title: Solid-phase synthesis of oxaliplatin-TAT peptide bioconjugates.
abstract: Platinum-based drugs play a crucial role in the fight against cancer. Oxaliplatin, which is used in the treatment of colorectal carcinoma, was the last platinum-based agent to be approved worldwide. However, the efficiency of the therapy is limited for example by a low accumulation of the drug in cancer cells. Cell-penetrating peptides (CPPs) are known to ease the cellular membrane transport and are used as vectors for low-molecular-weight drugs and drug carriers; of them, TAT peptides are the best-studied group. In this work, a TAT-peptide fragment (YGRKKRRQRRR) was for the first time conjugated to a platinum(IV) analog of oxaliplatin as a vehicle for membrane penetration. Solid-phase peptide synthesis and subsequent coupling with the platinum complex afforded mono- and difunctionalized conjugates, which were separated by preparative HPLC and characterized by analytical HPLC, ESI-MS, and (1)H NMR spectroscopy. Both conjugates are active in the low micromolar range in CH1 and SW480 human cancer cells, requiring much lower concentrations than the untargeted analogs for equal effects.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Sergey
authors.initials: S
authors.lastname: Abramkin
authors.forename: Seied M
authors.initials: SM
authors.lastname: Valiahdi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Mathea
authors.initials: S
authors.lastname: Galanski
authors.forename: Nils
authors.initials: N
authors.lastname: Metzler-Nolte
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin; D010446:Peptide Fragments / Q000737:chemistry*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077150:Oxaliplatin