Molecular Evoluation of Virus based Hydrogels for Cancer Therapy

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DESCRIPTION (provided by applicant): The goal of this research is to develop novel organic materials with tailorable properties whose formation is nucleated by viral particles. These materials will be applied to the development of new immunotherapies or localized delivery of chemotherapeutics. Specific Aims: (1) Utilize phage display to select viral particles that nucleate the formation of peptide hydrogels (2) Study the systemic trafficking and immune response produced by the hydrogels in a mouse model (3) Depending on the results of the first two aims, explore the use of virus-based hydrogels in immunotherapy or drug delivery Study Design: We will use phage display to select for viral particles that nucleate the formation of novel organic materials. By selecting for phage particles that bind to known gel-forming peptides, we will evolve a small library of virus-like particles that undergo reversible thermo-responsive gelation. These will be liquids when cool, but assemble into gels at physiological temperatures. Once gel-forming phage are selected for, they will be studied for their ability to elicit an immune response in a mouse model. Should the new materials be immunogenic, an immunotherapeutic path will be pursued. However, should the gel matrix attenuate the immunological response, a localized drug delivery system will be developed through directed evolution and/or small molecule activation. The evolutionary strategy will be accomplished by encapsulation of small molecules within viral particles that have been evolved to release their contents in the acidic environment associated with tumors. The latter route involves the introduction of a small molecule that perturbs the structure of the viral capsid, thus leading to drug release. Cancer is the second leading cause of death in the western world, resulting in nearly 600,000 deaths annually in the United States. Currently, most non-invasive cancer treatments result in crippling side-effects that rival the disease itself in ferocity. We aim to create new materials that will localize cancer therapy to a tumor site, thus enhancing the effectiveness of cancer therapy while reducing the systemic side-effects.