Inclusion Complexes Between β‐cyclodextrin and the Anticancer Drug 5‐Fluorouracil for its Solubilization: a Molecular Dynamics Study at Different Stoichiometries

Cyclodextrins (CDs) are natural macrocyclic oligosaccharides able to solubilize hydrophobic drugs in water improving their bioavailability, thanks to favorable noncovalent interactions particularly in their hydrophobic cavity. Using a simulation protocol proposed in previous work, in this theoretical study based on Molecular Mechanics (MM) and Molecular Dynamics (MD) methods, inclusion complexes between beta-cyclodextrin and 5-Fluorouracil (5-FU) are investigated. 5-FU is an anticancer drug hardly soluble in water used for more than 50 years. This drug is mainly administered by intravenous injection for the treatment of inner cancers or as a cream in the case of skin-related cancers. For drug delivery applications, it is important to characterize stable inclusion complexes at different drug concentrations in order to enhance the anticancer activity by maintaining lower dose, thus reducing cytotoxic effects on the normal cells, causing several negative impacts in the course of treatment. In this work, the structure and stability of the host-guest complexes beta-CD:5-FU in a 1:1 and 1:2 stoichiometries are investigated because this drug is relatively small compared to the size of the hydrophobic beta-CD cavity. The 5-FU complexes with CDs allow its solubilization, thanks to favorable van der Waals interactions. Interestingly, these intermolecular interactions in inclusion complexes may also affect the release profile. MD simulations are a powerful tool to evaluate interactions between hydrophobic anticancer drugs and hydrophilic carriers with an inner hydrophobic cavity such as CDs and oligosaccharides in general.