Biomedicine & Pharmacotherapy (Nov 2022)
Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann–Pick disease type C without hearing loss
- Yusei Yamada,
- Toru Miwa,
- Masaki Nakashima,
- Aina Shirakawa,
- Akira Ishii,
- Nanami Namba,
- Yuki Kondo,
- Toru Takeo,
- Naomi Nakagata,
- Keiichi Motoyama,
- Taishi Higashi,
- Hidetoshi Arima,
- Yuki Kurauchi,
- Takahiro Seki,
- Hiroshi Katsuki,
- Yasuyo Okada,
- Atsushi Ichikawa,
- Katsumi Higaki,
- Ken Hayashi,
- Kentaro Minami,
- Naoki Yoshikawa,
- Ryuji Ikeda,
- Yoshihide Ishikawa,
- Tomohito Kajii,
- Kyoko Tachii,
- Hiroki Takeda,
- Yorihisa Orita,
- Muneaki Matsuo,
- Tetsumi Irie,
- Yoichi Ishitsuka
Affiliations
- Yusei Yamada
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan; Corresponding author at: Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan.
- Toru Miwa
- Department of Otolaryngology-Head and Neck Surgery, Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgi-machi, Kita-ku, Osaka 530-8480, Japan
- Masaki Nakashima
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Aina Shirakawa
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Akira Ishii
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Nanami Namba
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Yuki Kondo
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Toru Takeo
- Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Naomi Nakagata
- Division of Reproductive Biotechnology and Innovation, Center for Animal Resources and Development (CARD), Institute of Resource Development and Analysis, Kumamoto University, 2–2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Keiichi Motoyama
- Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Taishi Higashi
- Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Hidetoshi Arima
- Laboratory of Evidence-Based Pharmacotherapy, Daiichi University of Pharmacy, 22-1 Tamagawa-machi, Minami-ku, Fukuoka 815-8511, Japan
- Yuki Kurauchi
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Takahiro Seki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Hiroshi Katsuki
- Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Yasuyo Okada
- Institute Biosciences, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
- Atsushi Ichikawa
- Institute Biosciences, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68 Koshien Kyuban-cho, Nishinomiya 663-8179, Japan
- Katsumi Higaki
- Research Initiative Center, Organization for Research Initiative and Promotion, Tottori University, 86 Nishi-cho, Yonago 683-8503, Japan
- Ken Hayashi
- Kawagoe Otology Institute, 103, Wakitamachi, Kawagoe-shi, Saitama 350-1122, Japan
- Kentaro Minami
- Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan
- Naoki Yoshikawa
- Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan
- Ryuji Ikeda
- Department of Pharmacy, University of Miyazaki Hospital, 5200 Kihara, Kiyotake-cho, Miyazaki 889-1692, Japan
- Yoshihide Ishikawa
- Department of Otolaryngology-Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Tomohito Kajii
- Department of Otolaryngology-Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Kyoko Tachii
- Department of Otolaryngology-Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Hiroki Takeda
- Department of Otolaryngology-Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Yorihisa Orita
- Department of Otolaryngology-Head and Neck Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan
- Muneaki Matsuo
- Department of Pediatrics, Faculty of Medicine, Saga University, 5-1-1, Nabeshima, Saga 849-8501, Japan
- Tetsumi Irie
- Department of Pharmaceutical Packaging Technology, Faculty of Life Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan
- Yoichi Ishitsuka
- Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan; Corresponding author.
- Journal volume & issue
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Vol. 155
p. 113698
Abstract
Niemann–Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application.
