Date of Award

2021

Degree Name

Pharmaceutical Sciences

College

School of Pharmacy

Type of Degree

M.S.

Document Type

Thesis

First Advisor

Dr. Cynthia Jones, Committee Chairperson

Second Advisor

Dr. Michael Hambuchen

Third Advisor

Dr. Brandon Henderson

Abstract

Diabetic skin wound is a common complication of diabetes that occurs in about 15% of diabetic patients and often requires prolonged hospitalization for its management and treatment. Natural polymers are used for wound dressing due to their biological adhesiveness, non-toxicity, and biodegradable nature. 5-Fluorouracil (FU) has been shown to alter adipokine expression which is implicated in cutaneous wound repair. Thus, our overall objective was to investigate the utility of chitosan (CS) gel for topical delivery of 5-FU to treat diabetic wounds. We prepared chitosan gel (2% w/w) in serial dilutions of 5-FU (25μg/mL, 2.5μg/mL, 0.25μg/mL, and 0.025μg/mL) and evaluated their stability, antimicrobial activity, and rheological properties. Human dermal fibroblast cells were exposed to each gel formulation under high glucose conditions. MTT, real-time polymerase chain reaction, and cell migration assays were used to determine cell viability, gene expression, and migration, respectively. We showed that 2% CS gel is stable at both refrigeration (4-8o C) and room temperatures (20-25o C), and exhibits non-Newtonian flow property, shear thinning behavior and weak viscoelasticity. At low concentrations (0.025μg/mL), there is antimicrobial activity of 5-FU against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-susceptible Staphylococcus aureus (RN1), and at high concentration (8.0μg/mL) against Escherichia coli. We also found that exposure to CS and 5-FU-CS gel at different concentrations decreases adipokine gene expression for resistin and PPARγ and improved cell migration. Our studies suggest CS can be formulated into a hydrogel for topical delivery, 5-FU-CS gel is potent against pathogenic bacteria found in diabetic wounds and has therapeutic effect on adipokine gene expression. The findings in this study offer a novel therapeutic delivery system for 5-FU for diabetic wound healing.

Subject(s)

Diabetes -- Complications -- Research.

Wounds and injuries -- Treatment -- Research.

Pharmacy -- Research.

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