(150q) Controlled Delivery of N-Acetylcysteine from PLGA Microparticles Prevents Oxidative Stress in Neural Stem Cells

Ischemic stroke is one of the leading causes of death and disability worldwide. Excessive production of reactive oxygen species (ROS) after a stroke induces oxidative stress and damages multiple components of brain tissues, including proteins, lipids, and DNA. Spatial and temporal control of antioxidant delivery is critical to obtain a proper therapeutic effect by scavenging ROS in such environments. Poly(lactic-co-glycolic acid) (PLGA) is a common polymer used to develop biomaterials for drug delivery applications. PLGA is a biocompatible and biodegradable polymer which degrades via hydrolysis. We can experimentally tune the drug release rate by controlling the parameters such as polymer molecular weight and ratio of lactide to glycolide. N-acetylcysteine (NAC) is a potent, FDA-approved, hydrophilic antioxidant with a free thiol group that can neutralize ROS. We used a modified water-in-oil-in-water (W/O/W) drug encapsulation method to fabricate microparticles with high loads of NAC. We achieved NAC load capacities ranging from 74 µg/mg to 95 µg/mg with this modified drug-loading approach, while the theoretical load of the traditional W/O/W encapsulation method is 33µg/mg. Particles sizes were characterized by dynamic light scattering (DLS), average diameters between 1.8-3.7 µm. Release profiles of NAC demonstrated an initial burst release. NAC released from 50:50 L:G, 0.75-0.95 IV PLGA microparticles retained robust radical scavenging activity, reducing the presence of radicals by up to 26 %, even after 2 weeks. Further, NAC PLGA microparticle treatments were administrated to two models of oxidative stress: a preventive treatment model and a rescue treatment model. Our results show that NAC released from PLGA microparticles positively affected neural stem cell (NSC) viability from radical-mediated oxidative stress. In the preventive treatment, the 50:50 L:G, 0.75-0.95 IV PLGA microparticles nearly doubled the relative metabolic activity (ATP/DNA) of the untreated condition from 13% to 25% after 24 hours of treatment. In future experiments, NSCs will be subjected to oxygen-glucose depravation to mimic ischemic stroke and further test the potential of NAC PLGA microparticles.