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Construction of a pH-responsive, ultralow-dose triptolide nanomedicine for safe rheumatoid arthritis therapy
Acta Biomaterialia ( IF 9.4 ) Pub Date : 2020-11-20 , DOI: 10.1016/j.actbio.2020.11.027
Yang Liu , Jianqiu Jin , Hao Xu , Chao Wang , Yanping Yang , Yongjian Zhao , Haihui Han , Tong Hou , Guoliang Yang , Li Zhang , Yongjun Wang , Weian Zhang , Qianqian Liang

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.



中文翻译:

用于安全性类风湿关节炎治疗的pH响应,超低剂量雷公藤甲素纳米药物的构建

类风湿关节炎(RA)是一种慢性自身免疫性疾病,以关节肿胀和疼痛,关节滑膜增生以及软骨和骨破坏为特征。雷公藤内酯醇(TP)是一种抗炎分子,但由于溶解性差和毒性极高,其用于RA的用途受到限制。在这项研究中,通过将TP封装到星形两亲嵌段共聚物POSS-PCL-b-PDMAEMA中,我们设计了一种pH敏感的TP负载纳米药物(TP @ NPs),以同时降低TP的毒性并改善其治疗效果。功效。TP @ NPs具有均匀的球形结构,流体动力学直径约为92 nm,并且具有明显的pH响应性。与游离TP相比,处理后的RAW264.7细胞的体外TP @ NPs降低了细胞毒性和细胞凋亡。和体内将吲哚菁绿标记的NPs静脉注射到胶原蛋白诱发的小鼠关节炎模型中表明,该工程化合物具有有效的药代动力学和药效学特征,同时表现出显着的软骨保护和抗炎作用,即使在50℃时仍具有更好的功效和可忽略的全身毒性与游离TP相比超低剂量。这些结果表明,TP @ NPs对于RA和其他自身免疫性疾病可能是一种安全有效的疗法。

更新日期:2021-01-28
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