| Autor: |
Smeets EMM; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., Dorst DN; Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands., Franssen GM; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., van Essen MS; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., Frielink C; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., Stommel MWJ; Department of Surgery, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., Trajkovic-Arsic M; Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany.; Division of Solid Tumour Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Centre, DKFZ, 69120 Heidelberg, Germany., Cheung PF; Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany.; Division of Solid Tumour Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Centre, DKFZ, 69120 Heidelberg, Germany., Siveke JT; Bridge Institute of Experimental Tumour Therapy, West German Cancer Centre, University Hospital Essen, University of Duisburg-Essen, 47057 Essen, Germany.; Division of Solid Tumour Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Centre, DKFZ, 69120 Heidelberg, Germany., Wilson I; ImaginAb, Inglewood, CA 90301, USA., Mascioni A; ImaginAb, Inglewood, CA 90301, USA., Aarntzen EHJG; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands., van Lith SAM; Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands. |
| Abstrakt: |
Fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, is a target for diagnosis and therapy in multiple tumour types. Strategies to systemically deplete FAP-expressing cells show efficacy; however, these induce toxicities, as FAP-expressing cells are found in normal tissues. FAP-targeted photodynamic therapy offers a solution, as it acts only locally and upon activation. Here, a FAP-binding minibody was conjugated to the chelator diethylenetriaminepentaacetic acid (DTPA) and the photosensitizer IRDye700DX (DTPA-700DX-MB). DTPA-700DX-MB showed efficient binding to FAP-overexpressing 3T3 murine fibroblasts (3T3-FAP) and induced the protein's dose-dependent cytotoxicity upon light exposure. Biodistribution of DTPA-700DX-MB in mice carrying either subcutaneous or orthotopic tumours of murine pancreatic ductal adenocarcinoma cells (PDAC299) showed maximal tumour uptake of 111 In-labelled DTPA-700DX-MB at 24 h post injection. Co-injection with an excess DTPA-700DX-MB reduced uptake, and autoradiography correlated with FAP expression in the stromal tumour region. Finally, in vivo therapeutic efficacy was determined in two simultaneous subcutaneous PDAC299 tumours; only one was treated with 690 nm light. Upregulation of an apoptosis marker was only observed in the treated tumours. In conclusion, DTPA-700DX-MB binds to FAP-expressing cells and targets PDAC299 tumours in mice with good signal-to-background ratios. Furthermore, the induced apoptosis indicates the feasibility of targeted depletion of FAP-expressing cells with photodynamic therapy. |
