An investigation of the therapeutic potential of phenylaminoalkyl selenides through mechanistic and biological studies and an exploration of ciber: the center of innovative biomaterial education and research
Cowan, Elizabeth Alice
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The overproduction of reactive oxygen species (ROS) have been linked to diseases and other pathologies. As therapeutic agents, antioxidants have been tested and some shown to attenuate these diseases by relieving oxidative stress. The May laboratory has previously developed a family of phenylaminoalkyl selenides and has demonstrated the antihypertensive and antioxidant properties of these compounds. To further understand the antioxidant property of these selenide compounds, the two step mechanism of the reaction between the selenoxide form and glutathione was investigated by stopped-flow and mass spectrometry, leading to the detection and characterization of a novel thioselenurane intermediate. Mass spectrometry studies supported the redox cycle of the selenide compounds as a straightforward cycle with no byproducts or side reactions and was the first evidence reported of a thioselenurane intermediate present in a reduction reaction of a selenoxide. The therapeutic potential of these compounds was further supported by cell and histological studies demonstrating their ability to alleviate the cardiotoxic effect of anthracyclines without affecting the anti-cancer property of the drugs. Codosage of a phenylaminoethyl selenide with Doxorubicin decreased the infiltration of inflammation cells in the myocardium of mice. Phenylaminoethyl selenides were also able to maintain the body weight of mice treated with Doxorubicin, compared to mice treated with Doxorubicin alone. In order to make the possibility of using Phenylaminoalkyl selenides as therapeutic agents or supplements with other agents, delivery of the compounds was investigated. N acetyl phenylaminoethyl selenides were successfully encapsulated into poly(lactic-co-glycolic) (PLGA) nanoparticles using the nanoprecipitation technique. An attempt was made to demonstrate the ability of these selenide- nanoparticles to reduce cellular oxidative stress caused by incubation with LPS. Future studies are needed to optimize the loading of the selenide compounds into nanocarriers and to demonstrate the ability of the encapsulated drug to work as the free drug. The long term goal of this research is to fully understand the potential of phenylaminoalkyl selenides as an efficient therapeutic agent for ailments derived from increased levels of ROS and a state of oxidative stress. As a supplemental project funded by the National Science Foundation, the Center for Innovative Biomaterial Education and Research (CIBER) was created. Enzymatically catalyzed reaction and polymerizations were investigated using Candida antarctica Lipase B (CALB). Several CALB catalyzed Michael addition reactions were successful and yielded compounds that could be used as future reactants and monomers. As an education requirement of the project a website was created in order to educate the public of the importance, sources and uses of biomaterials. The website provides information for all levels of students and educators. This center has allowed The Georgia Institute of Technology to form relationships and exchange programs with leading universities around the world allowing the exchange of knowledge and research in biomaterials.