Oxidative stress, the imbalance of free radical generation with antioxidant defenses, leads to cellular inflammation, apoptosis and cell death. This compromised environment results in debilitating diseases, such as oral mucositis (OM), atherosclerosis, and ischemia/reperfusion injury. Antioxidant therapeutics has been a proposed strategy to ameliorate these imbalances and maintain homeostatic environments. However, the success of these approaches, specifically curcumin, has been limited due to characteristics such as hydrophobicity and high reactivity when released as bolus doses to contest to oxidative stress induced diseases. The development of a controlled release system to aid in protection of the antioxidant capacity of curcumin, as well as a tunable system to aid in proper rate of release for disease can overcome these limitations. Previously, the use of a poly(beta-amino ester) (PBAE) chemistry has been developed in Dziubla and Hilt laboratories to provide desirable properties. The dynamic mechanical analysis and efficacy in cellular protection has been studied, yet the sensitivity and responsiveness of these polymers to abnormal environments found within oxidative stress compromised environments are unknown.
In this work, a series of networks were comprised of different molar ratios of modified acrylated curcumin, poly(ethylene glycol) diacrylate, and a primary diamine crosslinker to create tunable hydrolytically degradable crosslinked hydrogels. I hypothesized a consumption rate difference of free curcumin and curcumin as a released product from the crosslinked network in the presence of a free radical generating system. After the consumption profiles of each were reported differently, the experimental data was translated into a kinetic rate model to identify quantitative consumption rate parameters of curcumin and active film degradation products. The effect on the released products arose the question of curcumin consumption in other oxidizing environments. These networks were then investigated in low concentrations of a hydrogen peroxide insult, and interestingly showed sensitivity to hydrolysis by recovering significantly more curcumin at an accelerated rate of release. Identifying the sensitivity of these tunable networks to environmental stimuli, they were then presented to a series of low pH environments, which significantly reduced the degradation time, finding a dependence of rate of release on the weight loading of curcumin present within the film. To translate these responsive materials to an application-based system, the curcumin conjugated PBAE polymers were investigated as an oral rinse drug delivery system for the treatment of radiation-induced OM in a hamster model. Radiation-induced OM onset and severity was reduced with a 20 wt% microparticle loaded mucoadhesive system that releases curcumin over 24 hours, providing promising results of a therapeutic effect from curcumin when incorporated in to a controlled release delivery system.
Overall, curcumin conjugated PBAE polymers show selectivity of hydrolysis in abnormal environments related to oxidative stress. This information is beneficial to the proper design and loading of antioxidant therapeutics within crosslinked polymers, giving the ability to tune release to treat and deliver based on the environment’s insult. This can advance the potential use for antioxidant therapeutics in pharmaceutical applications in the future.
| Identifer | oai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:cme_etds-1086 |
| Date | 01 January 2018 |
| Creators | Jordan, Carolyn T. |
| Publisher | UKnowledge |
| Source Sets | University of Kentucky |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations--Chemical and Materials Engineering |
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