(526b) Stimulus-Responsive Antioxidant Drug Crystals and Their Health and Ecological Implications

The overproduction of reactive oxygen species (ROS) is a major concern in the pathogenesis of many diseases and the health of micro-organisms in ecological systems. Various antioxidants are being used to neutralize overproduced ROS and neutralize resulting oxidative stress. Polymer-directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through prolonged active pharmaceutical release. However, the delivery of most recrystallized antioxidants occurs through continuous dissolution independent of the ROS level. As result, ROS homeostasis is rarely achieved, which can elicit various host responses that hinder the healing process. This study demonstrates a unique method to assemble polymer-crystal complexes that modulate antioxidant release in response to the ROS level. We hypothesized that antioxidants recrystallized using a ROS-liable polymer would be triggered to dissolve when ROS levels increase. We examined this hypothesis and its broad application using two different antioxidants and ROS-liable polymers. The first model was catechin recrystallized using polyethyleneimine cross-linked with ROS-labile diselanediylbis-(ethane-2,1-diyl)-diacrylate. The second model was N-acetylcysteine recrystallized using dopamine conjugated hyaluronate cross-linked with ROS-labile selenocystamine. Both antioxidants crystallized with the ROS-labile polymer display accelerated dissolution proportional to the local H₂O₂ concentration. The ROS-responsive crystals were shown to protect both vascular and human corneal epithelial cells from oxidative insults by activating intracellular glutathione peroxidase expression and, in turn, inhibit an increase in the intracellular oxidative stress levels. In addition, the crystal systems were shown to alleviate changes in the heart rate of Daphnia manga exposed to oxidative media. We propose that the results from these studies would be impactful for improving the therapeutic efficacy of a broad array of drug compounds administered in oxidative environments.