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学科主题: 药学
题名:
Direct cytosolic siRNA delivery by reconstituted high density lipoprotein for target-specific therapy of tumor angiogenesis
作者: Ding, Yang1; Wang, Yazhe1; Zhou, Jianping1; Gu, Xiaochen2; Wang, Wei1; Liu, Congyan1; Bao, Xiuli1; Wang, Cheng1; Li, Yuanru1; Zhang, Qiang3
关键词: Reconstituted high density lipoprotein ; Cholesterol-conjugated siRNA ; Direct cytosolic delivery ; Vascular endothelial growth factor ; Tumor-selective accumulation ; Anti-angiogenic therapy
刊名: BIOMATERIALS
发表日期: 2014-08-01
DOI: 10.1016/j.biomaterials.2014.05.009
卷: 35, 期:25, 页:7214-7227
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Engineering, Biomedical ; Materials Science, Biomaterials
研究领域[WOS]: Engineering ; Materials Science
关键词[WOS]: POLYELECTROLYTE COMPLEX MICELLES ; APOLIPOPROTEIN-A-I ; SCAVENGER RECEPTOR ; ANTICANCER DRUGS ; RNA INTERFERENCE ; SELECTIVE UPTAKE ; CANCER-THERAPY ; BREAST-CANCER ; NANOPARTICLES ; CELLS
英文摘要:

We described here the mechanisms by which small interfering RNA (siRNA) molecules incorporated in reconstituted high density lipoprotein (rHDL) were efficiently transferred into the cytoplasm of cells to perform target-specific therapy of tumor angiogenesis. Using fluorescent-tagged apolipoprotein A-I (apoA-I) and cholesterol-conjugated siRNA (Chol-siRNA), it was confirmed with FACS and confocal microscopic measurements that Chol-siRNA-loaded rHDL nanoparticles (rHDL/Chol-siRNA complexes) were successfully established and apoA-I certainly was attached to the surface of Chol-siRNA-loaded lipoplexes (Lipos/Chol-siRNA complexes). Stably assembled rHDL/Chol-siRNA complexes demonstrated proper nanosize, quasi-spherical shape and improved nuclease protection over naked Chol-siRNA. It was also interesting to note that rHDL provided a highly effective approach to transfer Chol-siRNA across the membrane directly into the cytoplasm via the scavenger receptor BI (SR-BI)-mediated non-endocytotic mechanism, thereby bypassing endo-lysosomal trapping. We also showed clear evidence that the in vitro implementation of rHDL for Chol-siRNA-VEGF (Chol-siRNA targeting vascular endothelial growth factor gene) delivery markedly promoted RNA interference (RNAi)-mediated degradation of VEGF mRNA, resulting in down-regulation of secreted VEGF protein. In vivo fluorescence imaging indicated that near-infrared (NIR) dye Cy5 labeled Chol-siRNA-loaded rHDL nanoparticles (rHDL/Cy5-Chol-5iRNA complexes) displayed long circulation time, SR-BI positive tumor-selective targeting, and efficient cytosolic delivery capabilities. Furthermore, intravenous administration of Chol-siRNA-VEGF-loaded rHDL nanoparticles (rHDL/Chol-siRNA-VEGF complexes) significantly enhanced anti-tumor efficacy against breast cancer, decreased VEGF expression level, and inhibited formation of intratumoral microvessels at the tumor tissue. It was concluded that rHDL possessed therapeutic potential and versatility in mediating CholsiRNA-VEGF direct cytosolic delivery for target-specific anti-angiogenic therapy in breast cancer. (C) 2014 Elsevier Ltd. All rights reserved.

语种: 英语
所属项目编号: 81102398 ; 81273469 ; BK2011624 ; 20110096120003 ; JKVD2013011 ; CXZZ12_0316 ; SDD2012-03 ; SKLNMKF201305 ; J1030830
项目资助者: National Natural Science Foundation of China ; Natural Science Foundation of Jiangsu Province ; Ministry of Education Doctoral Program of Higher Specialized Research Fund project ; Fundamental Research Funds for the Central Universities ; Graduate Cultivation Innovative Project of Jiangsu Province ; School of Pharmacy, Fudan University &amp ; The Open Project Program of Key Lab of Smart Drug Delivery (Fudan University), Ministry of Education, China ; Open Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University ; National Found for Fostering Talents of Basic Science
WOS记录号: WOS:000338386800052
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内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/56143
Appears in Collections:北京大学药学院_期刊论文

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作者单位: 1.Univ Manitoba, Fac Pharm, Winnipeg, MB R3E 0T5, Canada
2.China Pharmaceut Univ, Dept Pharmaceut, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China
3.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China

Recommended Citation:
Ding, Yang,Wang, Yazhe,Zhou, Jianping,et al. Direct cytosolic siRNA delivery by reconstituted high density lipoprotein for target-specific therapy of tumor angiogenesis[J]. BIOMATERIALS,2014,35(25):7214-7227.
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