Systems‐level thinking for nanoparticle‐mediated therapeutic delivery to neurological diseases

Advanced Review

Chad Curtis, Mengying Zhang, Rick Liao, Thomas Wood, Elizabeth Nance

Published Online: Aug 25 2016

DOI: 10.1002/wnan.1422

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Neurological diseases account for 13% of the global burden of disease. As a result, treating these diseases costs $750 billion a year. Nanotechnology, which consists of small (~1–100 nm) but highly tailorable platforms, can provide significant opportunities for improving therapeutic delivery to the brain. Nanoparticles can increase drug solubility, overcome the blood–brain and brain penetration barriers, and provide timed release of a drug at a site of interest. Many researchers have successfully used nanotechnology to overcome individual barriers to therapeutic delivery to the brain, yet no platform has translated into a standard of care for any neurological disease. The challenge in translating nanotechnology platforms into clinical use for patients with neurological disease necessitates a new approach to: (1) collect information from the fields associated with understanding and treating brain diseases and (2) apply that information using scalable technologies in a clinically‐relevant way. This approach requires systems‐level thinking to integrate an understanding of biological barriers to therapeutic intervention in the brain with the engineering of nanoparticle material properties to overcome those barriers. To demonstrate how a systems perspective can tackle the challenge of treating neurological diseases using nanotechnology, this review will first present physiological barriers to drug delivery in the brain and common neurological disease hallmarks that influence these barriers. We will then analyze the design of nanotechnology platforms in preclinical in vivo efficacy studies for treatment of neurological disease, and map concepts for the interaction of nanoparticle physicochemical properties and pathophysiological hallmarks in the brain. WIREs Nanomed Nanobiotechnol 2017, 9:e1422. doi: 10.1002/wnan.1422 This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

Barriers to nanoparticle delivery to the brain. For a nanoparticle‐based therapeutic delivery system to be effective in the brain, it must be able to overcome the system of barriers in the brain. (a) Following systemic administration, a nanoparticle must avoid rapid clearance by the reticuloendothelial system (RES) and cross the blood–brain barrier (BBB), for example, via receptor‐mediated transcytosis or permeation across impaired tight junctions. The nanoparticle must then navigate the brain microenvironment by avoiding steric or adhesive interactions with the extracellular matrix (ECM) to reach diffuse disease sites. At the target site, the nanoparticle should provide site‐specific delivery extracellularly or be internalized via nonspecific fluid‐phase endocytosis, phagocytosis, or receptor‐mediated transport (inset). (b) Following local delivery, a nanoparticle must still navigate the extracellular space (ECS) and ECM, avoid clearance along the perivascular space (PVS) or into the ventricles, and provide site‐specific therapeutic action at a diseased cell. (c) Although the mechanism remains largely unknown, if a nanoparticle is delivered directly into the CSF, i.e., intraventricular, the nanoparticle will still need to cross the ependymal layer and navigate the ECS and ECM to reach target cells.

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Predictive design mapping of nanoparticle behavior as a function of nanoparticle physicochemical properties to overcome barriers to therapeutic delivery in the brain. Nanoparticle physicochemical properties (blue), including size, core material, surface charge, and surface coating, can influence the behavior of the nanoparticle in the brain, specifically the ability of a nanoparticle to overcome barriers to therapeutic delivery. However, pathophysiological hallmarks (red) influence these barriers, potentially altering the nanoparticle behavior. By looking at both nanoparticle properties and disease hallmarks, nanoparticles can be designed to avoid dead ends (red arrows) that will prevent the particle from achieving a therapeutic effect in the brain. Additional factors, such as shape and particle stiffness, will also affect therapeutic delivery, but these are less thoroughly studied in the brain.

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Physiology and biology‐based factors influencing nanoparticle delivery in the brain. The system of factors that change in the presence of an input (examples in blue) can positively or negatively impact common disease hallmarks (examples in red) and changes in blood–brain barrier (BBB) permeability, brain microenvironment, and cell behavior in the brain. These changes influence the ability of a nanoparticle to penetrate across the BBB, move within the brain parenchyma, and uptake into specific cells; however, as the map shows, none of the factors influencing nanoparticle delivery of a therapeutic can be viewed in isolation. Double‐headed arrows indicate a two‐way effect of similar directionality (i.e., pathological astrogliosis increases chronic inflammation, and chronic inflammation increases pathological astrogliosis). ROS/RNS, reactive oxygen/nitrogen species; MMP, matrix metalloproteases; NMDA, N‐methyl‐d‐aspartate.

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