The broad goal of our research is the design of materials that control the distribution and release of DNA from the surfaces of biomedical materials and devices. The safe, efficient, and controlled delivery of DNA to cells presents a formidable challenge and an obstacle to the clinical success of gene therapy. Conventional materials do not meet the technical or clinical demands of this rapidly growing field, particularly for applications that require release from surfaces or the predictable administration of multiple gene sequences. Degradable polymer matrices can be engineered to sustain the release of plasmid DNA using strategies similar to those previously developed for the delivery of proteins. However, these bulk materials lack the sophistication required to control the distribution of plasmid (or multiple plasmids) near the surface of the material. We have developed degradable multilayered materials that provide nanometer-scale control over the incorporation and subsequent release of polyanions, including DNA. This proposal is based on the hypothesis that multilayered polymer assemblies incorporating plasmid DNA can be used to direct the release of DNA to cells growing on the surfaces of these materials. The following Specific Aims are designed to exhaustively evaluate this hypothesis. They are: 1) To incorporate plasmid DNA into hydrolytically degradable polyelectrolyte films using a layer-by-layer approach, 2) To characterize the physical and chemical erosion profiles of plasmid-containing films and establish the structural integrity of released DNA, and 3) To evaluate functional DNA-containing films as substrates for cell attachment and as platforms to direct the transfection of adherent cells. Sophisticated new materials that control the distribution and release of plasmid DNA from the surfaces of biomedical materials will have a profound impact on the development of localized gene therapies and the continued advance of gene therapy into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB002746-02
Application #
6798605
Study Section
Special Emphasis Panel (ZRG1-SSS-2 (55))
Program Officer
Moy, Peter
Project Start
2003-09-05
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$226,667
Indirect Cost
Name
University of Wisconsin Madison
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Fredin, Nathaniel J; Flessner, Ryan M; Jewell, Christopher M et al. (2010) Characterization of nanoscale transformations in polyelectrolyte multilayers fabricated from plasmid DNA using laser scanning confocal microscopy in combination with atomic force microscopy. Microsc Res Tech 73:834-44
Saurer, Eric M; Jewell, Christopher M; Kuchenreuther, Jon M et al. (2009) Assembly of erodible, DNA-containing thin films on the surfaces of polymer microparticles: toward a layer-by-layer approach to the delivery of DNA to antigen-presenting cells. Acta Biomater 5:913-24
Liu, Xianghui; Yang, Jennifer W; Lynn, David M (2008) Addition of ""charge-shifting"" side chains to linear poly(ethyleneimine) enhances cell transfection efficiency. Biomacromolecules 9:2063-71
Jewell, Christopher M; Lynn, David M (2008) Multilayered polyelectrolyte assemblies as platforms for the delivery of DNA and other nucleic acid-based therapeutics. Adv Drug Deliv Rev 60:979-99
Pizzey, Claire L; Jewell, Christopher M; Hays, Melissa E et al. (2008) Characterization of the nanostructure of complexes formed by a redox-active cationic lipid and DNA. J Phys Chem B 112:5849-57
Hays, Melissa E; Jewell, Christopher M; Kondo, Yukishige et al. (2007) Lipoplexes formed by DNA and ferrocenyl lipids: effect of lipid oxidation state on size, internal dynamics, and zeta-potential. Biophys J 93:4414-24
Jewell, Christopher M; Fuchs, Stephen M; Flessner, Ryan M et al. (2007) Multilayered films fabricated from an oligoarginine-conjugated protein promote efficient surface-mediated protein transduction. Biomacromolecules 8:857-63
Zhang, Jingtao; Montanez, Sara I; Jewell, Christopher M et al. (2007) Multilayered films fabricated from plasmid DNA and a side-chain functionalized poly(beta-amino ester): surface-type erosion and sequential release of multiple plasmid constructs from surfaces. Langmuir 23:11139-46
Zhang, Jingtao; Fredin, Nathaniel J; Lynn, David M (2007) Apparent dewetting of ultrathin multilayered polyelectrolyte films incubated in aqueous environments. Langmuir 23:11603-10
Fredin, Nathaniel J; Zhang, Jingtao; Lynn, David M (2007) Nanometer-scale decomposition of ultrathin multilayered polyelectrolyte films. Langmuir 23:2273-6

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