EGFR-targeting peptide-coupled platinum(IV) complexes

• DOI: 10.1007/s00775-017-1450-7
• Publication Date: 2017-04-12T03:51:53Z
• Authors: Josef Mayr; Sonja Hager; Bettina Koblmüller; Matthias H. M. Klose; Katharina Holste; Britta Fischer; Karla Pelivan; Walter Berger; Petra Heffeter; Christian R. Kowol; Bernhard K. Keppler
• Keywords: MECHANISM; Platinum complexes; Organoplatinum Compounds; EGFR; CELL LUNG-CANCER; 104004 Chemical biology; Antineoplastic Agents; 01 natural sciences; DELIVERY; Structure-Activity Relationship; 03 medical and health sciences; 0302 clinical medicine; SDG 3 - Good Health and Well-being; Cell Line, Tumor; Humans; 104003 Inorganic chemistry; Cell Proliferation; Original Paper; Dose-Response Relationship, Drug; Molecular Structure; Anticancer drug; IN-VITRO; CHEMOTHERAPY; TRANSCYCLIZATION; 3. Good health; 0104 chemical sciences; 104004 Chemische Biologie; ErbB Receptors; HYDROGEN-PEROXIDE OXIDATION; SDG 3 – Gesundheit und Wohlergehen; LIGAND; Drug Screening Assays, Antitumor; GROWTH-FACTOR RECEPTOR; INHIBITORS; Peptides; 104003 Anorganische Chemie

The high mortality rate of lung cancer patients and the frequent occurrence side effects during therapy demonstrate need for more selective targeted drugs. An important well-established target treatment is occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still most therapeutics against cancer, we synthesized in this study first platinum(IV) complexes coupled to EGFR-targeting peptide LARLLT (and shuffled RTALLL as reference). Notably, HPLC–MS measurements revealed two different peaks with same molecular mass, which turned out be a transcyclization reaction linker between maleimide cysteine moiety. With regard EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays platinum uptake) on four cell lines verified expression levels were performed. Unexpectedly, results showed neither an enhanced activity nor expression-dependent uptake our new compounds. Consequently, fluorophore-coupled peptides re-evaluate targeting ability itself. However, also these molecules, flow cytometry no correlation drug levels. Taken together, successfully peptide; however, that not appropriate enhancing specific small-molecule into EGFR-overexpressing cells.