title: EGFR-targeting peptide-coupled platinum(IV) complexes.
abstract: The high mortality rate of lung cancer patients and the frequent occurrence of side effects during cancer therapy demonstrate the need for more selective and targeted drugs. An important and well-established target for lung cancer treatment is the occasionally mutated epidermal growth factor receptor (EGFR). As platinum(II) drugs are still the most important therapeutics against lung cancer, we synthesized in this study the first platinum(IV) complexes coupled to the EGFR-targeting peptide LARLLT (and the shuffled RTALLL as reference). Notably, HPLC-MS measurements revealed two different peaks with the same molecular mass, which turned out to be a transcyclization reaction in the linker between maleimide and the coupled cysteine moiety. With regard to the EGFR specificity, subsequent biological investigations (3-day viability, 14-day clonogenic assays and platinum uptake) on four different cell lines with different verified EGFR expression levels were performed. Unexpectedly, the results showed neither an enhanced activity nor an EGFR expression-dependent uptake of our new compounds. Consequently, fluorophore-coupled peptides were synthesized to re-evaluate the targeting ability of LARLLT itself. However, also with these molecules, flow cytometry measurements showed no correlation of drug uptake with the EGFR expression levels. Taken together, we successfully synthesized the first platinum(IV) complexes coupled to an EGFR-targeting peptide; however, the biological investigations revealed that LARLLT is not an appropriate peptide for enhancing the specific uptake of small-molecule drugs into EGFR-overexpressing cancer cells.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Mayr
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hager
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
authors.forename: Bettina
authors.initials: B
authors.lastname: Koblmüller
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Matthias H M
authors.initials: MHM
authors.lastname: Klose
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Holste
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Britta
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Karla
authors.initials: K
authors.lastname: Pelivan
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria.|Research Cluster ''Translational Cancer Therapy Research'', University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090, Vienna, Austria. petra.heffeter@meduniwien.ac.at.|Research Cluster ''Translational Cancer Therapy Research'', University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria. petra.heffeter@meduniwien.ac.at.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria. christian.kowol@univie.ac.at.|Research Cluster ''Translational Cancer Therapy Research'', University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria. christian.kowol@univie.ac.at.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Kowol
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.|Research Cluster ''Translational Cancer Therapy Research'', University of Vienna, Waehringer Strasse 42, A-1090, Vienna, Austria.
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010455:Peptides; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Anticancer drug; EGFR; Peptides; Platinum complexes