MACROMOLECULAR NITRIC OXIDE DONORS FOR THE TREATMENT OF DRUG-RESISTANT DISEASES

Drug resistance poses a great challenge to both infection and cancer treatments. Nitric oxide (NO), an endogenous mediator of immune function, represents an attractive alternative therapeutic due to its broad-spectrum antibacterial and anticancer activities and ability to sensitize resistant diseases to conventional drugs without fostering resistance. Several exogenous NO donors have been utilized to study NO’s potential to treat drug-resistant diseases. Unfortunately, understanding of the donor properties that lead to enhanced therapeutic efficacy remains limited. Biopolymer systems with diverse NO payloads and NO-release kinetics were selected to study the impact of donor identity and NO-release profiles on antibiofilm activity against Pseudomonas aeruginosa. A threshold NO level was needed to achieve biofilm dispersal, with longer-releasing systems being effective at lower concentrations. Similarly, prolonged NO release led to greater antibiotic sensitization, significantly reducing the tobramycin dose needed to eradicate the drug-resistant biofilms. Biopolymer systems with greater positive charge (e.g., from the presence of primary amines) resulted in the largest reduction in biofilm viscoelasticity. In a separate effort, the effects of NO-release kinetics and donor properties were explored for the treatment of melanoma, an aggressive cancer notorious for drug resistance, using hyaluronic acid (HA), cyclodextrin, and silica nanoparticle NO donors. Cytotoxicity against melanoma cells was dependent on NO payload, whereas toxicity against non-cancerous skin cells was primarily influenced by donor identity. Saccharide-based NO donors resulted in the widest therapeutic indices, a measure of potential drug utility. Studies using an artificial skin model revealed that small, neutral donors exhibited the greatest in vitro skin permeation. A Pluronic F127 organogel was optimized for the topical delivery of a cyclodextrin-based NO donor. This topical formulation maintained drug exposure in a pre-clinical animal model, reducing tumor growth and demonstrating the system’s therapeutic potential. Hyaluronic acid-coated silica nanoparticles were developed to facilitate potential targeting of NO delivery to cancer cells. Nanoparticle coating and NO loading were evaluated as a function of aminosilane modification, HA molecular weight, and HA concentration. Increased internalization of HA-coated nanoparticles by melanoma cells led to localized NO release and enhanced toxicity, with the low molecular weight HA coating resulting in the greater therapeutic indices.