Design and Optimization of Methotrexate-Loaded Polymeric Nanoparticles for Controlled Drug Delivery in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis is a chronic autoimmune disease that requires long-term treatment with disease-modifying anti-rheumatic drugs like methotrexate. However, conventional methotrexate therapy is limited by systemic toxicity, poor bioavailability, and frequent dosing, which reduce patient compliance and therapeutic outcomes. This study focuses on the design and optimization of methotrexate-loaded polymeric nanoparticles for controlled and targeted drug delivery in Rheumatoid arthritis. Using a systematic Design of Experiments approach and Response Surface Methodology, the influence of polymer concentration, drug-to-polymer ratio, and stirring speed on particle size, polydispersity index, and encapsulation efficiency was thoroughly investigated. The optimized nanoparticles demonstrated uniform size distribution, narrow polydispersity index, stable zeta potential, and high encapsulation efficiency. In vitro release studies confirmed sustained drug release following Higuchi and Korsmeyer–Peppas kinetics, indicating diffusion-controlled mechanisms. Cytotoxicity testing revealed that the nanoparticles exhibited lower cytotoxicity towards healthy cells compared to free methotrexate, confirming improved biocompatibility. These results highlight the potential of the developed system to minimize systemic side effects while maintaining therapeutic efficacy. Future studies should explore in vivo pharmacokinetics, biodistribution, and therapeutic performance to validate clinical applicability. The optimized methotrexate nanoparticles could offer a promising strategy to enhance Rheumatoid arthritis management through targeted, sustained, and patient-friendly drug delivery.