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Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with Photodynamic Therapy

Authors :
Esther M. M. Smeets
Daphne N. Dorst
Gerben M. Franssen
Merijn S. van Essen
Cathelijne Frielink
Martijn W. J. Stommel
Marija Trajkovic-Arsic
Phyllis F. Cheung
Jens T. Siveke
Ian Wilson
Alessandro Mascioni
Erik H. J. G. Aarntzen
Sanne A. M. van Lith
Source :
Cells; Volume 12; Issue 10; Pages: 1420, Cells, 12, 10, Cells, 12
Publication Year :
2023
Publisher :
Multidisciplinary Digital Publishing Institute, 2023.

Abstract

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 111In-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.

Details

Language :
English
ISSN :
20734409
Database :
OpenAIRE
Journal :
Cells; Volume 12; Issue 10; Pages: 1420
Accession number :
edsair.doi.dedup.....d44f8e31faa9619bd76ac17bd4aaefbf
Full Text :
https://doi.org/10.3390/cells12101420