Heparanase, an endo-β-glucuronidase, is the only known enzyme that is responsible for the cleavage of heparan sulfate chains of heparan sulfate proteoglycans. Its enzymatic activity plays a key role in remodeling and degradation of the extracellular matrix, generation of biologically active carbohydrate fragments, and liberation of effector molecules, such as growth factors and chemokines, that are bound to the heparan sulfate side chains. Overexpression of heparanase has been implicated in most types of cancers and various inflammatory diseases that usually involve extensive heparan sulfate degradation and extracellular matrix remodeling. Consequently, heparanase has been considered a biological target for various therapeutic applications. However, one of the major challenges in this research area is the development of robust and feasible heparanase probes to study the enzymes’ fundamental biology in the extracellular matrix, to provide heparanase-targeted diagnostics, and to aid in drug discovery efforts. Our lab has been developing various small-molecule-based heparanase activatable probes, and we have successfully developed chemical strategies that allow sensitive detection of heparanase activity in various contexts. Two-photon microscopy allows for deeper tissue penetration, excellent spatial resolution and efficient light detection with reduced photobleaching effects. Herein, we extend our chemical strategies to develop a heparanase-activatable two-photon fluorogenic probe for real-time detection of heparanase activity in animal models.

Activatable fluorogenic probe for two-photon imaging of heparanase <i>in vivo</i>

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Activatable fluorogenic probe for two-photon imaging of heparanase in vivo