Non-Invasive, Targeted Nanoparticle-Mediated Drug Delivery across a Novel Human BBB Model

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The blood–brain barrier (BBB) is a highly sophisticated system with the ability to regulate compounds transporting through the barrier and reaching the central nervous system (CNS). The BBB protects the CNS from toxins and pathogens but can cause major issues when developing novel therapeutics to treat neurological disorders. PLGA nanoparticles have been developed to successfully encapsulate large hydrophilic compounds for drug delivery. Within this paper, we discuss the encapsulation of a model compound Fitc-dextran, a large molecular weight (70 kDa), hydrophilic compound, with over 60% encapsulation efficiency (EE) within a PLGA nanoparticle (NP). The NP surface was chemically modified with DAS peptide, a ligand that we designed which has an affinity for nicotinic receptors, specifically alpha 7 nicotinic receptors, found on the surface of brain endothelial cells. The attachment of DAS transports the NP across the BBB by receptor-mediated transcytosis (RMT). Assessment of the delivery efficacy of the DAS-conjugated Fitc-dextran-loaded PLGA NP was studied in vitro using our optimal triculture in vitro BBB model, which successfully replicates the in vivo BBB environment, producing high TEER (≥230 Ω/cm2) and high expression of ZO1 protein. Utilising our optimal BBB model, we successfully transported fourteen times the concentration of DAS-Fitc-dextran-PLGA NP compared to non-conjugated Fitc-dextran-PLGA NP. Our novel in vitro model is a viable method of high-throughput screening of potential therapeutic delivery systems to the CNS, such as our receptor-targeted DAS ligand-conjugated NP, whereby only lead therapeutic compounds will progress to in vivo studies.
Original languageEnglish
Article number1382
Pages (from-to)1-23
Number of pages24
Issue number5
Publication statusPublished (in print/issue) - 30 Apr 2023

Bibliographical note

Funding Information:
This research was funded by The Dowager Countess Eleanor Peel Trust #325 and S.K. was funded by DEL, NI.

Funding Information:
Special thanks to the Dowager Countess Eleanor Peel Trust and The Department of Employment and Learning (DEL) Northern Ireland for their financial support of this work and Rachel Huey for her input.

Publisher Copyright:
© 2023 by the authors.


  • in vitro model
  • blood–brain barrier (BBB)
  • nanoparticles
  • drug delivery
  • targeted receptor-mediated transcytosis
  • ligand conjugation
  • nicotinic acetylcholine receptor


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