Even though the role of oxidative stress in a variety of disease states is known, strategies to alleviate this oxidative stress by antioxidants have not been able to achieve clinical success. Particularly, treatment of oxidative stress by small molecule antioxidants has not received due attention because of the challenges associated with its delivery. Antioxidant polymers, where small molecule antioxidants are incorporated into the polymer backbone, are an emerging class of materials that can address some of these challenges. In this work, biodegradable polymers incorporating phenolic antioxidants in the polymer backbone were synthesized. Antioxidant polymers were then characterized for their in vitro degradation, antioxidant release and their effect on oxidative stress levels (redox state) in the cells. Trolox, a water-soluble analogue of vitamin E, was polymerized to synthesize poly(trolox ester) with 100% antioxidant content which undergoes biodegradation to release trolox. Nanoparticles of poly(trolox ester) were able to suppress oxidative stress injury induced by metal nanoparticles in an in vitro cell injury model. In another study, we polymerized polyphenolic antioxidants (e.g. curcumin, quercetin) using a modified non-free-radical polymerization poly(β-amino ester) chemistry. This synthesis scheme can be extended to all polyphenolic antioxidants and allows tuning of polymer degradation rate by choosing appropriate co-monomers from a large library of monomers available for β-amino ester chemistry. Poly(antioxidant β-amino esters) (PABAE) were synthesized and characterized for their degradation, cytotoxicity and antioxidant activity. PABAE degradation products suppressed oxidative stress levels in the cells confirming antioxidant activity of degradation products.

There is an undeniable link between oxidative stress, inflammation, and disease. Currently, approaches using antioxidant therapies have been largely unsuccessful due to poor delivery and bioavailability. Responding to these limitations, we have developed classes of polymer and delivery systems that can overcome the challenges of antioxidant and anti-inflammatory therapy. In our initial studies, nanoparticles of poly(trolox), a polymeric form of trolox, were surface-modified with antibodies. This modification allows for specific targeting to endothelial cells, affording controllable and localized protection against oxidative stress. We have shown these targeted nanoparticles bind, internalize, and provide protection against oxidative stress generation and cytotoxicity from iron oxide nanoparticles. In a similar fashion, we have tested the ability of poly(trolox) to prevent rheumatoid arthritis in vivo. Poly(trolox) nanoparticles were encapsulated in a PEGylated polymer to enhance circulation and biocompatibility. These particles were shown to accumulate in inflamed joint tissue, recover natural antioxidant function, suppress protein oxidation, and inhibit inflammatory markers. Lastly, we developed a class of polyphenolic compounds utilizing a non-free radical based reaction chemistry of poly(β-amino esters). The polyphenol apigenin was investigated for its anti-inflammatory properties to inhibit inflammation-mediated tumor cell metastasis. PEGylated nanoparticles that incorporated apigenin poly(β-amino ester) were developed and found to retain their anti-inflammatory efficacy while providing a long term release profile. These inhibited the ability of tumor cells to adhere to inflamed vascular cells. We also have shown that these polymers can suppress markers of inflammation responsible in enhancing tumor cell adhesion.