# Intra-articular Methotrexate-Loaded Microsponge as an Adjuvant Strategy for Rheumatoid Arthritis: Localized Treatment with a Systemic Impact

## TL;DR

This study explores a new way to deliver methotrexate for rheumatoid arthritis using microsponges to reduce side effects and improve treatment effectiveness.

## Contribution

The novel contribution is the development of methotrexate-loaded microsponges for intra-articular delivery, offering sustained release and systemic immunomodulation.

## Key findings

- MTX-MSP provides sustained drug release in synovial fluid for 14 days with minimal burst effects.
- MTX-MSP outperforms free MTX in reducing inflammatory markers in RA synoviocytes.
- In vivo, MTX-MSP improves joint histology and suggests systemic immunomodulation.

## Abstract

Rheumatoid arthritis
(RA) is a debilitating autoimmune disease
characterized by chronic synovial inflammation and progressive joint
destruction. Methotrexate (MTX) remains the gold standard in RA therapy,
yet systemic administration often provides suboptimal joint targeting
and causes dose-limiting toxicity. This study investigates intra-articular
(IA) administration of an MTX-loaded Microsponge (MTX-MSP) as a localized
strategy to enhance drug retention while minimizing systemic exposure.
MTX-MSP is synthesized using hyaluronic acid-based cross-linking and
MTX loading. Drug release and carrier mass loss were evaluated in
a pathological human synovial fluid (HSF), and rheological and Fourier
transform infrared spectroscopy analyses assess viscoelastic behavior
and drug–carrier interactions. Biocompatibility and anti-inflammatory
activity are tested in primary RA fibroblast-like synoviocytes, while
therapeutic efficacy is evaluated in a collagen-induced arthritis
rat model. MTX-MSP provides sustained release in HSF for 14 days,
minimizes burst effects, and preserves structural integrity. Rheological
profiling confirms injectability and interaction with the pathological
synovial fluid, enhancing the elastic response. In vitro, MTX-MSP reduces IL-6, TNF-α, and IL-1β expression at
gene and protein levels, outperforming free MTX. In vivo, weekly IA injections improve histological scores in treated and
contralateral joints, suggesting systemic immunomodulation. MTX-MSP
thus achieves prolonged release, anti-inflammatory efficacy, and reduced
systemic toxicity, representing a promising IA formulation for RA
management.