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

• Published in: Journal of pharmaceutical sciences 2021-03, Vol.110 (3), p.1349-1364
• Main Authors: Islam, Yamir, Ehtezazi, Parinaz, Cashmore, Andrew, Marinsalda, Elena, Leach, Andrew G., Coxon, Christopher R., Fatokun, Amos A., Sexton, Darren W., Khan, Iftikhar, Zouganelis, Georgios, Downing, James, Pluchino, Stefano, Sivakumaran, Muttuswamy, Teixido, Meritxell, Ehtezazi, Touraj
• Format: Article
• Language: English
• Subjects: BBB model; Brain drug delivery; MMP-9; Peptides; Personalised medicine; Self-assembled nanoparticles
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2020.12.004

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