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Selective and Effective Cancer Treatments using Target‐Switchable Intracellular Bacterial Toxin Delivery Systems
Author(s) -
Park Seong Guk,
Choi Bongseo,
Bae Yoonji,
Lee Yu Geon,
Park Soo Ah,
Chae Young Chan,
Kang Sebyung
Publication year - 2020
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000043
Subject(s) - endocytosis , endosome , intracellular , cancer cell , diphtheria toxin , anthrax toxin , immunotoxin , epidermal growth factor receptor , microbiology and biotechnology , in vivo , cytosol , toxin , biology , receptor , cytotoxicity , in vitro , chemistry , cancer , biochemistry , recombinant dna , fusion protein , genetics , gene , enzyme
Targeted cancer therapies have been extensively tested with the purpose to selectively suppress tumor growth and to avoid harming healthy tissue. However, failure to escape endosomes upon receptor‐mediated endocytosis is a major obstacle limiting the efficacy of targeted cancer therapeutics. Here, novel target‐switchable intracellular toxin delivery systems (TiTDS) are presented which use the catalytic and translocation domain of diphtheria toxin (dtA‐T) as an intracellular toxin delivery platform and affibody molecules targeting human epidermal growth factor receptor 2 or epidermal growth factor receptor (HER2Afb or EGFRAfb) as target‐specific ligands. The intracellular toxin delivery platform and the affibody molecules are genetically fused with SpyCatcher (SC) protein and SpyTag (ST) peptide, respectively, to generate dtA‐T‐SC and ST‐HER2Afb or ST‐EGFRAfb modules. These modules can be individually purified and post‐translationally ligated to produce dtA‐T/HER2Afb or dtA‐T/EGFRAf. dtA‐T/HER2Afb and dtA‐T/EGFRAfb can selectively bind to their corresponding target cancer cells, efficiently enter the cells through receptor‐mediated endocytosis, successfully escape endosomes, and release toxins into the cytosol. They exhibit high target‐specific cytotoxicity in vitro and can significantly reduce tumor masses in vivo. TiTDS is a promising targeted cancer therapy platform because of its high target specificity, effective intracellular delivery of active toxins with improved therapeutic efficacy, and target switchability.