Perche F, Biswas S, Wang T, Zhu L, Torchilin V P
Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, 140 The Fenway, Room 230, 360 Huntington Avenue, Boston, MA 02115 (USA).
Angew Chem Int Ed Engl. 2014 Mar 24;53(13):3362-6. doi: 10.1002/anie.201308368. Epub 2014 Feb 19.
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). Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy. Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy. This led to the development of hypoxia imaging agents, and the use of hypoxia-activated anticancer prodrugs. 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. 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.
血管改变以及由此产生的肿瘤血流紊乱，导致在快速生长的肿瘤中出现具有氧张力梯度和急性缺氧（氧含量低于1.4%）的区域。由于缺氧在肿瘤发生和治疗抗性中所起的作用，它成为癌症治疗中的一个问题。实体瘤中治疗药物向缺氧区域的递送不足被认为是治疗抗性的原因之一。这促使了缺氧成像剂的开发以及缺氧激活抗癌前药的使用。在此，我们展示了首个利用由聚乙二醇2000、偶氮苯、聚乙烯亚胺（PEI）（1.8 kDa）和1,2 - 二油酰 - sn - 甘油 - 3 - 磷酸乙醇胺（DOPE）单元组成的纳米载体（该纳米载体称为PAPD）实现缺氧诱导的小干扰RNA（siRNA）摄取和沉默的例子，其中偶氮苯赋予了缺氧敏感性和特异性。我们报告了体外缺氧激活的绿色荧光蛋白（GFP）沉默以及静脉给药后在表达GFP的肿瘤中其表达下调的情况。所提出的纳米制剂代表了一种用于癌症靶向和siRNA递送的新型肿瘤环境响应模式。
