title: Rescue of mitochondrial function in parkin-mutant fibroblasts using drug loaded PMPC-PDPA polymersomes and tubular polymersomes.
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.
authors.affiliation: Biomedical Sciences, University of Sheffield, Firth Court, Western Bank, Sheffield S10 2TN, United Kingdom; SITraN, Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Yealland
authors.affiliation: Department of Chemistry, UCL, 20 Gordon Street, London WC1 H 0AJ, United Kingdom.
authors.forename: G
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: SITraN, Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, United Kingdom.
authors.forename: O
authors.initials: O
authors.lastname: Bandmann
authors.affiliation: SITraN, Neuroscience, University of Sheffield, 385a Glossop Road, Sheffield S10 2HQ, United Kingdom. Electronic address: H.Mortiboys@sheffield.ac.uk.
authors.forename: H
authors.initials: H
authors.lastname: Mortiboys
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured; D002793:Cholic Acids / Q000494:pharmacology*; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D053769:Nanocapsules / Q000008:administration & dosage* / Q000633:toxicity / Q000648:ultrastructure; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D011109:Polymethacrylic Acids / Q000494:pharmacology* / Q000633:toxicity; D014315:Triterpenes / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D000097245:Ursolic Acid
chemical_list: D000255:Adenosine Triphosphate; D002793:Cholic Acids; D053769:Nanocapsules; D010767:Phosphorylcholine; D011109:Polymethacrylic Acids; D014315:Triterpenes; D044767:Ubiquitin-Protein Ligases; D000097245:Ursolic Acid; C578682:poly(2-(methacryloyloxy)ethyl phosphorylcholine)-block-(2-(diisopropylamino)ethyl methacrylate); C111567:parkin protein; C007036:cholanic acid
keywords: Anisotropic nanoparticle; Mitochondria; PMPC-PDPA; Parkin; Parkinson’s disease; Polymersome