In vivo biodistribution of radiolabeled MMP-2/9 activatable cell-penetrating peptide probes in tumor-bearing mice.
Matrix metalloproteinases (MMPs) play a pivotal role in cancer progression and present therefore an interesting biomarker for early diagnosis, staging and therapy evaluation. Consequently, MMP-specific molecular imaging probes have been proposed for noninvasive visualization and quantification of MMP activity. An interesting approach is MMP-2/9 activatable cell-penetrating peptides (ACPP) that accumulate in the tumor tissue after activation. However, a recent study revealed that probe activation occurred already in the vasculature followed by nonspecific tumor targeting. In the latter study, biodistribution was determined 6 and 24 h post-ACPP injection. An alternative explanation could still be that the kinetics of tumor-specific activation is faster than that of blood activation plus subsequent nonspecific uptake in tumor. The aim of this study was to assess if tumor-specific ACPP activation occurs in mice with MMP-2/9 positive subcutaneous HT-1080 tumors at 3 h post-injection. As control, we studied the MMP-2/9 sensitive ACPP in mice bearing subcutaneous BT-20 tumors with low MMP-2/9 expression to test if probe cleavage correlates with tumoral MMP expression. Ex vivo biodistribution showed no improved tumoral ACPP activation in HT-1080 tumor-bearing mice at 3 h post-injection compared with previous reported data collected at 24 h post-injection. Furthermore, tumoral uptake and relative tumoral activation for ACPP were similar in both BT-20 and HT-1080 tumor-bearing mice. In conclusion, this study suggests that tumoral ACPP uptake in these tumor models originates from probe activation in the vasculature instead of tumor-specific MMP activation. Novel ACPPs that target tissue-specific proteases without nonspecific activation may unleash the full potential of the elegant ACPP concept.
Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands; Center for Imaging Research and Education, Eindhoven, The Netherlands.
Sander M J
SM
van Duijnhoven
Marc S
MS
Robillard
Klaas
K
Nicolay
Holger
H
Grüll
D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry; D003952:Diagnostic Imaging; D005260:Female; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry; D011859:Radiography; D011868:Radioisotopes / Q000737:chemistry; D014018:Tissue Distribution; D015533:Transcriptional Activation / Q000187:drug effects
D057846:Cell-Penetrating Peptides; D015335:Molecular Probes; D011868:Radioisotopes; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
activatable probe; cancer; dual-isotope; matrix metalloproteinase; molecular imaging