The application of personalized medicine to cancer therapeutics requires rapid assessment of therapeutic benefit to ensure that each patient is receiving the treatment that maximizes tumor cell death and minimizes harm to healthy tissue. Most chemotherapeutics exert their effect by inducing tumor cell apoptosis, a process that is mediated by the caspase enzymes. While caspases are present in all cells, they are only activated in cells actively undergoing apoptosis and therefore represent a target for activity-based molecular imaging. We have synthesized a series of substrate-based dipeptide probes for caspase 3 activity. Cleavage of the probe by caspases inside apoptotic cells results in the formation of two non-permeable fragments that are retained in the cell, thus amplifying the fluorescent signal. Modifications of the invariant aspartic acid in position P1 increase the cell permeability and metabolic stability while preserving much of the efficacy of the natural dipeptide substrate.

Cell permeable probes for targeted molecular imaging of caspase activity

245th National Meeting (2013)

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