title: Primary cardiomyocyte-targeted bioreducible polymer for efficient gene delivery to the myocardium.
abstract: A cardiomyocyte-targeted Fas siRNA delivery system was developed using primary cardiomyocyte (PCM) specific peptide-modified polymers with high transfection efficiency and low cytotoxicity. Primary cardiomyocyte (PCM) specific peptide, selected by phage display, was conjugated to bioreducible poly(cystamine bisacrylamide-diaminohexane, CBA-DAH) (PCD). The specificity of the PCM-modified polymer to cardiomyocytes was confirmed by competition study with free PCM ligand and by delivery to non-cardiomyocyte NIH 3T3 fibroblasts. The cellular binding and uptake of the PCM-polymer/pDNA polyplex was inhibited by addition of free PCM peptide. The impact of PCM conjugation on cellular uptake and transfection efficiency was greater in H9C2 rat cardiomyocytes than in NIH 3T3 cells. Fas siRNA/PCM-polymer polyplexes exhibited significant Fas gene silencing in rat cardiomyocytes under hypoxic conditions, leading to inhibition of cardiomyocyte apoptosis. These findings demonstrate the utility of the addition of a primary cardiomyocyte (PCM) specific peptide modification to a bioreducible polymer for targeted delivery of Fas siRNA to inhibit cardiomyocyte apoptosis.
authors.affiliation: Center for Controlled Chemical Delivery (CCCD), Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Hye Y
authors.initials: HY
authors.lastname: Nam
authors.forename: Arlo
authors.initials: A
authors.lastname: McGinn
authors.forename: Pyung-Hwan
authors.initials: PH
authors.lastname: Kim
authors.forename: Sung W
authors.initials: SW
authors.lastname: Kim
authors.forename: David A
authors.initials: DA
authors.lastname: Bull
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001672:Biocompatible Materials / Q000494:pharmacology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D020868:Gene Silencing / Q000187:drug effects; D018014:Gene Transfer Techniques; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010455:Peptides / Q000494:pharmacology; D011108:Polymers / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D010455:Peptides; D011108:Polymers; D034741:RNA, Small Interfering; D019014:fas Receptor