title: Reduction-responsive polypeptide nanogel delivers antitumor drug for improved efficacy and safety.
abstract: Chemotherapy plays an irreplaceable role in the treatment of various malignant tumors today. The traditional drug formulations lack of selectivity, cause serious damage to normal tissues, and can't achieve a desired therapeutic efficacy. For this situation, a facilely prepared reduction-responsive polypeptide nanogel was employed for targeting intracellular delivery of antitumor drug in this study. Doxorubicin (DOX) as a model drug was loaded into nanogel through a sequential dispersion and dialysis approach with a drug loading efficiency (DLE) of 56.8wt.%. The loading nanogel, i.e., NG/DOX, exhibited a medium hydrodynamic radius of 56.1±3.5nm, glutathione-accelerated DOX release, and efficient cellular uptake and proliferation inhibition. Moreover, NG/DOX exhibited upregulated intratumoral accumulation and improved antitumor efficacy toward HepG2 hepatoma-xenografted BALB/c nude mouse model compared with free drug. The enhanced tumor suppression of NG/DOX was further confirmed by the histopathological and immunohistochemical analyses. Furthermore, the excellent in vivo security of NG/DOX was systematically demonstrated by the variation detection of body weight, histopathological assay, levels of bone marrow cell micronucleus rate (BMMR) and white blood cells (WBCs), and detection of clinical parameters in corresponding organs and serum. With controllable large-scale preparation and fascinating properties in vitro and in vivo, the reduction-responsive polypeptide nanogel is revealed to exhibit great potential for on-demand intracellular delivery of antitumor drugs, and shows a good prospect for clinical chemotherapy.
  
  
  CONCLUSIONS
  The traditional drug formulations lack of selectivity, cause serious damage to normal tissues, and can't achieve a desired therapeutic effect. For this situation, a facilely prepared reduction-responsive polypeptide nanogel is employed for targeting intracellular delivery of antitumor drug in this study. The laden nanogel keeps structural integrity and less drug release in the circulatory system after intravenous injection, releases the payload triggered by the intracellular high concentration of GSH, and exhibits the excellent tumor inhibition and security in vivo. Furthermore, the other hydrophobic antitumor drugs can also be on-demand delivered by the smart nanogel. All of the above advantages confirm the bright prospect of reduction-responsive nanogel on the road of malignancy chemotherapy.
authors: Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China.
authors: Kexin
authors: K
authors: Huang
authors: Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China.
authors: Bo
authors: B
authors: Shi
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.
authors: Weiguo
authors: W
authors: Xu
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China. Electronic address: jxding@ciac.ac.cn.
authors: Jianxun
authors: J
authors: Ding
authors: Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China.
authors: Yu
authors: Y
authors: Yang
authors: Center for Biological Experiment, College of Basic Medicine, Jilin University, Changchun 130021, People's Republic of China. Electronic address: haiyan@jlu.edu.cn.
authors: Haiyan
authors: H
authors: Liu
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.
authors: Xiuli
authors: X
authors: Zhuang
authors: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China.
authors: Xuesi
authors: X
authors: Chen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000009:adverse effects / Q000138:chemical synthesis; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry; D004357:Drug Synergism; D005782:Gels / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D005782:Gels; D053769:Nanocapsules; D010455:Peptides; D004317:Doxorubicin
keywords: Chemotherapy efficacy; Controlled release; Polypeptide nanogel; Reduction-responsiveness; Security