Several lines of evidence suggest that �-cyclodextrin (�-CD) derivatives initiate the efflux of accumulated, unesterified cholesterol from the late endosomal/lysosomal compartments in Niemann Pick C (NPC) disease models. Unfortunately, repeated injections or continuous infusions of current �-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 �-CD polyrotaxanes has been developed using biocompatible PEG-PPG-PEG triblock copolymers. These compounds carry multiple copies of �-CD as shown by 1H NMR, 2D nuclear overhouser effect spectroscopy, gel permeation chromatography/multi-angle light scattering, analytical ultracentrifugation analysis, Matrix Assisted Laser Desorption/Ionization Mass Spectrometry and diffusion-ordered spectroscopy. Analysis of free �-cyclodextrin contamination in the compounds were made by reverse phase high pressure liquid chromatography. Dethreading kinetics were studied by reverse phase high pressure liquid chromatography, UV/Vis, and 1H 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 �-CD alone.

Synthesis, characterization, and evaluation of pluronic-based �-cyclodextrin polyrotaxanes for mobilization of accumulated cholesterol from Niemann-Pick type C fibroblasts

246th National Meeting (2013)

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