Cyclodextrins (CDs), the therapeutic candidates for Niemann–Pick disease type C (NPC), function dually as a shuttle and sink that catalytically enhance the cellular cholesterol flux. The shuttle/sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD–cholesterol complexation.
In this study, 2-hydroxypropyl-α-CD (HP-α-CD, DS: 3.3−5), HP-β-CD (DS: 4.4−4.6), 2-hydroxybutyl-β CD (HB-β-CD, DS: 4.1), HP-γ-CD (DS: 4.6) and 2-hydroxybutyl-γ-CD (HB-γ-CD, DS: 3.5), mono-6-O-α-glucosyl-β-CD (G1-β-CD, DS: 1), mono-6-O-α-maltosyl-β-CD (G2-β-CD, DS: 1), mono-6-O-α-glucosyl-γ-CD (G1-γ-CD, DS: 1) and mono-6-O-α-maltosyl-γ-CD (G2-γ-CD, DS: 1) were compared concerning their solubilizing effect on unesterified cholesterol and cytotoxicity.
The authors found that the ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking and with their cytotoxicity associated with cellular UC removal, respectively, in a cell culture model of NPC, suggesting that these complexes predominantly serve as a shuttle and sink, respectively. It was also identified that CD derivatives with a higher ability to form a 1:1 complex were more effective in extending lifespan in a mouse model of NPC when administered intracerebroventricularly. Notably, subcutaneous injection of γ-CD derivatives to mice caused less systemic and auditory toxicity compared with β-CD derivatives, whereas intratracerebroventricular administration induced hearing loss for all CD derivatives tested, except for a representative α-CD derivative that had no therapeutic effectiveness probably because of negligible
Yamada Y, Fukaura-Nishizawa M, Nishiyama A, Ishii A, Kawata T, Shirakawa A, Tanaka M, Kondo Y, Takeo T, Nakagata N, Miwa T, Takeda H, Orita Y, Motoyama K, Higashi T, Arima H, Seki T, Kurauchi Y, Katsuki H, Higaki K, Minami K, Yoshikawa N, Ikeda R, Matsuo M, Irie T, Ishitsuka Y. Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann-Pick disease type C treatment. Clin Transl Med. 2023 Aug;13(8):e1350. doi: 10.1002/ctm2.1350.