Archived record · Edyssy 2014

Therapeutic Delivery Of Anti-Mir Oligos To Hepatocellular Cancer

Agency

NIHNational Institutes of Health

Principal investigator

Kalpana Ghoshal

Institution

Ohio State University

Amount listed

$199,013

Period

April 1, 2011 to March 31, 2012

Abstract

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

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The record names Kalpana Ghoshal at Ohio State University as principal investigator. When a professor holds an award like this, part of the budget usually goes to people: graduate research assistants, a postdoc or a technician. Shorter awards are often one year of a renewing project, so check whether it was continued. Look up the investigator’s current awards before you write; a 2014 record is a lead, not a promise. Before you do, read up on how to approach a funded professor.

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