A Complete Substitutional Analysis of VIP for Better Tumor Imaging Properties

J Mol Recognit. May-Jun 2002;15(3):145-53. doi: 10.1002/jmr.565.


Since numerous tumor cells overexpress the vasoactive intestinal peptide (VIP) receptor subtype 1 (VPAC(1)), VIP-dye conjugates would be useful as contrast agents for in vivo imaging. However, proteolytic degradation of VIP in vivo limits their diagnostic use and highlights the need for structurally optimized VIP derivatives with improved pharmacokinetics. Here, we applied parallel nano-synthesis of cleavable peptides on cellulose membranes to perform a complete VIP substitutional analysis. The resulting 504 different VIP-dye analogs were tested for cell binding by flow cytometry. They provided a detailed analysis of amino acid positions essential for binding to VPAC(1) overexpressing cells. A generalized VIP-dye binding motif derived from the substitutional analysis results served as a reference point for further optimization. An [Arg8]-VIP-dye analog showed increased stability towards proteolytic degradation, good tumor-to-tissue contrast in mice and a longer half-life in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Contrast Media / chemical synthesis
  • Contrast Media / chemistry
  • Contrast Media / metabolism
  • Diagnostic Imaging / methods*
  • Drug Design
  • Endopeptidases / metabolism
  • Flow Cytometry
  • Fluorescent Dyes / chemistry
  • Half-Life
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Sequence Data
  • Neoplasms / diagnosis*
  • Protein Conformation
  • Rats
  • Receptors, Vasoactive Intestinal Peptide / genetics
  • Receptors, Vasoactive Intestinal Peptide / metabolism
  • Receptors, Vasoactive Intestinal Polypeptide, Type I
  • Static Electricity
  • Vasoactive Intestinal Peptide / chemical synthesis
  • Vasoactive Intestinal Peptide / chemistry*
  • Vasoactive Intestinal Peptide / metabolism


  • Contrast Media
  • Fluorescent Dyes
  • Receptors, Vasoactive Intestinal Peptide
  • Receptors, Vasoactive Intestinal Polypeptide, Type I
  • Vasoactive Intestinal Peptide
  • Endopeptidases