Design and Synthesis of Supramolecular Structures for the Controlled Release of Sulfur Signaling Species

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Virginia Tech

In the early 2000s, hydrogen sulfide (H₂S) was added to the family of molecules known as gasotransmitters, a class of endogenously produced and freely diffusing biological signaling molecules. Since this discovery, biologists and chemists have sought to understand the physiological roles of H₂S and to elucidate the potential benefits of exogenous H₂S delivery. As a result, many synthetic small molecule donor compounds have been created to deliver H₂S in response to various biologically relevant stimuli. Furthermore, macromolecular and supramolecular H₂S donor systems have been created to protect donors in the biological milieu, extend release kinetics, or control H₂S release conditions. Thus, H₂S-donating nanostructures with precisely tuned release rates provide invaluable tools for further investigating the biological roles and therapeutic potential of H₂S.

This work describes two polymer micelle systems for the controlled delivery of H₂S. The first system is based on H2S-releasing polymer amphiphiles with varying degrees of a plasticizing comonomer incorporated into the core-forming block. The glass transition temperature of the core-forming block varied predictably with incorporation of the plasticizing comonomer. Accordingly, the half-life of H₂S release decreased from 4.2 h to 0.18 h with increasing core-forming block mobility. The second system is based on H₂S releasing polymer amphiphiles with varying degrees of crosslinking in the core-forming block. The crosslinked system was designed to achieve control over H₂S release rate with minimal dilution of donor in the core-forming block. The half-life of H₂S release increased from 117 min to 210 min with increasing crosslink density in the core-forming block, further demonstrating that H₂S release rates can be precisely controlled by tuning micelle core mobility.

Beyond control over H₂S release rate, further study of the biological roles of H₂S requires donor systems with precisely triggered release. To this end, this dissertation also discusses efforts to investigate fundamental micelle–unimer relationships. This section includes an evaluation of the impact of core-forming block mobility on micelle–unimer coexistence utilizing a model polymer amphiphile system. Unimer populations correlated with glass transition temperatures of the core-forming block, suggesting the need to consider micelle core mobility when discussing polymer chain phase behavior of amphiphilic block copolymers. Finally, this work discloses new methods for the radical polymerization of poly(olefin sulfones) with control over molecular weight. POSs are a unique class of polymers with great potential for stimuli-responsive depolymerization to generate sulfur dioxide (SO₂), a signaling gas related to H₂S.

hydrogen sulfide, sulfur dioxide, polymer micelles, drug delivery, reversible addition-fragmentation chain-transfer polymerization