Solid-phase synthesis of oxaliplatin-TAT peptide bioconjugates

Dalton Trans. 2012 Mar 14;41(10):3001-5. doi: 10.1039/c2dt12024k. Epub 2012 Jan 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Chemistry Techniques, Synthetic / methods*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / chemistry*
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Peptide Fragments / chemistry*
  • tat Gene Products, Human Immunodeficiency Virus / chemistry*

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Peptide Fragments
  • tat Gene Products, Human Immunodeficiency Virus
  • Oxaliplatin