(194e) Design of a Targeted Delivery System Based On Antioxidant-Loaded Biodegradable Nanoparticles for Neuroprotection in Cell Culture Model of Neurological Disease

In many neurodegenerative diseases such as Parkinson’s (PD), Huntington’s and Alzheimer’s, there is a progressive loss of structure or function of neurons, including death of neurons.. The prevalence of these diseases is increasing along with the median age of our population. Mitochondrial dysfunction, oxidative and nitrative stress have been implicated in number of neurodegenerative diseases including PD.  The existing treatment approaches for these diseases are symptomatic and fail to prevent the progression of the neurodegenerative process. Mitochondrial targeted antioxidants have been recently shown to protect against Parkinsonian toxicant, -methyl-4-phenylpyridinium (MPP⁺) -induced production of reactive oxygen and nitrogen species production (ROS/RNS). Polyanhydride nanoparticles can be designed as a delivery system to elicit unique cellular responses such as particle internalization and directed intracellular trafficking. Through encapsulation of the payload within the polyanhydride particles, sustained release of these compounds can be achieved. Altering the polymer chemistry, functionalizing the particle surface, and/or controlling particle size enable the release of payload to targeted regions within the cell.

In this work we investigate the ability of biodegradable polyanhydride nanoparticles to enhance the delivery of mitochondrial targeted antioxidants to protect against MPP⁺. The antioxidant utilized in these studies was apocyanin functionalized with a mitochondrial targeting ligand, mitoapocyanin. Using poly(sebacic acid) nanoparticles, we designed a delivery system for targeted release of mitoapocyanin to mitochondria of cells. The performance of the designed delivery system was evaluated for neuroprotection against MPP⁺-induced cell death in both the MN9D dopaminergic cell line and mouse primary neurons. Cellular uptake of particles was evaluated by confocal microscopy of particles loaded with quantum dots. Intracellular trafficking of the particles to the mitochondria was evaluated by co-localization of the particle and mitochondria by confocal microscopy and confirmed by transmission electron microscopy.