title: Synthesis, characterization, and evaluation of pluronic-based β-cyclodextrin polyrotaxanes for mobilization of accumulated cholesterol from Niemann-Pick type C fibroblasts.
abstract: Several lines of evidence suggest that β-cyclodextrin (β-CD) derivatives initiate the efflux of accumulated, unesterified cholesterol from the late endosomal/lysosomal compartment in Niemann Pick C (NPC) disease models. Unfortunately, repeated injections or continuous infusions of current β-CD therapies are required to sustain suppression of symptoms and prolong life. In an effort to make CD treatment a more viable option by boosting efficacy and improving pharmacokinetics, a library of Pluronic surfactant-based β-CD polyrotaxanes has been developed using biocompatible poly(ethylene glycol) (PEG)-polypropylene glycol (PPG)-PEG triblock copolymers. These compounds carry multiple copies of β-CD as shown by (1)H NMR, 2D nuclear Overhouser effect spectroscopy, gel permeation chromatography/multiangle light scattering, analytical ultracentrifugation analysis, matrix assisted laser desorption/ionization mass spectrometry, and diffusion-ordered spectroscopy. Analyses of free β-cyclodextrin contamination in the compounds were made by reverse phase high pressure liquid chromatography and hydrophilic interaction liquid chromatography. Dethreading kinetics were studied by reverse phase high pressure liquid chromatography, UV/vis, and (1)H NMR analysis. Filipin staining studies using npc2(-/-) fibroblasts show significant reversal of cholesterol accumulation after treatment with polyrotaxane compounds. The rate and efficacy of reversal is similar to that achieved by equivalent amounts of monomeric β-CD alone.
authors.affiliation: Department of Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47904, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Collins
authors.forename: Leslie A
authors.initials: LA
authors.lastname: McCauliff
authors.forename: Seok-Hee
authors.initials: SH
authors.lastname: Hyun
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lake N
authors.initials: LN
authors.lastname: Paul
authors.forename: Aditya
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Klaus
authors.initials: K
authors.lastname: Zick
authors.forename: Mary
authors.initials: M
authors.lastname: Wirth
authors.forename: Judith
authors.initials: J
authors.lastname: Storch
authors.forename: David H
authors.initials: DH
authors.lastname: Thompson
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003505:Cyclodextrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D015394:Molecular Structure; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020442:Poloxamer / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043862:Rotaxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D003505:Cyclodextrins; D006023:Glycoproteins; C104585:NPC2 protein, human; D043862:Rotaxanes; D033921:Vesicular Transport Proteins; C475673:polyrotaxane; D020442:Poloxamer; D002784:Cholesterol
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