Differential mode of cholesterol inclusion with 2‐hydroxypropyl‐cyclodextrins increases safety margin in treatment of Niemann‐Pick disease type C

Abstract

Background and Purpose Niemann‐Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2‐hydroxypropyl‐γ‐cyclodextrin (HP‐γ‐CD), a cyclic octasaccharide with a larger cavity than HP‐β‐CD, as a candidate drug to treat NPC. However, the molecular target of HP‐γ‐CD with respect to NPC and its potential for clinical application are still unclear. Experimental Approach We investigated the mode of interaction between HP‐γ‐CD and cholesterol by phase‐solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP‐γ‐CD compared with HP‐β‐CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted. Key Results HP‐γ‐CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP‐β‐CD. In vitro, HP‐γ‐CD and HP‐β‐CD amelioration of NPC‐related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP‐β‐CD shifted to the highly soluble 2:1 complex whereas that of HP‐γ‐CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP‐γ‐CD conferred it with significantly reduced toxicity compared with HP‐β‐CD, but equal efficacy in treating a mouse model of NPC. Conclusions and Implications HP‐γ‐CD can serve as a fine‐tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP‐β‐CD in terms of ototoxicity and pulmonary toxicity.

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann–Pick disease type C treatment

“…[11][12][13][14][15][16][17] We previously identified that 2-hydroxypropyl-γ-CD (HP-γ-CD), a γ-CD derivative with a larger cavity diameter than HP-β-CD, fine-tunes UC solubilization by forming a distinct UC inclusion mode from HP-β-CD and restores cholesterol balance in cells and murine models of NPC more safely than HP-β-CD. [18][19][20] We further reported the safety advantages and favourable physicochemical properties of chemically pure, mono-branched CD derivatives with α-1,6-linked maltosyl derivatives over HP-β-CD in NPC experimental models. [21][22][23] In another approach, we synthesized several drug delivery system-based derivatives targeting affected organs to improve the bioavailability of highly excretable CDs.…”

Searching, Structural Determination, and Diagnostic Performance Evaluation of Biomarker Molecules for Niemann–Pick Disease Type C Using Liquid Chromatography/Tandem Mass Spectrometry

“… 39 , 40 ) At present, a variety of agents are being investigated for improved efficacy in the treatment of NPC. 41 , 42 )…”

Terminal Structure of Triethylene Glycol-Tethered Chains on β-Cyclodextrin-Threaded Polyrotaxanes Dominates Temperature Responsivity and Biointeractions

“…A critical property of β-CDs in pharmaceutical and biomedical applications is the formation of inclusion complexes with a variety of guest molecules, including small molecular drugs and cholesterol. , The pharmacological applications of β-CDs have recently gained increasing attention due to their potential therapeutic effect on various metabolic diseases such as Niemann-pick type C disease, − Alzheimer’s disease, atherosclerosis, and diabetic kidney disease . β-CDs are believed to interact with intracellular cholesterol and improve cholesterol metabolic abnormalities, resulting in the proclaimed therapeutic effects. − Due to high water solubility, low toxicity, and excellent cholesterol inclusion ability, 2-hydroxypropyl β-CD (HP-β-CD) has been widely utilized in these studies − ,− However, the effective dose of HP-β-CD for the treatment of metabolic diseases is typically quite high (ca. 4000 mg/kg), owing to its rapid renal clearance and low tissue accumulation. , Such a high dosage of HP-β-CD has been reported to cause tissue injury and ototoxicity. − …”