Differential mode of cholesterol inclusion with 2-hydroxypropyl-cyclodextrins increases safety margin in treatment of Niemann-Pick disease type C.
Br J Pharmacol
; 178(13): 2727-2746, 2021 07.
Article
en En
| MEDLINE
| ID: mdl-33782944
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-ß-cyclodextrin (HP-ß-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-ß-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. EXPERIMENTALAPPROACH:
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-ß-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted. KEYRESULTS:
HP-γ-CD solely formed a 11 inclusion complex with cholesterol with an affinity similar to that of HP-ß-CD. In vitro, HP-γ-CD and HP-ß-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-ß-CD shifted to the highly soluble 21 complex whereas that of HP-γ-CD maintained solely the 11 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-ß-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-ß-CD in terms of ototoxicity and pulmonary toxicity.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Ciclodextrinas
/
Enfermedad de Niemann-Pick Tipo C
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón