Tools
Tools
Islam, Y, Ehtezazi, P, Cashmore, A, Marinsalda, E, Leach, AG, Coxon, CR, Fatokun, AA, Sexton, DW, Khan, I, Zouganelis, GD, Downing, J, Pluchino, S, Sivakumaran, M, Teixido, M and Ehtezazi, T (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 Sciences, 110 (3). pp. 1349-1364. ISSN 0022-3549
|
Text
The Inclusion of a Matrix Metalloproteinase-9 Responsive Sequence in Self-assembled Peptide-based Brain-Targeting Nanoparticles.pdf - Accepted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (3MB) | Preview |
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | 1115 Pharmacology and Pharmaceutical Sciences |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | Elsevier |
| Date Deposited: | 03 Mar 2022 10:29 |
| Last Modified: | 03 Mar 2022 10:30 |
| DOI or ID number: | 10.1016/j.xphs.2020.12.004 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/14184 |
 |
View Item |