nanogels were transported to lysosomes and then the loaded DOX was released to nucleus triggered by lysosomal pH and cytoplasmic high GSH. MTT analysis showed that DOX-loaded nanogels could efficiently inhibit the proliferation of HepG2 cells. In vivo animal studies demonstrated that DOX-loaded nanogels were accumulated and penetrated in tumor tissues more efficiently than free DOX. Meanwhile, DOX-loaded nanogels exhibited stronger tumor inhibition activity and fewer side effects. This study indicated that pH/redox dual-responsive nanogels might present a prospective platform for intracellular drug controlled release in cancer therapy.
在开发理想的抗癌药物递送系统中，癌细胞内药物的高效积累和释放仍然是一个关键挑战。在此，通过沉淀聚合构建了基于N-异丙基丙烯酰胺（NIPAM）和丙烯酸（AA）、由N,N'-双（丙烯酰基）胱胺（BAC）交联的聚（N-异丙基丙烯酰胺-ss-丙烯酸）（P(NIPAM-ss-AA)）纳米凝胶。该纳米凝胶在体外和肿瘤细胞中表现出pH/氧化还原双重响应的阿霉素（DOX）释放行为，其中在溶酶体pH（pH 4.5）和胞质还原（10 mM谷胱甘肽（GSH））条件下，DOX从纳米凝胶中的释放加速。此外，对负载DOX的纳米凝胶的细胞内追踪证实，纳米凝胶和负载的DOX主要通过脂筏/小窝介导的内吞作用同时进入细胞后，负载DOX的纳米凝胶被转运至溶酶体，然后在溶酶体pH和细胞质高GSH的触发下，负载的DOX释放至细胞核。MTT分析表明，负载DOX的纳米凝胶可有效抑制HepG2细胞的增殖。体内动物研究表明，负载DOX的纳米凝胶比游离DOX更有效地在肿瘤组织中积累和渗透。同时，负载DOX的纳米凝胶表现出更强的肿瘤抑制活性和更少的副作用。本研究表明，pH/氧化还原双重响应纳米凝胶可能为癌症治疗中的细胞内药物控释提供一个有前景的平台。
