Effect of Nanoparticle Composition, Size, Shape, and Stiffness on Penetration Across the Blood–Brain Barrier

The delivery of therapeutics to the brain in an efficient, noninvasive manner continues to be a major unmet need in the field of drug delivery. One significant impediment to brain delivery results from the existence of the physical yet dynamic blood–brain barrier (BBB). Despite the many, often complex strategies that currently exist to breach the BBB, adequate delivery of effective therapeutics from the bloodstream continues to remain quite low. Nanotechnology has emerged as a promising tool for brain delivery, but little is known about the important particle parameters that influence delivery. Here, we synthesized and characterized a library of nanoparticles with distinct properties ranging from size, shape, stiffness, and composition to investigate and identify the key attributes influencing particle uptake and transport for brain delivery. To accomplish this task, an in vitro human BBB model was developed and validated using human cerebral microvascular endothelial cells (hCMEC/D3). Particle uptake and apparent permeability coefficients (Papp) were then determined for each particle group. To elucidate the roles of different parameters on particle uptake and transport across the BBB, the predominant mechanisms of endocytosis were also investigated. Our results show that particle composition yielded the greatest impact on penetration across the BBB model. This work lays the foundation and provides new insights into the role of particle parameters on penetration across the BBB.