Microenvironmental Enzyme-Responsive Methotrexate Modified Quercetin Micelles for the Treatment of Rheumatoid Arthritis

Abstract

Xiuying Li,1 Xin Wang,1 Xiuwu Qu,1 Ningning Shi,1 Qinqing Li,1 Zhifang Yan,1 Yandong Li,2 Yingli Wang3 1Shanxi Key Laboratory of Innovative Drug for the Treatment of Serious Diseases Basing on the Chronic Inflammation, Shanxi University of Chinese Medicine, Jinzhong, People’s Republic of China; 2Xi’an International Medical Center Hospital, Xi’an, People’s Republic of China; 3Shanxi Modern Traditional Chinese Medicine Engineering Laboratory, Shanxi University of Chinese Medicine, Jinzhong, People’s Republic of ChinaCorrespondence: Yandong Li; Yingli Wang, Email [email protected]; [email protected]: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease involving synovial inflammation and joint destruction. Although therapeutic drugs for RA have some efficacy, they usually cause severe side effects and are expensive. RA is characterized by synovial hyperplasia, intra-articular hypoxia, upregulated expression of matrix metalloproteinases, and excessive accumulation of reactive oxygen species. The adverse microenvironment further aggravates activated macrophage infiltration. Therefore, controlling the microenvironment of diseased tissues and targeting the activated macrophages have become new therapeutic targets in RA patients.Methods: Here, microenvironment-targeting micelles (PVGLIG-MTX-Que-Ms) were synthesized using the thin film hydration method. In the inflammatory microenvironment, PVGLIG was cleaved by the highly expressed MMP-2, PEG5000 was eliminated, MTX was exposed, macrophage activation was targeted, and Que enrichment was enhanced. The cytotoxicity, targeting, antioxidant, and anti-inflammatory properties of drug-loaded micelles were tested in vitro. The drug-loaded micelles were used to treat CIA rats. In vivo targeting, expression of serum inflammatory factors, immunohistochemistry of the articular cartilage, and changes in immunofluorescence staining were observed.Results: The developed micelles had a particle size of (89.62 ± 1.33) nm and a zeta potential of (− 4.9 ± 0.53) mV. The IC50 value of PVGLIG-MTX-Que-Ms (185.90 ± 6.98) μmol/L was significantly lower than that of free Que (141.10 ± 6.39) μmol/L. The synthesized micelles exhibited slow-release properties, low cytotoxicity, strong targeting abilities, and significant anti-inflammatory effects in vitro. In vivo, the drug-loaded micelles accumulated at the joint site for a long time. PVGLIG-MTX-Que-Ms significantly reduced joint swelling, improved bone destruction, and decreased the expression of serum inflammatory factors in CIA rats.Conclusion: The smart-targeting micelles PVGLIG-MTX-Que-Ms with strong targeting, anti-inflammatory, cartilage-protective, and other multiple positive effects are a promising new tool for RA treatment.Keywords: matrix metalloproteinases, quercetin, macrophages, methotrexate, anti-inflammatory

Keywords

• matrix metalloproteinases
• quercetin
• macrophages
• methotrexate
• anti-inflammatory