title: Proteases in cancer drug delivery.
abstract: 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.
authors.affiliation: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Immunobiology, B-3000 Leuven, Belgium.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vandooren
authors.affiliation: KU Leuven, University of Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Immunobiology, B-3000 Leuven, Belgium.
authors.forename: Ghislain
authors.initials: G
authors.lastname: Opdenakker
authors.affiliation: Institute of Cancer Therapeutics, School of Life Sciences, University of Bradford, Bradford, Yorkshire BD7 1DP, UK.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.affiliation: School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK; The Genome Analysis Centre, Norwich Research Park, Norwich NR4 7UH, UK. Electronic address: dylan.edwards@uea.ac.uk.
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Edwards
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016503:Drug Delivery Systems; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D010447:Peptide Hydrolases
keywords: Cathepsin; Legumain; Metalloproteinase; Nanoparticles; Prodrug; Urokinase