PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder.
PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder.
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DOI：
10.1038/srep31750
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发表时间：
2016-08-30
影响因子：
4.6
通讯作者：
Sahay G
中科院分区：
文献类型：
--
作者：
Brown A;Patel S;Ward C;Lorenz A;Ortiz M;DuRoss A;Wieghardt F;Esch A;Otten EG;Heiser LM;Korolchuk VI;Sun C;Sarkar S;Sahay G
2-羟丙基-β-环糊精（HPβCD）是一种胆固醇清除剂，目前正在进行治疗尼曼匹克C-1型（NPC 1）的2b/3期临床试验，NPC 1是一种致命的神经退行性疾病，源于胆固醇在内/溶酶体中的异常蓄积。不幸的是，预防进行性神经变性所需的极高剂量的HPβCD会加剧耳毒性、肺毒性和基于自噬的细胞缺陷。我们提出了意想不到的证据，即聚乙二醇（PEG）-脂质缀合物能够从Npc 1突变体（Npc 1 −/−）细胞的内/溶酶体中清除胆固醇。在本文中，我们表明，在临界胶束浓度以上形成12 nm胶束的二硬脂酰-磷脂酰乙醇胺-PEG（DSPE-PEG）在Npc 1-/-细胞中富含胆固醇的晚期内体内大量积累。这可能导致胆固醇溶解和从溶酶体渗漏。高通量筛选显示，DSPE-PEG与HPβCD组合协同作用以流出胆固醇，而不显著加重自噬缺陷。这些众所周知的赋形剂可用作治疗NPC 1病症的混合物。将DSPE-PEG胶束中的PEG链长从350 Da增加到30 kDa，或增加与HPβCD包装的脂质体阵列中的DSPE-PEG含量，可改善胆固醇的排出，而能够形成胶束的Pluronic嵌段共聚物在高浓度下显示出轻微的影响。我们假设基于PEG-脂质的纳米载体可以作为有效治疗溶酶体贮积症的生物活性药物递送系统。
2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.
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