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theses

Traditionally, bioactive small molecules suffer from various drawbacks, such as poor bioavailability, and require multiple dosages, which can lead to a myriad of side effects. To overcome the inherent limitations of small molecules, biodegradable controlled delivery vehicles were developed in which the active is chemically incorporated into a polymer backbone. Through the incorporation of actives into controlled delivery vehicles, high drug loading systems can be developed with tunable release profiles. Moreover, by utilizing biodegradable systems, potential adverse side effects can be avoided in vivo. This dissertation focuses on the design, synthesis, and characterization of actives chemically incorporated into controlled delivery vehicles for diverse antioxidant and tyrosinase inhibition applications. In recent years antioxidant biomaterials have received considerable attention owing to mounding evidence demonstrating the detrimental impact of free radicals, specifically the development of cardiovascular disorders, neurodegenerative diseases, and cancer. Thus, poly(anhydride-esters) comprised of naturally occurring antioxidants, namely syringic and vanillic acid, were developed. Antioxidant-based poly(anhydride-esters) exhibited near-zero order release profiles, offering sustained antioxidant that could be modulated by the antioxidant degree of methoxy substitution. Further, these polymers were cytocompatible at therapeutically relevant concentrations and provided antioxidant activity upon degradation. To extend antioxidant therapies beyond released bioactives, oxalate esters were incorporated into a ferulic acid-based poly(anhydride-ester). Ferulic acid is a potent antioxidant commonly utilized in biomedical and cosmetic formulations, whereas aromatic oxalate ester linkages are known to be highly labile towards hydrogen peroxide, a reactive oxygen species precursor. In vitro release studies indicated that polymer degradation and corresponding release of free FA was not solely dependent on hydrophobicity; despite higher hydrophobicity, these oxalate-containing polymers degraded faster than previously published, more hydrophilic ferulic acid-based polymers. Moreover, released ferulic acid maintained antioxidant activity whereas the polymer displayed hydrogen peroxide scavenging activity. Traditional bioactive-based poly(anhydride-ester) synthesis involves at minimum a two-step method, accomplished via melt-condensation or solution polymerization. Thus, to reduce raw material consumption and increase synthetic efficiency, bioactive-based poly(anhydride-esters) containing aliphatic dicarboxylic acid-linkages and bioactives, salicylic and p-hydroxybenzyl acid, were synthesized via one-pot melt-condensation polymerizations. One-pot salicylic acid-based poly(anhydride-esters) were further evaluated against analogous polymers synthesized via established methods, possessing statistically similar polymer and thermal properties while drastically reducing reaction time and solvent usage. Interestingly, p-hydroxybenzyl acid-based poly(anhydride-ester) synthesis was temperature-dependent, as higher reaction temperatures facilitated polyester formation. Kojic acid, a skin-lightening agent with potent tyrosinase inhibition activity, undergoes pH-mediated, thermal-, and photo-degradation in cosmetic formulations, reducing its efficacy. Previous research suggested that bioactive-based polymers stabilized labile antioxidants in solution. Therefore, poly(carbonate-esters) and polyesters comprised of kojic acid and natural diaicds were prepared. In vitro hydrolytic degradation analyses revealed kojic acid release was drastically influenced by polymer backbone composition (e.g., poly(carbonate-ester) vs. polyester), linker molecule (aliphatic vs. heteroatom-containing), and release conditions (physiological vs. skin mimicking media). Tyrosinase inhibition assays demonstrated that aliphatic kojic acid dienols, the major degradation products under skin mimicking conditions, were more potent then kojic acid itself, whereas cytocompatibility tests demonstrated all dienols to be less cytotoxic than kojic acid at concentrations well above therapeutic levels. Additionally, the most lipophilic dienols, as determined by log P analysis, were statistically more effective than kojic acid at inhibiting melanin production in mammalian cells.

ETD_7526

Ph.D.

Includes bibliographical references

by Jonathan James Faig

doi:10.7282/T3B27XKB

ETD doctoral

The author owns the copyright to this work.