Inhibitor-decorated Polymer Conjugates Targeting Fibroblast Activation Protein

0481818 - ÚOCHB 2018 RIV US eng J - Journal Article
Dvořáková, Petra - Bušek, P. - Knedlík, Tomáš - Schimer, Jiří - Etrych, Tomáš - Kostka, Libor - Stollinová Šromová, L. - Šubr, Vladimír - Šácha, Pavel - Šedo, A. - Konvalinka, Jan
Inhibitor-decorated Polymer Conjugates Targeting Fibroblast Activation Protein.
Journal of Medicinal Chemistry. Roč. 60, č. 20 (2017), s. 8385-8393. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MZd(CZ) NV15-31379A; GA MŠMT(CZ) LM2015064; GA MŠMT LO1302
Institutional support: RVO:61388963 ; RVO:61389013
Keywords : dipeptidyl peptidase IV * metastatic colorectal cancer * integral membrane protease
OECD category: Biochemistry and molecular biology; Polymer science (UMCH-V)
Impact factor: 6.253, year: 2017

Proteases are directly involved in cancer pathogenesis. Expression of fibroblast activation protein (FAP) is upregulated in stromal fibroblasts in more than 90% of epithelial cancers and is associated with tumor progression. FAP expression is minimal or absent in most normal adult tissues, suggesting its promise as a target for the diagnosis or treatment of various cancers. Here, we report preparation of a polymer conjugate (an iBody) containing a FAP-specific inhibitor as the targeting ligand. The iBody inhibits both human and mouse FAP with low nanomolar inhibition constants but does not inhibit close FAP homologues dipeptidyl peptidase IV, dipeptidyl peptidase 9, and prolyl oligopeptidase. We demonstrate the applicability of this iBody for the isolation of FAP from cell lysates and blood serum as well as for its detection by ELISA, Western blot, flow cytometry, and confocal microscopy. Our results show the iBody is a useful tool for FAP targeting in vitro and potentially also for specific anticancer drug delivery.
Permanent Link: http://hdl.handle.net/11104/0277469