Whereas
protease inhibitors have been developed successfully against
hypertension and
viral infections, they have failed thus far as
cancer drugs. With advances in
cancer profiling we now better understand that the
tumor "degradome" (i.e. the repertoire of
proteases and their natural inhibitors and interaction partners) forms a complex network in which specific nodes determine the global outcome of manipulation of the
protease web. However, knowing which
proteases are active in the
tumor micro-environment, we may tackle
cancers with the use of
Protease-Activated
Prodrugs (PAPs). Here we exemplify this concept for metallo-,
cysteine and
serine proteases. PAPs not only exist as small molecular adducts, containing a cleavable substrate sequence and a latent
prodrug, they are presently also manufactured as various types of nanoparticles. Although the emphasis of this review is on PAPs for treatment, it is clear that
protease activatable probes and nanoparticles are also powerful tools for imaging purposes, including
tumor diagnosis and staging, as well as visualization of
tumor imaging during microsurgical resections.