Islam, Y (2021) NOVEL ENZYME-RESPONSIVE SELF ASSEMBLED PEPTIDE NANOCARRIERS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES. Doctoral thesis, Liverpool John Moores University.

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Abstract

With an estimated worldwide cost over $1 trillion just for dementia, diseases of the central nervous system pose a major problem to health and healthcare systems, with significant socio-economic implications for sufferers and society at large. In the last two decades, numerous strategies and technologies have been developed and adapted to achieve drug penetration into the brain, evolving alongside our understanding of the physiological barriers between the brain and surrounding tissues. The blood brain barrier (BBB) has been described as the major barrier for drug delivery to the brain (1). In this project, novel enzyme-responsive self-assembled peptide nanoparticles were developed for drug delivery to the brain. An enzyme, matrix metalloproteinase (MMP)-9, is crucial in the pathogenesis of neurodegenerative diseases has been targeted for our studies due to it’s overexpression in neurodegenerative diseases and also due to it’s function as a protease, allowing selective release of drug cargo in the brain of ND patients. Firstly, state of the art statistical and molecular modelling was used to predict the best substrate for MMP 9 by assigning a Y-score. These predictions were tested by employing novel fluorine (19F) NMR spectroscopy. Novel MMP-9 sequences were identified, especially TY-26, that are better than those in previously reported studies. Secondly, novel enzyme-responsive self assembled peptide nanoparticles were successfully synthesized with different combinations of MMP-9 sensitive and brain-targeting ligands. Most of the formulations self-assembled without sonication to form nanoparticles of 41-200 nm diameter with a zeta potential/ surface charge of 2-48 mV. The critical micelle concentration for all the self- assembled peptide nanoparticles calculated were around 7-110 mg/L. The encapsulation capacity ranged from 40-80%. TY-28, TY-39 and TY-44 were among the highest encapsulation capacity nano formulations. Nanoparticles formulations were found to be MMP-9 sensitive and all formulations exhibited different release patterns of a model drug in the presence of external xvii stimuli. Novel enzyme-responsive self-assembled peptide nanoparticles were found to be least cytotoxic at lower concentration, however at higher concentration they were found to be cytotoxic, showing a range of cell viabilities. In vitro uptake of enzyme-responsive self-assembled peptide nanoparticles was confirmed by confocal microscopy and flow cytometry. Enzyme-responsive self-assembled peptide nanoparticles showed up to 40-70% permeability when investigated by in vitro hCMEC/D3 blood-brain barrier model in healthy (50 ng) and diseased (100 ng) conditions. In vivo studies suggested that the enzyme-responsive self-assembled peptide nanoparticles managed to get into the brain of mice. Although in full body scans, no significant signal was observed, ex vivo experiments showed that enzyme-responsive self-assembled nanoparticles managed to permeate into the brain. These enzyme-responsive self-assembled peptide nanoparticles can be used to deliver drug molecules such as siRNA into brain.

Item Type:	Thesis (Doctoral)
Uncontrolled Keywords:	Blood brain barrier (BBB); NPs brain drug delivery; Self-assembly; Peptide NPs; Enzyme-responsive NPs; MMP-9 sensitive NPs; Brain targeting NPs; Personalised medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RM Therapeutics. Pharmacology R Medicine > RT Nursing
Divisions:	Pharmacy & Biomolecular Sciences
Date Deposited:	14 Apr 2021 09:42
Last Modified:	01 May 2023 00:50
DOI or ID number:	10.24377/LJMU.t.00014777
Supervisors:	Ehetezazi, T, Leach, A and Coxon, C
URI:	https://researchonline.ljmu.ac.uk/id/eprint/14777

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