The scope of this project is to establish whether magnetite or iron oxide (IO) nanoprobes, specific for tumor markers such as c-Met (tyrosine kinase receptor for the hepatocyte growth/scatter factor) or VEGF-R2 (vascular endothelial growth factor receptor), can be used therapeutically to inhibit or diminish glioma tumor growth in experimental rodent models. We plan to develop and synthesize IO nanoprobes, or characteristic tumor antigen-specific antibody tagged IO-based MRI contrast agents, for the in vivo detection of molecular events associated with tumor malignancy or angiogenesis in rat glioma models. We will assess the ability of these IO nanoprobes to detect malignant tumor markers such as c-MET, over-expressed in tumors that are invasive in nature, and VEGF-R2, which is associated with angiogenesis in malignant tumors, in an experimental C6 rat glioma model. It has also been recently established that IO nanoparticles can induce hyperthermia by being subjected to an alternating magnetic field (AMF), and that this may be used as a possible therapeutic modality against tumors. In a novel approach, we wanted to combine the therapeutic nature of the IO nanoparticles, and the specificity of tumor marker specific nanoprobes to direct hyperthermia therapy to malignant tumors targeted by anti-c-Met or anti-VEGF-R2 nanoprobes. Molecular magnetic resonance imaging (mMRI) will be used to assess the nanoprobe specificity for either c-Met or VEGF-R2, and morphological MRI will be used to assess the therapeutic efficacy of the nanoprobes on glioma growth in a rat glioma model. It is important that validation steps are initially studied in experimental animal models prior to the development of methods for clinical diagnosis and/or treatment. The advantages of MRI as a molecular imaging modality are a higher spatial resolution (5m) and the ability to obtain morphological, physiological and metabolic information in a single imaging session.
The specific aims that we will use to assess tumor marker specific nanoprobes as potential diagnostic and therapeutic agents are as follows: (1) Assess tumor marker specific magnetite nanoprobes in their ability to detect markers associated with tumor malignancy and angiogenesis, and (2) assess anti-tumor therapeutic effect of nanoprobes when used with an alternating magnetic field.
For specific aim 1, we plan to covalently bind the IO nanoparticles to cross-linked IO (CLIO) in conjunction with anti-VEGF-R2 Ab or anti-c-Met Ab, so that they can be used as vascular nanoprobes. Dextran-based CLIO contrast agents have been previously used as 'blood pool'agents. The IO nanoprobes will be tested in a C6 rat glioma model extensively used in our laboratory. For a non-specific control, a normal non-immune rat IgG will be coupled to the CLIO moiety.
For specific aim 2, the focus will be to combine the tumor marker specificity of the nanoprobes to target malignant tumors, and to utilize the IO component on these compounds as a means of generating hyperthermia via an alternating magnetic field (100 kHz to 500 kHz frequency range) as a possible anti-tumor therapeutic treatment. We plan to subject C6 glioma-bearing rats to alternating magnetic fields (AMF), following administration of IO nanoprobes targeting either c-Met or VEGF-R2, and monitor tumor growth via MRI. Controls will be treated with non-specific IO nanoparticles (containing normal non-immune rat IgG) and subjected to an AMF. The proposed research is highly innovative and involves the research and development of molecular targeting agents, magnetic nanoprobes, and therapeutic options associated with these nanoprobes, that can be used to inhibit the growth and possibly eradicate malignant gliomas. Our plan is to incorporate the potential hyperthermia therapeutic effect of the nanoparticles in combination with the specificity of targeting tumor markers on malignant tumors. This combination of concepts has never been attempted before by targeting c- MET or VEGF-R2 within a glioma model. The development of in vivo biomedical research tools to assess the detection of potential tumor biomarkers may have a significant impact on future diagnostic approaches to be used in the early detection of human gliomas. In addition, this project will also assess the chemo-preventative capabilities of potential agents in their ability to prevent malignant glioma formation. To accomplish the goals of the project we have compiled a multi-institutional team from the Oklahoma Medical Research Foundation (OMRF), Oklahoma State University (OSU), and the University of Central Oklahoma (UCO), with expertise in mMRI, nanoparticles, radiofrequency bio-engineering, and cancer therapeutics.

Public Health Relevance

This project is focused on developing and assessing tumor marker specific magnetite or iron oxide (IO) nanoprobes in their ability to detect tumor markers in vivo, and in addition be used as anti-cancer therapeutic agents. IO nanoprobes, such as ultrasmall superparamagnetic iron oxides (USPIOs) have recently become popular as molecular reporting probes with the use of molecular magnetic resonance imaging (mMRI). We propose to develop and assess IO nanoprobes with the use of molecular magnetic resonance imaging (mMRI) in a rodent glioma model to follow molecular markers associated with tumor malignancy and angiogenesis, and to utilize the nanoprobes themselves as potential therapeutic agents. Studying a potentially effective anti- tumor therapeutic agent, as well as developing novel in vivo diagnostic and predictive procedures may significantly impact patient prognosis and survivability in the future.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Cancer Biomarkers Study Section (CBSS)
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Menkens, Anne E
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Oklahoma Medical Research Foundation
Oklahoma City
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