Research Areas: DNA Nanotechnology, Biomolecular Engineering, Targeted Drug & Gene Delivery, Peptide Hydrogels, Biopolymers
DNA Nanotechnology - The field of DNA nanotechnology has transformed DNA from a material that stores genetic information into a construction tool that can be used to build 3D scaffolds and devices with nanoscale features. There are a variety of strategies that can be used to create DNA nanostructures, each that use a combination of many different single stranded DNA (ssDNA) sequences that when mixed together and subjected to specific annealing conditions can produce double stranded DNA segments that organize into highly uniform structures of the desired shape. In our group we use a different approach where we start with a single hydrophilic ssDNA sequence and conjugate it to a hydrophobic tail to form an amphiphilic molecule. The amphiphilic nature of the conjugate induces spontaneous assembly of the molecules when added to an aqueous environment. Our ssDNA-amphiphiles, containing a random nucleic acid headgroup or an aptamer, can adopt a variety of self-assembled structures including twisted and helical bilayer nanotapes and nanotubes. The ability to create DNA nanotubes from ssDNA-amphiphiles is particularly exciting, and our goal is to design and engineer different nanotubes and other DNA nanostructures that will be used for targeted delivery of small molecules and nucleic acids to tissues of interest.
Multi-Targeted Gene & Drug Delivery - Currently, the main problems associated with systemic drug administration are the necessity of a large drug dose to achieve high local concentration, non-specific toxicity and other adverse side-effects due to high drug doses, even biodistribution throughout the body and lack of specific affinity for the pathological site. Targeted drug delivery can bring a solution to all these problems. Our goal is to engineer multi-targeted therapeutic systems that could aid recognition of the site of interest and delivery of the therapeutic load into a variety of target cells. Therefore, higher degree of specificity for cancer cells could be achieved by designing a modular multi-targeted non-viral system that introduces simultaneous targeting of multiple overexpressed cancer surface receptors as the first level of targeting at the extracellular level. Subsequently, transcriptional targeting is introduced as the second level of specific targeting. Our studies provide an insight into the mechanisms by which surface molecules, such as peptide-amphiphile ligands and polymers, modulate the non-viral nanoparticle behavior, and will contribute significantly to the rational design and engineering of gene and drug delivery systems with improved targeting functionality.
Multicomponent Peptide Hydrogels for Tissue Engineering - The design of nanofiber scaffolds has been a key objective in tissue engineering as they structurally mimic the natural extracellular matrix (ECM) found in tissues. In an attempt to provide a nanofiber scaffold with ligands that can promote cell adhesion and ECM production, we propose the use of our peptide-amphiphile (peptide conjugated to a lipid-like tail or a polymer) nanofibers as a potential scaffold for tissue engineering. The peptide-amphiphiles self assemble into nanofibers in an aqueous environment and form hydrogels. Our goal is to functionalize the hydrogels with various peptides that mimic cell binding and growth factor binding domains combined in a modular fashion to produce defined, multicomponent hydrogels, optimized to support the culture and differentiation of different cells, including induced pluripotent stem cells (iPSCs). By optimizing peptide ligand presentation and mechanical properties in the peptide-amphiphile gel system we aim to see improved adhesion, survival and enhanced differentiation efficiency of different cells entrapped in the gel.
- Adil, M.M., Levine, R.M., and Kokkoli, E. "Increasing Cancer-Specific Gene Expression Targeting Overexpressed α5β1 Integrin and Upregulated Transcriptional Activity of NF-κB", Mol. Pharm., 2014, 11 (3): 849–858.
- Pearce, T.R., Waybrant, B., and Kokkoli, E. "The Role of Spacers on the Self-Assembly of DNA Aptamer-Amphiphiles into Micelles and Nanotapes", Chem. Commun., 2014, 50 (2): 210 - 212.
- Waybrant, B., Pearce, T.R., Wang, P., Sreevatsan, S., and Kokkoli, E. "Development and Characterization of an Aptamer Binding Ligand of Fractalkine Using Domain Targeted SELEX", Chem. Comm., 2012, 48 (80): 10043-10045.
- Shroff, K., Rexeisen, E.L., Arunagirinathan, M.A., and Kokkoli, E. "Fibronectin-Mimetic Peptide-Amphiphile Nanofiber Gels Support Increased Cell Adhesion and Promote ECM Production", Soft Matter, 2010, 6 (20): 5064-5072.
- Kokkoli, E., Mardilovich, A., Wedekind, A., Rexeisen, E.L., Garg, A., and Craig, J.A. "Self-Assembly and Applications of Biomimetic and Bioactive Peptide-Amphiphiles", Soft Matter, 2006, 2 (12): 1015-1024.
- Mardilovich, A., Craig, J.A., McCammon, M.Q., Garg, A., and Kokkoli, E. "Design of a Novel Fibronectin-Mimetic Peptide-Amphiphile for Functionalized Biomaterials", Langmuir, 2006, 22 (7): 3259-3264.
- Mardilovich, A., and Kokkoli, E. "Biomimetic Peptide-Amphiphiles for Functional Biomaterials: The Role of GRGDSP and PHSRN", Biomacromolecules, 2004, 5 (3): 950-957.