Supramolecular self-assembly and perfected in vitro/vivo property of 5-fluorouracil and ferulic acid on the strength of double optimized strategy: The first 5-fluorouracial-phenolic acid nutraceutical cocrystal with synergistic antitumor efficacy

For highlighting the predominance of phenolic acid nutraceutical ferulic acid (FR) in regulating in vivo/vitro performances of anticancer drug 5-fluorouracil (Flu), and strengthening their cooperativity in antitumor effect, thus achieving a major breakthrough in the development of drug-nutraceutical cocrystal with synergistic antitumor action, a cocrystallization strategy of dual optimization is created, in which both in vivo and vitro natures of Flu are improved by exploiting FR's excellent physicochemical property, and meanwhile Flu's anticancer effects are promoted by exerting the assistant antitumor peculiarity of FR. Such dual optimization of FR for Flu in physicochemical properties and anticancer activities is beneficial to realizing synergistic augmentation effect by playing the cooperativeness of Flu and FR in anticancer ability. Based on this idea, a novel cocrystal of Flu and FR, namely, Flu-FR-H2O, is successfully assembled as the first 5-fluorouracil-nutraceutical cocrystal with synergistic antitumor effect, and its explicit structure is resolved. The single-crystal X-ray diffraction demonstrates that Flu and FR have a ratio of 1:1 with one equivalent of solvent water in the cocrystal, where one-dimensional hydrogen-bonding helixes and FR-Flu hydrogen-bonding pairs, together construct a three-dimensional supramolecular network. By combining experimental evaluation with theoretical analysis, the in vitro/vivo pharmaceutical properties are scientifically investigated. The results discover that the permeability and aqueous solubility of Flu are respectively elevated by 5.08 and 1.64 folds, which has brought about the ameliorated pharmacokinetics, performing prolonged retention time and increased oral bioavailability. More interestingly, the cocrystal shows synergistic inhibition ability of Flu and FR against the tested tumor cell strains, hence laying the groundwork for reducing the dosage and even toxic side effects of Flu. As a result of that the present research not only provides a new strategy for Flu to optimize its physicochemical properties and antitumor activities simultaneously, but also offers some opinions for the development of synergistic antitumor pharmaceutical cocrystals.