This is a competing renewal application that builds on the instrumentation and expertise developed in the course of the previous funding periods. We propose to investigate the feasibility of extending the current magnetic cell separation methods to applications relying on the cell's own, natural (intrinsic) magnetization. The application rests on the hypothesis that there is a link between malignant cell transformation and an increase in the cell magnetic susceptibility. The supporting evidence comes from a large body of data from other studies on the magnetic properties of tissues, in particular, from electron (spin) paramagnetic resonance, EPR, and studies of solid tumors. Additional supporting evidence comes from our own data on the magnetic field-induced motion (magnetophoresis) in physiologic electrolyte solutions of cancer cell lines (HeLa and Hep 3B), that demonstrate statistically greater velocity compared to controls (oxygenated red blood cells). We have shown an additional increase in the cell magnetophoretic mobility following the addition of soluble iron compounds to the culture media, suggesting an effect of intracellular iron uptake on the cell magnetization. The proposed effort is divided between:
Specific Aims : SA1: To investigate the molecular mechanism for the observed increase in magnetophoretic mobility (MM) in selected cancer cell lines as compared to matched normal cells. In collaboration with experts in cell tracking velocimetry (Dr. Chalmers) and EPR spectrometry (Dr. Kuppusamy) at the subcontract site (The Ohio State University), the effect of iron in the medium on the cell magnetophoretic mobility and the increased intracellular paramagnetic content will be investigated on cancer cell lines. SA2: To improve the sensitivity and resolution of the cell magnetophoretic mobility analyzer, the Cell Tracking Velocimetry (CTV). The increase of magnetophoretic mobility resolution by a factor up to 10 fold will be accomplished by increasing the magnetic energy density and field gradient of the apparatus, by improving the imaging capability of the cell tracking hardware and software, and by including corrections for fluid dynamics artifacts in collaboration with an expert in field-flow fractionation (Dr. Williams). SA3: To measure the magnetic susceptibility of selected primary tumors at a single cell level against a baseline of normal blood cells. Primary tumor cell lines will be tested against normal controls for differences in the magnetophoretic mobility, in collaboration with an expert oncologist (Dr. Borden). SA4: To test the feasibility of the label-less, magnetic cancer cell separation on model blood cell suspensions. The proposed strategy is based on the soluble - rather than particulate - iron transport processes, and may therefore be more finely tuned to the pathobiology of the cancer cell than is practiced today. It could have a profound impact on how the magnetic cell separation is practiced and utilized and could complement and extend the applications of the already existing magnetic cell separation methods.

Public Health Relevance

There is an intense interest in identifying cancer biomarkers for improved diagnosis and prognosis in the treatment of the disease. One particularly promising application is the detection, enumeration and analysis of circulating tumor cells (CTC's) in blood. There is evidence of abnormal paramagnetic contributions to the magnetic susceptibility of cells that have undergone malignant transformation coming from the laboratories collaborating on this grant application. We propose to systematically investigate this effect by using our state-of-the-art magnetic research facilities that include the magnetic cell separation laboratory and electron (spin) paramagnetic resonance (EPR) spectrometry facility available at the primary (Cleveland Clinic) and the subcontract (The Ohio State University) sites. The proposed research could have a profound impact on the magnetic separation methods in application to biomedical research and the treatment of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ossandon, Miguel
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Chalmers, J J; Jin, X; Palmer, A F et al. (2017) Femtogram Resolution of Iron Content on a Per Cell Basis: Ex Vivo Storage of Human Red Blood Cells Leads to Loss of Hemoglobin. Anal Chem 89:3702-3709
Mahajan, Kalpesh D; Nabar, Gauri M; Xue, Wei et al. (2017) Mechanotransduction Effects on Endothelial Cell Proliferation via CD31 and VEGFR2: Implications for Immunomagnetic Separation. Biotechnol J 12:
Sivaraman, Balakrishnan; Swaminathan, Ganesh; Moore, Lee et al. (2017) Magnetically-responsive, multifunctional drug delivery nanoparticles for elastic matrix regenerative repair. Acta Biomater 52:171-186
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Wu, Yongqi; Park, Kyoung-Joo Jenny; Deighan, Clayton et al. (2016) Multiparameter Evaluation of the Heterogeneity of Circulating Tumor Cells Using Integrated RNA In Situ Hybridization and Immunocytochemical Analysis. Front Oncol 6:234
Joshi, Powrnima; Kooshki, Mitra; Aldrich, Wayne et al. (2016) Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells. Clin Exp Metastasis 33:829-838
Swaminathan, Ganesh; Sivaraman, Balakrishnan; Moore, Lee et al. (2016) Magnetically Responsive Bone Marrow Mesenchymal Stem Cell-Derived Smooth Muscle Cells Maintain Their Benefits to Augmenting Elastic Matrix Neoassembly. Tissue Eng Part C Methods 22:301-11
Sumari, Deborah; Grimberg, Brian T; Blankenship, D'Arbra et al. (2016) Application of magnetic cytosmear for the estimation of Plasmodium falciparum gametocyte density and detection of asexual stages in asymptomatic children. Malar J 15:113
Buck, Amy; Moore, Lee R; Lane, Christopher D et al. (2015) Magnetic separation of algae genetically modified for increased intracellular iron uptake. J Magn Magn Mater 380:201-204
Joshi, Powrnima; Williams, P Stephen; Moore, Lee R et al. (2015) Circular Halbach array for fast magnetic separation of hyaluronan-expressing tissue progenitors. Anal Chem 87:9908-15

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