Enhanced Gefitinib Cytotoxicity in the Presence of Cyclodextrins: In-Vitro and Biophysical Studies Towards Potential Therapeutic Interventions for Cancer

Gefitinib (Iressa^®) is an inhibitor of EGFR tyrosine kinase, used in the treatment of lung and other cancers. Its efficient use is severely hampered by very low solubility in water which can be improved by inclusion complexation with cyclodextrins. We have assayed the cytotoxic activity of gefitinib in two pediatric neuroblastoma tumor cell lines expressing EGFR at different levels and found that in the presence of two methylated β-cyclodextrin derivatives (DMβCD, TMβCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) the efficacy of the drug increased significantly. The effects were more pronounced in the presence of HPβCD and, as expected, in the cell line with higher EGFR expression. Biophysical studies were carried out using X-ray crystallography, NMR spectroscopy and molecular dynamics simulations to identify the structure of gefitinib in complex with the above cyclodextrin derivatives. The crystal structure confirms highly dynamic inclusion of gefitinib and the NMR experiments and molecular dynamics simulations show that in solution there is a preference for occupation of the cyclodextrin cavity by the chlorofluorophenol group of gefitinib.