(4aj) 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.