Investigation of Controlled Drug Release from Polymeric Microparticles on Models of Oxidative Disease and Tissue Development

Prolonged oxidative stress characterizes many well-studied diseases of the central nervous system (CNS), including stroke. In 2015, stroke claimed the lives of over 140,000 US citizens and from 2013-2014 cost $40.1 billion. An important aspect of stroke pathology, brain oxidative stress, persists for up to 1 week following stroke, motivating the need for temporal control of antioxidant drug delivery. N-acetylcysteine (NAC) is a potent small-molecule antioxidant. Poly(lactic-co-glycolic acid) (PLGA) microparticles have long been used to deliver encapsulated drugs with temporal control, but encapsulation of small hydrophilic molecules via traditional emulsion methods has been a challenge due to rapid mass transport of small molecules out of particle pores. We have developed an alteration to the existing water-in-oil-in-water (W/O/W) drug encapsulation method that dramatically improves loading efficiency: doping external water phases with drug to mitigate drug diffusion out of the particle during fabrication. NAC-doped particles exhibited high loads and improved outcomes of monolayer oligodendrocyte progenitor cells (OPCs) experiencing multiple doses of hydrogen peroxide by increasing the intracellular glutathione content and preserving cellular viability relative to the injury control. NAC-doped microparticles also protected OPC viability and morphology from toxicity of photoinitiators, molecules commonly used in contact with cells to form hydrogels. To slow and lengthen the duration of antioxidant release, the hydrophobic prodrug BDP-NAC was encapsulated within the core of core/ shell microparticles. These core/ shell microparticles protected OPC growth and viability from seven daily doses of hydrogen peroxide. Drug delivery is also useful for proper neural development, encompassing both anterior (i.e., forebrain and midbrain) and posterior (i.e., hindbrain and spinal cord) tissue components, which appears to require opposing spatial gradients of a morphogen and its inhibitor. To meet this need, we designed microparticles that released active BMP-4, a morphogen, and its inhibitor Dkk-1, showing the potential use of microparticles in spatially guiding neural tissue development. Thus, polymeric microparticles have the potential to provide temporally controlled drug therapy beneficial in neural disease and tissue development.