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

Yamir Islam, Parinaz Ehtezazi, Andrew Cashmore, Elena Marinsalda, Andrew G. Leach, Christopher R. Coxon, Amos A. Fatokun, Darren W. Sexton, Iftikhar Khan, Georgios Zouganelis, James Downing, Stefano Pluchino, Muttuswamy Sivakumaran, Meritxell Teixido, Touraj Ehtezazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)1349-1364
Number of pages16
JournalJournal of Pharmaceutical Sciences
Volume110
Issue number3
Early online date15 Dec 2020
DOIs
Publication statusE-pub ahead of print - 15 Dec 2020

Keywords / Materials (for Non-textual outputs)

  • BBB model
  • Brain drug delivery
  • MMP-9
  • Peptides
  • Personalised medicine
  • Self-assembled nanoparticles

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