Caffeic Acid Modified Nanomicelles Inhibit Articular Cartilage Deterioration and Reduce Disease Severity in Experimental Inflammatory Arthritis

作者：Akshay Vyawahare, Ravi Prakash, Chandrashekhar Jori, Aneesh Ali, Syed Shadab Raza, Rehan Nabi Khan · 发表于：ACS Nano · 年份：2022 · DOI：10.1021/acsnano.2c07027 · 被引用次数：54 · 研究领域：Nuclear Receptors and Signaling、Macrophage Migration Inhibitory Factor、RNA Interference and Gene Delivery

Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDA-approved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG- b -PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG- b -PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CA-conjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therap...