Development and Characterization of a pH-Sensitive Nanocarrier System for Targeted Delivery of Methotrexate in Rheumatoid Arthritis

Abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by joint inflammation and destruction. Methotrexate (MTX) is a frontline therapy but suffers from systemic toxicity and poor targeting. This study aimed to develop a pH-sensitive nanocarrier system for targeted MTX delivery to improve therapeutic efficacy and reduce side effects.

Methods: pH-responsive nanocarriers were prepared using biocompatible polymers via ionic gelation and nanoprecipitation methods. The formulations were optimized for particle size, drug loading, and pH-triggered release. Characterization included dynamic light scattering (DLS), electron microscopy, encapsulation efficiency, and drug-polymer interaction analysis. In vitro drug release was evaluated under physiological (pH 7.4) and acidic (pH ~6) conditions, alongside cytotoxicity and cellular uptake studies in macrophage cells. In vivo efficacy was assessed using an adjuvant-induced arthritis rat model, measuring paw swelling, histopathology, and pro-inflammatory cytokine levels.

Results: The optimized nanocarriers showed uniform nanosize (~150 nm), negative zeta potential, and high encapsulation efficiency (>85%). They exhibited sustained, pH-triggered MTX release, enhanced macrophage uptake, and reduced cytotoxicity compared to free MTX. In vivo, MTX-loaded nanocarriers significantly decreased inflammation, joint damage, and cytokine biomarkers compared to free drug and controls.

Conclusion: The pH-sensitive nanocarrier system effectively targets MTX delivery to inflamed RA tissues, enhancing therapeutic efficacy while minimizing systemic toxicity. This approach holds promise for clinical translation in RA treatment, with further studies needed to address scale-up and long-term safety.