The Hammond research group focuses on the self-assembly of polymeric nanomaterials, with a major emphasis on the use of electrostatics and other complementary interactions to generate functional materials with highly controlled architecture. The uniting theme of the lab – the understanding and use of secondary interactions to guide materials assembly at surfaces and in solution – encompasses three major areas of research:
1) Layer-by-layer controlled release thin film coatings for biomedical implants that address bone regeneration, wound healing, tissue engineering and transdermal delivery from microneedle platforms,
2) Nanoparticle drug carriers for targeted nanoparticle drug, gene, and siRNA delivery for cancer treatment using unique platforms that enable combination and sequenced delivery strategies
3) Artificial polypeptides and polymeric nucleic acids designed to engage biology and build novel drug delivery systems, hydrogels, and tissue scaffolds
Charge-based Assembled Biomaterials for Regenerative Medicine
Our lab has developed approaches around the incorporation of surface-erodible, hydrolytically degradable components in coatings for sequential or simultaneous multi-drug release. These advances led to the controlled release of proteins and biologic factors from conformal coatings of implants and scaffolds that yield physiologically relevant amounts delivered locally over extended periods of up to multiple weeks. Very recent results from our research group indicate the success of delivery of bFGF, BMP-2, VEGF and PDGF, as well as nucleic acids such as plasmid DNA and siRNA. We have applied electrostatic layer-by-layer and other polymer self-assembly processes toward biomaterials for applications including tissue engineering and wound healing, including diabetic ulcer wound healing, soft tissue wounds and antifibrotic healing processes. By directly incorporating siRNA to knock down specific proteases, we have also shown the promise of nucleic acid delivery directly to wound sites, and the use of DNA as a vaccine delivered with microneedle technology.
Targeted Nanoparticle Delivery
By adapting the methods of layer-by-layer (LbL) from large surfaces to nanoparticles, it is possible to gain many of the same advantages described above toward the design of nanoparticles that can target cancer based on size and molecular targeting, while enabling the release of multiple agents optimized to achieve maximum impact and synergistic cancer cell death. The Hammond lab has applied these LbL concepts to nanoparticles to address the targeting of cancer. The nanoparticle systems can be tuned to release an agent such as an inhibitor or siRNA that blocks the defense mechanisms of tumors, followed by delivery of a chemotherapy drug that can then exhibit enhanced efficacy. Additional approaches include micellar assemblies with siRNA and ligand-cluster dendritic block copolymers that provide a means of enhanced targeting. The lab has recently investigated concatenated siRNA approaches using rolling circle transcription toward the design of self-generated porous polymeric RNA microcarriers, which break down into short siRNA strands once within the targeted cells, to yield highly potent and concentrated doses of siRNA.
Functionalizable Polypeptides and Polymeric siRNA
The controlled polymerization of N-carboxyanhydride monomers provides a means of generating synthetic polypeptides; however, until recently, only native amino acids were incorporated along the backbone. Our lab introduced an alkyne functionalized monomer, propargyl-L-glutamate, that enables the use of click chemistry post-polymerization, thus allowing the generation of a broad range of different functional side groups. Poly(propargyl-L-glutamate) (PPLG), and similar polypeptides subsequently introduced, has enabled a broad range of new approaches to designing artificial polypeptide systems with properties that engage or mimic biology. On the other hand, interesting new biological macromolecules can be engineered from nucleic acids. Other synthetic methods in our laboratory have included the use of rolling circle transcription to create periodic-shRNA (pshRNA) consisting of hundreds of repeat units. We have found that these polymeric forms of siRNA can yield activation of immunological pathways that facilitate further tumor cell death, while also inducing knockdown of targeted genes. Applications of these systems are toward active or responsive drug delivery systems, responsive hydrogels and synthetic glycosylated polypeptide scaffolds.
