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)"""""""".
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.
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