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（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。改变的microRNA（miRNAs）表达谱是恶性细胞的标志。我们和其他人已经表明，miR-155和miR-181 b的上调在肝癌发生中起着重要作用。相反，通过转染anti-miR耗尽miR-181 b可以抑制裸鼠中HCC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颗粒（LN）将在肝癌小鼠模型中作为抗miR寡核苷酸的体内递送载体进行评估。我们的支持数据表明，这些纳米颗粒确实主要在肝肿瘤的上皮细胞中上传，并且miRNA被成功地递送到肿瘤细胞。这些LNP现在将被进一步修饰以将抗miR 155和抗miR 181 b递送至HCC。具体目标是：1。合成、表征和体外评估肝靶向半乳糖基化脂质纳米粒（GLN）用于在HCC细胞中递送抗miR。2.检查抗miR对小鼠暴露于二乙基亚硝胺（DEN）（一种肝脏致癌物）后产生的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，他们在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方面具有专业知识，这将可能导致HCC新型治疗策略的临床转化。该提案也符合计划公告的使命/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）"。 公共卫生关系：肝细胞癌（HCC）的新治疗方法的迫切需要是必要的，因为HCC的发病率在美国大大增加，他们的预后差，这种癌症对目前可用的治疗方案的反应差。MicroRNA是一类在哺乳动物体内发挥重要作用的小分子RNA。它们的畸变经常导致人类癌症。本项目的重点是开发纳米颗粒作为针对致癌microRNA的反义寡核苷酸的递送系统，以治疗小鼠模型中的肝细胞癌。对正常细胞的毒性是常规抗癌药物的主要问题。这些研究的成功将为使用半乳糖基化脂质纳米颗粒的靶向递送系统用于这种不治之症的抗mir治疗开辟道路。因此，在动物模型（临床前试验）中建立抗-mir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。