A pH-Driven indomethacin-loaded nanomedicine for effective rheumatoid arthritis therapy by combining with photothermal therapy

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by inflammatory micro-environments in the joints. Indomethacin (IND), a conventional nonsteroidal anti-inflammatory drug (NSAID), has been used for the therapy of RA. However, the poor solubility and serious side effects of oral administration of IND significantly limit its efficacy. In this study, we have synthesized biomimetic IND-loaded Prussian blue (PB) nanoparticles (IND@PB@M@HA) with hyaluronic acid (HA) modification for increasing the solubility and targeting the ability of IND to the inflamed joints. The application of hybrid cell membranes on the NPs endowed immune escape of IND@PB@M@HA NPs, which accordingly extended the circulation time in the blood. In vitro assay demonstrated that the combination of nanomedicine and photothermal therapy produced a powerful anti-inflammatory effect by reducing the levels of inflammatory factors and cell viability of activated macrophages and NPs possessed obvious pH-responsiveness. In vivo assay demonstrated that the nanomedicine for synergistic photothermal therapy exhibited desirable pharmacodynamics and pharmacokinetic properties at ultra-low drug dosage in a rat model of adjuvant-induced arthritis, which was confirmed by inflammatory suppression, bone erosion remission, and negligible adverse effects. In summary, the proposed nanomedicine has the potential role for targeted anti-inflammatory therapy of RA.

Keywords:

• Rheumatoid arthritis
• indomethacin
• Prussian blue nanoparticles
• targeted delivery
• biomimetic membrane
• photothermal therapy

Author contributions

Shengtao Hu conducted the research, analysed the data, and drafted the manuscript. Ye Lin helped with all of experiments and contributed to data analysis of the draft of the manuscript. Chunyi Tong performed cell culture. Hong Huang and Ouyang Yi performed in vivo experiments. Zongshun Dai and Zhaoli Su contributed to data analysis and artwork preparation. Xiong Cai and Bin Liu designed the research, discussed the experiments, analysed the data, and revised the manuscript.

Disclosure statement

The authors declare that they have no conflict of interest.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was funded by grants from the Science and Technology Innovation Megaproject and Science and Technology Innovation Program of Hunan Province (2020SK1020 and XKJ[2021]43-2021RC4035). Additionally, this work was supported by the Hunan Furong Distinguished Scholar Program (XJT[2020]58), Hunan 121 Training Project for Innovative Talents (XRSH[2019]192), Chinese Academy of Engineering Academician Liang Liu’s Workstation of Hunan University of Chinese Medicine (HNUCM) (XKXT[2020]34), and the National First-class Disciple Construction Project of Chinese Medicine of HNUCM (XXKZ[2018]3).