KSEF KCF: Biodegradable Antioxidant Polymers for Controlled Delivery of Antioxidants

Oxidative stress is a key process in a multitude of pathological conditions (e.g., hyperoxia, chronic ulcerations, and aging). Oxidants produced by cells and released by leukocytes damage tissue1, inducing a vicious cycle of inflammation, edema, thrombosis and dysfunction, further propagating primary disease conditions. Beyond just disease development, the biomaterial-induced inflammatory response is inextricably linked to cellular oxidative stress, where inflammatory cells like macrophages release a plethora of inflammatory cytokines and reactive oxygen and nitrogen species (ROS & RNS).2-4 Indeed, the detection of biomaterial-induced ROS is currently being used to characterize the inflammatory host tissue response to the biomaterial, in both in vitro and in vivo models.5-6 In the case of biodegradable polymers, this inflammatory response is often a result of the local accumulation of polymer degradation products.7-9 Strategies which can suppress this localized toxicity can theoretically extend the biocompatibility window for a variety of degradable materials. Conjugation of antioxidants to polymers is one such attempt that has been demonstrated to suppress biomaterial-induced inflammation and oxidative stress.3,10-13 However, antioxidant polymers have classically had a low percent antioxidant content compared to the bulk material as the polymer chemistry does not allow for incorporation of wide range of antioxidants. Previously, our lab has developed a polyester polymer composed entirely of the antioxidant, trolox, a water-soluble analogue of tocopherol) with 100% antioxidant content.14-15 While this material has been shown to effectively inhibit oxidative stress induced by metal nanoparticles, poly(trolox ester) degradation is limited by its lack of hydrolytic degradation leaving very little to no control over its degradation rate. Recently, a modified non-free-radical polymerization poly(â-amino ester) (PBAE) chemistry16 has been developed as a platform to synthesize antioxidant polymers with tunable properties. This method takes advantage of the vast libraries of acrylate and amine monomers that have been studied to tune PBAE properties. 17-18 Another important advantage of this PBAE chemistry is that it can be extended to all polyphenolic antioxidants. Acrylate functionalized antioxidants, quercetin multiacrylate (QMA) and curcumin multiacrylate (CMA) were synthesized and reacted with commercially available diacrylate and primary diamine monomer to result in a crosslinked network of poly (antioxidant â-amino ester) (PAâAE). Degradation rate of the polymer was dependant on content of the hydrophobic antioxidant monomer and can be controlled by appropriate choice of commercially available monomers. PAâAE degradation products possessed antioxidant activity and suppressed oxidative stress levels in the cells in the absence of any injury. When oxidative injury was induced in endothelial cell monolayer, treatment with degradation products of PAâAE protected endothelial cells from disruption in endothelial barrier in an in vitro model as measured by transendothelial electrical resistance.