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Reactive Oxygen Species–Responsive Celastrol-Loaded Bilirubin Nanoparticles for the Treatment of Rheumatoid Arthritis

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Abstract

Celastrol (CLT) has shown anti-rheumatic activity against rheumatoid arthritis, while its poor water solubility and high organ toxicity restrict its further therapeutic applications. To mitigate these challenges, a reactive oxygen species (ROS)–responsive nanoparticle was developed for celastrol delivery based on the excessive ROS at the pathologic sites, which was synthesized by conjugating bilirubin to a polyethylene glycol (PEG) chain. The PEGylated bilirubin self-assembled into nanoparticle (BRNP) in aqueous solution had a hydrodynamic diameter of around 68.6 nm, and celastrol was loaded into BRNP (CLT/BRNP) with a drug encapsulation efficiency of 72.6% and a loading capacity of 6.6%. In vitro study revealed that CLT/BRNP exhibited the capacity of scavenging intracellular ROS and down-regulating the level of nitric oxide after it was effectively internalized by activated macrophages. Furthermore, in adjuvant-induced arthritis rats, BRNP was accumulated preferentially at inflamed joints, alleviating the joint swelling and bone erosion, which significantly decreased the secretion of pro-inflammatory cytokines to suppress the RA progression. Importantly, CLT/BRNP markedly enhanced its anti-arthritic effect and attenuated the toxic effect compared with free celastrol. Taken together, our results suggested that CLT/BRNP could be used for targeted drug delivery in rheumatoid arthritis.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 81673363).

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Authors and Affiliations

  1. Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, China

    Xuan Zhao, Chengyuan Huang, Meiling Su, Yu Ran, Ying Wang & Zongning Yin

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Xuan Zhao: Substantial contributions to the conception or design of the work and the acquisition, analysis.

Chengyuan Huang: Drafting the work or revising it critically for important intellectual content.

Meiling Su: Acquisition of data for the work.

Yu Ran: Analysis of data for the work.

Ying Wang: Drafting the work or revising it critically for important intellectual content.

Zongning Yin: Final approval of the version to be published.

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Correspondence to Zongning Yin.

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Zhao, X., Huang, C., Su, M. et al. Reactive Oxygen Species–Responsive Celastrol-Loaded Bilirubin Nanoparticles for the Treatment of Rheumatoid Arthritis. AAPS J 24, 14 (2022). https://doi.org/10.1208/s12248-021-00636-3

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