Metforminium 5-fluorouracilate: the first codrug molecular salt of 5-fluorouracil demonstrating perfected in vitro/vivo characteristics and synergic antitumor effects

In order to exert the ability of biguanide metformin (MET) in optimizing biopharmaceutical properties of conventional antitumor drug 5-fluorouracil (5-FU), and further to explore synergism potentials of the biguanide drugs in the anticancer medications, a synergistic efficacy enhancement route driven through codrug salification is developed, in which the proton transference procedure is actuated through the acid-base gap, which causes optimizations in physicochemical properties and pharmacokinetic behaviors for 5-FU, and furthermore efficacy enhancement by playing adjuvant antitumor effect of biguanide drugs. Under this path, a novel codrug molecular salt metforminium 5-fluorouracilate (FU-MET) is successfully prepared as the first case of dual-drug molecular salification for 5-FU, and subjected to structural characterizations by single-crystal/powder X-ray diffraction and other techniques, confirming the existence of charge-assist hydrogen bonds and secondary helical patterns which affect physicochemical characters. The dissolubility and permeability of 5-FU are proved to be simultaneously improved after assembling the codrug, which are theoretically supported by the results from molecular electrostatic potential, Hirshfeld surface analyses and frontier molecular orbit. Furthermore, the perfection in physicochemical natures of the present codrug also lead to optimization in pharmacokinetic behaviors with prolonged half-life and higher bioavailability over pure 5-FU. More encouragingly, significant reduction in IC50 values against tumor cell lines evidence the strengthened tumor inhibition of the present molecular salt, where the synergetic effect of MET with 5-FU is found according to the CI values less than 1.0. Our present findings not only start a dual-drug molecular salification case for 5-FU with the novel crystalline codrug possessing application foreground, but contribute for exploring the possibilities of biguanide represented by MET in antitumor medication.