An epidermal growth factor receptor-targeted and endoplasmic reticulum-localized organic photosensitizer toward photodynamic anticancer therapy

• DOI: 10.1016/j.ejmech.2019.111625
• Publication Date: 2019-08-14T11:34:03Z
• Authors: Xuan Zhao; Haixia Ma; Juanjuan Chen; Fengling Zhang; Xiao Jia; Jinping Xue
• Keywords: Membrane Potential, Mitochondrial; Photosensitizing Agents; Cell Death; Dose-Response Relationship, Drug; Molecular Structure; Antineoplastic Agents; Endoplasmic Reticulum; 01 natural sciences; 0104 chemical sciences; 3. Good health; ErbB Receptors; Structure-Activity Relationship; Photochemotherapy; Humans; Organosilicon Compounds; Drug Screening Assays, Antitumor; Reactive Oxygen Species; Cells, Cultured; Cell Proliferation

The endoplasmic reticulum (ER), as the largest organelle in eukaryotic cells, plays complex but pivotal roles in multiple intracellular metabolic functions, including biosynthesis, sensing, and signal transduction, especially in proteins folding and post-translation modification. The ER is regarded as a promising target for anticancer therapy. Based on previous tumor-targeted photodynamic therapy (PDT), we chemically modified the phthalocyanine-based photosensitizer molecule with the small molecular anticancer-targeting drug erlotinib and the ER-targetable moiety methyl sulfonamide to develop an advanced photosensitizer EB-ER-Pc that can specifically target the subcellular organelle ER of EGFR-overexpressing cancer cells. The in vitro experiments show that the dual-target photosensitizer EB-ER-Pc can generate ROS in situ in the ER of the tumor target region to induce ER stress, upregulate Ca2+ ion level, and decrease mitochondrial membrane potential (MMP) to mediate cancer cells death and ablation. The results suggest that EB-ER-Pc is a promising candidate for effective photodynamic cancer therapy.