Tools
Tools
Islam, Y, Khalid, A, Pluchino, S, Sivakumaran, M, Teixidò, M, Leach, AG, Fatokun, AA, Downing, J, Coxon, CR and Ehtezazi, T (2020) Development of Brain Targeting Peptide Based MMP-9 Inhibiting Nanoparticles for the Treatment of Brain Diseases with Elevated MMP-9 Activity. Journal of Pharmaceutical Sciences, 109 (10). pp. 3134-3144. ISSN 0022-3549
|
Text
Development of Brain Targeting Peptide Based MMP-9-Repository.docx.pdf - Accepted Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (1MB) | Preview |
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | 1115 Pharmacology and Pharmaceutical Sciences |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | Elsevier |
| Related URLs: | |
| Date Deposited: | 05 Aug 2020 09:56 |
| Last Modified: | 04 Sep 2021 06:51 |
| DOI or ID number: | 10.1016/j.xphs.2020.06.021 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/13448 |
 |
View Item |