Niemann-Pick C1 affects the gene delivery efficacy of degradable polymeric nanoparticles.
Niemann-Pick C1 affects the gene delivery efficacy of degradable polymeric nanoparticles.
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DOI：
10.1021/nn501630h
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发表时间：
2014-08-26
期刊：
影响因子：
17.1
通讯作者：
Anderson, Daniel G.
中科院分区：
文献类型：
--
作者：
Eltoukhy, Ahmed A.;Sahay, Gaurav;Cunningham, James M.;Anderson, Daniel G.
尽管进行了大量的研究工作，但改进的纳米颗粒药物载体的合理设计仍然具有挑战性，部分原因是对纳米颗粒进入靶细胞和转运的决定因素的理解有限。最近的研究表明，尼曼-匹克C1（NPC 1），溶酶体膜蛋白，介导细胞中胆固醇的运输，参与内体逃逸和随后的感染引起的丝状病毒，它的缺乏促进脂质纳米粒子封装siRNA的保留和功效。在这里，我们报告NPC 1缺陷导致可降解阳离子基因递送聚合物聚（β-氨基酯）（PBAE）介导的内化和转染效率显著降低。PBAE利用胆固醇和动力蛋白依赖的内吞途径，这些被发现在NPC 1缺陷细胞中严重受损。相比之下，NPC 1的缺乏对聚乙烯亚胺或Lipofectamine 2000介导的DNA摄取的影响较小。引人注目的是，在中国仓鼠卵巢细胞中稳定过表达人NPC 1与PBAE增强的基因摄取（3倍）和转染（10倍）相关。这些发现揭示了NPC 1在影响纳米颗粒运输的内吞机制的调节中的作用。我们推测，深入了解进入和内体逃逸的位点可能会导致高效的纳米药物输送技术。
Despite intensive research effort, the rational design of improved nanoparticulate drug carriers remains challenging, in part due to a limited understanding of the determinants of nanoparticle entry and transport in target cells. Recent studies have shown that Niemann-Pick C1 (NPC1), the lysosome membrane protein that mediates trafficking of cholesterol in cells, is involved in the endosomal escape and subsequent infection caused by filoviruses, and that its absence promotes the retention and efficacy of lipid nanoparticles encapsulating siRNA. Here, we report that NPC1 deficiency results in dramatic reduction in internalization and transfection efficiency mediated by degradable cationic gene delivery polymers, poly(β-amino ester)s (PBAEs). PBAEs utilized cholesterol and dynamin-dependent endocytosis pathways, and these were found to be heavily compromised in NPC1-deficient cells. In contrast, the absence of NPC1 had minor effects on DNA uptake mediated by polyethylenimine or Lipofectamine 2000. Strikingly, stable overexpression of human NPC1 in chinese hamster ovary cells was associated with enhanced gene uptake (3-fold) and transfection (10-fold) by PBAEs. These findings reveal a role of NPC1 in the regulation of endocytic mechanisms affecting nanoparticle trafficking. We hypothesize that in-depth understanding sites of entry and endosomal escape may lead to highly efficient nanotechnologies for drug delivery.
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影响因子：
3.5
作者：
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通讯作者：
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通讯作者：
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作者：
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