Construction of a pH-responsive, ultralow-dose triptolide nanomedicine for safe rheumatoid arthritis therapy

• Published in: Acta biomaterialia Vol. 121; pp. 541 - 553
• Main Authors: Liu, Yang, Jin, Jianqiu, Xu, Hao, Wang, Chao, Yang, Yanping, Zhao, Yongjian, Han, Haihui, Hou, Tong, Yang, Guoliang, Zhang, Li, Wang, Yongjun, Zhang, Weian, Liang, Qianqian
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2021; Elsevier BV
• Subjects: Animals; Apoptosis; Arthritis; Arthritis, Rheumatoid - drug therapy; Autoimmune diseases; Biocompatibility; Block copolymers; Cartilage; Collagen; Cytotoxicity; Diterpenes; Epoxy Compounds; Hydrogen-Ion Concentration; Hyperplasia; Inflammation; Intravenous administration; Mice; Nanomedicine; Nanotechnology; pH effects; Pharmacodynamics; Pharmacokinetics; Pharmacology; Phenanthrenes - pharmacology; POSS-PCL-b-PDMAEMA; Rheumatoid arthritis; Toxicity; Triptolide; Rheumatoid arthritis; Triptolide; POSS-PCL-b-PDMAEMA
• ISSN: 1742-7061; 1878-7568; 1878-7568
• DOI: 10.1016/j.actbio.2020.11.027

Rheumatoid arthritis (RA) is a chronicautoimmune disease, marked by joint swelling and pain, articular synovial hyperplasia, as well as cartilage and bone destruction. Triptolide (TP) is an anti-inflammatory molecule but its use to treat RA is limited due to poor solubility and extremely high toxicity. In this study, by encapsulating TP into a star-shaped amphiphilic block copolymer, POSS-PCL-b-PDMAEMA, we engineered a pH-sensitive TP-loaded nanomedicine (TP@NPs) to simultaneously reduce the toxicity of TP and improve its therapeutic efficacy. TP@NPs shows a uniform spherical structure with a hydrodynamic diameter of ~92 nm and notable pH-responsiveness. In vitro TP@NPs showed reduced cytotoxicity and cell apoptosis of treated RAW264.7 cells compared to free TP. And in vivo intravenous injection of indocyanine green-labeled NPs into a collagen-induced arthritis model in mice showed that the engineered compound had potent pharmacokinetic and pharmacodynamic profiles, while exhibiting significant cartilage-protective and anti-inflammatory effects with a better efficacy and neglible systemic toxicity even at an ultralow dose compared to free TP. These results suggest that TP@NPs may be a safe and effective therapy for RA and other autoimmune diseases. [Display omitted]