Targeted Delivery of Hydrogen Sulfide: Synthesis and Application of Small Molecule Hydrogen Sulfide Donors
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Date
2022-10-04
Authors
Gilbert, Annie
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Publisher
University of Oregon
Abstract
Hydrogen sulfide (H2S) is an important gaseous signaling molecule that is endogenously produced. Over the past couple of decades, several biological functions of H2S have been recognized, including the ability of H2S to promote angiogenesis, osteogenesis, anti-inflammation, and antioxidant effects. Although these physiological effects make H2S an ideal therapeutic for regenerative medicine, the gaseous state and high reactivity of H2S make the small molecule challenging to administer to biological systems. To address these challenges, small molecule H2S donors have been developed that react with biological analytes or environments to produce H2S in a slow, sustained manner. Despite the expansive library of H2S donors, several of these H2S sources still lack spatial control over H2S delivery which leads to inefficiency and significantly different biological outcomes due to off-target H2S effects.The research in this dissertation follows two main aims 1) to improve the localization of H2S delivery by developing targeted H2S donors and 2) to develop and apply H2S donors to bone healing applications. Chapter I is a review of activatable COS-based H2S donors that build a foundation for developing targeted H2S donor platforms. Chapter II uses a passive localization approach in developing an acid-labile COS-based H2S donor that produces H2S within a specific pH window. Chapter III describes the development of a library of organelle-targeted COS-based H2S donors to study subcellular H2S effects. Chapter IV is a review of the roles of reactive sulfur species in bone and serves as a transition into work towards targeting H2S delivery in bone healing applications. Chapter V provides an H2S-releasing biomaterial using the previously developed N-acetylcysteine tetrasulfide (NACS4) H2S donor. Furthermore, this chapter investigates the effects of NACS4 on the osteogenic differentiation of human mesenchymal stem cells to predict the therapeutic activity of NACS4-loaded biomaterials in healing bone defects. Lastly, Chapter VI reports the development of an alkaline phosphatase activated COS-based H2S donor to target H2S delivery within the bone healing process. This dissertation includes previously published and unpublished co-authored materials.
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Keywords
Bone regeneration, Chemical tools, Hydrogen Sulfide, Organelle-targeting