Development of Brain Targeting Peptide Based MMP-9 Inhibiting Nanoparticles for the Treatment of Brain Diseases with Elevated MMP-9 Activity

Yamir Islam, Khalid Aneesa, Stefano Pluchino, Muttuswamy Sivakumaran, Meritxell Teixidò, Andrew Leach, Amos A. Fatokun, James Downing, Christopher Coxon, Touraj Ehtezazi

Research output: Contribution to journalArticle

Abstract

Latent and active levels of cerebral matrix metalloproteinase 9 (MMP-9) are elevated in neurological diseases and brain injuries, contributing to neurological damage and poor clinical outcomes. This study aimed developing peptide-based nanoparticles with ability to cross the blood-brain-barrier (BBB) and inhibit MMP-9. Three amphiphilic peptides were synthesised containing brain-targeting ligands (HAIYPRH or CKAPETALC) conjugated with MMP-9 inhibiting peptide (CTTHWGFTLC) linked by glycine (spacer) at the N-terminus, and the peptide sequences were conjugated at the N- terminus to cholesterol. 19F-NMR assay was developed to measure MMP-9 inhibition. Cell toxicity was evaluated by the LDH assay, and dialysis studies were conducted with/without fetal bovine serum. An in vitro model was employed to evaluate the ability of nanoparticles crossing the BBB. The amphiphilic peptide (Cholesterol-GGGCTTHWGFTLCHAIYPRH) formed nanoparticles (average size of 202.8 nm) with ability to cross the BBB model. MMP-9 inhibiting nanoparticles were non-toxic to cells, and reduced MMP-9 activity from kobs of 4.5×10-6s-1 to complete inhibition. Dialysis studies showed that nanoparticles did not disassemble by extreme dilution (40 folds), but gradually hydrolysed by serum enzymes. In conclusion, the MMP-9 inhibiting nanoparticles reduced the activity of MMP-9, with acceptable serum stability, minimal cell toxicity and ability to cross the in vitro BBB model.
Original languageEnglish
Pages (from-to)3134-3144
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume109
Issue number10
Early online date2 Jul 2020
DOIs
Publication statusPublished - Oct 2020

Keywords

  • Blood-brain-barrier
  • Brain drug delivery
  • MMP-9 inhibitor
  • Nanoparticles

ASJC Scopus subject areas

  • Pharmaceutical Science

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