Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid
Systemic delivery of siRNA to tumors using a lipid nanoparticle containing a tumor-specific cleavable PEG-lipid
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DOI：
10.1016/j.biomaterials.2011.02.045
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发表时间：
2011-06-01
期刊：
影响因子：
14
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Hatakeyama, Hiroto;Akita, Hidetaka;Harashima, Hideyoshi
此前，我们开发了一种多功能包膜型纳米器件(MEND)，用于高效地运送核酸。对于肿瘤的修复，聚乙二醇化是一种有用的方法，它通过增强通透性和滞留(EPR)效应，提供更长的体循环和肿瘤聚集。然而，聚乙二醇化会抑制细胞摄取和随后的内体逃逸。为了克服这一点，我们开发了一种在富含基质金属蛋白酶(MMPs)的环境中裂解的聚乙二醇肽-药物(PPD)。在这项研究中，我们报告了通过使用PPD修饰的Mend(PPD-MEND)系统地将siRNA递送到肿瘤中。一项体外研究表明，与传统的聚乙二醇修饰的Mend相比，PPD修饰促进了细胞摄取和内体逃逸。为了平衡系统稳定性和高效活性，进一步将PPD-MEND与PEG-DSPE共修饰。结果，与未治疗相比，全身给药优化的PPD-MEND导致肿瘤中约70%的沉默活性。最后，安全性评价表明，PPD-MEND没有肝脏毒性和天然免疫刺激作用。此外，在肝和脾组织的DNA微阵列分析中，与未修饰的PEGMEND相比，PPD-MEND的基因变化较少，这是因为肝和脾中的蓄积较少。(C)2011爱思唯尔有限公司。保留所有权利。
Previously, we developed a multifunctional envelope-type nano device (MEND) for efficient delivery of nucleic acids. For tumor delivery of a MEND, PEGylation is a useful method, which confers a longer systemic circulation and tumor accumulation via the enhanced permeability and retention (EPR) effect. However, PEGylation inhibits cellular uptake and subsequent endosomal escape. To overcome this, we developed a PEG-peptide-DOPE (PPD) that is cleaved in a matrix metalloproteinase (MMP)-rich environment. In this study, we report on the systemic delivery of siRNA to tumors by employing a MEND that is modified with PPD (PPD-MEND). An in vitro study revealed that PPD modification accelerated both cellular uptake and endosomal escape, compared to a conventional PEG modified MEND. To balance both systemic stability and efficient activity, PPD-MEND was further co-modified with PEG-DSPE. As a result, the systemic administration of the optimized PPD-MEND resulted in an approximately 70% silencing activity in tumors, compared to non-treatment. Finally, a safety evaluation showed that the PPD-MEND showed no hepatotoxicity and innate immune stimulation. Furthermore, in a DNA microarray analysis in liver and spleen tissue, less gene alternation was found for the PPD-MEND compared to that for the PEGunmodified MEND due to less accumulation in liver and spleen. (C) 2011 Elsevier Ltd. All rights reserved.