Nanomedicine strategies for central nervous system (CNS) diseases

Abstract

The blood-brain barrier (BBB) is a crucial part of brain anatomy as it is a specialized, protective barrier that ensures proper nutrient transport to the brain, ultimately leading to regulating proper brain function. However, it presents a major challenge in delivering pharmaceuticals to treat central nervous system (CNS) diseases due to this selectivity. A variety of different vehicles have been designed to deliver drugs across this barrier to treat neurodegenerative diseases, greatly impacting the patient's quality of life. The two main types of vehicles used to cross the BBB are polymers and liposomes, which both encapsulate pharmaceuticals to allow them to transcytose the cells of the BBB. For Alzheimer's disease, Parkinson's disease, multiple sclerosis, and glioblastoma brain cancer, there are a variety of different nanoparticle treatments in development that increase the bioavailability and targeting ability of existing drugs or new drug targets to decrease symptoms of these diseases. Through these systems, nanomedicine offers a new way to target specific tissues, especially for the CNS, and treat diseases without the systemic toxicity that often comes with medications used currently.

Keywords: Alzheimer’s; Parkinson’s; blood-brain barrier; cancer; central nervous system disease; glioblastoma; multiple sclerosis; nanomedicine.

FIGURE 1

Longitudinal representation of blood-brain barrier anatomy. (Image created using Biorender.com. Inspired by (Sofroniew and Vinters, 2010; Jo et al., 2013; Cabezas et al., 2014; Daneman and Prat, 2015; Serlin et al., 2015; Herland et al., 2016; Stephen and Barrand, 2016; Dong, 2018; Gastfriend et al., 2018; Ayloo and Gu, 2019; Kim et al., 2019; Kadry et al., 2020; Galea, 2021; Rice et al., 2022)).

FIGURE 2

Nanomedicine pathways across BBB endothelial cells. Passive diffusion requires no energy or specific targeting, this pathway is only utilized by small molecules or ions essential to proper brain function. Active transport requires ATP in order to induce the uptake of nanoparticles by ATP-binding cassette (ABC) transporters. Carrier-mediated transcytosis functions as a solute-carrier complex that allows transport across cells. Receptor-mediated transcytosis specifically targets a known receptor on the surface of brain endothelial cells, promoting uptake into the cell within an endosome. (Image created using Biorender.com. Inspired by (Brown et al., 2020; Laura Del AmoCano et al., 2021)).

FIGURE 3

Current research in AD nanotherapeutics. (A) siBACE1 therapy mechanistic schematic. (B) In vitro cellular uptake of the Gal-NP loaded with siRNA in Neuro-2a cells using Cy5 to label the NPs. The siRNA localization is traced in green. (C) In vivo time lapse biodistribution. Reproduced from (Zhou Yutong et al., 2020).

FIGURE 4

In vitro BBB delivery for the treatment of cancer. (A). In vitro Transwell model schematic displaying the experimental design for NP delivery. Reproduced from (Tan et al., 2020). (B). Confocal imaging results from the in vitro Transwell experiment of the cellular uptake of the NPs into the C6 cancer cells. Reproduced from (Tan et al., 2020).

FIGURE 5

BBB dysfunction during PD schematic. Reproduced from (Cabezas et al., 2014).

FIGURE 6

In vivo Parkinson’s disease modeling and NP delivery. Observation of BBB penetration using dpf Zebrafish model. Green fluorescence indicates effective cellular uptake of NPs. Reproduced from (Zhao et al., 2020).