Browsing by Author "Leach, David Gilbert"

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    Multidomain Peptide Biomaterials for Enhanced Delivery of Anti-Cancer Immunotherapies
    (2020-04-22) Leach, David Gilbert; Hartgerink, Jeffrey D
    In cancer research, it is increasingly clear that standard drug administration strategies are insufficient to resolve advanced disease states. While monotherapies using systemically delivered drugs can effectively treat many classes of diseases, cancer represents a uniquely complex challenge that demands a sophisticated response. One strategy researchers are using combines anti-cancer immunotherapies with biomaterial-based delivery vehicles. Biomaterials, such as preformed implantable scaffolds and injectable soft materials, possess powerful synergies with immunotherapies. Immunotherapies on their own typically have poor delivery properties, and often require repeated high-dose injections that result in serious off-tumor effects and/or limited efficacy. Rationally designed biomaterials can allow for discrete localization and controlled release of immunotherapeutic agents, and have been shown to improve outcomes in the treatment of cancers. In this thesis, we developed biomaterial systems to control the release and presentation of anti-cancer therapeutics, with the goal of overcoming many of the problems limiting cancer immunotherapy. Multidomain peptide (MDP) biomaterials were optimized for localized delivery of both small molecules and biologics, allowing for focused dose concentrations and extended therapy presentation. In the first project, a Stimulator of Interferon Genes (STING) agonist was delivered from a cationic MDP hydrogel via intratumoral injection, showing direct cancer cell cytotoxicity and 6-fold enhanced tumor treatment efficacy compared to STING agonist alone. More advanced formulations were also developed, allowing for co-delivery of STING agonists and checkpoint inhibitor antibodies from a single intratumoral hydrogel injection. In a second project, a drug-mimicking hydrogel was developed as a novel anti-cancer biomaterial without any exogenously loaded factors. Specifically, the hydrogel was designed to mimic a small molecule inhibitor of inducible Nitric Oxide Synthase (iNOS) called N6-(1-iminoethyl)-L-lysine (L-NIL). The ‘L-NIL-MDP’ hydrogel had comparable bioactivity to L-NIL, able to inhibit iNOS and affect tumor biology over an extended period of time. In ongoing work, the L-NIL-MDP was combined with STING agonists and immunotherapeutic antibodies to create a superior second-generation anti-tumor formulation termed SynerGel. Fundamentally, the work described herein expands the toolbox of available biomaterial designs that can be used for enhanced drug delivery applications.