Reducible poly(amido ethylenimine)s for gene delivery

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Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Christensen, Lane
Title Reducible poly(amido ethylenimine)s for gene delivery
Date 2007-05
Description Much has been learned from the success and, more so, from the early failures of gene therapy, thereby providing a realistic therapeutic alternative for a variety of diseases and genetic disorders in the foreseeable future. Carrier mediated toxicity and low expression has hampered the use of nonviral carriers in vivo. The purpose of this research was to develop a new glass of gene carrier by synthesizing polymers consisting of reducible ethylenimine monomeric units aimed at taking advantage of the cellular redox gradient between the intra-and intercellular environment. These polymers were prepared and characterized for their potential over existing cationic nonviral gene carries. The first section of this dissertation addresses the synthesis and characterization of the class of reducible polymers termed disulfide reducible poly(amido ethylenimine)s (SS-PAEIs). Specifically, three polymers were synthesized varying only in the length of the ethylenimine monomer used in the Michael addition synthesis with cystamine bisacrylamide. The polymers were optimized with respect to their particle size, charge potential, buffering capacity, degree of branching, cellular toxicity and their role in medicating reporter gene expression in a variety of cell lines. Results showed that all three SS-PAEIs facilitate high levels of gene expression up to 20 x higher than the postitive control without significant interaction in the presence of serum proteins or without compromising levels of toxicity. Multiple experiments using these carriers also showed the release of plasmid DNA (pDNA) was dependent upon the oxidative environment. The second half of the dissertation covers the transition from in vitro characterization to therapeutic gene delivery via SS-PAEI polymers in vitro and in vivo. Delivery of hyposia-inducible VEGF plasmid showed up to 76 x higher VIGF expression in primay rat cardiomyoblasts under hypoxic conditions compared to normal conditions. More importantly, a significant amount of VEGF was detected around the region of infarct in ischemic rabbit myocardium four days after injection. In addition, construction and delivery of an eNOS plasmid showed significant levels of delivery in primary human adult cardiac progenitor cells compared to a control carrier leading to the future plans of efficacy experiments in vivo.
Type Text
Publisher University of Utah
Subject Polymetric Drug Delivery System; Gene Therapy
Subject MESH Polymers; DNA
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Reducible poly(amido ethylenimine)s for gene delivery." Spencer S. Eccles Health Sciences Library. Print version of "Reducible poly(amido ethylenimine)s for gene delivery." available at J. Willard Marriott Library Special Collection. RS43.5 2007 .C48.
Rights Management Christensen, Lane.
Format Medium application/pdf
Format Extent 4,946,003 bytes
Identifier undthes,5086
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 4,946,017 bytes
ARK ark:/87278/s6wq05pv
Setname ir_etd
Date Created 2012-04-24
Date Modified 2012-04-24
ID 191908
Reference URL