Bio-responsive self-assembled nanoparticles of fatty acid prodrugs of sulfapyridine for the management of Rheumatoid arthritis.

Despite significant advancements in medical research, the treatment of rheumatoid arthritis (RA) is still challenging due to limitations associated with the conventional therapies, which include low tissue specificity, poor retention within inflamed joints, and systemic toxicity. Sulfapyridine (SP), a second-line drug for the management of RA, has low solubility and permeability, classifying is as a BCS class IV drug. To overcome these limitations, SP was chemically conjugated with fatty acid (FA) side chains to make amphiphilic prodrugs that formed nanostructures on self-assembly in aqueous milieu. Among the synthesized prodrugs, heptanoyl and oleoyl derivates i.e., SP-Hept and SP-Ole were selected as lead candidates for further pharmacological evaluation due to their favorable self-assembly behaviour and physicochemical properties. Both prodrugs spontaneously formed uniform sized spherical nanoparticles (NPs) with high colloidal stability, which was better maintained under refrigerated storage. In vitro cytotoxicity studies using L929 fibroblast cells demonstrated reduced toxicity for the prodrugs compared to the parent drug. Controlled and selective release of SP was confirmed via pH- and enzyme-responsive hydrolysis in chemical buffers, human plasma, synovial fluid, and simulated synovial fluid (SSF)., notably, SP-Hept showed greater sensitivity to acidic conditions and esterase activity, whereas SP-Ole was preferentially cleaved by collagenase. In a complete Freund's adjuvant (CFA)-induced rat arthritis models, treatment with these NPs significantly alleviated paw swelling and joint inflammation by downregulating inflammatory mediators. Histological and radiographic analyses confirmed preservation of joint architecture and cartilage integrity, while hematological and biochemical parameters were restored toward normal levels. Overall, these findings highlight the potential of SP-Hept and SP-Ole NPs as a precisely tunable, localized drug delivery platform for improved RA management.