Governing Transport Principles for Nanotherapeutic Application in the Brain

Abstract

Neurological diseases account for a significant portion of the global disease burden. While research efforts have identified potential drugs or drug targets for neurological diseases, most therapeutic platforms are still ineffective at reaching the target location selectively and with high yield. Restricted transport, including passage across the blood-brain barrier, through the brain parenchyma, and into specific cells, is a major cause of ineffective therapeutic delivery. However, nanotechnology is a promising, tailorable platform for overcoming these transport barriers and improving therapeutic delivery to the brain. We provide a transport-oriented analysis of nanotechnology's ability to navigate these transport barriers in the brain. We also provide an opinion on the need for technology development for increasing our capacity to characterize and quantify nanoparticle passage through each transport barrier. Finally, we highlight the importance of incorporating the effect of disease, metabolic state, and regional dependencies to better understand transport of nanotherapeutics in the brain.

Figure 1.. Block flow diagram of nanotherapeutic transport in the brain.

After systemic administration, nanotherapeutics enter the brain through the BBB. From the BBB, nanotherapeutics enter the perivascular or ECS. From the perivascular space, nanotherapeutics either exit the brain through the ventricles or move to the extracellular space. From the ECS, neurons or glia can internalize the nanotherapeutic. [Created with BioRender.com]

Figure 2.. Schematic of nanoparticle transport routes across the BBB.

Nanoparticles (yellow) can passively diffuse (A) through endothelial cell membranes, or (B) between endothelial cells. Alternatively, nanoparticles can be actively (C) effluxed or internalized via: (D) receptor-mediated, (E) carrier-mediated, (F) adsorptive-mediated, or (G) cell-mediated endocytosis and transcytosis. [Created with BioRender.com]

Figure 3.. Schematic of nanoparticle transport within the brain ECS.

(A) Nanoparticles (green) able to cross the BBB can be transported via convection along the perivascular spaces of the neurovascular unit, as indicated by the dashed arrows. Arrows are bidirectional as the directionality of this flow remains an ongoing debate. Nanoparticles can also access brain parenchyma, where diffusion down a concentration gradient drives transport through the highly tortuous brain ECS. (B) Diffusion is hindered by the presence of brain ECM, which forms three-dimensional mesh-like structures out of hyaluronic acid, glycoproteins, and proteoglycans. [Created with BioRender.com]