A novel sustained-release formulation of 5-fluorouracil-phenylalanine cocrystal self-assembled by cocrystal-entrapped micelle strategy displays enhanced antitumor efficacy

In order to simultaneously perfect the release behavior and antiproliferation effect of anticarcinogen 5-fluorouracil (Fu), and achieve the dual optimization with both long-term efficacy and high-performance, thus gaining bran-new insights into the development of functional nano-formulation for anticancer pharmaceutical cocrystals, a cocrystal-entrapped micelle self-assembly strategy is proposed by integrating nanomicellar preparation and cocrystallization technologies together. Therein, the physico-chemical properties of Fu are regulated by cocrystallization technique, improving its antitumor activity; while the long-term efficacy can be maintained by giving full play to superiority of nanomicellar preparation technology. Along this line, the zwitterionic cocrystal of Fu with l-phenylalanine (Phe), viz. Fu-Phe, previously reported by our group with superior antitumor activities has been encapsulated into nanocarriers PEG-PCL, successfully assembling into cocrystal micelles, which feature the spherical particles of 182.8 nm with good uniformity and dispersion. The in vitro/vivo traits of the cocrystal micelles are systematically investigated by combining theoretical calculations with experimental tests. The outcomes suggest that the entrapment efficiency and drug loading for the obtained cocrystal micelles are far beyond Fu itself micelles, which has also been revealed by the simulation study of the interaction energy between PEG-PCL and the loaded drugs based on the theoretical calculations of electrostatic potential together with geometric optimization. The excellent encapsulation effects of the cocrystal micelles have not only given rise to ameliorated antitumor ability with low IC50 values, but eventually brought about the better in vivo pharmacokinetics with enhanced bioavailability and extended half-life. Noticeably, the present cocrystal micelles also display significant sustained-release ability relative to Fu micelles, which lays a cornerstone for further realizing the long lasting-efficacy and reducing frequent administration and even toxicity. These findings provide an innovative dosage form for Fu cocrystal with long-acting and high efficiency, thus breaking fresh pathway for the formulation development of antitumor pharmaceutical cocrystals.