A bioactive and biodegradable vitamin C stearate-based injectable hydrogel alleviates experimental inflammatory arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory joint disorder affecting nearly 1% of the global population. In RA, synovial joints are infiltrated by inflammatory mediators and enzymes, leading to articular cartilage deterioration, joint damage, and bone erosion. Herein, the 9-aminoacridine-6-O-stearoyl-L-ascorbic acid hydrogel (9AA-SAA hydrogel) was formulated by the heat-cool method and further characterized for surface charge, surface morphology, rheology, and cytocompatibility. Furthermore, we evaluated the therapeutic efficacy of the 9AA-SAA hydrogel, an enzyme-responsive drug delivery system with on-and-off switching capabilities based on disease severity against collagen-induced experimental arthritis in Wistar rats. The anti-inflammatory action of the US FDA-approved drug 9-aminoacridine (9AA) was revealed which acted through nuclear receptor subfamily 4 group A member 1 (NR4A1), an anti-inflammatory orphan nuclear receptor that inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, we have explored the role of ascorbic acid, an active moiety of 6-O-stearoyl-L-ascorbic acid (SAA), in promoting the production of collagen production through ten-eleven translocation-2 (TET2) upregulation. Targeting through NR4A1 and TET2 could be the probable mechanism for the treatment of experimental arthritis. The combination of 9AA and ascorbic acid demonstrated enhanced therapeutic efficacy in the 9AA-SAA hydrogel, significantly reducing the severity of experimental arthritis. This approach, in contrast to existing treatments with limited effectiveness, presents a promising and more effective strategy for RA treatment by mitigating inflammation in experimental arthritis.

Highly Biocompatible Smart Injectable Hydrogel for the Management of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that severely affects joints and restricts locomotion. Various treatment regimens are available for RA, providing short-term relief from pain, but long-term relief from the disease is still not available. Evidently, cytokines play a crucial role in the pathophysiology of the disease. However, aberrant immune responses, genetic dispositions, viral infections, or toxicants are some possible causative mediators of RA. The synovial fluid of rheumatoid arthritis patients encompass cytokines, especially osteoclastogenic cytokines, and invasion factors such as macrophage colony-stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL). Moreover, tumor necrosis factor-α (TNF-α) and interleukins (IL-1, 6, and 17) intensify osteoclast differentiation and activation. Therefore, in order to restrict the cytokine expression, we used budesonide as a therapeutic lead and encapsulated it into a highly biocompatible hydrogel system. The hydrogel system developed by us is enzyme-responsive and provides sustained drug release flow over an extended period of time. This hydrogel is characterized by ζ-potential analysis, field-emission scanning electron microscopy (FE-SEM), and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, and it is further encapsulated with budesonide (glucocorticoids) for therapeutic purposes. Evidently, Bud-loaded ER-hydrogel showed improvement in joint physiology compared to the disease group and downregulated the inflammatory markers.

Cortisone-loaded stearoyl ascorbic acid based nanostructured lipid carriers alleviate inflammatory changes in DSS-induced colitis.

Ulcerative colitis is a chronic inflammatory disease which poorly affects the colon and spreads toward the rectum over time. Cortisone (CRT) is a corticosteroid clinically used for the management of inflammatory diseases like colitis and other inflammatory bowel diseases. Due to some physicochemical properties' cortisone has limited potency in clinics. To overcome drug-related problems, we successfully prepared lipid nanocarriers with generally regarded as safe (GRAS) materials approved by USFDA. The present study aimed to assess the therapeutic efficacy of CRT-loaded 6-o-stearoyl ascorbic acid (SAA) nanostructured lipid carriers (NLCs) against DSS-induced colitis mice. Formulation and characterizations of reported nanostructured lipid carrier were performed according to our previously optimized parameters. The average hydrodynamic diameter of NLCs was 182 nm as measured by DLS with 81.14 % encapsulation efficacy. TEM, AFM and SEM images analysis confirmed its spherical appearance. hTERT-BJ cells viability up to a dose of 500 µg/ml shows cytocompatible characteristics of blank NLCs. CRT-loaded NLCs treatment normalizes physically observed parameters such as disease activity index, weight variation etc. These NLCs were able to significantly reduce the severity of colitis in terms of colon histoarchitecture, regaining of the goblet cells, mucins secretions, inhibition of proinflammatory cytokines etc. Treatment with CRT-loaded NLCs effectively downregulated the overexpression of inflammatory enzymes like cyclooxygenase-2 (COX-2), Inducible nitric oxide synthase (iNOS) etc. The results of this study concluded that these CRT-encapsulated NLCs efficiently manage the disease severity induced by DSS.

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

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.