Niemann-Pick Type C disease (NPC) is a panethnic, heterogeneous, and extremely rare metabolic disorder characterized by a disruption of normal cholesterol trafficking within the cells of the body. There are no FDA approved treatments currently available for NPC patients. Recently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) has shown efficacy as an NPC therapeutic by increasing overall lifetime of NPC mice, delaying neurodegeneration, and decreasing the total cholesterol burden within a variety of organs. Although promising, HP-β-CD treatment is hampered by poor CD bioavailability and pharmacokinetic profile after systemic injection, with large percentages of the injected dose rapidly lost through renal filtration. To address these shortcomings, we sought to design a family of high molecular weight, HP-β-CD pro-drug polyrotaxane (PR) delivery vehicles, capable of increasing the efficacy of a given injected dose by improving residence time and bioavailability. PR can effectively diminish the cholesterol pool within the liver, spleen, and kidney at molar concentrations that are 10-to-100-fold lower than monomeric HP-β-CD. In addition to this proof-of-concept, use of PR scaffolds with differing physiochemical properties reveal structure-activity relationships in which PR characteristics were found to play both decisive and subtle roles in therapeutic efficacy toward unesterified cholesterol clearance. PR threading and polymer core characteristics appear to greatly influence therapeutic efficacy, with increased threading and hydrophobicity producing increased efficacy. Inclusion of negatively-charged β-CD derivatives increases solubility without impacting their cholesterol reduction capacity. In addition, PR scaffolds exhibit absorption, pharmacokinetics, and biodistribution patterns that are significantly altered from monomeric HP-β-CD. These findings suggest that PR scaffolds hold great promise as potential treatments for visceral disease in NPC patients.

Structure-Activity relationships on the <i>in vivo </i>therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin:pluronic polyrotaxanes in Niemann-Pick type C disease

253rd National Meeting (2017)

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Structure-Activity relationships on the in vivo therapeutic efficacy of 2-hydroxypropyl-β-cyclodextrin:pluronic polyrotaxanes in Niemann-Pick type C disease