title: Multifunctional cationic polyurethanes designed for non-viral cancer gene therapy.
abstract: Nano-polyplexes from bioreducible cationic polymers have a massive promise for cancer gene therapy. However, the feasibility of cationic polyurethanes for non-viral gene therapy is so far not well studied. In this work, a linear cationic polyurethane containing disulfide bonds, urethane linkages and protonable tertiary amino groups was successfully generated by stepwise polycondensation reaction between 2,2'-dithiodiethanol bis(p-nitrophenyl carbonate) and 1,4-bis(3-aminopropyl)piperazine (BAP). We confirmed that the cationic polyurethane (denoted as PUBAP) displayed superior gene delivery properties to its cationic polyamide analogue, thus causing higher in vitro transfection efficiency in MCF-7 and SKOV-3 cells. Besides, further folate-PEGylation and hydrophobic deoxycholic acid (DCA) conjugation to amino-containing PUBAP can be conducted to afford multifunctional polyurethane gene delivery system. After optimization, folate-decorated nano-polyplexes from the PUBAP conjugated with 8 folate-PEG chains and 12 DCA residues exhibited superb colloidal stability under physiological conditions, and performed rapid uptake via folate receptor-mediated endocytosis, efficient intracellular gene release and nucleus translocation into SKOV-3 cells in vitro and in vivo. Importantly, PUBAP based polyplexes possess low cytotoxicity as a result of PUBAP biodegradability. Therefore, marked growth inhibition of SKOV-3 tumor xenografted in Balb/c nude mice was achieved with negligible side effects on the mouse health after intravenous administration of PUBAP based polyplexes with a therapeutic plasmid encoding for TNF-related apoptosis-inducing ligand. This work provides a new insight into biomedical application of bio-responsive polyurethanes for cancer therapy.
  
  
  CONCLUSIONS
  In this study, we have confirmed that disulfide-based cationic polyurethane presents a new non-viral vector for gene transfer and cancer gene therapy. The significance of this work includes: (1) design and synthesis of a group of novel disulfide-based cationic polyurethane by non-isocyanate chemistry; (2) comparative study of transfection activity between cationic polyurethanes and cationic polyamides; (3) feasibility of bioreducible cationic polyurethanes for in vivo cancer gene therapy.
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Tang
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Shi
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Shanghai East Hospital, Institute for Biomedical Engineering and Nanoscience, Tongji University School of Medicine, Tongji University, 200092 Shanghai, PR China. Electronic address: chaolin@tongji.edu.cn.
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
mesh_terms: D000818:Animals; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011140:Polyurethanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D011140:Polyurethanes
keywords: Cationic polyurethane; Disulfide; Gene therapy; Targeting