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Caffeic Acid Modified Nanomicelles Inhibit Articular Cartilage Deterioration and Reduce Disease Severity in
Akshay Vyawahare1, Ravi Prakash2, Chandrashekhar Jori1
1Chemical Biology Unit, Institute of Nano Science and Technology, Knowledge City, Sector-81, Sahibzada Ajit Singh Nagar, Mohali, Punjab140306, India.
Abstract:
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 therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.
Insights
This study developed novel nanomicelles encapsulating 9-aminoacridine and caffeic acid for rheumatoid arthritis (RA) treatment. The nanomicelles effectively reduced inflammation, joint damage, and bone erosion in an RA model, offering a promising new therapy.
Area of Science:
- Nanomedicine and Drug Delivery
- Rheumatology and Immunology
- Molecular Pharmacology
Background:
- Rheumatoid arthritis (RA) is an inflammatory disease driven by inflammatory stimuli.
- NR4A1 is an anti-inflammatory nuclear receptor crucial for protecting against RA inflammation.
- Current RA treatments often focus on symptom management with limited efficacy.
Purpose of the Study:
- To explore the anti-inflammatory potential of 9-aminoacridine (9AA) and caffeic acid (CA) for RA treatment.
- To develop and characterize 9AA-encapsulated, CA-conjugated nanomicelles (9AA-NMs) for enhanced RA therapy.
- To evaluate the therapeutic efficacy of 9AA-NMs in an experimental model of RA.
Main Methods:
- Synthesis of methoxy polyethylene glycol-polycaprolactone (mPEG-b-PCL) block copolymer.
- Conjugation of caffeic acid (CA) to mPEG-b-PCL micelles and incorporation of 9-aminoacridine (9AA).
- Formulation of nanomicelles (approx. 190 nm) via solvent evaporation, assessing drug loading and release kinetics.
- Evaluation of 9AA-NMs in an experimental RA model, analyzing inflammatory markers, joint damage, and cartilage integrity.
Main Results:
- Formulated 9AA-NMs exhibited optimal drug loading and sustained drug release.
- 9AA-NMs significantly alleviated RA symptoms, including inflammation, joint damage, bone erosion, and swelling.
- Significant reduction in collagen destruction in articular cartilage was observed.
- The mechanism involves simultaneous NF-κB inhibition by 9AA and CA, and NR4A1 activation by 9AA, suppressing HIF-1α.
Conclusions:
- The combined therapeutic effect of 9AA and CA within nanomicelles enhances efficacy against inflammatory arthritis.
- 9AA-NMs demonstrate marked therapeutic efficacy in reducing RA severity, surpassing current pain management drugs.
- This novel nanomicelle formulation offers a disease-modifying approach for rheumatoid arthritis treatment.
