EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer
| Autor: | William P.J. Leenders, Inge Ebisch, Valentina Palacio-Castañeda, Jelske M de Jong, Wouter P. R. Verdurmen, Dirk van den Brand, Mark A.J. Gorris, Mark R G Goldman, Leon F.A.G. Massuger, Sanne A. M. van Lith, Roland Brock, Stijn T Couwenbergh |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] medicine.medical_treatment targeted photodynamic therapy Photodynamic therapy lcsh:RC254-282 Article 03 medical and health sciences chemistry.chemical_compound All institutes and research themes of the Radboud University Medical Center 0302 clinical medicine In vivo Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] Medicine Photosensitizer Binding site Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] business.industry Epithelial cell adhesion molecule medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens In vitro 030104 developmental biology ovarian cancer Oncology chemistry DARPin 030220 oncology & carcinogenesis Cancer research designed ankyrin repeat protein business Ovarian cancer epithelial cell adhesion molecule Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] |
| Zdroj: | Cancers, Vol 12, Iss 1762, p 1762 (2020) Cancers Volume 12 Issue 7 Cancers, 12 Cancers, 12, 7 |
| ISSN: | 2072-6694 |
| Popis: | Ovarian cancer is the most lethal gynecological malignancy due to late detection associated with dissemination throughout the abdominal cavity. Targeted photodynamic therapy (tPDT) aimed at epithelial cell adhesion molecule (EpCAM), overexpressed in over 90% of ovarian cancer metastatic lesions, is a promising novel therapeutic modality. Here, we tested the specificity and activity of conjugates of EpCAM-directed designed ankyrin repeat proteins (DARPins) with the photosensitizer IRDye 700DX in in vitro and in vivo ovarian cancer models. EpCAM-binding DARPins (Ec1: Kd = 68 pM Ac2: Kd = 130 nM) and a control DARPin were site-specifically functionalized with fluorophores or IRDye 700DX. Conjugation of anti-EpCAM DARPins with fluorophores maintained EpCAM-specific binding in cell lines and patient-derived ovarian cancer explants. Penetration of DARPin Ec1 into tumor spheroids was slower than that of Ac2, indicative of a binding site barrier effect for Ec1. DARPin-IRDye 700DX conjugates killed EpCAM-expressing cells in a highly specific and illumination-dependent fashion in 2D and 3D cultures. Furthermore, they effectively homed to EpCAM-expressing subcutaneous OV90 xenografts in mice. In conclusion, the high activity and specificity observed in preclinical ovarian cancer models, combined with a high specificity in patient material, warrant a further investigation of EpCAM-targeted PDT for ovarian cancer. |
| Databáze: | OpenAIRE |
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