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Abstract
Cell death plays an integral role in physiology, including turnover of cells in the gastrointestinal tract, the menstrual cycle and the immune system. Imbalance of this process is also associated with disease. Excessive cell death is characteristic of vascular disorders, neurodegenerative diseases, myelodysplastic syndromes, ischemia/reperfusion injury and organ transplant rejection, among others. Cell death also plays a role in the treatment of disease. In cancer for example, most chemotherapeutics, radiation treatments and anti-hormonal agents act by inducing death of cancer cells. Given the prevalence of cell death in normal physiology and disease, noninvasive imaging of this process is likely to have wide application in biological research and ultimately in patient diagnosis and management.
I have described a small, synthetic organoarsenical GSAO (4-(N-(S-glutathionylacetyl)amino)phenylarsonous acid) that when tagged with various reporter groups can be used to noninvasively image cell death within the body. Tagged GSAO enters the cell during the mid-late stages of cell death coincident with loss of plasma membrane integrity. The probe is retained in the cytosol predominantly by covalent reaction with closely-spaced cysteine thiols near the C-terminus of the 90-kDa heat shock protein (Hsp90). Hsp90 is the most abundant molecular chaperone of the eukaryotic cytoplasm and plays a role in a number of fundamental cellular pathways.
GSAO has been tagged with optical or radioisotope reporting groups and validated in in vitro and in vivo models of cell death. Near infra-red conjugates of GSAO have been used to noninvasively image cell death in mouse tumours and brain cryolesions by fluorescence, while a radio-labelled GSAO has been used to noninvasively image tumour cell death in mice using SPECT/CT.