Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease
Polyrotaxane-based systemic delivery of β-cyclodextrins for potentiating therapeutic efficacy in a mouse model of Niemann-Pick type C disease
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DOI：
10.1016/j.jconrel.2017.11.016
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发表时间：
2018-01-10
影响因子：
10.8
通讯作者：
Yui, Nobuhiko
中科院分区：
文献类型：
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作者：
Tamura, Atsushi;Yui, Nobuhiko
C型尼曼-匹克病（NPC）是一种以胆固醇在溶酶体中蓄积为特征的致死性代谢紊乱。虽然2-羟丙基β-环糊精（HP-β-CD）促进胆固醇排泄，延长NPC疾病动物模型的寿命，但它需要极高的剂量。我们开发了酸不稳定的基于β-CD的聚轮烷（PRX），其包含沿着用酸可裂解的终止分子封端的聚合物链缠绕的多个β-CD，用于增强β-CD在NPC疾病中的治疗功效。酸不稳定PRX在酸性溶酶体下解离并在溶酶体中释放螺纹β-CD，其在低于HP-β-CD的浓度下促进NPC疾病模型细胞中的胆固醇排泄。在本研究中，研究了PRX在NPC疾病小鼠模型中的治疗效果。每周给予PRX显著延长了小鼠的寿命并抑制了神经变性，即使在500 mg/kg的剂量下，该剂量明显低于先前报道的HP-β-CD剂量。组织胆固醇的详细分析显示，PRX治疗显著抑制NPC小鼠模型中胆固醇的组织积累，但不改变野生型小鼠中的胆固醇含量。因此，酸不稳定PRX是增强β-CD治疗NPC疾病的功效的有希望的候选物。
Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl beta-cyclodextrin (HP-beta-CD) promotes the excretion of cholesterol and prolongs the life span in animal models of NPC disease, it requires extremely high dose. We developed acid-labile beta-CD-based polyrotaxanes (PRXs) comprising multiple beta-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of beta-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded beta-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-beta-CD. In this study, the therapeutic effect of the PRXs in a mouse model of NPC disease was investigated. Weekly administration of the PRXs significantly prolonged the life span and suppressed neurodegeneration in mice, even at a dose of 500 mg/kg, a markedly lower dose than previously reported for HP-beta-CD. Detailed analysis of tissue cholesterol revealed that PRX treatment markedly suppressed the tissue accumulation of cholesterol in the NPC mouse model, but did not alter cholesterol content in wild-type mice. Acid-labile PRX is therefore a promising candidate for potentiating the efficacy of beta-CD in the treatment of NPC disease.