title: Polymeric Nanostructure Compiled with Multifunctional Components To Exert Tumor-Targeted Delivery of Antiangiogenic Gene for Tumor Growth Suppression.
abstract: Nucleic acid-based therapy has emerged as a revolutionary methodology for treatment of the diseases related to protein dysfunction; however, lack of systemically applicable synthetic delivery systems limits its current usage in local applications, particularly for DNA-based therapy with regard to the poor bioavailability in the systemic administrations. To overcome this obstacle, we compiled multiple chemistry-based strategies into the manufacture of the gene delivery formulations to pursue improved tolerability of DNA to the enzymatic degradation in the biological milieu and prolonged retention in the systemic circulation. Here, we constructed a distinctive multilayered functional architecture: plasmid DNA (pDNA) was electrostatically complexed with cationic poly(lysine) (polyplex) as the interior pDNA reservoir, which was further cross-linked by redox-responsive disulfide cross-linking to minimize the occurrence of polyplex disassembly through exchange reaction with the biological charged components. Still, the pDNA reservoir was spatially protected by a sequential thermoresponsive poly(N-isopropylacrylamide) palisade as the intermediate barrier and a biocompatible hydrophilic poly(ethylene glycol) (PEG) shell with the aim of preventing the accessibility of the biological species, particularly the nuclease degradation to the pDNA payload. Subsequent investigations validated the utilities of these strategies in accomplishing prolonged blood retention. In an attempt to apply this method for tumor therapy, ligand cyclic (Arg-Gly-Asp) peptide was attached at the distal end of PEG, validating prompted tumor-targeted delivery and gene expression of the loaded antiangiogenic gene at the targeted tumor cells and accordingly exerting antiangiogenesis of the tumors for abrogation of tumor growth. Together with its excellent safe profile, the proposed formulation suggests potential utility as a practical gene delivery system for treatment of intractable diseases.
authors: CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering , Suzhou 215163, China.|Deparment of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors: Qixian
authors: Q
authors: Chen
authors: State Key Laboratory of Polymer Physics and Chemistry Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, China.
authors: Ruogu
authors: R
authors: Qi
authors: School of Public Health, Dalian Medical University , No. 9 West Section Lvshun South Road, Dalian 116044, China.
authors: Xiyi
authors: X
authors: Chen
authors: Department of Neurosurgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200127, China.
authors: Xi
authors: X
authors: Yang
authors: Department of Urology, Zhongnan Hospital, Wuhan University , Wuhan 430071 China.
authors: Xing
authors: X
authors: Huang
authors: State Key Laboratory of Polymer Physics and Chemistry Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, China.
authors: Haihua
authors: H
authors: Xiao
authors: Department of Urology, Zhongnan Hospital, Wuhan University , Wuhan 430071 China.
authors: Xinhuan
authors: X
authors: Wang
authors: CAS Key Laboratory of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering , Suzhou 215163, China.
authors: Wenfei
authors: W
authors: Dong
mesh_terms: D045744:Cell Line, Tumor; D018014:Gene Transfer Techniques; D006801:Humans; D008823:Micelles; D049329:Nanostructures; D009369:Neoplasms; D010957:Plasmids; D011092:Polyethylene Glycols; D011108:Polymers; D014162:Transfection
chemical_list: D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols
keywords: multilayer; polyplex micelle; thermoresponsive; tumor gene therapy; tumor vasculature targeting