Photoimmunotheranostic agents for triple-negative breast cancer diagnosis and therapy that can be activated on demand

Abstract

// Manal Amoury 1, * , Dirk Bauerschlag 2, * , Felix Zeppernick 3 , Verena von Felbert 4 , Nina Berges 1 , Stefano Di Fiore 5 , Isabell Mintert 3 , Andreas Bleilevens 6 , Nicolai Maass 2 , Karen Bräutigam 7 , Ivo Meinhold-Heerlein 3 , Elmar Stickeler 3 , Stefan Barth 8, 9, * , Rainer Fischer 5, 10, * , Ahmad Fawzi Hussain 3, * 1 Department of Experimental Medicine and Immunotherapy, Institute of Applied Medical Engineering, Helmholtz-Institute for Biomedical Engineering, 52074 Aachen, Germany 2 Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany 3 Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, 52074 Aachen, Germany 4 Department of Dermatology, University Hospital RWTH Aachen, 52074 Aachen, Germany 5 Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany 6 Department of Nuclear Medicine, University Hospital RWTH Aachen, 52074 Aachen, Germany 7 Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, 23538 Lübeck, Germany 8 Department of Pharmaceutical Product Development, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, 52074 Aachen, Germany 9 Current address: Institute of Infectious Disease and Molecular Medicine (IDM), Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa 10 Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany * These authors contributed equally to this work Correspondence to: Ahmad Fawzi Hussain, email: ahmad.hussain@rwth-aachen.de Keywords: breast cancer, theranostics, photodynamic therapy, molecular targeting, antibody-based therapy Received: April 20, 2016      Accepted: May 29, 2016      Published: July 19, 2016 ABSTRACT Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye ® 700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62–165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.