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Cancer Cell-Targeted siRNA Delivery by Folate-Conjugated Gold-siRNA-PEG/PEI Nanop

通过叶酸缀合金-siRNA-PEG/PEI Nanop 进行癌细胞靶向 siRNA 递送

基本信息

批准号：
7980323
负责人：
Faqing Huang
金额：
$ 43.5万
依托单位：
UNIVERSITY OF SOUTHERN MISSISSIPPI
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7980323
关键词：
A549 Affect Apoptosis Area Cancer Cell Growth Cancer cell line Cell Death Cell division Cell membrane Cell physiology Cells Cervical Cessation of life Chemistry Dendrimers Development Down-Regulation Endocytosis Essential Genes Figs - dietary Folate Folic Acid Gene Delivery Gene Expression Gene Targeting Genes Gold Heart Diseases Hela Cells High Pressure Liquid Chromatography Human Hydrolysis In Vitro Individual Inhibition of Apoptosis Inhibition of Cancer Cell Growth Investigation KB Cells Label Lead Life Lipofectamine Liposomes Luc Gene Luciferases Lung Malignant Neoplasms Mediating Methods Molecular Weight Nature Normal Cell Organism Ovarian Pathway interactions Polyethylene Glycols Polyethyleneimine Polymers Preparation Property Proteins RNA RNA Interference Radioisotopes Reagent Research Ribonucleases Series Side Small Interfering RNA Specificity Spectrum Analysis Structure System Testing Therapeutic Time Toxic effect Toxin Transfection Transmission Electron Microscopy United States Viral Viral Vector base cancer cell cancer therapy caspase-8 cell growth cytotoxicity expectation experience folate-binding protein functional genomics gel electrophoresis light scattering nanoparticle next generation novel public health relevance survivin targeted delivery therapeutic development tool zeta potential

项目摘要

DESCRIPTION (provided by applicant): Cancer is the second leading course for all deaths in the United States, surpassed only slightly by heart disease. Although down-regulation of gene expression by siRNA has been shown to be both potent and target gene-specific, there is currently no therapeutically acceptable method for siRNA delivery that targets only cancer cells with high efficiency without affecting normal cells. In the proposed research, we will prepare, characterize, and test a novel folate-conjugated multicomponent gold-siRNA nanoplex system, which permits cancer cell-specific delivery of the nanoplexes through folate receptor-assisted endocytosis. The gold-siRNA nanoplex will be assembled stepwise from pre-made gold nanoparticles and chemically and enzymatically synthesized thioRNA and thioRNA-PEG-folate conjugates. Extensive characterization will be performed by NMR, HPLC, gel electrophoresis, dynamic light scattering, zeta potential, and transmission electron microscopy. Using different cancer cell lines (A549, KB, HeLa, and SKOV3), we will analyze intracellular delivery efficiency, specific gene knockdown, and cellular function studies including inhibition of cell growth and cell death. It is expected that the proposed research will develop a new siRNA delivery system based on actively targeted gold nanoparticles. Effective down-regulation of essential genes [survivin and CASP8AP2 (caspase 8 associated protein 2, an apoptosis factor)] will lead to inhibition of cancer cell growth and cancer cell death. PUBLIC HEALTH RELEVANCE: The proposed project will develop a novel folate-conjugated Au-siRNA nanoplex system. Specific siRNA delivery to cancer cells and efficient down-regulation of gene expression will be achieved by the Au-siRNA nanoplex. Knockdown of essential genes will cause cancer cell growth inhibition and cancer cell death. The research may lead to the development of therapeutic siRNA delivery systems for cancer treatment.

描述（由申请人提供）：癌症是美国所有死亡的第二大原因，仅略高于心脏病。尽管已经显示通过siRNA下调基因表达是有效的和靶基因特异性的，但是目前还没有治疗上可接受的方法用于siRNA递送，其以高效率仅靶向癌细胞而不影响正常细胞。在拟议的研究中，我们将制备，表征和测试一种新的叶酸缀合的多组分金-siRNA纳米复合物系统，该系统允许通过叶酸受体辅助的内吞作用对纳米复合物进行癌细胞特异性递送。金-siRNA纳米复合物将从预制的金纳米颗粒和化学和酶促合成的硫代RNA和硫代RNA-PEG-叶酸缀合物逐步组装。将通过NMR、HPLC、凝胶电泳、动态光散射、zeta电位和透射电子显微镜进行广泛表征。使用不同的癌细胞系（A549，KB，HeLa和SKOV 3），我们将分析细胞内递送效率，特异性基因敲除和细胞功能研究，包括细胞生长和细胞死亡的抑制。预计拟议的研究将开发一种基于主动靶向金纳米颗粒的新siRNA递送系统。有效下调必需基因[生存素和CASP 8AP 2（半胱天冬酶8相关蛋白2，一种凋亡因子）]将导致癌细胞生长抑制和癌细胞死亡。公共卫生相关性：该项目将开发一种新的叶酸缀合的Au-siRNA纳米复合物系统。特异性siRNA递送至癌细胞和基因表达的有效下调将通过Au-siRNA纳米复合物实现。必需基因的敲除将导致癌细胞生长抑制和癌细胞死亡。这项研究可能会导致开发用于癌症治疗的治疗性siRNA递送系统。