Photodynamic Quenched Cathepsin Activity Based Probes for Cancer Detection and Macrophage Targeted Therapy

Yael Ben-Nun, Institute for Drug Research, The School of Pharmacy, The Hebrew University, Jerusalem, Israel
Emmanuelle Meriquiol, Institute for Drug Research, The School of Pharmacy, The Hebrew University, Jerusalem, Israel
Alexander Brandis, Department of Plant Sciences, Weizmann Institute of Science, Rehovot, Israel
Boris Turk, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
Avigdor Scherz, Department of Plant Sciences, Weizmann Institute of Science, Rehovot, Israel
Galia Blum, Institute for Drug Research, The School of Pharmacy, The Hebrew University, Jerusalem, Israel

Elevated cathepsins levels and activities are found in several types of human cancer, making them valuable biomarkers for detection and targeting therapeutics. We aim to combine cysteine cathepsins quenched activity-based probes (qABPs) with Photodynamic Therapy (PDT) to develop theranostic probes that enable both detection and treatment of cancer. qABPs are small molecules that become fluorescent upon activity-dependent covalent modification of a protease target. Cell ablation using PDT is achieved by light activation of a photosensitizer (PS) that leads to an oxidative insult to its surrounding. Our qABPs carry a PS and a quencher that is removed upon covalent modification by active cathepsins allowing the PS to regenerate its fluorescence and PD properties. Out of our library of PS-qABPs, a selected probe allowed rapid non-invasive imaging of subcutaneous tumors and specific macrophage apoptosis by light treatment. The PS-qABPs technology results in a stable covalent linkage of the PS to the tumor tissue generating a functional theranostic tool.