Ultrasound-targeted microbubble destruction augmented synergistic therapy of rheumatoid arthritis via targeted liposomes.

Rheumatoid arthritis (RA) can lead to joint destruction and deformity, which is an essential reason for the loss of young and middle-aged labor force. However, the treatment of RA is still filled with challenges. Though the dexamethasone, one of the glucocorticoids, is commonly used in the treatment of RA, its clinical use is limited because of the high-dose and long-term use, unsatisfactory therapeutic effects, and various side-effects. Ultrasound-targeted microbubble destruction (UTMD) can augment the ultrasonic cavitation effects and trigger drug release from targeted nanocarriers in the synovial cavity, which makes it a more effective synergistic treatment strategy for RA. In this work, we aim to utilize the UTMD effect to augment the synergistic therapy of RA by using the polyethylene glycol (PEG)-modified folate (FA)-conjugated liposomes (LPs) via loading with dexamethasone sodium phosphate (DexSP) (DexSP@LPs-PEG-FA). The UTMD-mediated DexSP@LPs-PEG-FA for targeted delivery of DexSP including synergistic ultrasonic cavitation effect and drug therapy were investigated through in vitro RAW264.7 cell experiments and in vivo collagen-induced arthritis SD rat model animal expeiments. As a result, the DexSP releasing from targeted liposomes was improved under the UTMD effect. Likewise, the folate-conjugated liposomes displayed targeting association to RAW264.7 cells. Together with the application of ultrasound and microbubbles, liposomes-delivered DexSP potently reduced joints swelling, bone erosion, and inflammation in both joint and serum with a low dose. These results demonstrated that the UTMD-mediated folate-conjugated liposomes are not only a promising method for targeted synergistic treatment of RA but also may show high potential for serving as nanomedicines for many other biomedical fields.