Degradable Polymers for the Controlled Delivery of Bioactive Small Molecules

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.