Water-soluble antioxidant derivative poly(triethylene glycol methyl acrylate-co-α-tocopheryl acrylate) as a potential prodrug to enable localized neuroprotection

Implantable microelectrode arrays (MEA) hold enormous hope for individuals with sensory or motor deficits. However, long-term function of MEA remains a critical hurdle. The objective of this study was to synthesize an antioxidant prodrug that can be delivered to the neural tissue around the implant and present a pharmacological depot to combat the injurious oxidative stress around the MEA. In this report, monomers of triethylene glycol methyl acrylate and α-tocopheryl acrylate, a synthetic derivative of the antioxidant α-tocopherol (vitamin E, Ve), were copolymerized to obtain poly(triethylene glycol methyl acrylate-co-α-tocopheryl acrylate) (PVT) with different compositions. In contrast to the poor water solubility of Ve, solubility of the PVT prodrug in water can reach as high as 3.1 mg ml(-1) (equivalent to 500 μM Ve) by tuning the copolymer composition. To demonstrate the applicability of the prodrug for MEA implants, PVT was successfully deposited on silicon substrates with poly(acrylic acid) (PAA) or tannic acid (TA) using the layer-by-layer technique mediated by hydrogen bonding. Ellipsometry and quartz crystal microbalance data showed that the multilayers of PAA/PVT were destructible at physiological pH. In contrast, multilayers of TA/PVT were stable. The PVT prodrug was non-cytotoxic toward A172 human astrocytes. Furthermore, PVT was able to protect astrocytes against oxidative stress exerted by H(2)O(2) in vitro. Using a free radical scavenging assay, the protection mechanism was attributed to the hydrolysis of the labile ester linkage and release of the active Ve.