title: One-Step "Click Chemistry"-Synthesized Cross-Linked Prodrug Nanogel for Highly Selective Intracellular Drug Delivery and Upregulated Antitumor Efficacy.
abstract: Polymeric prodrugs formed by the conjugation of drugs onto polymers have shown great promise in cancer therapy because of the enhancement of water solubility, elimination of premature drug release, and the improvement of pharmacokinetics. To integrate the two advantages of upregulated stability during circulation and selective release of drug in cancer cells, a pH and reduction dual-sensitive prodrug nanogel (CLP) was synthesized via a simple one step "click chemistry". CLP was spherically shaped with a uniform diameter of 60.6 ± 13.7 nm and exhibited great stability in size against large volume dilution, high salt concentration, and long-time incubation in phosphate-buffered saline. Owing to the presence of hydrazone-bonded doxorubicin (DOX) and disulfide cross-linker, CLP released minimal amount (7.8%) of drug under normal physiological pH (i.e., 7.4) condition. But it released 85.5% of the loaded DOX at endosomal pH (i.e., 5.5) plus the presence of 5.0 mM GSH in 120 h. CLP could be effectively internalized by tumor cells and subsequently release DOX in the intracellular environment, resulting in effective proliferation inhibition of HeLa and MCF-7 cells. Furthermore, compared with free DOX and non-cross-linked prodrug micelle (NCLP), CLP accumulated more in tumor site but less in the normal organs, so that CLP performed the enhanced antitumor efficiency and reduced side-toxicities toward the MCF-7 human breast cancer xenograft nude mouse model. With convenient fabrication, favorable stability, controlled release properties, optimized biodistribution, and enhanced suppression of tumor growth, CLP held great potential for optimal antitumor therapy.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Ding
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.|University of Chinese Academy of Sciences , 19A Yuquan Road, Beijing 100049, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic; D057930:Click Chemistry; D004317:Doxorubicin; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000080385:Nanogels; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D011355:Prodrugs; D014018:Tissue Distribution
chemical_list: D000903:Antibiotics, Antineoplastic; D000080385:Nanogels; D011355:Prodrugs; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011094:Polyethyleneimine
keywords: cancer therapy; click chemistry; cross-linking; intracellular drug delivery; prodrug; responsiveness