Glutathione-degradable drug-loaded nanogel effectively and securely suppresses hepatoma in mouse model

Abstract

Xingang Liu,1 Jianmeng Wang,2 Weiguo Xu,3 Jianxun Ding,3 Bo Shi,4 Kexin Huang,4 Xiuli Zhuang,3 Xuesi Chen31Department of Critical Care Medicine, 2Department of Geriatrics, The First Hospital of Jilin University, 3Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 4Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun, People’s Republic of ChinaAbstract: The reduction-responsive polymeric nanocarriers have attracted considerable interest because of a significant higher concentration of intracellular glutathione in comparison with that outside cells. The smart nanovehicles can selectively transport the antitumor drugs into cells to improve efficacies and decrease side effects. In this work, a facilely prepared glutathione-degradable nanogel was employed for targeting intracellular delivery of antitumor drug (ie, doxorubicin [DOX]). DOX was loaded into nanogel through a sequential dispersion and dialysis approach with a drug loading efficiency of 56.8 wt%, and the laden nanogel (noted as NG/DOX) showed an appropriate hydrodynamic radius of 56.1±3.5 nm. NG/DOX exhibited enhanced or improved maximum tolerated dose on healthy Kunming mice and enhanced intratumoral accumulation and dose-dependent antitumor efficacy toward H22 hepatoma-xenografted mouse model compared with free drug. In addition, the upregulated antitumor efficacy of NG/DOX was further confirmed by the histopathological and immunohistochemical analyses. Furthermore, the excellent in vivo security of NG/DOX was confirmed by the detection of body weight, histopathology, and biochemical indices of corresponding organs and serum. With controllable large-scale preparation and fascinating in vitro and in vivo properties, the reduction-responsive nanogel exhibited a good prospect for clinical chemotherapy.Keywords: antitumor efficacy, chemotherapy, controlled release, nanogel, reduction-responsiveness, security