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：
7547265
负责人：
Adam Brian Braunschweig
金额：
$ 4.96万
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 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7547265
关键词：
A549 Adenocarcinoma Adverse effects Age Antineoplastic Agents Antisense DNA Antisense Oligonucleotides Apoptosis Apoptosis Inhibitor Area Awareness Benign Binding Biological 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/Paclitaxel 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 Health Priorities 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 Pathway interactions Pharmaceutical Preparations Phase Polymerase Chain Reaction Polymers Predisposition Process Property Proteins Public Health Quality of life Quantum Dots RNA RNA Interference RNA Interference Pathway Race Range 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 cancer cell cancer diagnosis cancer therapy cancer type career cell type chemotherapeutic agent chemotherapy clinical application cytotoxicity density 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 receptor binding scaffold size survivin therapeutic gene therapeutic target therapy development tool 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，这是美国的主要死亡原因。尽管密集的研究工作已导致癌症患者的5年生存率的总体提高，但诊断患有肺癌和乳腺癌的患者的生存率只有名义上改善了生活质量和生存率。 RNAi是一种酶介导的途径，它使用短距离RNA寡核苷酸（siRNA）来专门降解靶基因的靶序序和敲低表达。 siRNA有望对癌症进行新的治疗方法，因为在癌细胞中过表达的某些基因的下调可能会诱导凋亡（细胞死亡），同时使正常细胞不受影响。结果，这些基因是siRNA治疗的有吸引力的治疗靶标。然而，由于细胞外递送和寡核苷酸的摄取，siRNA疗法的发展受到了阻碍。金纳米颗粒寡脱氧核苷酸生物偶联物是无毒的反义剂，可在细胞膜上递送寡核苷酸，增加对核酸酶的耐药性，并明确地敲低基因表达。这项研究建议的目的是开发siRNA金纳米颗粒剂，以使肺和乳腺癌模型中的Survivin基因沉默，最终诱导细胞死亡。 siRNA纳米颗粒剂将通过固相合成，溶液方法和金硫醇化学制备。这些反义剂的细胞摄取和特定基因沉默能力将通过基因表达分析（PCR和Western blot）定量确定不同模型细胞系。此外，除了siRNA之外，还将添加到纳米颗粒支架中增加癌细胞吸收siRNA纳米颗粒的靶向剂。这种治疗癌症的创新策略有可能为癌症患者的生存率和生活质量提供实质性改善，同时使用纳米技术的基本进步来洞悉疾病功能和治疗。该研究计划将使我能够在跨学科环境中工作，探索使用纳米技术探索疾病的治疗和功能。我希望在我从事大学教职员工的独立职业中，开发和研究这个反义平台将是一种宝贵的经历，他们的研究致力于将纳米技术的工具应用于与健康相关的问题。癌症是美国死亡的主要原因，治疗这种疾病是公共卫生的重点。拟议的研究使用纳米技术来敲除致癌的基因，这将导致治疗乳腺癌和肺癌的强大疗法。