Therapeutic Delivery Strategies to Mitigate Anthracycline-Induced Cardiotoxicity and Promote Cardiac Repair

Anthracycline chemotherapeutics such as doxorubicin are widely used in cancer treatment but are limited by dose-dependent cardiotoxicity that can result in irreversible cardiac dysfunction. Existing cardioprotective strategies remain insufficient and often lack clinical translatability. The overarching goal of this dissertation was to develop clinically relevant nanomedicine-based drug delivery systems to mitigate chemotherapy-induced cardiotoxicity and ischemic myocardial injury while preserving therapeutic efficacy. This work focuses on the rational design of lipid-based and extracellular vesicle–inspired nanocarriers for targeted delivery of cardioprotective therapeutics. Phosphatidylserine-based liposomes encapsulating MAP4K4 inhibitor DMX-5804 were engineered and demonstrated a cardioprotective effect in a murine model of anthracycline induced cardiovascular toxicity. Additionally, this dissertation explores extracellular vesicles as biologically derived delivery platforms. Their isolation and characterization from primary sources in a large animal model are shown, as well as their preservation and storage using lyophilization and cryopreservation techniques. Collectively, this work demonstrates cardiovascular therapeutics that can be used to prevent and treat highly prevalent afflictions in patients.