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Short-Interfering RNA-Gold Nanoparticle Bioconjugates: A New Cancer Therapy

短干扰 RNA-金纳米粒子生物缀合物：一种新的癌症疗法

基本信息

批准号：
7695547
负责人：
Adam Brian Braunschweig
金额：
$ 5.17万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7695547
关键词：
A549 Adenocarcinoma Adverse effects Age Antineoplastic Agents Antisense DNA Antisense Oligonucleotides Apoptosis Apoptosis Inhibitor Area Awareness Benign Binding Biology Breast Breast Cancer Cell Breast Cancer Model Bypass Cancer Detection Cancer Etiology Cancer Patient Cancerous Candidate Disease Gene Cause of Death Cell Death Cell Line Cell membrane Cell model Cells Cessation of life Chemical Agents Chemistry Chemosensitization Cisplatin Cleaved cell Clinical Code Complex Dendrimers Development Diagnosis Diagnostic Disease Dose Down-Regulation Drug Delivery Systems ERBB2 gene Early Diagnosis Effectiveness Environment Enzymes Faculty Feedback Galectin 1 Gene Expression Gene Expression Regulation Gene Family Gene Mutation Gene Silencing Gene Silencing Pathway Gene Targeting Genes Genetic Genetic Transcription Goals Gold Growth Health Heart Diseases Human Genome Hybrids Interdisciplinary Study Knock-out Knowledge Lead Left Length Life Link Lipids Liposomes Lung Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Messenger RNA Methods Modeling Monitor Nanotechnology Nanotubes National Cancer Institute Natural regeneration Neoplasm Metastasis Normal Cell Normal tissue morphology Nucleic Acids Nucleotides Oligonucleotides Oncogenes Paclitaxel Pathway interactions Pharmaceutical Preparations Phase Polymers Predisposition Process Property Proteins Quality of life Quantum Dots RNA RNA Interference RNA Interference Pathway Race Relative (related person)Research Research Proposals Resistance Resources S Phase Scientist Site Small Interfering RNA Solid Solutions Specificity Staging Sulfhydryl Compounds Surface Survival Rate System Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Human Experimentation Toxic effect Transfection United States Universities Virus Western Blotting Woman Work base biological systems cancer cell cancer diagnosis cancer therapy cancer type career cell type chemotherapeutic agent chemotherapy clinical application cytotoxicity density disease diagnosis dosage experience extracellular folate-binding protein improved innovation insight knock-down lung small cell carcinoma malignant breast neoplasm member men multidisciplinary nanomaterials nanoparticle nanosized novel nuclease particle prevent programs protein complex public health priorities receptor binding scaffold survivin therapeutic gene therapeutic target therapy development tool treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): In 2006, cancer surpassed heart disease as the leading cause of death in the United States. While intensive research efforts have led to an overall improvement in the 5-year survival rate of cancer patients, those diagnosed with lung and breast cancer have experienced only nominal improvements in quality of life and survival rate. RNAi is an enzyme-mediated pathway that uses short-interfering RNA oligonucleotides (siRNAs) to specifically degrade a target sequence and knockdown expression of the target gene. siRNAs are promising new treatments for cancer because down-regulation of certain genes, such as survivin, that are over-expressed in cancer cells can induce apoptosis (cell death), while leaving normal cells unaffected. As a result, these genes are attractive therapeutic targets for siRNA therapy. Development of siRNA therapeutics, however, has been hampered by inefficient extracellular delivery and uptake of the oligonucleotides. Gold nanoparticle oligodeoxynucleotide bioconjugates are non-toxic antisense agents that deliver oligonucleotides across the cell membrane, increase resistance to nucleases, and knockdown gene expression specifically. The objective of this research proposal is to develop siRNA gold-nanoparticle agents to silence the survivin gene in lung and breast cancer models, ultimately inducing cell-death. The siRNA nanoparticle agents will be prepared by solid phase synthesis, solution methods and gold-thiol chemistry. The cellular uptake and specific gene silencing ability of these antisense agents will be quantitatively determined for different model cell lines using gene-expression analysis (PCR and Western Blot). Additionally, targeting agents that increase the uptake of the siRNA nanoparticles by cancer cells will be added to the nanoparticle scaffold in addition to the siRNAs. This innovative strategy for the treatment of cancer has the potential to create substantive improvements in survival rates and quality of life for cancer patients, while using fundamental advances in nanotechnology to provide insight into the function and treatment of disease. This research program will allow me to build upon my scientific background by working in an interdisciplinary environment exploring the treatment and functioning of disease using nanotechnology. I expect that developing and studying this antisense platform will be a valuable experience as I start an independent career as a university faculty member whose research is devoted to applying the tools of nanotechnology to health-related issues. Cancer is the leading cause of death in the United States and treatment of this disease is a public health priority. The proposed research uses nanotechnology to knock out cancer-causing genes, which will lead to powerful therapies for treating breast and lung cancer.

描述（由申请人提供）：2006年，癌症超过心脏病成为美国的主要死亡原因。虽然密集的研究工作已经导致癌症患者的5年生存率的总体改善，但那些被诊断患有肺癌和乳腺癌的患者在生活质量和生存率方面只经历了名义上的改善。RNAi是一种酶介导的途径，其使用短干扰RNA寡核苷酸（siRNA）来特异性降解靶序列并敲低靶基因的表达。siRNA是有希望的癌症新疗法，因为在癌细胞中过度表达的某些基因（如生存素）的下调可以诱导细胞凋亡（细胞死亡），同时使正常细胞不受影响。因此，这些基因是siRNA治疗的有吸引力的治疗靶标。然而，siRNA治疗剂的开发受到寡核苷酸的低效细胞外递送和摄取的阻碍。金纳米颗粒寡脱氧核苷酸生物缀合物是无毒的反义试剂，其递送寡核苷酸穿过细胞膜，增加对核酸酶的抗性，并特异性地敲低基因表达。这项研究计划的目的是开发siRNA金纳米粒子试剂，以沉默肺癌和乳腺癌模型中的生存素基因，最终诱导细胞死亡。siRNA纳米颗粒试剂将通过固相合成、溶液方法和金-硫醇化学来制备。将使用基因表达分析（PCR和Western印迹）定量测定不同模型细胞系中这些反义药物的细胞摄取和特异性基因沉默能力。此外，除了siRNA之外，增加癌细胞对siRNA纳米颗粒的摄取的靶向剂将被添加到纳米颗粒支架中。这种治疗癌症的创新策略有可能大大提高癌症患者的生存率和生活质量，同时利用纳米技术的根本进步来深入了解疾病的功能和治疗。这项研究计划将使我能够建立在我的科学背景下，在跨学科的环境中工作，探索使用纳米技术治疗和发挥疾病的作用。我希望开发和研究这个反义平台将是一个宝贵的经验，因为我开始了一个独立的职业生涯，作为一个大学教师，其研究致力于应用纳米技术的工具，以健康相关的问题。癌症是美国的主要死因，治疗这种疾病是公共卫生的优先事项。这项拟议中的研究使用纳米技术来敲除致癌基因，这将导致治疗乳腺癌和肺癌的强大疗法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Spectroscopic tracking of molecular transport junctions generated by using click chemistry.

DOI：
10.1002/anie.200806028
发表时间：
2009
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Chen X;Braunschweig AB;Wiester MJ;Yeganeh S;Ratner MA;Mirkin CA
通讯作者：
Mirkin CA

Force- and time-dependent feature size and shape control in molecular printing via polymer-pen lithography.

DOI：
10.1002/smll.200901538
发表时间：
2010-05-21
期刊：
SMALL
影响因子：
13.3
作者：
Liao, Xing;Braunschweig, Adam B.;Zheng, Zijian;Mirkin, Chad A.
通讯作者：
Mirkin, Chad A.

"Force-feedback" leveling of massively parallel arrays in polymer pen lithography.

DOI：
10.1021/nl904200t
发表时间：
2010-04-14
期刊：
Nano letters
影响因子：
10.8
作者：
Liao X;Braunschweig AB;Mirkin CA
通讯作者：
Mirkin CA

Thermodynamic forecasting of mechanically interlocked switches.

机械联锁开关的热力学预测。

DOI：
10.1039/b911874h
发表时间：
2009
期刊：
Organic & biomolecular chemistry
影响因子：
3.2
作者：
Olson,MarkA;Braunschweig,AdamB;Ikeda,Taichi;Fang,Lei;Trabolsi,Ali;Slawin,AlexandraMZ;Khan,SaeedI;Stoddart,JFraser
通讯作者：
Stoddart,JFraser

Solvent and temperature induced switching between structural isomers of Rh(I) phosphinoalkyl thioether (PS) complexes.

溶剂和温度诱导 Rh(I) 膦烷基硫醚 (PS) 配合物结构异构体之间的转换。