(626b) Design of a Slow-Releasing Antioxidant Drug Delivery System for Stroke | AIChE

(626b) Design of a Slow-Releasing Antioxidant Drug Delivery System for Stroke

Authors 

Murphy, N. - Presenter, University of Virginia
Lampe, K., University of Virginia
On average someone dies of a stroke every 4 minutes in the US. Ischemic stroke is due to a loss of blood supply to the brain and is accompanied by an abundance of reactive oxygen species (ROS) that contribute to death of cells and tissues of the central nervous system (CNS). The effects of ROS occur up to 7 days after stroke. N-acetylcysteine (NAC) is an FDA-approved potent antioxidant. A hydrophobic derivative of NAC, Bpin-disulfide prodrug-N-acetylcysteine (BDP-NAC), was recently reported to be a ROS-responsive prodrug. BDP-NAC is more amenable to encapsulation and slow release from hydrophobic polymer microparticles (MPs) due to its hydrophobicity. To tune drug release, we propose poly(lactic-co-glycolic acid) (PLGA) core-shell nano/microparticles encompassing a core phase loaded with drug encapsulated by a shell capping layer. Loading drugs into the core phase mitigates burst release and results in slow, zero-order release profiles.

MPs fabricated with a PLGA:poly(L-lactic acid) (PLLA) ratio of 2:1 via the oil-in-oil-in-water emulsion method comprised a PLGA core and a PLLA shell. PLLA localized with the PLGA core, while PLGA did not localize with the PLLA shell (Fig. 1A). Core-shell particles released BDP-NAC faster than particles without a polymer shell over 5 days (Fig. 1B). While the desired purpose of core-shell MPs for the application of stroke is to slow and prolong antioxidant drug release, this result is in agreement with PLLA shell-encpasulated BDP-NAC. It is expected that shell-encapsulated drug would release faster, and core-encapsulated drug would release slower, than from a particle with a single polymer (i.e. no polymer shell). Thus, core-shell MPs were fabricated which release BDP-NAC in a manner dependent on particle morphology. Ongoing work aims to fabricate core-shell MPs with core-localized BDP-NAC and to characterize the ability of BDP-NAC core-shell particles to protect oligodendrocyte progenitor cells from sustained daily doses of ROS. These MPs have the potential to protect cells and tissues of the CNS from prolonged oxidative stress, which is a hallmark of the post-stroke pathology.

Figure 1. Particle characterization (A) Confocal image of core-shell particles fabricated with 2:1 PLGA:PLLA showing PLGA in green and PLLA in red. (B) BDP-NAC release profiles of particles with and without polymer shell. Error bars represent SEM.