title: In vivo delivery of nucleic acids via glycopolymer vehicles affords therapeutic infarct size reduction in vivo.
abstract: Using a new class of nontoxic and degradable glycopolymer-based vehicles termed poly(glycoamidoamine)s, we demonstrate virus-like delivery efficacy of oligodeoxynucleotide (ODN) decoys to cardiomyoblasts (H9c2), primary cardiomyocytes, and the mouse heart. These glycopolymers bind and compact ODN decoys into nanoparticle complexes that are internalized by the cell membrane and mediate nuclear uptake of DNA in 90+% of cultured primary cardiomyocytes and 87% of the mouse myocardium. Experimental results reveal that decoys delivered via these glycopolymers block the activation of the transcription factor NF-κB, a major contributor to ischemia/reperfusion injury. Decoy complexes formed with glycopolymer T4 significantly blocked downstream gene expression of Cox-2 and limited myocardial infarction in vivo, phenocopying a transgenic mouse model. These promising delivery vehicles may facilitate high-throughput genetic approaches in animal models. Additionally, the low toxicity, biodegradation, and outstanding delivery efficacy suggest that these nanomedicines may be clinically applicable for gene regulatory therapy.
authors.affiliation: Department of Pharmacology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Tranter
authors.forename: Yemin
authors.initials: Y
authors.lastname: Liu
authors.forename: Suiwen
authors.initials: S
authors.lastname: He
authors.forename: James
authors.initials: J
authors.lastname: Gulick
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Ren
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: W Keith
authors.initials: WK
authors.lastname: Jones
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Reineke
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D015870:Gene Expression; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006352:Heart Ventricles / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D032386:Myoblasts, Cardiac / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058726:Nanoconjugates / Q000627:therapeutic use / Q000648:ultrastructure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014161:Transduction, Genetic
chemical_list: D016328:NF-kappa B; D058726:Nanoconjugates; D009838:Oligodeoxyribonucleotides; D011108:Polymers