Mukesh K. Gupta

Reperfusion after ischemia causes additional cellular damage, known as reperfusion injury, for which there is still no effective remedy. Poloxamer (P)188, a tri-block copolymer-based cell membrane stabilizer (CCMS), has been shown to provide protection against hypoxia/reoxygenation (HR) injury in various models by reducing membrane leakage and apoptosis and improving mitochondrial function. Interestingly, substituting one of its hydrophilic poly-ethylene oxide (PEO) blocks with a (t)ert-butyl terminus added to the hydrophobic poly-propylene oxide (PPO) block yields a di-block compound (PEO-PPOt) that interacts better with the cell membrane lipid bi-layer and exhibits greater cellular protection than the gold standard tri-block P188 (PEO75-PPO30-PEO75). For this study, we custom-made three different new di-blocks (PEO113-PPO10t, PEO226-PPO18t and PEO113-PPO20t) to systemically examine the effects of the length of each polymer block on cellular protection in comparison to P188. Cellular protection was assessed by cell viability, lactate dehydrogenase release, and uptake of FM1-43 in mouse artery endothelial cells (ECs) following HR injury. We found that di-block CCMS were able to provide the same or better EC protection than P188. Our study provides the first direct evidence that custom-made di-block CCMS can be superior to P188 in improving EC membrane protection, raising their potential in treating cardiac reperfusion injury.

Nanoparticle (NP) supra‐assembly offers unique opportunities to tune macroscopic hydrogels’ mechanical strength, material degradation, and drug delivery properties. Here, synthetic, reactive oxygen species (ROS)‐responsive NPs are physically cross‐linked with hyaluronic acid (HA) through guest‐host chemistry to create shear‐thinning NP/HA hydrogels. A library of triblock copolymers composed of poly(propylene sulfide)‐ b ‐poly(N, N ‐dimethylacrylamide)‐ b ‐poly(N, N ‐dimethylacrylamide‐ co ‐N‐(1‐adamantyl)acrylamide) are synthesized with varied triblock architectures and adamantane grafting densities and then self‐assembled into NPs displaying adamantane on their surface. Self‐assembled NPs are mixed with β‐cyclodextrin grafted HA to yield eighteen NP/HA hydrogel formulations. The NP/HA hydrogel platform demonstrates superior mechanical strength to HA‐only hydrogels, susceptibility to oxidative/enzymatic degradation, and inherent cell‐protective, antioxidant function. The performance of NP/HA hydrogels is shown to be affected by triblock architecture, guest/host grafting densities, and HA composition. In particular, the length of the hydrophilic second block and adamantane grafting density of self‐assembled NPs significantly impacts hydrogel mechanical properties and shear‐thinning behavior, while ROS‐reactivity of poly(propylene sulfide) protects cells from cytotoxic ROS and reduces oxidative degradation of HA compared to HA‐only hydrogels. This study provides insight into polymer structure‐function considerations for designing hybrid NP/HA hydrogels and identifies antioxidant, shear‐thinning hydrogels as promising injectable delivery platforms for small molecule drugs and therapeutic cells.