Therapeutic delivery of anti-miR oligos to hepatocellular cancer

抗 miR 寡核苷酸治疗肝细胞癌

基本信息

批准号：
8233291
负责人：
Kalpana Ghoshal
金额：
$ 16.58万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8233291
关键词：
Animal Model Antineoplastic Agents Antisense Oligonucleotides Attention Behavior Biological Biology Blood Circulation Carcinogens Carrier Proteins Cause of Death Cell Communication Cell Line Cells Charge Clinical DNA Data Development Diethylnitrosamine Disease Drug Delivery Systems Drug Formulations Effectiveness Employee Strikes Epithelial Cells Etiology Evaluation Exposure to Future Galactose Goals Growth Hepatocarcinogenesis Human In Vitro Incidence Lead Lipids Liquid substance Liver Liver neoplasms Magnetic Resonance Imaging Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mammals Measures Medicine MicroRNAs Mission Molecular Biology Molecular Profiling Multi-Drug Resistance Mus NIH Program Announcements Nanostructures Nanotechnology Normal Cell Nude Mice Oblimersen Oligonucleotides Oncogenes Oncogenic Particle Size Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Prevention Primary carcinoma of the liver cells RNA Regimen Research Personnel Role Small RNA Specificity Staging Surface System TIMP3 gene Tail Therapeutic Therapeutic Effect Time Toxic effect Transfection Translations Treatment Efficacy Treatment Protocols Tumor Suppressor Proteins United States Up-Regulation Veins Weight biomaterial compatibility cancer cell cancer therapy cancer type cell type design effective therapy improved in vivo inhibitor/antagonist interest large scale production leukemia migration mimetics mortality mouse model multidisciplinary nanoparticle nanoscience neoplastic cell novel outcome forecast preclinical study response small molecule success targeted delivery trafficking treatment strategy tumor tumor growth uptake zeta potential

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a lethal disease for which current therapy is of limited effectiveness. Altered microRNAs (miRNAs) expression profile is a signature of malignant cells. We and others have shown that upregulation of miR-155 and miR-181b plays important roles in hepatocarcinogenesis. Conversely, miR-181b depletion by transfection of anti-miR can inhibit growth of HCC cells in nude mice. In this project, novel lipid nanoparticles (LNs) recently developed by us (Lee labs) will be evaluated as in vivo delivery vehicles for anti-miR oligonucleotides in mouse models of HCC. Our supporting data show that these nanoparticles are indeed predominantly uploaded in epithelial cells of the liver tumors and miRNAs are successfully delivered to the tumor cells. These LNPs will now be further modified to deliver anti-miR 155 and anti-miR181b to HCCs. The Specific Aims are: 1. Synthesize, characterize and evaluate in vitro the liver-targeted galactosylated lipid nanoparticles (GLNs) for anti-miR delivery in HCC cells. 2. Examine therapeutic potential of anti-miRs against HCCs developed in mice upon exposure to diethylnitrosamine (DEN), a liver carcinogen. This project will be carried out by a multidisciplinary team of investigators with expertise in miR molecular biology and pharmacology, drug delivery as well as nanoparticle synthesis and characterization that will potentially lead to clinical translation of a novel treatment strategy for HCC. This proposal also fits well with the mission/goal of the program announcements: "Nanoscience and Nanotechnology in Biology and Medicine (PAR-07-271)" and "Etiology, Prevention, and Treatment of Hepatocellular Carcinoma (PA-08-244)".

描述（由申请人提供）：肝细胞癌（HCC）是一种致命疾病，当前治疗的有效性有限。改变的microRNA（miRNA）表达谱是恶性细胞的特征。我们和其他人表明，miR-155和miR-181b的上调在肝癌发生中起着重要作用。相反，通过转染抗MIR的miR-181b耗竭可以抑制裸鼠HCC细胞的生长。在这个项目中，美国最近开发的新型脂质纳米颗粒（LNS）将被评估为HCC小鼠模型中抗MIR寡核苷酸的体内递送车。我们的支持数据表明，这些纳米颗粒确实主要是在肝肿瘤的上皮细胞中上载，而miRNA成功地将其成功地递送到肿瘤细胞中。现在，将进一步修改这些LNP，以将抗MIR 155和抗MIR181B传递给HCC。具体目的是：1。合成，表征和评估肝靶向的半乳糖基化脂质纳米颗粒（GLNS），用于HCC细胞中的抗MIR递送。 2。检查抗肝癌二乙基硝基胺（DEN）后，抗MIRS对HCC的治疗潜力。该项目将由一个多学科的研究人员团队进行，具有miR分子生物学和药理学，药物递送以及纳米颗粒合成和表征的专业知识，这可能会导致HCC新型治疗策略的临床翻译。该提案还非常符合该计划公告的使命/目标：“生物学和医学领域的纳米科学和纳米技术（PAR-07-271）”和“肝细胞癌（PA-08-244）的病因，预防和治疗” 。