Gene delivery with in-situ crosslinking polymer networks generates long-term systemic protein expression.
Two polyethylene oxide-based delivery systems comprised of reacting PEG polymers were designed for the delivery of DNA expression vectors. The polymers are formulated with the DNA and injected into the muscle, wherein a crosslinked matrix forms in-situ. The matrix resembles a viscous solution (formulation A) or a gel (formulation B). The reacting PEG polymers do not interact with, but entrap the DNA. The formation of the matrix does not affect the supercoiling of the incorporated DNA. The polymers are biocompatible and biodegradable due to the presence of hydrolytically labile bonds in one of the components. Measurement of degradation in vivo suggests that a significant amount of the polymer disappears from the injected muscle by 28 days post injection. Administration to mice of SEAP plasmid DNA formulated with the PEG polymers results in SEAP expression. Expression levels are similar to those of unformulated DNA, but the duration of gene expression is significantly longer in immunocompetent animals receiving the formulated DNA. Significantly lower anti-SEAP IgG titers are elicited by network-formulated DNA relative to unformulated DNA, even though expression levels are comparable. The data suggests that the matrix extends duration of expression by reducing the anti-SEAP immune response so that these delivery systems may be useful for prolonged gene expression following a single intramuscular injection.
Roy
Krishnendu
K
Department of Biomedical Engineering, The University of Texas at Austin, Austin, Texas 78712, USA.
Wang
Daqing
D
Hedley
Mary Lynne
ML
Barman
Shikha P
SP
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D003432:Cross-Linking Reagents; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D016503:Drug Delivery Systems; D005782:Gels / Q000737:chemistry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007074:Immunoglobulin G / Q000276:immunology; D009132:Muscles / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D010957:Plasmids; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers
D003432:Cross-Linking Reagents; D005782:Gels; D007074:Immunoglobulin G; D011108:Polymers; D011092:Polyethylene Glycols; D004247:DNA; D000469:Alkaline Phosphatase