title: PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder.
abstract: 2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1(-/-)) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1(-/-) cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.
authors: Anna
authors: A
authors: Brown
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.
authors: Siddharth
authors: S
authors: Patel
authors: Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Carl
authors: C
authors: Ward
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.
authors: Anna
authors: A
authors: Lorenz
authors: Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Mauren
authors: M
authors: Ortiz
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.
authors: Allison
authors: A
authors: DuRoss
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.
authors: Fabian
authors: F
authors: Wieghardt
authors: Department of Biomedical Engineering, Collaborative Life Science Building, Oregon Health Science University, Portland OR, USA.
authors: Amanda
authors: A
authors: Esch
authors: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom.
authors: Elsje G
authors: EG
authors: Otten
authors: Department of Biomedical Engineering, Collaborative Life Science Building, Oregon Health Science University, Portland OR, USA.
authors: Laura M
authors: LM
authors: Heiser
authors: Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom.
authors: Viktor I
authors: VI
authors: Korolchuk
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.|Department of Radiation Medicine, School of Medicine, Oregon Health Science University, Portland OR, USA.
authors: Conroy
authors: C
authors: Sun
authors: Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Sovan
authors: S
authors: Sarkar
authors: Department of Pharmaceutical Sciences, College of Pharmacy, Collaborative Life Science Building, Oregon State University, Portland OR, USA.|Department of Biomedical Engineering, Collaborative Life Science Building, Oregon Health Science University, Portland OR, USA.
authors: Gaurav
authors: G
authors: Sahay
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins; D018345:Mice, Knockout; D008823:Micelles; D008954:Models, Biological; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy*; D010714:Phosphatidylethanolamines / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics; D012997:Solvents / Q000494:pharmacology*
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D047908:Intracellular Signaling Peptides and Proteins; D008823:Micelles; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D010714:Phosphatidylethanolamines; D011506:Proteins; D012997:Solvents; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; D002784:Cholesterol