There is a need for smart biomaterials for the improved treatment of fungal infections. With a limited antifungal drug repertoire and the spread of drug resistant strains complicating the treatment of topical and systemic fungal infections, we sought to develop advanced biomaterials that can control drug delivery, improve the efficacy of antifungals, and prevent biofilm formation. This thesis specifically focuses on the development of 1) nanoparticles to increase antifungal drug efficacy while reducing associated drug toxicity, 2) hydrogel systems for the target-triggered delivery of antifungals, and 3) antimicrobial catheter coatings that prevent biofilm formation. To develop antifungal nanoparticles, we encapsulated the hydrophobic and difficult to administer drug anidulafungin into liposomes. These 100 nm particles significantly increased the antifungal efficacy of anidulafungin against Candida biofilms and improved survival of Candida infected Galleria mellonella larvae compared to free drug. We also developed hydrogels that spatiotemporally control delivery of antifungal therapeutics by responding solely to fungal enzymes, localizing drugs to the site of infection and reducing unnecessary exposure. Our hydrogels were rendered degradable by incorporating a cleavable peptide in the poly(ethylene glycol) (PEG) hydrogel backbone that specifically responded to Candida secreted aspartic proteases (Saps), enzymes that aid in infection pathogenesis. These drug-loaded hydrogels degraded specifically in the presence of Candida albicans, eliminating the fungal burden within 24 hours, but remained stable in uninfected murine wound fluid for seven days. Our studies demonstrated how polymer concentration and Sap-peptide catalytic efficiency can be used to control hydrogel degradation and drug release rates. Finally, we developed polyurethane coatings encapsulating a repurposed drug with antimicrobial properties, auranofin. When applied to catheters, these coatings prevented methicillin resistant Staphylococcus aureus biofilm formation for over 20 days after daily challenges with the bacteria. The biomaterials developed in this work can serve as platforms for increasing hydrophobic drug solubility, controlling release of therapeutics, enhancing their efficacy and limiting unwanted toxicity, potentially reducing susceptibility to drug resistance development, in turn extending drug utility.
Vera-Gonzalez, Noel Amado,
"Combating Candida Fungal Infections: Nanoparticles and Responsive Drug Delivery Systems"
(2020).
Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.26300/ey86-bw96
