Low nanogel stiffness favors nanogel transcytosis across an in vitro blood-brain barrier

Laís Ribovski; Edwin de Jong; Olga Mergel; Guangyue Zu; Damla Keskin; Patrick van Rijn; Inge S Zuhorn

doi:10.1016/j.nano.2021.102377

Low nanogel stiffness favors nanogel transcytosis across an in vitro blood-brain barrier

Nanomedicine. 2021 Jun:34:102377. doi: 10.1016/j.nano.2021.102377. Epub 2021 Feb 20.

Authors

Laís Ribovski¹, Edwin de Jong², Olga Mergel², Guangyue Zu², Damla Keskin², Patrick van Rijn², Inge S Zuhorn³

Affiliations

¹ University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering, Groningen, The Netherlands; University of São Paulo, Physics Institute of São Carlos, Nanomedicine and Nanotoxicology Group, São Carlos, SP, Brazil.
² University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering, Groningen, The Netherlands.
³ University of Groningen, University Medical Center Groningen, Department of Biomedical Engineering, Groningen, The Netherlands. Electronic address: i.zuhorn@umcg.nl.

PMID: 33621652
DOI: 10.1016/j.nano.2021.102377

Abstract

Transport of therapeutics across the blood-brain barrier (BBB) is a fundamental requirement for effective treatment of numerous brain diseases. However, most therapeutics (>500 Da) are unable to permeate through the BBB and do not achieve therapeutic doses. Nanoparticles (NPs) are being investigated to facilitate drug delivery to the brain. Here, we investigate the effect of nanoparticle stiffness on NP transport across an in vitro BBB model. To this end, fluorescently labeled poly(N-isopropylmethacrylamide) (p(NIPMAM)) nanogels' stiffness was varied by the inclusion of 1.5 mol% (NG1.5), 5 mol% (NG5), and 14 mol% (NG14) N,N'-methylenebis(acrylamide) (BIS) cross-linker and nanogel uptake and transcytosis was quantified. The more densely cross-linked p(NIPMAM) nanogels showed the highest level of uptake by polarized brain endothelial cells, whereas the less densely cross-linked nanogels demonstrated the highest transcytotic potential. These findings suggest that nanogel stiffness has opposing effects on nanogel uptake and transcytosis at the BBB.

Keywords: Blood–brain barrier; Nanogel; Nanoparticles; Stiffness; Transcytosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / chemistry
Blood-Brain Barrier*
Cell Line
Endothelium, Vascular / cytology
Fluorescent Dyes / chemistry
Humans
In Vitro Techniques
Nanogels / chemistry*
Polymers / chemistry

Substances

Acrylamides
Fluorescent Dyes
Nanogels
Polymers
methacrylamide