Yealland, G., Battaglia, G., Bandmann, O. orcid.org/0000-0003-3149-0252 et al. (1 more author) (2016) Rescue of mitochondrial function in parkin-mutant Fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes. Neuroscience Letters. ISSN 0304-3940
Abstract
Mutations in parkin cause autosomal recessive Parkinsonism and mitochondrial defects. A recent drug screen identified a class of steroid-like hydrophobic compounds able to rescue mitochondrial function in parkin-mutant fibroblasts. Whilst these possess therapeutic potential, the size and high hydrophobicity of some may limit their ability to penetrate the blood-brain barrier from systemic circulation, something that could be improved by novel drug formulations. In the present study, the steroid-like compounds Ursolic Acid (UA) and Ursocholanic Acid (UCA) were successfully encapsulated within nanoscopic polymersomes formed by poly(2-(methacryloyloxy)ethyl phosphorylcholine)–poly(2-di-isopropylamino)ethyl methacrylate) (PMPC-PDPA) and separated into spherical and tubular morphologies to assess the effects of nanoparticle mediated delivery on drug efficacy. Following incubation with either morphology, parkin-mutant fibroblasts demonstrated time and concentration dependent increases in intracellular ATP levels, resembling those resulting from treatment with nascent UA and UCA formulated in 0.1% DMSO, as used in the original drug screen. Empty PMPC-PDPA polymersomes did not alter physiological measures related to mitochondrial function or induce cytotoxicity. In combination with other techniques such as ligand functionalisation, PMPC-PDPA nanoparticles of well-defined morphology may prove a promising platform for tailoring the pharmacokinetic profile and organ specific bio-distribution of highly hydrophobic compounds.
Metadata
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Copyright, Publisher and Additional Information: | © 2016 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). | ||||
Keywords: | Parkinson’s disease; Mitochondria; Parkin; Polymersome; Anisotropic nanoparticle; PMPC-PDPA | ||||
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
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Funding Information: |
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 27 Jul 2016 12:51 | ||||
Last Modified: | 27 Jul 2016 12:51 | ||||
Published Version: | http://dx.doi.org/10.1016/j.neulet.2016.06.065 | ||||
Status: | Published | ||||
Publisher: | Elsevier | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1016/j.neulet.2016.06.065 |