Therapeutic delivery of anti-miR oligos to hepatocellular cancer

抗 miR 寡核苷酸治疗肝细胞癌

• 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
• 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

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）是一种致死性疾病，目前的治疗效果有限。microRNAs （miRNAs）表达谱的改变是恶性细胞的一个特征。我们和其他人已经证明miR-155和miR-181b的上调在肝癌发生中起重要作用。相反，通过转染anti-miR来消耗miR-181b可以抑制裸鼠HCC细胞的生长。在这个项目中，我们（Lee实验室）最近开发的新型脂质纳米颗粒（LNs）将被评估为肝癌小鼠模型中抗mir寡核苷酸的体内递送载体。我们的支持数据表明，这些纳米颗粒确实主要上传到肝脏肿瘤的上皮细胞中，并且mirna成功地传递到肿瘤细胞中。这些LNPs现在将被进一步修改以向hcc递送anti-miR 155和anti-miR181b。具体目标是：1。合成、表征和评估肝靶向半乳糖基化脂质纳米颗粒（gln）在HCC细胞中的抗mir递送。2. 研究抗mirs对小鼠暴露于二乙基亚硝胺（DEN）（一种肝癌致癌物）后发展的hcc的治疗潜力。该项目将由一个多学科的研究团队进行，他们在miR分子生物学和药理学、药物输送以及纳米颗粒合成和表征方面具有专业知识，这将有可能导致一种新的HCC治疗策略的临床转化。该提案也非常符合项目公告的使命/目标：“生物学和医学中的纳米科学和纳米技术（PAR-07-271）”和“肝细胞癌的病因学、预防和治疗（PA-08-244）”。