Synthetic Biomaterials for Enhancing the Delivery and Effectiveness of DNA-Based Therapeutics

Over the past several decades, synthetic materials have contributed dramatically to new prophylactic and therapeutic treatments for a range of illness and disease, but drug delivery – the time, concentration, location, and specificity with which biological cargo is delivered – continues to be a major obstacle for medicine. My research interests are focused on designing and exploiting synthetic materials to achieve increased levels of control over the delivery of biological cargo. During this poster session I will highlight examples from my graduate and postdoctoral research which demonstrate the utility of synthetic biomaterials for enhancing the delivery of drugs, proteins, and nucleic acids in vitro and in vivo, and more recently, in the context of translational research focused on vaccination and immunotherapy [1-9]. Building on this past work, I will describe my plans to nucleate a distinct, independent research program at the interface of immunology and materials engineering.

During my graduate work, I took advantage of the properties of synthetic polymers and lipids to achieve high levels of spatial and temporal control over the delivery of nucleic acids and proteins.  One major research area centered on the use of degradable multilayered polyelectrolyte coatings incorporating synthetic polyamines and DNA or proteins [4-6]. By incubating cells with substrates coated with ultrathin multilayered assemblies containing DNA encoding green fluorescent protein, we achieved localized gene expression (transfection) in up to 40% of cells without the aid of additional transfection agents.  DNA-containing films fabricated on the surfaces of intravascular stents were conformal and robust, and able to withstand the mechanical forces associated with arterial deployment in vivo. Further, these coatings mediated significant levels of reporter gene expression in an in vivo rabbit model. Like cationic polymers, cationic lipids have also been widely investigated as gene delivery agents owing to their ability to aggregate with DNA to form lipid/DNA complexes which efficiently transport DNA into cells. Thus, a second research area focused on a cationic, ferrocene-containing lipid which has a charge density that can be reversibly transformed – using chemical or electrochemical methods – from +1 (reduced) to +3 (oxidized) [7-9]. We discovered that complexes prepared from reduced lipid yield high levels of transfection, while lipoplexes prepared using oxidized lipid yield very low levels of transfection, and we identified corresponding differences in the physical properties of these assemblies. Conventional lipids are typically active immediately upon formation and this presents a challenge for strategies aimed at achieving spatial or temporal control over the delivery of DNA to specific cells or tissue. Thus, our approach provides a means to address this challenge by permitting activation of DNA delivery through modulation of lipid redox state.

More recently, my research has focused on developing biomaterial-mediated strategies for improving DNA vaccination and immunotherapy. Our approach is based on enhancing vaccination through controlled delivery of antigen-encoding DNA and a novel class of immunomodulatory small molecules. We synthesized micro and nanoparticles with a core of poly(lactide-co-glycolide) or other bioresorbable polymers enveloped by a conformal phospholipid bilayer shell using a emulsion/solvent evaporation process. Inclusion of charged or reactive lipids enabled reversible association of plasmid DNA with the surface of these materials and facilitated the prolonged expression of DNA-encoded antigens in vivo.  To enhance the function of these particles in vaccination, we encapsulated small-molecule immunomodulators in the particle core designed to amplify or tune the quality of immune responses generated following vaccination.  Using optimized particle formulations, the ability of these materials to modulate immune responses following immunization with model antigens and HIV-relevant antigens was also investigated. Biomaterials permit levels of control over drug delivery that are not currently achievable using conventional vaccination regiments, thus this approach could serve as a route for enhancing existing DNA vaccination strategies for HIV, and hold relevance for the broader vaccine field.

Selected References

1. C. M. Jewell and D. M. Lynn, “Multilayered Polyelectrolyte Assemblies as Platforms for the Delivery of DNA and Other Nucleic Acid-Based Therapeutics.” Advanced Drug Delivery Reviews 2008, 60, 979-999.

2. C. M. Jewell and D. M. Lynn, “Surface-Mediated Delivery of DNA: Cationic Polymers Take Charge.” Current Opinion in Colloid and Interface Science 2008, 13, 395-402.

3. D. J. Irvine and C. M. Jewell, “Vaccine and Immunotherapy Delivery”, Comprehensive Biomaterials, Ed. P. Ducheyne, Elsevier Press, 2010 – in press.

4. C.M. Jewell, J. Zhang, N. J. Fredin, D.M. Lynn, “Multilayered Polyelectrolyte Films Promote the Direct and Localized Delivery of DNA to Cells.” Journal of Controlled Release 2005, 106, 214-223.

5. C. M. Jewell, J. Zhang, N. J. Fredin, M. R. Wolff, T. A. Hacker, D. M. Lynn, “Release of Plasmid DNA from Intravascular Stents Coated with Ultrathin Multilayered Polyelectrolyte Films.” Biomacromolecules 2006, 7, 2483-2491.

6. C. M. Jewell*, S. M. Fuchs*, R. M. Flessner, R. T. Raines, D. M. Lynn, “Multilayered Films Fabricated from an Oligoarginine-Conjugated Protein Promote Efficient Surface-Mediated Protein Transduction.” Biomacromolecules 2007, 8, 857-863.

7. N. L. Abbott, C. M. Jewell, M. E. Hayes, Y. Kondo, D. M. Lynn, “Ferrocene-Containing Cationic Lipids: Influence of Redox States on Cell Transfection.” Journal of the American Chemical Society 2005, 127, 11576-11577.

8. C. M. Jewell, M. E. Hayes, Y. Kondo, N. L. Abbott, D. M. Lynn, “Ferrocene-Containing Cationic Lipids for the Delivery of DNA: Oxidation State Determines Transfection Activity.” Journal of Controlled Release 2006, 112, 129-138.

9. C. M. Jewell, M. E. Hays, Y. Kondo, N. L. Abbott, and D. M. Lynn, “Chemical Activation of Lipoplexes Formed from DNA and a Redox-Active, Ferrocene-Containing Cationic Lipid.” Bioconjugate Chemistry 2008, 19, 2120-2128.