Nanoparticle and cell-mediated brain delivery in complex blood brain barrier models

Abstract

Delivery of therapeutics to the brain in an efficient, non-invasive manner continues to be a major unmet hurdle in the field of drug delivery. Unlike for other easily accessible organs, such as the skin, targeting and delivering therapeutics into the brain remains a challenge. One significant impediment to brain delivery results from the existence of the physical, yet dynamic blood brain barrier (BBB). Regarded as one of the most impenetrable barriers of the body, the BBB of a healthy individual actively protects the brain from exposure to foreign entities in the blood but is often the rate limiting step in the transport of therapeutics to the brain. Despite the many strategies, often complex, to breach the BBB, adequate delivery of effective therapeutics from the blood stream continues to remain quite low. Nanotechnology and cell-mediated carriers have emerged as promising tools for brain delivery but little is known about what particle parameters may enable delivery. Here, a library of nanoparticles with distinct properties (i.e. size, shape, stiffness, and composition) was investigated to identify key attributes influencing nanoparticle adhesion, uptake and transport as well as for their influence on modulating the migration behavior of immune cells in trafficking across static in vitro BBB models. Two dynamic flow-based human in vitro BBB models were developed to further assess particle adhesion and transport in real-time and under physiologically-relevant conditions. By combining static, dynamic flow-based, and in vivo BBB models, one set of particle parameters (i.e. shape) was investigated for its role in enhancing a particle’s targeting ability for an inflamed cerebral endothelium. Collectively, this work provides new insights of how particle parameters can be modulated to enable delivery to the brain in a non-invasive manner.