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10.1038/srep31750 http://scihub22266oqcxt.onion/10.1038/srep31750 C5004151!5004151 !27572704     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=27572704 &cmd=llinks): Failed to open stream: HTTP request failed! 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PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder |pdf=|usr=}}{{27572704 }} gab.com Text PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder JO: Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=27572704 #FOAvip 2-Hydroxy-propyl-?-cyclodextrin (HP?CD), 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 HP?CD 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 HP?CD, 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 HP?CD, 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. Twit Text FOAVip PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder ????Sci Rep http://www.kidney.de/pget.php?&tw=1&pmid=27572704 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=27572704 #FOAvip English Wikipedia <ref>{{Cite pmid|27572704 }}</ref> PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder #MMPMID27572704 Brown A ; Patel S ; Ward C ; Lorenz A ; Ortiz M ; DuRoss A ; Wieghardt F ; Esch A ; Otten EG ; Heiser LM ; Korolchuk VI ; Sun C ; Sarkar S ; Sahay G Sci Rep 2016[Aug]; 6 (ä): 31750 PMID27572704 show ga 2-Hydroxy-propyl-?-cyclodextrin (HP?CD), 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 HP?CD 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 HP?CD, 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 HP?CD, 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. |*Micelles [MESH] |2-Hydroxypropyl-beta-cyclodextrin/pharmacology [MESH] |Animals [MESH] |Cells, Cultured [MESH] |Cholesterol/*metabolism [MESH] |Drug Synergism [MESH] |Fibroblasts/drug effects [MESH] |Intracellular Signaling Peptides and Proteins [MESH] |Mice, Knockout [MESH] |Models, Biological [MESH] |Niemann-Pick C1 Protein [MESH] |Niemann-Pick Disease, Type C/*drug therapy [MESH] |Phosphatidylethanolamines/*pharmacology [MESH] |Polyethylene Glycols/*pharmacology [MESH] |Proteins/genetics [MESH]PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 (epmc).pdf DeepDyve Pubget Overpricing