title: Novel zinc phthalocyanine as a promising photosensitizer for photodynamic treatment of esophageal cancer.
abstract: Photodynamic therapy (PDT) has gathered much attention in the field of cancer treatment and is increasingly used as an alternative solution for esophageal cancer therapy. However, there is a constant need for improving the effectiveness and tolerability of the applied photosensitizers (PS). Here, we propose tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) as a promising PS for photodynamic treatment of esophageal cancer. ZnPc-induced phototoxicity was studied in two human esophageal cancer cell lines: OE-33 (adenocarcinoma) and Kyse-140 (squamous cell carcinoma). In vitro studies focused on the uptake and intracellular distribution of the novel ZnPc as well as on its growth inhibitory potential, reactive oxygen species (ROS) formation and the induction of apoptosis. The chicken chorioallantoic membrane assay (CAM assay) and studies on native Wistar rats were employed to determine the antineoplastic and antiangiogenic activity of ZnPc-PDT as well as the tolerability and safety of non-photoactivated ZnPc in vivo. ZnPc was taken up by cancer cells in a dose- and time-dependent manner and showed a homogeneous cytoplasmic distribution. Photoactivation of ZnPc-loaded (1-10 µM) cells led to a dose-dependent growth inhibition of esophageal adenocarcinoma and squamous cell carcinoma cells of >90%. The antiproliferative effect was based on ROS-induced cytotoxicity and the induction of mitochondria-driven apoptosis. In vivo studies on esophageal tumor plaques grown on the CAM revealed pronounced antiangiogenic and antineoplastic effects. ZnPc-PDT caused long-lasting changes in the vascular architecture and a marked reduction of tumor feeding blood vessels. Animal studies confirmed the good tolerability and systemic safety of ZnPc, as no changes in immunological, behavioral and organic parameters could be detected upon treatment with the non-photoactivated ZnPc. Our findings show the extraordinary photoactive potential of the novel ZnPc as a photosensitizer for PDT of esophageal cancer.
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Weronika
authors.initials: W
authors.lastname: Kuzyniak
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jacob
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, Gdansk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Glac
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Berkholz
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gustav
authors.initials: G
authors.lastname: Steinemann
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Hoffmann
authors.affiliation: Federal Institute for Materials Research and Testing (BAM), Division Biophotonics, Berlin, Germany.
authors.forename: Eugeny A
authors.initials: EA
authors.lastname: Ermilov
authors.affiliation: Department of Chemistry, Gebze Technical University, Gebze, Turkey.
authors.forename: Ayşe Gül
authors.initials: AG
authors.lastname: Gürek
authors.affiliation: Department of Chemistry, Gebze Technical University, Gebze, Turkey.
authors.forename: Vefa
authors.initials: V
authors.lastname: Ahsen
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Nitzsche
authors.affiliation: Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Höpfner
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000628:therapy*; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D054833:Isoindoles; D009942:Organometallic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D017967:Zinc Compounds
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007211:Indoles; D054833:Isoindoles; D009942:Organometallic Compounds; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; D017967:Zinc Compounds; C052159:Zn(II)-phthalocyanine