Niemann-Pick type C (NPC) disease is a fatal metabolic disorder characterized by the lysosomal accumulation of cholesterol. Although 2-hydroxypropyl β-cyclodextrin (HP-β-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 β-CD-based polyrotaxanes (PRXs) comprising multiple β-CDs threaded along a polymer chain capped with acid-cleavable stopper molecules for potentiating therapeutic efficacy of β-CD in NPC disease. The acid-labile PRXs dissociate under the acidic lysosomes and release threaded β-CDs in lysosomes, which promotes cholesterol excretion in NPC disease model cells at lower concentration than HP-β-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-β-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 β-CD in the treatment of NPC disease.

Niemann-Pick C型（NPC）疾病是一种致命的代谢性疾病，其特征是胆固醇的溶酶体积累。尽管2-羟丙基β-环糊精（HP-β-CD）在NPC疾病的动物模型中可促进胆固醇排泄并延长寿命，但它需要极高的剂量。我们开发了对酸不稳定的基于β-CD的聚轮烷（PRX），其包含多个沿着沿酸可裂解的阻滞剂分子封端的聚合物链穿线的β-CD，以增强β-CD在NPC疾病中的治疗功效。酸不稳定的PRX在酸性溶酶体下解离并释放溶酶体中的带螺纹的β-CD，从而以低于HP-β-CD的浓度促进NPC疾病模型细胞中的胆固醇排泄。在这项研究中，研究了PRXs在NPC疾病小鼠模型中的治疗作用。每周施用PRX可以显着延长小鼠的寿命并抑制神经变性，即使以500 mg / kg的剂量使用，也比以前报道的HP-β-CD剂量要低得多。对组织胆固醇的详细分析显示，PRX处理可显着抑制NPC小鼠模型中胆固醇的组织蓄积，但不会改变野生型小鼠中的胆固醇含量。因此，酸不稳定的PRX是增强β-CD在治疗NPC疾病中的功效的有前途的候选者。但并未改变野生型小鼠的胆固醇含量。因此，酸不稳定的PRX是增强β-CD在治疗NPC疾病中的功效的有前途的候选者。但并未改变野生型小鼠的胆固醇含量。因此，酸不稳定的PRX是增强β-CD在治疗NPC疾病中的功效的有前途的候选者。