Tetrandrine nanocrystals for rheumatoid arthritis: enhanced therapeutic efficacy associated with reduced JAK1 and STAT3 expression.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent pain and a significant decline in quality of life. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, exhibits significant antipyretic, analgesic, and anti-inflammatory effects. However, its low solubility in water limits its clinical applications. Objective: This study focuses on the preparation of tetrandrine nanocrystals (Tet-NCs) using ultrasound technology and evaluates their therapeutic effects and potential mechanisms in a rat model of adjuvant arthritis (AA). METHODS: The AA model was induced using Freund's complete adjuvant (FCA). Tet-NCs were prepared via ultrasound technology and administered at varying doses. The efficacy of Tet-NCs was compared with that of Tet tablets and indomethacin tablets. The assessed outcomes include joint swelling, arthritis scores, pathological changes in the joints, levels of inflammatory factors (interleukin-6, interleukin-1β, tumor necrosis factor-α, prostaglandin E2, cyclooxygenase-2, vascular endothelial growth factor A, and matrix metalloproteinase-3) in joint cavities and serum, as well as the angiogenesis in synovial tissues and the expression of key proteins-Janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3). KEY FINDINGS: Experimental data indicate that the average particle size of the optimized Tet-NCs is 124.30 nm, with a polydispersity index (PDI) of 0.27. The therapeutic effects of low-dose Tet-NCs were comparable to those of Tet tablets, while medium- and high-dose Tet-NCs were significantly more effective than Tet tablets in reducing ankle joint swelling, lowering inflammatory factors levels, and protecting joint structure, and showed no statistically significant difference from indomethacin under the tested conditions. Furthermore, the expression levels of JAK1 and STAT3 in the AA model were significantly reduced by both medium- and high-dose Tet-NCs (all P < .001). CONCLUSION: This study demonstrates that Tet-NCs provide superior therapeutic effects in RA compared to conventional Tet tablets, and their mechanism of action may involve the regulation of inflammation through inhibition of the JAK1/STAT3 signaling pathway. Consequently, Tet-NCs show potential for further development as a novel anti-arthritic agent, although their clinical applicability remains to be validated in future studies. Clinical trial number: not applicable.