(456d) Biodegradable Nanoparticle-Based Delivery System for Enhanced Blood-Brain Barrier Transport Utilizing Macrophage Carriage

A major barrier in the treatment of many neurological or neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, is the inability of therapeutics to cross the blood-brain barrier (BBB). The prevalence of these diseases is increasing with the median age of our population. Among several strategies to improve therapeutic transport across the BBB is the use of a carriage system based on macrophages. Using this method, improved drug delivery into the central nervous system can occur through ingress of drug-loaded macrophages across the BBB, or via macrophages and brain endothelial cells cell-to-cell contact and drug transfer. Polyanhydride nanoparticle-based delivery systems have been designed to elicit unique cellular responses such as particle internalization and activation of antigen presenting cells such as dendritic cells and macrophages. 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 enables the release of payload to targeted regions within the body.

In this work we investigate the ability of various formulations of biodegradable polyanhydride nanoparticles to enhance the delivery of therapeutic compounds across the BBB. These formulations showed limited toxicity to primary human monocytes, macrophages and brain endothelial cells. Cellular uptake of particles within monocytes and macrophages and the subsequent transport of internalized particles (loaded with a fluorescent imaging agent) to brain endothelial cells were evaluated by confocal microscopy. Quantification of transport of the various nanoparticle formulations was accomplished using flow cytometry. The results suggest that polyanhydride chemistry and surface functionalization of the nanoparticles can be used to enhance the transport and uptake of these particles by primary human brain endothelial cells when macrophages are used for carriage.