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Review
. 2022 Jun 10:13:325-346.
doi: 10.1146/annurev-chembioeng-092220-030853. Epub 2022 Mar 23.

Nanotherapeutics and the Brain

Andrea Joseph  1 , Elizabeth Nance  2
Affiliations
Review

Nanotherapeutics and the Brain

Andrea Joseph et al. Annu Rev Chem Biomol Eng. .

Abstract

Brain disease remains a significant health, social, and economic burden with a high failure rate of translation of therapeutics to the clinic. Nanotherapeutics have represented a promising area of technology investment to improve drug bioavailability and delivery to the brain, with several successes for nanotherapeutic use for central nervous system disease that are currently in the clinic. However, renewed and continued research on the treatment of neurological disorders is critically needed. We explore the challenges of drug delivery to the brain and the ways in which nanotherapeutics can overcome these challenges. We provide a summary and overview of general design principles that can be applied to nanotherapeutics for uptake and penetration in the brain. We next highlight remaining questions that limit the translational potential of nanotherapeutics for application in the clinic. Lastly, we provide recommendations for ongoing preclinical research to improve the overall success of nanotherapeutics against neurological disease.

Keywords: blood–brain barrier; brain delivery; brain distribution; brain parenchyma; nanomedicine.

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Figures

Figure 1
Figure 1
(a) Physiological barriers to nanoparticle transport to the brain after systemic and local delivery. (b) Administration routes for brain-targeted nanoformulations. Figure adapted from images created with BioRender.com.
Figure 2
Figure 2
General and governing design considerations for nanoparticle transport, without the use of targeting ligands, across the BBB and penetration within the brain parenchyma. (a) Nanoparticle size is an important factor in BBB penetration, but nanoparticles 200 nm or larger are more highly restricted in penetrating within the brain parenchyma. Panel adapted with permission from Reference (left) and Reference (right). (b) Surface charge is a key determinant in a nanoparticle’s ability to overcome an impaired BBB. Representative images of dendrimer nanoparticles (red) show that neutral and anionic charged dendrimers can localize in cells (green) in the injured brain, in regions where BBB impairment is present. Cationic charged dendrimers cannot navigate the impaired BBB. Panel adapted with permission from Reference . (c) Nanoparticle colloidal stability can decrease with increasing calcium concentrations in the brain parenchyma. Particles that are densely PEG coated (red) can retain colloidal stability at body temperature in the presence of increasing Ca2+ concentration. Panel adapted with permission from Reference . (d) Nanoparticle shape and size influence nanoparticle Papp across brain endothelial cells, particularly for nanoparticles larger than 200 nm. PS rods with an aspect ratio of 2 (2AR-PS-R) had significantly greater Papp than spherical 500-nm-PS nanoparticles (500-PS) and rod-shaped particles with an aspect ratio of 5 (5AR-PS-R). Panel adapted with permission from Reference . (e, left) Nanoparticles can be functionalized through several chemical surface moieties. (Middle) Nanoparticles functionalized with PEG (green) can diffuse and penetrate within the brain parenchyma compared to non-PEG-coated nanoparticles (red) (adapted with permission from Reference 70). (Right) Presentation of different surfactant moieties on the nanoparticle surface can alter nanoparticle (red) ability to bypass the BBB. Particles formulated in P80 localize in neurons (green), whereas particles formulated in Pluronic® F127 or PVA or with no surfactant (DI H2O) remain localized in the vascular space (adapted with permission from Reference 67). Abbreviations: BBB, blood–brain barrier; P80, polysorbate 80; PEG, poly(ethylene glycol); Papp, apparent permeability; PS, polystyrene; PVA, polyvinyl alcohol.
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