James L. Hedrick           

Our program approaches a set of clustered problems of fundamental and therapeutic interest. For example, the discovery and refinement of antibiotics was one of the crowning achievements in the 20^th century that revolutionized healthcare treatment. If properly dosed, they could eradicate infection. Unfortunately, this therapeutic specificity of antibiotics also leads to their undoing as under-dosing (incomplete kill) allows for minor mutative changes that mitigate the effect of the antibiotic leading to resistance development. The pervasiveness of drug-resistant infections is a global health issue with significant healthcare, economic and societal burdens. A similar situation exist in cancer treatments, where multiple chemotherapeutics and chemosensitizers are required to mitigate resistance and loss of efficacy. We have developed numerous platform technologies based on rationally designed macromolecules that address key issues in multi-drug resistant diseases including cancer as well as bacterial, and viral infections. Supramolecular structures were developed for cancer therapy that target both cancer cells and cancer stem cells, mitigate drug resistance, and metastasis. Membrane-disruptive macromolecular antimicrobials for treatment of infections were demonstrated in vitro and in vivo, and shown to have efficacy and selectivity against multidrug-resistant A. baumannii and MRSA without inducing toxicity. We have demonstrated a general and broad-spectrum strategy to prevent viral infections using multi-functional macromolecules that inhibit viruses such as influenza, Zika, Ebola, and HBV. In each case, the dynamic nature of the non-covalent hydrogen bonding and ionic interactions allows these polymers to co-evolve concurrently with the disease, thereby preventing resistance without loss in effectiveness.

In a second example, living organisms have evolved a variety of interfaces and barriers to control the trafficking of small and large molecules in and out of cells, organs and tissues.  Many diseases require the encapsulation, transport and release of foreign agents into healthy cells (viral and bacterial infections). An understanding of these processes is critical to the illumination of the molecular mechanism of disease, but also provides a guide to developing strategies to deliver therapeutic agents to specific cells and tissues. Nature's ability to assemble macromolecules into highly cooperative and functional assemblies provides an inspiration for our efforts do devise synthetic design criteria to interrogate and exploit the relationship between molecular structure, non-covalent interactions and processing conditions to create new functional macromolecular assemblies. The targeting and controlled release of therapeutic agents or probe molecules to specific organs and specific cells in the body is one of the major challenges in developing more effective therapies.  Central to this goal are the many materials challenges associated with the encapsulation, transport and release of such agents at a specific time and place in the exceedingly complicated and dynamic environment of living organisms. We have developed modular self-assembly strategies to investigate the use of non-covalent interactions to assemble multifunctional assemblies that can encapsulate small molecules, genetic materials and probes, and reach its target through active and passive targeting. Using this approach, we have developed hydrogels that can encapsulate and release antibodies in a controlled manner to improve patient’s compliance and increase treatment efficacy.

The foundation for this platform is based on an organocatalytic approach to the synthesis of biocompatible/degradable macromolecules with precisely defined molecular weights, end-group fidelity and backbone functionality.