THERAPEUTIC H2S DELIVERY:
Hydrogen sulfide (H2S) is known primarily as a foul-smelling, toxic pollutant. However, H2S is also a vital biological signaling gas, produced endogenously via enzymatic conversion of cysteine. Along with carbon monoxide (CO) and nitric oxide (NO), H2S is recognized as the third member of the class of signaling gases known as gasotransmitters. The physiological roles of H2S are still being discovered, and it is of interest as a therapeutic in a wide variety of disease and conditions. However, the majority of biological studies on H2S have been carried out with systemically administered small molecule H2S donors, primarily Na2S and NaHS, which have little tissue specificity and the potential for off-target effects. As a result, delivering H2S to a desired site of action at therapeutic dosages remains difficult, and new methods to control the dosage, rate, location, and timing of H2S delivery are needed (Figure 1).
Figure 1. Methods of H2S delivery. Reproduced from Qian and Matson Adv. Drug Deliv. Rev. 2017, 110-111, 137.
We focus on the development of small molecules, polymers, gels, and polymer assemblies that release H2S and related compounds in response to specific triggers. Collectively called H2S donors, these compounds allow us to control the delivery of H2S in order to study its (patho)physiological roles and evaluate its therapeutic potential.
The expansion of controlled polymerization techniques over the past two decades has enabled the construction of polymers with complex topologies. Bottlebrush polymers contain a polymer backbone with densely grafted polymer side chains, which force the backbone polymer into an extended conformation. These types of polymers may have applications as supersoft elastomers, vibration damping materials, and as nano-objects of controlled dimensions. We are pursuing new synthetic routes to bottlebrush polymers using a variety of polymerization techniques, including reversible addition-fragmentation transfer (RAFT) polymerization, atom transfer radical polymerization (ATRP), and ring-opening metathesis polymerization (ROMP).
Bottlebrush polymers are typically synthesized via 3 different synthetic strategies: grafting-from, grafting-to, and grafting-through. Recently we began investigating a 4th synthetic strategy using RAFT polymerization, termed “transfer-to.” RAFT transfer-to polymerization is a unique route toward the synthesis of bottlebrush polymers. During this process, the polymeric radical detaches from the bottlebrush backbone, propagates freely in solution, and returns to the backbone via a chain-transfer reaction. At first glance it appears similar to grafting-from, but transfer-to is ultimately quite different (Figure 2). The transfer-to strategy has the advantage over grafting-from that radical-radical coupling reactions between adjacent polymer side chains or between bottlebrush macromolecules does not occur. Therefore, very high molecular weight bottlebrush polymers can be synthesized using this method. We are interested in exploiting this advantage to prepare a variety of bottlebrush polymers with high molecular weights and narrow molecular weight distributions.
Figure 2. Comparison of the RAFT grafting-from (A) and RAFT transfer-to (B) methods for bottlebrush polymer synthesis. Reproduced from Foster, Radzinksi, and Matson, J. Poly. Sci., Part A: Polym. Chem. 2017, 55, 2865-2876.
We are also interested in preparing polymers with shape asymmetry. Our current interest is in polymers that are cone-shaped, which may have interesting rheological and self-assembly properties. We prepare these cone-shaped polymers, termed tapered bottlebrush polymers, via a grafting-through strategy termed sequential addition of macromonomers ring-opening metathesis polymerization (SAM-ROMP). Using this method we have prepared bottlebrush polymers with systematically varied side-chain molecular weights ranging from 1–10 kg/mol (Figure 3).
Figure 3. Synthesis of tapered bottlebrush polymers via SAM-ROMP. Reproduced from Radzinski, Foster, Scannelli, Weaver, Arrington, and Matson, ACS Macro Lett. 2017, 6, 1175-1179.
NEW RENEWABLE AND DEGRADABLE POLYMERS:
New degradable materials made from renewable feedstocks are desperately needed. We aim to apply modern polymer chemistry to renewable and degradable polymers, most notably polyesters and polysaccharides, to make new copolymers and polymer blends that have useful properties. We recently described a method to make a photo- and biodegradable thermoplastic elastomer based on polylactide (Figure 4). Current efforts are focused on blending polylactide and cellulose-based polymers with synthetic, bio-renewable polymers.
Figure 4. Chemical structure and images (before and after irradiation) of a photo-degradable thermoplastic elastomer based on polylactide. Reproduced from Arrington, Waugh, Radzinski, and Matson. Macromolecules, 2017, 50, 4180-4187.
PEPTIDE-BASED RESPONSIVE AND BIOACTIVE MATERIALS:
Peptides exhibit rich, well-defined secondary structures, which in some cases change in response to a shift in temperature, pH, or other stimuli. Elastin-like peptides (ELPs) are thermoresponsive peptides inspired by the natural protein elastin. Comprised of a repeating pentameric sequence, linear ELPs have been widely studied as polymers that respond to temperature by changing their secondary structure and ultimately their solubility. Branched and dendritic ELPs, however, have received little attention. We have developed synthetic methods to make dendritic ELPs with high molecular weights, and we have discovered the branched structure of dendritic ELPs causes a shift in their transition temperature upon heating (Figure 5). We are now focused on incorporating branched ELPs into viscoelastic gels, with the goal of multiplying changes in peptide secondary structure across several orders of magnitude, from the molecular scale to the macroscale. Determining structure-property relationships in these peptide-based materials and measuring their effects on cell viability, proliferation, and differentiation are our major goals in this area of research.
Figure 5. Schematic illustration of the phase-change behavior of dendritic ELPs. Reproduced from Zhou, Shmidov, Matson, and Bitton. Colloids Surf. B 2017, 153, 141-151.