In vivo delivery of nucleic acids via glycopolymer vehicles affords therapeutic infarct size reduction in vivo

Michael Tranter, Yemin Liu, Suiwen He, James Gulick, Xiaoping Ren, Jeffrey Robbins, W. Keith Jones, Theresa M. Reineke

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)601-608
Number of pages8
JournalMolecular Therapy
Volume20
Issue number3
DOIs
StatePublished - Mar 2012

Bibliographical note

Funding Information:
This work was supported by NIH grants HL63034 and HL091478 (W.K.J.), R21EB007244 (T.M.R.), and P01HL69779 (J.R.). T.M.R. also thanks the Beckman Young Investigator Award and Alfred P. Sloan Fellowship programs for support of this project. M. Tranter was supported by an Integrative Graduate Education and Research traineeship from the National Science Foundation. We thank the University of Cincinnati College of Medicine Dean’s Discovery Fund and the University of Cincinnati Institute for Nanoscale Science and Technology for early support of this work. We thank Jackie Belew for support in maintaining mouse breeding colonies and Katye Fichter for performing the MTT assay. University of Cincinnati and W.K.J. have interest in patents based upon oligodeoxynucleotide delivery, these patents have not been licensed and W.K.J. receives no royalties. T.M.R. is a consultant to Techulon, Inc. Techulon has recently licensed the poly(glycoamidoamines) polymers (University of Cincinnati) and is currently marketing one formulation as Glycofect Transfection Reagent. The other authors declared no conflict of interest.

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