The C2 domain of synaptotagmin I, which binds to anionic phospholipids in cell membranes, was shown to bind to the plasma membrane of apoptotic cells by both flow cytometry and confocal microscopy. Conjugation of the protein to superparamagnetic iron oxide nanoparticles allowed detection of this binding using magnetic resonance imaging. Detection of apoptotic cells, using this novel contrast agent, was demonstrated both in vitro, with isolated apoptotic tumor cells, and in vivo, in a tumor treated with chemotherapeutic drugs.
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Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995).
Mattson, M.P., Culmsee, C. & Yu, Z.F. Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 301, 173–187 (2000).
Kavantzas, N.G., Lazaris, A.C., Agapitos, E.V., Nanas, J. & Davaris, P.S. Histological assessment of apoptotic cell death in cardiomyopathies. Pathology 32, 176–180 (2000).
Kablelitz, D. Apoptosis, graft rejection, and transplantation tolerance. Transplantation 65, 869–875 (1998).
Meyn, R.E. et al. Heterogeneity in apoptosis development in irradiated murine tumours of different histologies. Int. J. Radiat. Biol. 64, 583–591 (1993).
Meyn, R.E., Stephens, L.C., Hunter, N.R. & Milas, L. Apoptosis in murine tumours treated with chemotherapy agents. Anti-Cancer Drugs 6, 443–450 (1995).
Williams, S.N.O., Anthony, M.L. & Brindle, K.M. Induction of apoptosis in two mammalian cell lines results in increased levels of fructose-1,6-bisphosphate and CDP-choline as determined by 31P MRS. Magn. Reson. Med. 40, 411–420 (1998).
Blankenberg, F.G. et al. Quantitative analysis of apoptotic cell death using proton nuclear magnetic resonance spectroscopy. Blood 89, 3778–3785 (1997).
Nunn, A.V.W. et al. Characterisation of secondary metabolites associated with neutrophil apoptosis. FEBS Lett. 392, 295–298 (1996).
Hakumaki, J.M., Poptani, H., Sandmair, A.-M., Yla-Herttuala, S. & Kauppinen, R.A. 1H MRS detects polyunsaturated fatty acid accumulation during gene therapy of glioma: Implications for the in vivo detection of apoptosis. Nature Med. 5, 1323–1327 (1999).
Poptani, H. et al. Monitoring thymidine kinase and ganciclovir-induced changes in rat malignant glioma in vivo by nuclear magnetic resonance imaging. Cancer Gene Ther. 5, 101–109 (1998).
Emoto, K., Toyama-Sorimachi, N., Karasuyama, H., Inoue, K. & Umeda, M. Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp. Cell Res. 232, 430–434 (1997).
Martin, S.J. et al. Early redistribution of plasma-membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: Inhibition by overexpression of Bcl-2 and Abl. J. Exp. Med. 182, 1545–1556 (1995).
Blankenberg, F.G. et al. In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc. Natl. Acad. Sci. USA 95, 6349–6354 (1998).
Weber, D.A. & Ivanovic, M. Ultra-high-resolution imaging of small animals: Implications for preclinical and research studies. J. Nucl. Cardiol. 6, 332–344 (1999).
Davletov, B.A. & Sudhof, T.C. A single C2 domain from synaptogamin I is sufficient for high affinity Ca2+/phospholipid binding. J. Biol. Chem. 268, 26386–26390 (1993).
Weissleder, R. et al. Ultrasmall superparamagnetic iron oxide (USPIO): Characterization of a new class of contrast agents for MR imaging. Radiology 175, 489–493 (1990).
Bortner, C.D., Hughes, F.M. & Cidlowski, J.A. A primary role for K+ and Na+ efflux in the activation of apoptosis. J. Biol. Chem. 272, 32436–32442 (1997).
Sakurai, H. et al. Early radiation effects in highly apoptotic murine lymphoma xenografts monitored by 31P magnetic resonance spectroscopy. Int. J. Radiat. Oncol. Biol. Phys. 41, 1157–1162 (1998).
Taylor, A.M. et al. Safety and preliminary findings with the intravascular contrast agent NC100150 injection for MR coronary angiography. J. Magn. Reson. Imag. 9, 220–227 (1999).
Weissleder, R. et al. In vivo magnetic resonance imaging of transgene expression. Nature Med. 6, 351–354 (2000).
Louie, A.Y. et al. In vivo visualization of gene expression using magnetic resonance imaging. Nature Biotech. 18, 321–325 (2000).
Lewin, M. et al. Tat peptide-derivatized magnetic nanoparticles allow in vivo tracking and recovery of progenitor cells. Nature Biotech. 18, 410–414 (2000).
Sutton, R.B., Davletov, B.A., Berghuis, A.M., Sudhof, T.C. & Sprang, S.R. Structure of the first C2 domain of synaptotagmin I: A novel Ca2+/phospholipid-binding fold. Cell 80, 929–938 (1995).
Hasegawa, M. et al. Small-diameter composite composed of water-soluble carboxypolysaccharide and magnetic iron oxide. EP 0656368 A1 (1993).
Dutton, A.H., Tokuyasu, K.T. & Singer, S.J. Iron-dextran antibody conjugates: General method for simultaneous staining of two components in high-resolution immunoelectron microscopy. Proc. Natl. Acad. Sci. USA 76, 3392–3396 (1979).
Shen, T.T., Weissleder, R., Papisov, M., Bogdanov, A. & Brady, T.J. Monocrystalline iron oxide nanocompounds (MION): Physicochemical properties. Magn. Reson. Med. 29, 599–604 (1993).
Molday, R.S. & McKenzie, D. Immunospecific ferromagnetic iron-dextran reagents for the labeling and magnetic separation of cells. J. Immunol. Methods 52, 353–367 (1982).
Gong, J., Traganos, F. & Darzynkiewicz, Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal. Biochem. 218, 314–319 (1994).
This work was supported by grants from the Cancer Research Campaign and the Medical Research Council, UK. We would like to thank Ray Hicks for help with the flow cytometry and Lyn Carter and Jeremy Skepper for help with tumor sectioning and confocal microscopy.
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Zhao, M., Beauregard, D., Loizou, L. et al. Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med 7, 1241–1244 (2001). https://doi.org/10.1038/nm1101-1241
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