Photodynamic molecular beacon triggered by fibroblast activation protein on cancer-associated fibroblasts for diagnosis and treatment of epithelial cancers

J Med Chem. 2009 Jan 22;52(2):358-68. doi: 10.1021/jm801052f.

Abstract

Fibroblast activation protein (FAP) is a cell-surface serine protease highly expressed on cancer-associated fibroblasts of human epithelial carcinomas but not on normal fibroblasts, normal tissues, and cancer cells. We report herein a novel FAP-triggered photodynamic molecular beacon (FAP-PPB) comprising a fluorescent photosensitizer and a black hole quencher 3 linked by a peptide sequence (TSGPNQEQK) specific to FAP. FAP-PPB was effectively cleaved by both human FAP and murine FAP. By use of the HEK293 transfected cells (HEK-mFAP, FAP(+); HEK-vector, FAP(-)), systematic in vitro and in vivo experiments validated the FAP-specific activation of FAP-PPB in cancer cells and mouse xenografts, respectively. FAP-PPB was cleaved by FAP, allowing fluorescence restoration in FAP-expressing cells while leaving non-expressing FAP cells undetectable. Moreover, FAP-PPB showed FAP-specific photocytotoxicity toward HEK-mFAP cells whereas it was non-cytotoxic toward HEK-Vector cells. This study suggests that the FAP-PPB is a potentially useful tool for epithelial cancer detection and treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / physiology*
  • Biomarkers, Tumor / physiology*
  • Blotting, Western
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Fibroblasts / cytology
  • Flow Cytometry
  • Gelatinases
  • Humans
  • Immunohistochemistry
  • Membrane Proteins
  • Mice
  • Microscopy, Confocal
  • Neoplasms, Glandular and Epithelial / diagnosis*
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / pathology
  • Photochemotherapy*
  • Serine Endopeptidases / physiology*

Substances

  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Membrane Proteins
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases