Interaction of a new anticancer prodrug, gemcitabine–squalene, with a model membrane☆Coupled DSC and XRD study

Gemcitabine is an anticancer nucleoside analogue active against a wide variety of solid tumors. However it is rapidly deaminated to an inactive metabolite, leading to short biological half-life and induction of resistance. A new prodrug of gemcitabine, coupling squalene to gemcitabine (GemSq), has been designed to overcome the above drawbacks. It has been previously shown that this prodrug displays significantly higher anticancer activity than gemcitabine against leukemia. In the present study the structural modifications of dipalmitoylphosphatidylcholine (DPPC) model membranes induced by increasing concentrations of GemSQ have been investigated using small and wide angle X-ray scattering (SWAXS) and differential scanning calorimetry (DSC). At room temperature an unusual inverse bicontinuous cubic phase formed over a broad composition range. The basic bilayer structure displayed an intermediate order between those of the gel and fluid phases of DPPC. A reversible transition to a fluid lamellar phase occurred upon heating. The transitions between these two phases were governed by different mechanisms depending on the GemSq concentration in the membrane. Finally, the biological relevance of these observations for the cytotoxic activity of GemSq has been discussed.