Therapeutic delivery of anti-miR oligos to hepatocellular cancer

抗 miR 寡核苷酸治疗肝细胞癌

• 批准号: 8130160
• 负责人: Kalpana Ghoshal
• 金额: $ 19.9万
• 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/8130160
• 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)". PUBLIC HEALTH RELEVANCE: The urgent need for new treatments for hepatocellular cancer (HCC) is warranted because incidence of HCC is increasing considerably in the United States, their dismal prognosis and the poor response of this cancer to treatment regimen currently available. MicroRNAs are small RNAs that play important role in mammals. Their aberrations often lead to cancer in humans. This project focuses on the development of nanoparticles as delivery system of antisense oligos against oncogenic microRNAs to treat hepatocellular carcinomas in mouse models. Toxicity to normal cells is a major problem of conventional anticancer drugs. The success of these studies will open the way to the targeted delivery system using galactosylated lipid nanoparticles for anti-mir therapy for this incurable disease. Thus, establishing therapeutic efficacy of anti-mirs in an animal model (in preclinical trial) would be a major milestone in the treatment of this deadly disease in the near future.

描述(申请人提供)：肝细胞癌是一种致命的疾病，目前的治疗方法效果有限。改变的microRNAs(MiRNAs)表达谱是恶性细胞的标志。我们和其他人已经证明miR-155和miR-181b的上调在肝癌的发生中起着重要的作用。反之，通过转染抗miR基因来耗尽miR-181b可以抑制裸鼠肝癌细胞的生长。在这个项目中，我们(Lee Labs)最近开发的新型脂质纳米粒(LNS)将作为抗miR寡核苷酸的体内递送载体在小鼠肝细胞癌模型中进行评估。我们的支持数据表明，这些纳米颗粒确实主要上传到肝肿瘤的上皮细胞中，并且miRNAs成功地输送到肿瘤细胞中。这些LNPs现在将被进一步改造，以将抗miR 155和抗miR181b的抗体输送到HCCs。其具体目的是：1.合成、表征和体外评价肝靶向半乳糖基化脂质纳米粒(GLN)在肝癌细胞中的表达。2.检测小鼠在二乙基亚硝胺(DEN)致癌物质作用下产生的抗MIR对肝癌的治疗潜力。该项目将由一个具有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的专业知识的多学科研究人员团队进行，这将有可能导致一种新的肝癌治疗策略的临床翻译。这项建议也与计划宣布的使命/目标很好地契合：“生物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、预防和治疗(PA-08-244)”。 公共卫生相关性：迫切需要新的治疗方法来治疗肝细胞癌，因为在美国，肝细胞癌的发病率正在大幅增加，其预后很差，而且这种癌症对现有治疗方案的反应很差。MicroRNAs是一种在哺乳动物中发挥重要作用的小RNA。它们的异常通常会导致人类患癌症。本项目致力于开发纳米粒子作为针对致癌microRNAs的反义寡核苷酸的递送系统来治疗小鼠肝细胞癌。对正常细胞的毒性是传统抗癌药物的主要问题。这些研究的成功将为使用半乳糖化脂质纳米粒用于这种不治之症的抗mir治疗的靶向递送系统开辟道路。因此，在动物模型中(在临床前试验中)建立抗MIRS的治疗效果将是在不久的将来治疗这种致命疾病的一个重要里程碑。