To reduce the side effects of methotrexate and increase its anti-inflammatory effect, we developed a drug delivery system, dextran sulfate-modified methotrexate-loaded layered double hydroxide nanocomposites (LDH-MTX-DS), with both targeting and pH-sensitivity for the treatment of rheumatoid arthritis. The nanocomposites had a mean particle size of 303.1 ± 8.07 nm, zeta potential of - 12.4 ± 0.7 mV, encapsulation efficiency of 49.64%, and loading efficiency of 16.81%. In vitro release experiments demonstrated that the drug was released faster in PBS at pH 5.5 than at pH 7.4, which reflected the pH-sensitivity of this system. Cellular uptake assays displayed higher cellular uptake rate of the dextran sulfate-modified targeting carrier compared with that of a non-targeting carrier (P < 0.01), which indicated that the LDH-MTX-DS could actively target scavenger receptors on the surface of activated RAW 264.7 cells. In vivo pharmacodynamic experiments showed that, after the second (P < 0.001) and third (P < 0.05) administrations, the preparation group exhibited significantly improved therapeutic efficacy in adjuvant-induced arthritis (AIA) rats when compared with free MTX alone. These results indicated that this drug delivery system was promising in the treatment of rheumatoid arthritis. Graphical abstract.
Keywords: Dextran sulfate; Layered double hydroxides; Methotrexate; Rheumatoid arthritis; Scavenger receptor; pH-sensitive.