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

Overview

Journal Int J Nanomedicine

Publisher Dove Medical Press

Specialty Biotechnology

Date 2024 Apr 11

PMID 38601347

Authors

Xiuying Li

Xin Wang

Xiuwu Qu

Ningning Shi

Qinqing Li

Zhifang Yan

Yandong Li

Yingli Wang

Affiliations

Soon will be listed here.

Abstract

Purpose: 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, PEG 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 IC 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.

References

Yu C, Liu H, Guo C, Chen Q, Su Y, Guo H . Dextran sulfate-based MMP-2 enzyme-sensitive SR-A receptor targeting nanomicelles for the treatment of rheumatoid arthritis. Drug Deliv. 2022; 29(1):454-465. PMC: 8855847. DOI: 10.1080/10717544.2022.2032482. View

Yao Q, Liu Y, Kou L, Tu Y, Tang X, Zhu L . Tumor-targeted drug delivery and sensitization by MMP2-responsive polymeric micelles. Nanomedicine. 2019; 19:71-80. PMC: 6599579. DOI: 10.1016/j.nano.2019.03.012. View

Song Y, Gao N, Yang Z, Zhang L, Wang Y, Zhang S . Characteristics, polarization and targeted therapy of mononuclear macrophages in rheumatoid arthritis. Am J Transl Res. 2023; 15(3):2109-2121. PMC: 10086900. View

Kong J, Jeong G, Yoo S . The use of animal models in rheumatoid arthritis research. J Yeungnam Med Sci. 2022; 40(1):23-29. PMC: 9946911. DOI: 10.12701/jyms.2022.00773. View

Smolen J, Aletaha D, McInnes I . Rheumatoid arthritis. Lancet. 2016; 388(10055):2023-2038. DOI: 10.1016/S0140-6736(16)30173-8. View

Kumazawa Y, Kawaguchi K, Takimoto H . Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor alpha. Curr Pharm Des. 2006; 12(32):4271-9. DOI: 10.2174/138161206778743565. View

Nogueira E, Sarria M, Azoia N, Antunes E, Loureiro A, Guimaraes D . Internalization of Methotrexate Conjugates by Folate Receptor-α. Biochemistry. 2018; 57(49):6780-6786. DOI: 10.1021/acs.biochem.8b00607. View

Zhang L, Zhang Y, Pan J . Immunopathogenic mechanisms of rheumatoid arthritis and the use of anti-inflammatory drugs. Intractable Rare Dis Res. 2021; 10(3):154-164. PMC: 8397820. DOI: 10.5582/irdr.2021.01022. View

McInnes I, Schett G . Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017; 389(10086):2328-2337. DOI: 10.1016/S0140-6736(17)31472-1. View

10.

Angulo-Pachon C, Pozo V, Miravet J . Alkaline cations dramatically control molecular hydrogelation by an amino acid-derived anionic amphiphile. J Colloid Interface Sci. 2023; 635:524-534. DOI: 10.1016/j.jcis.2022.12.134. View

11.

Mateen S, Zafar A, Moin S, Khan A, Zubair S . Understanding the role of cytokines in the pathogenesis of rheumatoid arthritis. Clin Chim Acta. 2016; 455:161-71. DOI: 10.1016/j.cca.2016.02.010. View

12.

Zheng X, Yu X, Wang C, Liu Y, Jia M, Lei F . Targeted co-delivery biomimetic nanoparticles reverse macrophage polarization for enhanced rheumatoid arthritis therapy. Drug Deliv. 2022; 29(1):1025-1037. PMC: 8979516. DOI: 10.1080/10717544.2022.2057616. View

13.

Wang K, Yin C, Ye X, Chen Q, Wu J, Chen Y . A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis. Small. 2023; 19(21):e2207319. DOI: 10.1002/smll.202207319. View

14.

Goyal A, Agrawal N . Quercetin: A Potential Candidate for the Treatment of Arthritis. Curr Mol Med. 2021; 22(4):325-335. DOI: 10.2174/1566524021666210315125330. View

15.

Guo R, Zhang X, Yan D, Yu Y, Wang Y, Geng H . Folate-modified triptolide liposomes target activated macrophages for safe rheumatoid arthritis therapy. Biomater Sci. 2021; 10(2):499-513. DOI: 10.1039/d1bm01520f. View

16.

Boutet M, Courties G, Nerviani A, Le Goff B, Apparailly F, Pitzalis C . Novel insights into macrophage diversity in rheumatoid arthritis synovium. Autoimmun Rev. 2021; 20(3):102758. DOI: 10.1016/j.autrev.2021.102758. View

17.

Tang M, Zeng Y, Peng W, Xie X, Yang Y, Ji B . Pharmacological Aspects of Natural Quercetin in Rheumatoid Arthritis. Drug Des Devel Ther. 2022; 16:2043-2053. PMC: 9250769. DOI: 10.2147/DDDT.S364759. View

18.

Jia N, Gao Y, Li M, Liang Y, Li Y, Lin Y . Metabolic reprogramming of proinflammatory macrophages by target delivered roburic acid effectively ameliorates rheumatoid arthritis symptoms. Signal Transduct Target Ther. 2023; 8(1):280. PMC: 10374631. DOI: 10.1038/s41392-023-01499-0. View

19.

Liu W, Zhang Y, Zhu W, Ma C, Ruan J, Long H . Sinomenine Inhibits the Progression of Rheumatoid Arthritis by Regulating the Secretion of Inflammatory Cytokines and Monocyte/Macrophage Subsets. Front Immunol. 2018; 9:2228. PMC: 6168735. DOI: 10.3389/fimmu.2018.02228. View

20.

Dai Z, Tu Y, Zhu L . Multifunctional Micellar Nanocarriers for Tumor-Targeted Delivery of Hydrophobic Drugs. J Biomed Nanotechnol. 2016; 12(6):1199-210. DOI: 10.1166/jbn.2016.2249. View