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Front. Bioeng. Biotechnol. | doi: 10.3389/fbioe.2019.00049

Designing and characterisation of a novel delivery system for improved cellular uptake by brain using dendronised Apo-E-derived peptide

 Shafaq Al-Azzawi1, 2, Dhafir Masheta1, 2, Anna L. Guildford1, 3,  Gary Phillips1, 3 and  Matteo Santin1*
  • 1Centre for Regenerative Medicine and Devices, School of Pharmacy and Bimolecular Sciences, University of Brighton, United Kingdom
  • 2College of Pharmacy, University of Babylon, Iraq
  • 3Tissue Click Ltd, United Kingdom

Neurodegenerative diseases (ND) are characterised by the progressive loss of neuronal structure or function mostly associated with neuronal death. The presence of the blood–brain barrier (BBB) is considered the main obstacle that prevents the penetration of almost all drugs rendering the diseases untreatable. Currently, one of the most promising approaches for drug delivery to the brain is by employing endogenous transcytosis to improve endothelial cell uptake. This study aimed to exploit this potential route of enhanced drug uptake through the design and characterisation of low generations lysine dendrons with further functionalisation of dendron with ApoE-derived peptide (AEP) ligand to improve cellular uptake and targeting of delivery to the brain. Dendrons and peptide were synthesised using solid phase peptide chemistry and the products were characterised by mass spectrometry and high performance liquid chromatography which confirmed the successful synthesis of dendrons and functionalisation with the AEP. Cell viability and lactate dehydrogenase release were conducted to study the cytotoxicity of the materials against an immortalised brain endothelial cell line (bEnd.3) which demonstrated that no toxicity was seen at the concentration range used (up to 400 µM) for up to 48 h incubation. Cellular uptake of the synthesised molecules was examined using confocal microscopy and flow cytometer which clearly showed the cellular uptake of the dendronised carrier systems and that the highest percentage of cellular uptake was achieved with the AEP-functionalised dendron. This study has therefore demonstrated the successful synthesis of dendronised carrier systems with the potential to act as carriers for improved delivery and targeting the brain.

Keywords: Dendrons, APOE, blood brain barrier, Transcytosis of brain endothelial cells, Neurode generation

Received: 25 Sep 2018; Accepted: 28 Feb 2019.

Edited by:

Mauro Alini, AO Foundation, Switzerland

Reviewed by:

Elizabeth R. Balmayor, Technische Universität München, Germany
Matteo D'Este, AO Foundation, Switzerland  

Copyright: © 2019 Al-Azzawi, Masheta, Guildford, Phillips and Santin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Matteo Santin, Centre for Regenerative Medicine and Devices, School of Pharmacy and Bimolecular Sciences, University of Brighton, Brighton, United Kingdom,