title: A light-controlled switch after dual targeting of proliferating tumor cells via the membrane receptor EGFR and the nuclear protein Ki-67.
abstract: Using nanotechnology for optical manipulation of molecular processes in cells with high spatial and temporal precision promises new therapeutic options. Especially tumor therapy may profit as it requires a combination of both selectivity and an effective cell killing mechanism. Here we show a dual targeting approach for selective and efficient light-controlled killing of cells which are positive for epidermal growth factor receptor (EGFR) and Ki-67. Liposomes with the covalently linked EGFR antibody Erbitux enabled selective uptake of FITC-labeled Ki-67 antibody TuBB-9 in EGFR-positive cells pre-loaded with the photoactive dye BPD. After irradiation at 690 nm, BPD disrupted the endosomal membranes and delivered the antibodies to the nucleoli of the cells. The second irradiation at 490 nm activated the FITC-labeled TuBB-9, which caused inactivation of the Ki-67 protein and subsequent cell death via apoptosis. Efficient cell killing was possible at nanomolar concentrations of TuBB-9 due to the effective transport by immune liposomes and the high efficacy of the Ki-67 light-inactivation. Delivery of the liposomal constructs and cell destruction correlated well with the EGFR expression pattern of different cell lines (HeLa, OVCAR-5, MCF-7, and human fibroblasts), demonstrating an excellent selectivity.
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.|Institute of Biomedical Optics, University of Lübeck, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.
authors.forename: Sijia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Institute of Biomedical Optics, University of Lübeck, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.
authors.forename: Gereon
authors.initials: G
authors.lastname: Hüttmann
authors.affiliation: Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, 23845 Borstel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Scholzen
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Biomedical Analytical Technology and Instrumentation, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P. R. China.
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Biomedical Optics, University of Lübeck, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Vogel
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom St, Boston, MA 02114, USA.
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
authors.affiliation: Institute of Biomedical Optics, University of Lübeck, Peter-Monnik-Weg 4, 23562 Lübeck, Germany.
authors.forename: Ramtin
authors.initials: R
authors.lastname: Rahmanzadeh
mesh_terms: D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism*; D008027:Light; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D061986:MCF-7 Cells; D009928:Organ Specificity; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011166:Porphyrins / Q000494:pharmacology; D011485:Protein Binding; D000077362:Verteporfin
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D008081:Liposomes; D017319:Photosensitizing Agents; D011166:Porphyrins; D000077362:Verteporfin; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab