title: Zinc finger-inspired nanohydrogels with glutathione/pH triggered degradation based on coordination substitution for highly efficient delivery of anti-cancer drugs.
abstract: Biodegradable materials used for drug delivery are of great demand due to their ability to degrade into low molecular weight species and further excrete from the body by metabolism. Herein, we report a new kind of zinc(II) crosslinked poly(methacrylic acid) nanohydrogels (ZCLNs) inspired by zinc finger proteins with dual stimuli-triggered degradation (glutathione and pH) for the first time. Compared with the disulfide bond crosslinked nanohydrogels, this new kind of ZCLNs is beneficial to the degradation of a wide range of cells, including normal cells. Ex vivo fluorescence images showed that the DOX-loaded folate-PEG conjugated zinc(II)-crosslinked polymeric nanohydrogels (FPZCLNs-15) preferentially accumulated in tumor tissue and the accumulation in normal tissues was much less compared with DOX-loaded PZCLNs-15 (non-targeted nanohydrogels) and free DOX, the FPZCLNs-15 (targeting system) delivered DOX to the tumor site with approximately 3.6- and 1.6-fold higher than free DOX and PZCLNs-15, respectively. Meanwhile, the PZCLNs-15 and FPZCLNs-15 reduced the concentration of DOX in the heart by 3.2- and 5.0-fold respectively, as compared to the free DOX. Moreover, a superior tumor growth inhibition and negligible damage to normal organs like the heart and kidney, which is reported to be vulnerable to DOX-associated side effects, are further demonstrated.
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
authors.forename: Zihao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
authors.forename: Jiaxun
authors.initials: J
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
authors.forename: Luyan
authors.initials: L
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
authors.forename: Yongjing
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Molecular Engineering of Polymers and Department of Macromolecular Science, Laboratory of Advanced Materials, Fudan University, Shanghai 200433, China. Electronic address: ccwang@fudan.edu.cn.
authors.forename: Changchun
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016503:Drug Delivery Systems; D065546:Drug Liberation; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D006863:Hydrogen-Ion Concentration; D008807:Mice, Inbred BALB C; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011109:Polymethacrylic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D015032:Zinc / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D016335:Zinc Fingers
chemical_list: D000970:Antineoplastic Agents; D020100:Hydrogels; D011109:Polymethacrylic Acids; C552831:poly(ethylene glycol)-folate; C030613:polymethacrylic acid; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005492:Folic Acid; D005978:Glutathione; D015032:Zinc
keywords: Coordination substitution; Folate-PEG conjugation; Glutathione/pH triggered degradation; Targeted drug delivery; Zinc(II)-crosslinked nanohydrogels