Targeting an MMP-9-activated prodrug to multiple myeloma-diseased bone marrow: a proof of principle in the 5T33MM mouse model.
Multiple myeloma (MM) is an incurable B-cell cancer characterised by the monoclonal proliferation of tumour cells in the bone marrow (BM). It has been described that matrix metalloproteinases (MMPs) and especially MMP-9 is secreted by MM cells. In this study, we investigated the possibility to exploit MMP-9 activity to activate prodrugs and to target MM cells as a new tumour-specific therapy. Cleavage of the prodrug EV1-FITC by MMP-9 resulted in release of fluorescence which can be used as a measure of prodrug activation. The 5T33MM mouse model was used in this proof-of-principle study. The prodrug was activated in a higher amount by addition to MMP-9-producing 5T33MMvv cells, homogenates from tumour-bearing organs (BM, spleen) and isolated 5T33MM-diseased BM and spleen cells compared to non-MMP-9-producing 5T33MMvt cells and homogenates/cells from non-tumour-bearing organs/mice, as measured by fluorescence release. This fluorescence release could be inhibited by the MMP-2/MMP-9-specific inhibitor, CTT. Activation of the prodrug in the 5T33MM spleen and BM homogenates was confirmed by chromatography. EV1-fluorescein isothiocyanate injection into 5T33MM-diseased animals resulted in a higher fluorescence release by the isolated BM and spleen cells compared to injection into healthy animals. In conclusion, MMP-9 activity can be used to activate prodrugs that target MM.
Van Valckenborgh
E
E
Department of Haematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
Mincher
D
D
Di Salvo
A
A
Van Riet
I
I
Young
L
L
Van Camp
B
B
Vanderkerken
K
K
D000818:Animals; D001711:Biotransformation; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D005453:Fluorescence; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D009928:Organ Specificity / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
C504716:1-(3-(fluoresceinylthioureidoalanyl-alanyl-alanyl-L-leucyl-glycyl-L-norvalyl-L-prolylamino)propylamino)anthracene-9,10-dione; D005452:Fluoresceins; D009842:Oligopeptides; D011355:Prodrugs; D020780:Matrix Metalloproteinase 9