title: Synthesis of 2-hydroxypropyl-β-cyclodextrin/pluronic-based polyrotaxanes via heterogeneous reaction as potential Niemann-Pick type C therapeutics.
abstract: Five polyrotaxanes were synthesized by threading 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) onto a variety of α,ω-ditriethylenediamino-N-carbamoyl-poly-(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic) triblock copolymers using a two-pot strategy under heterogeneous, nonaqueous conditions. The threaded HP-β-CD units were retained on the pseudopolyrotaxane precursors by end-capping the branched diamine termini with sodium 2,4,6-trinitrobenzene sulfonate. Inclusion of the Pluronic copolymers within the HP-β-CD cavities was more favorable in nonpolar solvents, such as diethyl ether and n-hexane, both of which gave better coverage ratios than polar solvents. (1)H NMR and MALDI-TOF were used to estimate the average molecular weights of the purified polyrotaxane products. A globular morphology of aggregated polyrotaxanes was observed by tapping-mode AFM imaging of dried samples. Treatment of Niemann-Pick C (NPC) type 2-deficient fibroblasts with the polyrotaxane derivatives produced substantial reductions in sterol accumulation, as seen by diminished filipin staining in these cells, suggesting that Pluronic-based polyrotaxanes may be promising vehicles for delivery of HP-β-CD to cells with abnormal cholesterol accumulation.
authors.affiliation: Department of Chemistry, Purdue University , 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Yawo A
authors.initials: YA
authors.lastname: Mondjinou
authors.forename: Leslie A
authors.initials: LA
authors.lastname: McCauliff
authors.forename: Aditya
authors.initials: A
authors.lastname: Kulkarni
authors.forename: Lake
authors.initials: L
authors.lastname: Paul
authors.forename: Seok-Hee
authors.initials: SH
authors.lastname: Hyun
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wu
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: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004705:Endocytosis; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005372:Filipin / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D052556:Niemann-Pick Disease, Type C / Q000188:drug therapy*; D020442:Poloxamer / Q000737:chemistry / Q000378:metabolism; D043862:Rotaxanes / Q000737:chemistry / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D003505:Cyclodextrins; D004337:Drug Carriers; D043862:Rotaxanes; D047392:beta-Cyclodextrins; C475673:polyrotaxane; D020442:Poloxamer; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D005372:Filipin; D002784:Cholesterol