Microwave hyperthermia-responsible flexible liposomal gel as a novel transdermal delivery of methotrexate for enhanced rheumatoid arthritis therapy.Methotrexate (MTX) as an anti-inflammatory drug for the treatment of rheumatoid arthritis (RA) through oral and injectable administration is still problematic in the clinic.  Herein, a MTX-loaded thermal-responsible flexible liposome (MTFL) incorporated within a carbomer-based gel was prepared as a novel transdermal agent (MTFL/Gel) for effective treatment of RA.  It was found that MTFL had an average size of approximately 90 nm, which could rapidly release the drug under thermal conditions.  Moreover, the results suggested MTFL/Gel could lead to a remarkably enhanced RA treatment when in combination with microwave hyperthermia.  The superior ability of MTFL/Gel to alleviate RA response was attributed to the excellent skin permeation, thermal-responsible drug release, and synergistic anti-arthritic effect of MTX chemotherapy and microwave-induced hyperthermia therapy.  Overall, the MTFL/Gel with dual deformable and thermal-responsible performances could be used as a novel promising transdermal agent for enhanced treatment of RA.
THERM