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Fibroblast Activation Protein-Targeting Minibody-IRDye700DX for Ablation of the Cancer-Associated Fibroblast with
Esther M M Smeets1, Daphne N Dorst2, Gerben M Franssen1
1Department of Medical Imaging, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
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.
Insights
Fibroblast activation protein (FAP)-targeted photodynamic therapy using DTPA-700DX-MB effectively targets pancreatic tumors in mice. This approach shows promise for selectively eliminating FAP-expressing cells with minimal toxicity.
Area of Science:
- Oncology
- Biomedical Engineering
- Photodynamic Therapy
Background:
- Fibroblast activation protein (FAP) is a key target in cancer-associated fibroblasts, crucial for tumor growth and metastasis.
- Systemic FAP-targeting strategies face toxicity issues due to FAP expression in normal tissues.
- Photodynamic therapy (PDT) offers localized treatment upon light activation, minimizing off-target effects.
Purpose of the Study:
- To develop and evaluate a novel FAP-targeted photodynamic therapy agent, DTPA-700DX-MB, for cancer treatment.
- To assess the binding affinity, tumor uptake, and therapeutic efficacy of DTPA-700DX-MB in preclinical models.
Main Methods:
- Conjugation of a FAP-binding minibody with diethylenetriaminepentaacetic acid (DTPA) and photosensitizer IRDye700DX.
- In vitro cytotoxicity assays on FAP-overexpressing fibroblasts.
- In vivo biodistribution studies using radiolabeled DTPA-700DX-MB in tumor-bearing mice.
- Evaluation of therapeutic efficacy via PDT in murine pancreatic ductal adenocarcinoma models.
Main Results:
- DTPA-700DX-MB demonstrated efficient binding to FAP-expressing cells and dose-dependent phototoxicity.
- Maximal tumor uptake of radiolabeled DTPA-700DX-MB was observed at 24 hours post-injection.
- Autoradiography confirmed tumor-specific uptake correlating with FAP expression.
- In vivo PDT with DTPA-700DX-MB induced apoptosis specifically in treated tumors.
Conclusions:
- DTPA-700DX-MB effectively targets FAP-expressing cells and pancreatic tumors in mice with favorable signal-to-background ratios.
- The induced apoptosis confirms the potential of FAP-targeted PDT for selective cancer cell depletion.
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