Hypoxia-targeted siRNA delivery.
Hypoxia-targeted siRNA delivery.
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DOI：
10.1002/anie.201308368
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发表时间：
2014-03-24
影响因子：
16.6
通讯作者：
Torchilin, V P
中科院分区：
文献类型：
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作者：
Perche, F;Biswas, S;Wang, T;Zhu, L;Torchilin, V P
血管系统的改变和由此产生的混乱的肿瘤血流导致在快速生长的肿瘤中出现氧分压梯度和急性缺氧(小于1.4 %氧)的区域。1由于其在肿瘤发生和治疗抵抗中的作用，缺氧是癌症治疗中的一个问题。1， 2实体瘤中治疗药物输送不足被认为是抵抗治疗的原因之一。1， 3这导致了低氧显像剂的发展。在这里，我们展示了第一个使用纳米载体来诱导缺氧诱导的siRNA摄取和沉默的例子，该纳米载体由聚乙二醇 2000、偶氮苯、聚乙烯亚胺 (1.8kDa)和1，2-二油基-sn-甘油-3-磷酸乙醇胺(DOPE)单元(简称 )组成，其中偶氮苯提高了缺氧的敏感性和特异性。所提出的纳米制剂代表了一种新的肿瘤环境响应模式，用于癌症靶向和siRNA递送。
Altered vasculature and the resultant chaotic tumor blood flow lead to the appearance in fast‐growing tumors of regions with gradients of oxygen tension and acute hypoxia (less than 1.4 % oxygen).1 Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy.1, 2 Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy.1, 3 This led to the development of hypoxia imaging agents,4 and the use of hypoxia‐activated anticancer prodrugs.2a Here we show the first example of the hypoxia‐induced siRNA uptake and silencing using a nanocarrier consisting of polyethyleneglycol 2000, azobenzene, polyethyleneimine (PEI)(1.8 kDa), and 1,2‐dioleyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE) units (the nanocarrier is referred to as PAPD), where azobenzene imparts hypoxia sensitivity and specificity.4a We report hypoxia‐activated green fluorescent protein (GFP) silencing in vitro and its downregulation in GFP‐expressing tumors after intravenous administration. The proposed nanoformulation represents a novel tumor‐environment‐responsive modality for cancer targeting and siRNA delivery.