Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model

Abstract

Background Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%–16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules. Objective The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution. Methods Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF-α levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments. Results Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 175±17 nm and span of 1.6±0.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment ( P <0.0001); however, this effect was achieved earlier, on day 21 ( P <0.0001), by MTX-LNC, and this formulation had reduced both TNF-α ( P =0.001) and IL-1α ( P =0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX. Conclusion The MTX-LNC were better than the MTX solution at reducing proinflammatory cytokines and T-cell-derived cytokines such as interferon-gamma and interleukin-17A. This result, combined with the reduction in the dose required for therapy, shows that MTX-LNC are a very promising system for the treatment of RA.

Targeted Reinforcement of Macrophage Reprogramming Toward M2 Polarization by IL-4-Loaded Hyaluronic Acid Particles

“…Autoimmune disorders (ADs) are categorized as chronic diseases derived from an imbalance between stimulatory and regulatory mechanisms of the immune system, strongly affected by the genetic predisposition and environmental condition. 1−4 The trigger of immune pathways and systemic inflammatory responses in AD may result in the damage of healthy tissues by over-reacted immune cells. Many of the proposed immunoregulatory approaches against ADs are developed based on the blockage of the interaction between antigen-presenting cells and T cells.…”

Intra-articular therapy with methotrexate or tumor necrosis factor inhibitors in rheumatoid arthritis: a systematic review

“…Therefore, there may be some rationale behind repeated IA injections of MTX and indeed the 2018 study in our analysis showed a response [ 12 ]. These pharmacodynamics have generated an interest in developing conjugated compounds to provide longer retention of IA MTX [ 22 ]. For reference, the half-life of IA triamcinolone acetonide is between 3.2 and 6.4 days [ 23 ].…”