The Inclusion of a Matrix Metalloproteinase-9 Responsive Sequence in Self-assembled Peptide-based Brain-Targeting Nanoparticles Improves the Efficiency of Nanoparticles Crossing the Blood-Brain Barrier at Elevated MMP-9 Levels

Journal article


Islam, Yamir, Ehtezazi, Parinaz, Cashmore, Andrew, Marinsalda, Elena, Leach, Andrew G., Coxon, Christopher R., Fatokun, Amos A., Sexton, Darren W., Khan, Iftikhar, Downing, James, Pluchino, Stefano, Sivakumaran, Muttuswamy, Teixido, Meritxell, Ehtezazi, Touraj and Zouganelis, George 2020. The Inclusion of a Matrix Metalloproteinase-9 Responsive Sequence in Self-assembled Peptide-based Brain-Targeting Nanoparticles Improves the Efficiency of Nanoparticles Crossing the Blood-Brain Barrier at Elevated MMP-9 Levels. Journal of Pharmaceutical Science. https://doi.org/10.1016/j.xphs.2020.12.004
AuthorsIslam, Yamir, Ehtezazi, Parinaz, Cashmore, Andrew, Marinsalda, Elena, Leach, Andrew G., Coxon, Christopher R., Fatokun, Amos A., Sexton, Darren W., Khan, Iftikhar, Downing, James, Pluchino, Stefano, Sivakumaran, Muttuswamy, Teixido, Meritxell, Ehtezazi, Touraj and Zouganelis, George
Abstract

This study investigated whether the inclusion of a matrix metalloproteinase-9 (MMP-9) responsive sequence in self-assembled peptide-based brain-targeting nanoparticles (NPs) would enhance the blood-brain barrier (BBB) penetration when MMP-9 levels are elevated both in the brain and blood circulation. Brain-targeting peptides were conjugated at the N-terminus to MMP-9-responsive peptides, and these were conjugated at the N-terminus to lipid moiety (cholesteryl chloroformate or palmitic acid). Two constructs did not have MMP-9-responsive peptides. NPs were characterised for size, charge, critical micelle concentration, toxicity, blood compatibility, neural cell uptake, release profiles, and in vitro BBB permeability simulating normal or elevated MMP-9 levels. The inclusion of MMP-9-sensitive sequences did not improve the release of a model drug in the presence of active MMP-9 from NPs compared to distilled water. 19F NMR studies suggested the burial of MMP-9-sensitive sequences inside the NPs making them inaccessible to MMP-9. Only cholesterol-GGGCKAPETALC (responsive to MMP-9) NPs showed <5% haemolysis, <1 pg/mL release of IL-1β at 500 μg/mL from THP1 cells, with 70.75 ± 5.78% of NPs crossing the BBB at 24 h in presence of active MMP-9. In conclusion, brain-targeting NPs showed higher transport across the BBB model when MMP-9 levels were elevated and the brain-targeting ligand was responsive to MMP-9.

KeywordsMMP-9; Brain Drug Delivery; Self-Assembled Nanoparticles; BBB Model; Peptides; Personalised Medicine
Year2020
JournalJournal of Pharmaceutical Science
Journal of Pharmaceutical Sciences
PublisherElsevier BV
ISSN0022-3549
Digital Object Identifier (DOI)https://doi.org/10.1016/j.xphs.2020.12.004
Web address (URL)http://hdl.handle.net/10545/625533
https://www.elsevier.com/tdm/userlicense/1.0/
hdl:10545/625533
Publication dates14 Dec 2020
Publication process dates
Deposited18 Jan 2021, 14:29
Accepted07 Dec 2020
ContributorsLiverpool John Moores University, University of Manchester, Heriot-Watt University, Edinburgh, University of Derby, University of Cambridge, Peterborough City Hospital, Edith Cavell Campus, Bretton Gate Peterborough and Barcelona Institute of Science and Technology, Barcelona, Spain
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