Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China.
J Control Release. 2021 Jul 10;335:38-48. doi: 10.1016/j.jconrel.2021.05.008. Epub 2021 May 7.
Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel anti-inflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-α-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.
类风湿关节炎（RA）的特征是炎症的爆发。中性粒细胞是炎症爆发的主要罪魁祸首，是第一个被募集到发炎关节的炎症细胞，并通过刺激趋化因子的释放来促进自身的募集。在这里，基于中性粒细胞，我们建立了一种新型的抗炎“盾牌和剑兵”策略，即使用低分子量肝素 - TOS 纳米粒子（LT NPs）。亲水性片段低分子量肝素（LMWH）作为盾牌，通过与炎症内皮细胞上的 P 选择素结合来抑制黏附级联反应，从而阻止中性粒细胞的跨血管运动。协同作用下，募集的中性粒细胞分泌的基质金属蛋白酶-9（MMP-9）减少，这是因为疏水性片段 d-α-生育酚琥珀酸（TOS）作为一把剑，降解关节软骨的主要成分。在胶原诱导性关节炎（CIA）小鼠模型中，LT NPs 表现出显著的靶向作用，并在包裹一线抗 RA 药物甲氨蝶呤后表现出突出的治疗效果。我们的工作证明了对中性粒细胞的多阶段操作是可行且有效的，为 RA 治疗提供了新概念。
