Delivery of Nanoparticles and Macromolecules across the Blood–Brain Barrier

Abstract

Treatment of brain-related diseases is challenging due to the presence of the blood-brain barrier (BBB), a hurdle that prevents most foreign matter from entering the brain. While macromolecules and nanoparticles represent an increasing fraction of the therapeutic landscape in general, their limited ability to cross the BBB has hindered their clinical impact in treating diseases of the central nervous system. Here the various routes for entry of macromolecular therapeutics into the brain are discussed, as well as the methods used to enhance their transport. Particular emphasis is placed on highlighting quantitative trends and mechanistic insights into how the macromolecular transport can be improved, discussing novel enhancement strategies, and identifying areas in need of more detailed investigations. Overall, this review shows several promising advances and continued progress towards a more complete understanding of how macromolecule and nanoparticle design and delivery strategy characteristics can be leveraged to improve the treatment of brain diseases.

BBB pathophysiology independent delivery of siRNA in traumatic brain injury

“…PS 80-coated NPs have been previously employed to promote drug delivery into brain for multiple applications, including glioblastoma (32,42). However, it is difficult to directly compare brain accumulation observed in our study with literature due to the differences in particle type, drug type, and disease/animal model (21). Nevertheless, to our knowledge, the use of PS 80-coated NPs for brain delivery of siRNA in TBI treatment has never been explored previously.…”

“…We achieved this by combined modulation of surface coating chemistry and coating density on nanoparticles, which maximized their active transport through BBB. Incorporating certain surface coatings on NPs has been previously shown to augment their active penetration across BBB in multiple brain diseases (21)(22)(23)(24). However, a surface coating that can facilitate active transport of siRNA NPs across BBB in TBI has not been reported previously.…”

Size, shape, and flexibility influence nanoparticle transport across brain endothelium under flow

“…One of the major issues in treating brain diseases is crossing the blood–brain barrier (BBB), perhaps the body's most exclusive transport barrier. The BBB is notoriously difficult to cross; the microvascular endothelial cells that form the neurovascular unit are characterized by several restrictive features, including the expression of tight junction complexes, a lack of fenestrations, and low pinocytic activity . As a result, there has been significant research into methods for improving nanoparticle transport through the BBB, using ideas ranging from physically disrupting the endothelium using ultrasound combined with microbubbles, to coating nanoparticles with ligands that enhance transcytosis, to using live cells as delivery vehicles .…”

Nanomedicine Revisited: Next Generation Therapies for Brain Cancer

“…[ 47,49 ] Nevertheless, limitations of conventional free drug approaches still apply and are magnified in immunotherapy‐based approaches where systemic toxicity can be prohibitive and crossing the blood‐brain barrier difficult. [ 50,51 ] Therapies specific to BTICs are elusive due to the variability of markers and ligands observed on BTICs as well as their ability to change over time. [ 48 ] Although nanomedicines that specifically target BTICs and leverage therapeutic targets exclusive to BTICs are yet to be developed, nanotechnology offers a tremendous opportunity to enhance the efficacy of recent developments in BTIC‐focused GBM therapies.…”

“…[ 96–98 ] In addition, systemic treatment for brain cancer requires crossing the BBB. [ 51 ] As such, relying on the EPR effect alone in nanomedicine design may not be sufficient to treat brain cancer without additional targeting strategies.…”