Year of Publication
Doctor of Philosophy (PhD)
Chemical and Materials Engineering
Dr. Thomas D. Dziubla
Polymers have deep roots as drug delivery tools, and are widely used in clinical to private settings. Currently, however, numerous traditional therapies exist which may be improved through use of polymeric biomaterials. Through our work with infectious and oxidative stress disease prevention and treatment, we aimed to develop application driven, enhanced therapies utilizing new classes of polymers synthesized in-house. Applying biodegradable poly(β-amino ester) (PBAE) polymers, covalent-addition of bioactive substrates to these PBAEs avoided certain pitfalls of free-loaded and non-degradable drug delivery systems. Further, through variation of polymer ingredients and conditions, we were able to tune degradation rates, release profiles, cellular toxicity, and material morphology.
Using these fundamentals of covalent drug-addition into biodegradable polymers, we addressed two problems that exist with the treatment of patients with high-risk wound-sites, namely non-biodegradability that require second-surgeries, and free-loaded antibiotic systems where partially degraded materials fall below the minimum inhibitory concentration, allowing biofilm proliferation. Our in situ polymerizable, covalently-bound vancomycin hydrogel provided active antibiotic degradation products and drug release which closely followed the degradation rate over tunable periods.
With applications of antioxidant delivery, we continued with this concept of covalent drug addition and modified a PBAE, utilizing a disulfide moiety to mimic redox processes which glutathione/glutathione disulfide performs. This material was found to not only be hydrolytically biodegradable, but tunable in reducibility through cleavage of the disulfide crosslinker, forming antioxidant groups of bound-thiols, similar to drugs currently used in radioprotective therapies. The differential cellular viability of degradation products containing disulfide or antioxidant thiol forms was profound, and the antioxidant form significantly aided cellular resistance to a superoxide attack, similar to that of a radiation injury.
Pathophysiological oxidation in the form of radiation injury or oxidative stress based diseases are often region specific to the body and thus require specific targeting, and nanomaterials are widely researched to perform this. Utilizing a tertiary-amine base-catalyst, we were able to synthesize a high drug content (20-26 wt%) version of the disulfide PBAE previously unattainable. The reduced version of this material created a linear-chain polymer capable of single-emulsion nanoparticle formulation for use with intravenous antioxidant delivery applications instead of local.
Digital Object Identifier (DOI)
Lakes, Andrew L., "BIOACTIVE POLY(BETA-AMINO ESTER) BIOMATERIALS FOR TREATMENT OF INFECTION AND OXIDATIVE STRESS" (2016). Theses and Dissertations--Chemical and Materials Engineering. 57.