Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann?Pick disease type C without hearing loss
Fine-tuned cholesterol solubilizer, mono-6-O-α-D-maltosyl-γ-cyclodextrin, ameliorates experimental Niemann?Pick disease type C without hearing loss
复制标题
微调胆固醇增溶剂，单-6-O-α-D-麦芽糖基-γ-环糊精，改善实验性尼曼？皮克病 C 型但无听力损失
DOI：
10.1016/j.biopha.2022.113698
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发表时间：
2022
影响因子：
7.5
通讯作者：
Tachi
中科院分区：
文献类型：
--
作者：
Yamada Y;Miwa T;Nakashima M;Shirakawa A;Ishii A;Namba N;Kondo Y;Takeo T;Nakagata N;Motoyama K;Higashi T;Arima H;Kurauchi Y;Seki T;Katsuki H;Okada Y;Ichikawa A;Higaki K;Hayashi K;Minami K;Yoshikawa N;Ikeda R;Ishikawa Y;Kajii T;Tachi
C型尼曼-匹克病（NPC）是一种细胞内胆固醇异常转运导致神经退行性变和肝脾肿大的致死性疾病。具有不同程度2-羟丙基取代度的环状七糖，2-羟丙基-β-环糊精（HP-β-CD），作为强胆固醇增溶剂，正在临床试验中研究用于治疗这种疾病，但其物理化学性质和耳毒性仍然令人担忧。本研究评价了单6-O-α-麦芽糖基-γ-CD（mono-6-O-α-maltosyl-γ-CD，G2-γ-CD）治疗鼻咽癌的潜力。我们发现G2-γ-CD改善了NPC模型小鼠的表现，并且在小鼠中显示出比HP-β-CD更低的耳毒性。为了研究这些CD差异性耳毒性背后的分子作用机制，我们进行了胆固醇溶解度分析，质子核磁共振光谱和分子建模，并估计G2-γ-CD的胆固醇包合模式仅保持1：1包合复合物，而HP-β-CD在更高浓度下转变为高度可溶的2：1包合复合物。我们预测协会的CD与胆固醇与疾病衰减的档案和听觉细胞毒性使用特定的细胞模型的这些差异复合。G2-γ-CD具有良好的生物相容性和物理化学性质，可作为一种精细调节的胆固醇增溶剂用于鼻咽癌的治疗。
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.