Degradable Polymers for the Controlled Delivery of Bioactive Small Molecules
| dc.contributor.author | Swilley, Sarah Nicole | en |
| dc.contributor.committeechair | Matson, John | en |
| dc.contributor.committeemember | Schulz, Michael | en |
| dc.contributor.committeemember | Whittington, Abby Rebecca | en |
| dc.contributor.committeemember | Deck, Paul A. | en |
| dc.contributor.department | Chemistry | en |
| dc.date.accessioned | 2025-01-18T09:01:10Z | en |
| dc.date.available | 2025-01-18T09:01:10Z | en |
| dc.date.issued | 2025-01-17 | en |
| dc.description.abstract | Gasotransmitters are endogenous small molecule gases that are freely permeable to membranes and possess biological signaling functions. The three recognized gasotransmitters are carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S). H2S is featured in this work, as well as persulfides (RSSH), which also have similar functions to H2S (e.g., angiogenesis) and are the presumed signaling products of H2S but are less studied. Other compounds that are considered potential gasotransmitters include methane, sulfur dioxide, hydrogen cyanide, and nitroxyl (HNO). This dissertation covers compounds that release HNO, which possesses similar functions to NO (cardioprotection and vasodilation) but has been studied much less. While HNO, H2S, and RSSH have vital biological functions, they also have short half-lives in vivo (seconds to minutes), thus necessitating the development of prodrugs, also called donor compounds, that can release these reactive species over a biologically relevant time scale. While donor compounds extend the release rate of such small molecule gases, they do not have the ability to release drugs as slowly and continuously as endogenous gasotransmitter-generating enzymes do. As such, polymeric delivery systems have been developed to extend the release of drugs, and in the case of gasotransmitters this more closely mimics in vivo production of HNO/H2S/RSSH. Polymeric systems have been employed to modulate gasotransmitter delivery to control drug release rate, location, and longevity precisely. H2S has been employed in numerous polymeric systems, as discussed in Chapter 2, but there is a significant gap in the literature focusing on polymeric donors for HNO/RSSH. Researchers need to develop novel materials that demonstrate an extended release of these small molecules to better understand the effects of long-term exogenous delivery of HNO/RSSH/H2S which exist fleetingly in vivo. Therefore, materials that release a continuous, well characterized amount of gasotransmitters are vital for biologists to understand long-term effects of such short-lived gasses. The aim of this dissertation, in part, is to hopefully inspire the development of novel HNO/RSSH/H2S releasing systems. In Chapter 3 we discuss an HNO-donating polymer. Here we demonstrate a simple system derived from polyethylene glycol (PEG) and sulfonated polystyrene (PSS). We synthesized a polymeric version of Piloty's acid — a well-known HNO donor — by converting the PSS into a Piloty's acid motif in a two-step process. We found that by simply changing the block ratio of PEG and PSS, we were able to vary the release rate of HNO over an order of magnitude. In Chapter 4 we focus on the development of depolymerizable H2S donors encapsulated within polymer micelles. We report the synthesis of two classes of monomers, one derived from norbornene and one from acrylates. We anticipate that the results from this study will further direct and impact the study of exogenous H2S-releasing materials. In Chapter 5 we discuss electrospun polymer films made of poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) with embedded RSSH donors. We found that the RSSH donors can rescue cells from H2O2 exposure and do not interfere with angiogenesis in HMVECs. We report the fabrication, characterization, and drug release studies of the polymer fiber mats. Lastly, the appendix included at the end of this dissertation briefly discusses the synthesis of a novel depolymerizable poly(thiourethane) derived from a pyrrole monomer. | en |
| dc.description.abstractgeneral | Polymers, long chains of repeating units, are found everywhere. From biological polymers such as starch or cellulose to commercial plastics that come from crude oil sources, applications of natural and synthetic polymers have grown exponentially over the last century. While most people associate polymers with plastic water bottles or shopping bags, researchers have developed ways to harness the power of these long-chain molecules for drug delivery. Common examples of polymer drug delivery systems include nicotine patches and controlled-release drug capsules such as Allegra D. As scientists push the limits of drug delivery and more advanced materials are developed, the quality of human life could improve drastically. The potential for this industry can be seen by the sheer magnitude of money that has been put toward drug delivery devices – the market is expected to reach $2.2 trillion within the next two years. In this dissertation we highlight three separate projects focusing on the delivery of gasotransmitters from polymer systems. Gasotransmitters are small gases that are produced in the cells of bacteria, plants, fungi, and animals. To be considered a gasotransmitter, the gas has to be able to enter or exit cells freely and also have specific biological functions. There are three currently accepted gasotransmitters: nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S). The first chapter of this work briefly discusses the biological importance of these gases. Each of the aforementioned gasotransmitters possesses key biological functions such as anti-inflammatory properties, protection of the cardiovascular system from injury, and encouraging the growth of new blood cells. Despite their helpful effects, gasotransmitters exist fleetingly in the body, existing for only seconds to minutes before being converted into a different molecule. Therefore, if researchers want to exploit the therapeutic potential of these gases, we must develop small molecules donors of these gasotransmitters, termed prodrugs. A prodrug is a compound that is administered in an inactive form, but upon a triggering event, e.g., a change in pH, or through the body's metabolism of the compound, an active therapeutic is released. Numerous research groups, including ours, have developed and examined the biological effects of gasotransmitter-releasing prodrugs. To push the efficacy of these prodrugs even further, we can incorporate them within polymer drug delivery systems, as is discussed throughout this dissertation. When a drug or a prodrug is used in a drug delivery system, the release rate and location, circulation time, and other critical properties are carefully tuned. In the case of the work reported here, we set out to develop different delivery systems to control the release of H2S (Chapter 4), persulfides (RSSH, Chapter 5), and nitroxyl (HNO, Chapter 3); while not officially recognized as part of the gasotransmitter family, RSSH and HNO are closely related to H2S and NO respectively. Both RSSH and HNO are significantly less studied than the gasotransmitters and developing systems that can help biologists elucidate the effects of RSSH/HNO from H2S/NO could provide a better understanding of how to treat different disease states. | en |
| dc.description.degree | Doctor of Philosophy | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:41558 | en |
| dc.identifier.uri | https://hdl.handle.net/10919/124257 | en |
| dc.language.iso | en | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | hydrogen sulfide | en |
| dc.subject | nitroxyl | en |
| dc.subject | persulfide | en |
| dc.subject | drug delivery | en |
| dc.title | Degradable Polymers for the Controlled Delivery of Bioactive Small Molecules | en |
| dc.type | Dissertation | en |
| thesis.degree.discipline | Chemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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