ABSTRACT
Methotrexate (MTX) injection has a short half-life and significant toxic side effects. In order to overcome the demerits of MTX injection, MTX@COF was prepared for subcutaneous injection by loading MTX in crosslinked cyclodextrin metal-organic framework (COF) in this study. The cationic lipid material (2, 3-dioleoyl-propyl)-trimethylamine (DOTAP) was then coated on the MTX@COF surface by solvent evaporation. Different surface charge characteristics were observed in the coated MTX@COF@DOTAP with no significant change in particle morphology. The in vitro release behaviors of sustained-release particles were investigated in water and phosphate buffer (pH 7.4), and the in vivo release characteristics were evaluated for pharmacokinetics in rats. The in vitro release results showed that the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 6 h was 92.70%, 36.31% and 18.19% in water, respectively; the cumulative release of MTX, MTX@COF and MTX@COF@DOTAP within 4 h was 90.82%, 79.37% and 58.30% in phosphate buffer, respectively; the results showed that MTX@COF can significantly delay the release of MTX, the modification to MTX@COF by DOTAP can further delay the release of MTX. Pharmacokinetic studies in rats showed that the mean retention time [MRT(0-t)] and the time to peak (Tmax) of the subcutaneous injection of MTX@COF@DOTAP group were significantly prolonged compared with the MTX@COF group and the MTX group. The area under the concentration-time curve [AUC(0-t)] of the MTX@COF@DOTAP subcutaneous injection group was 1.8 times high as that of the MTX group. In this study, MTX@COF@DOTAP particles had a certain sustained-release effect, and could prolong the bioavailability of MTX by subcutaneous injection, which provided a new idea for the development of new MTX dosage forms.