Targeted delivery and enhanced cytotoxicity of cetuximab-saporin by photochemical internalization in EGFR-positive cancer cells

Mol Pharm. Mar-Apr 2007;4(2):241-51. doi: 10.1021/mp060105u. Epub 2007 Jan 31.

Abstract

Photochemical internalization (PCI) is a novel technology of macromolecular delivery. By PCI, endocytosed membrane-impermeable therapeutic drugs are photochemically released from entrapment in endo-lysosomal compartments to the cytosol of target cells. In the present report, we describe the in vitro proof-of-concept for PCI of cetuximab-saporin, an immunotoxin targeting EGFR-expressing cells. This immunotoxin consists of the chimeric murine-human IgG1 monoclonal antibody cetuximab (C225 or Erbitux) bound to the type I ribosome-inactivating protein toxin saporin by a biotin-streptavidin linkage. The photochemical treatment enhanced the cytotoxicity of the immunotoxin in a synergistic manner in three different EGFR-expressing carcinoma cell lines derived from different tumor tissues (colorectal, HCT-116; prostate, DU-145; and epidermis, A-431). Both cytotoxicity of cetuximab-saporin and epifluorescence of Alexa488-cetuximab were evaluated by competition with cetuximab demonstrating specific binding and uptake of cetuximab-saporin in EGFR positive cells. In the EGFR-negative uterine sarcoma cell line MES-SA, neither binding nor preferential accumulation of Alexa488-cetuximab was detected. In addition, PCI enhanced the cytotoxicity of cetuximab-saporin to the same extent as streptavidin-saporin in the MES-SA cells. In conclusion, PCI enhances selectivity of the cytotoxicity of the immunotoxin cetuximab-saporin in EGFR-expressing cells.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal* / pharmacokinetics
  • Antibodies, Monoclonal* / pharmacology
  • Antibodies, Monoclonal, Humanized
  • Cell Line, Tumor
  • Cell Survival
  • Cetuximab
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems / methods*
  • Drug Synergism
  • ErbB Receptors / metabolism*
  • Humans
  • Light
  • Models, Biological
  • Neoplasms / drug therapy*
  • Phosphorylation
  • Photochemotherapy
  • Saponins / pharmacology*

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Saponins
  • ErbB Receptors
  • Cetuximab