Characterization of hydroxypropyl-betacyclodextrins used in the treatment of Niemann-Pick Disease type C1
Characterization of hydroxypropyl-betacyclodextrins used in the treatment of Niemann-Pick Disease type C1
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DOI：
10.1371/journal.pone.0175478
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发表时间：
2017-04-17
期刊：
影响因子：
3.7
通讯作者：
Darling, Allan J.
中科院分区：
文献类型：
--
作者：
Yergey, Alfred L.;Blank, Paul S.;Darling, Allan J.
2-羟丙基-β-环糊精（HP β CD）作为治疗罕见的常染色体隐性遗传、神经退行性溶酶体贮积症C1型尼曼-皮克病（NPC 1）的潜在治疗干预措施，最近受到关注。值得注意的是，HP β CD制剂不是由单一分子物质组成，而是环糊精环羟丙基化程度不同的物质的复杂混合物。取代度是复杂混合物的一个关键方面，因为它影响与其他分子的结合，从而可能调节生物效应。VTS-270（Kleptose HPB）和Trappsol（R）Cyclo（TM）是正在研究中的HP β CD产品，可作为NPC 1的新型治疗药物。本工作的目的是比较这两种不同的产品，分析的基础上的离子分布和丰度曲线，使用质谱法作为评估产品之间的关键分子差异的手段。该方法采用电喷雾电离和分析与线性低场离子迁移率四极杆飞行时间仪器。我们观察到两种产品的羟丙基数量（取代度）存在显著差异，Trappsol Cyclo中的羟丙基数量大于VTS-270。两种样品的主要离子均为铵加合物。每个主要离子的同位素簇显示双电荷的铵加合物的同二聚体。此外，两种产物均显示来自质子和铵加合的双电荷同二聚体。也存在双电荷异二聚体，但在Trappsol Cyclo中比在VTS-270中更强烈。根据VTS-270和Trappsol Cyclo之间在取代度、复杂混合物的组成和指纹图谱以及杂质谱方面观察到的分析差异，不能认为这些产品相同;目前尚不清楚这些差异的潜在生物学和临床意义。
2-Hydroxypropyl-beta-cyclodextrin (HP beta CD) has gained recent attention as a potential therapeutic intervention in the treatment of the rare autosomal-recessive, neurodegenerative lysosomal storage disorder Niemann-Pick Disease Type C1 (NPC1). Notably, HP beta CD formulations are not comprised of a single molecular species, but instead are complex mixtures of species with differing degrees of hydroxypropylation of the cyclodextrin ring. The degree of substitution is a critical aspect of the complex mixture as it influences binding to other molecules and thus could potentially modulate biological effects. VTS-270 (Kleptose HPB) and Trappsol (R) Cyclo (TM) are HP beta CD products under investigation as novel treatments for NPC1. The purpose of the present work is to compare these two different products; analyses were based on ion distribution and abundance profiles using mass spectrometry methodology as a means for assessing key molecular distinctions between products. The method incorporated electrospray ionization and analysis with a linear low-field ion mobility quadrupole time-of-flight instrument. We observed that the number of hydroxypropyl groups (the degrees of substitution) are substantially different between the two products and greater in Trappsol Cyclo than in VTS-270. The principal ions of both samples are ammonium adducts. Isotope clusters for each of the major ions show doubly charged homodimers of the ammonium adducts. In addition, both products show doubly charged homodimers from adduction of both a proton and ammonium. Doubly charged heterodimers are also present, but are more intense in Trappsol Cyclo than in VTS-270. Based on the analytical differences observed between VTS-270 and Trappsol Cyclo with respect to the degree of substitution, the composition and fingerprint of the complex mixture, and the impurity profiles, these products cannot be considered to be the same; the potential biological and clinical implications of these differences are not presently known.