Photochemical internalization of epidermal growth factor receptor-targeted drugs
Appears in the following Collection
- Farmasøytisk institutt 
AbstractLack of specificity of anticancer drug treatments represents a major limitation for cancer cure. Thus, novel strategies are required to increase the selectivity of cancer therapeutics. Adverse effects can be reduced by drug delivery systems which decrease uptake in normal cells and target the drug to the cancer cells. This can be achieved by linking the drug to a carrier, i.e. an antibody or ligand which specifically recognizes cancer cells. In addition, limited penetration through the plasma membrane is a major obstacle for macromolecular therapy and a modality for cytosolic drug delivery is therefore warranted.
The present thesis concerns epidermal growth factor receptor (EGFR) targeting toxins delivered by photochemical internalization (PCI) as a possible modality for selective treatment of cancer. It was found that PCI of EGFR targeting toxins exerts a 3-fold selectivity towards cancer cells: (i) the photosensitizer is preferentially retained in tumour tissues, (ii) the light is directed only to the tumour area and (iii) utilization of an anticancer drug which targets EGFR positive cancer cells. Studies on protein signal transduction revealed, however, possible interactions between the EGFR targeting drugs and photochemical reactions and the method therefore needs to be optimized with respect to the targeting moiety as well as the treatment protocol.
List of publications
I: Weyergang A., Selbo P.K., and Berg K. (2006): Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF-saporin. J.Control Release. 111: 165-173.
II: Yip W.L., Weyergang A., Berg K., Tønnesen H.H., and Selbo P.K. (2007): Targeted delivery and enhanced cytotoxicity of cetuximab-saporin by photochemical internalization in EGFR-positive cancer cells. Mol.Pharm. 4:241-251.
III: Weyergang A., Selbo P.K., and Berg K. (2007): Y1068 phosphorylation is the most sensitive target of disulfonated tetraphenylporphyrin-based photodynamic therapy on epidermal growth factor receptor. Mol.Cancer Ther. 7:1740-1750.
V: Weyergang A., Kaalhus O., and Berg K. (2008): Photodynamic targeting of EGFR does not predict the treatment outcome in combination with the EGFR tyrosine kinase inhibitor Tyrphostin AG1478. Photochem.Photobiol.Sci. 7, 1032–1040.
VI: Weyergang A. and Berg K. (2008): Photodynamic therapy in combination with Tyrphostin AG1478 and Cetuximab act distinctly on EGFR and downstream signalling causing opposite cytotoxic responses. Submitted