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
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Spine Institute, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Key Laboratory of theory and therapy of muscles and bones, Ministry of Education (Shanghai University of Traditional Chinese Medicine), 1200 Cailun Road, Shanghai 201203, China.
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, 725 South Wanping Road, Shanghai 200032, China; Shanghai Key Laboratory of Advanced Polymeric Materials, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Acta Biomater. 2021 Feb;121:541-553. doi: 10.1016/j.actbio.2020.11.027. Epub 2020 Nov 20.
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.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为关节肿胀和疼痛、关节滑膜增生以及软骨和骨破坏。雷公藤甲素（TP）是一种抗炎分子，但由于其溶解性差和毒性极高，其用于治疗RA受到限制。在本研究中，通过将TP封装到星形两亲性嵌段共聚物POSS-PCL-b-PDMAEMA中，我们设计了一种pH敏感的载TP纳米药物（TP@NPs），以同时降低TP的毒性并提高其治疗效果。TP@NPs呈现出均匀的球形结构，流体动力学直径约为92 nm，具有显著的pH响应性。在体外，与游离TP相比，TP@NPs对RAW264.7细胞的细胞毒性和细胞凋亡降低。在体内，将吲哚菁绿标记的纳米颗粒静脉注射到小鼠胶原诱导性关节炎模型中表明，该工程化合物具有强大的药代动力学和药效学特征，同时与游离TP相比，即使在超低剂量下也表现出显著的软骨保护和抗炎作用，且全身毒性可忽略不计。这些结果表明，TP@NPs可能是治疗RA和其他自身免疫性疾病的一种安全有效的疗法。
