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.
Highlights
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, the prevalence of which is expected to increase in the coming years [1]
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 Adenosine Triphosphate (ATP) levels, resembling those resulting from treatment with nascent UA and UCA formulated in 0.1% Dimethyl Sulfoxide (DMSO), as used in the original drug screen
Summary
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, the prevalence of which is expected to increase in the coming years [1]. Mitochondrial dysfunction has been observed in familial and sporadic forms of PD [2,3]. In particular we and others have described mitochondrial dysfunction in fibroblasts derived from patients with parkin mutations, the most common identifiable cause of early onset, familial PD [4,5]. We demonstrated that UCA and UDCA produced therapeutic effects in parkin knock-down mouse cortical neurons, and fibroblasts from patients with G2019S LRRK2 mutations, the most common known cause of familial PD and a gene implicated in sporadic PD [7,8]. Evidence elsewhere has demonstrated neuroprotective effects of UA [9,10] These compounds have therapeutic potential in at least some forms of PD
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