(118d) Extending the Bioavailability of Hydrophilic Antioxidants for Metal Ion Detoxification Via Crystallization with Polysaccharide Dopamine

Although metal ions, such as silver and gold, have been shown to have strong antimicrobial properties, their potential toxic effects on human and environmental health have gained interest with improved understanding of their mechanisms to promote oxidative stress. More specifically, silver ions released from nanoparticle formulations can depolarize the mitochondrial membrane, increase intracellular reactive oxygen species (ROS) production, and neutralize endogenous antioxidant activity. The prolonged survival of ROS can denature lipids and proteins and lead to abnormal cell behavior. As such, a drug delivery system that can maintain ROS-homeostasis through the scavenging of overproduced ROS would nullify the toxic effects of metal ion accumulation.

Polymer-directed assembly of small molecule antioxidants has attracted attention as a way to control drug release and efficacy. These systems usually rely on a polymeric excipient that can help form amorphic solid dispersions that decrease the crystallinity of hydrophobic antioxidants resulting in improved bioavailability. However, for hydrophilic drugs such as N-acetylcysteine (NAC), both a direct scavenger of ROS and a prodrug for glutathione, an increase in crystallinity is desired for prolonged release and redox control. In our system, to further increase NAC release we designed a polymer excipient with thermodynamically favorable interactions with NAC, that can form stabilized colloidal antioxidant crystals. Herein we report a unique antioxidant crystal that dissolves sustainably through polymer-stabilization using sodium hyaluronate conjugated with dopamine (HA-dopa).

In our approach, we explore the role of dopamine incorporation into crystal stabilizing polymers and quantify the balanced trade-off between drug–polymer interactions and competing polymer–polymer interactions to yield the most stable colloidal form. The addition of HA-dopa in the crystallization of NAC resulted in a colloidal crystal assembly with a 5-fold extended release profile. We hypothesize that the extended release of NAC from the colloidal crystals would directly control the intracellular oxidative stress levels and lead to maintained cellular function. We explored this hypothesis with two model systems exposed to AgNO₃; cardiomyocytes to explore metal ion effects on human health and Daphnia magna to explore metal ion effects on ecological health. In both systems we illustrate that the colloidal crystals maintain intracellular ROS levels equal to healthy populations but no treatment or treatment with non-stabilized crystals have elevated levels. Furthermore, we show that deviations from ROS-homeostasis lead to deviations in metabolic function, ATP levels, and abnormal contracting/beating behavior. 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.