Department of Pharmaceutics, School of Pharmacy , Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education , Shanghai 201203 , China.
Innovation Research Institute of Traditional Chinese Medicine , Shanghai University of Traditional Chinese Medicine , Shanghai 201203 , China.
Nano Lett. 2019 Jan 9;19(1):124-134. doi: 10.1021/acs.nanolett.8b03439. Epub 2018 Dec 10.
The targeted delivery of therapeutics to sites of rheumatoid arthritis (RA) has been a long-standing challenge. Inspired by the intrinsic inflammation-targeting capacity of macrophages, a macrophage-derived microvesicle (MMV)-coated nanoparticle (MNP) was developed for targeting RA. The MMV was efficiently produced through a novel method. Cytochalasin B (CB) was applied to relax the interaction between the cytoskeleton and membrane of macrophages, thus stimulating MMV secretion. The proteomic profile of the MMV was analyzed by iTRAQ (isobaric tags for relative and absolute quantitation). The MMV membrane proteins were similar to those of macrophages, indicating that the MMV could exhibit bioactivity similar to that of RA-targeting macrophages. A poly(lactic- co-glycolic acid) (PLGA) nanoparticle was subsequently coated with MMV, and the inflammation-mediated targeting capacity of the MNP was evaluated both in vitro and in vivo. The in vitro binding of MNP to inflamed HUVECs was significantly stronger than that of the red blood cell membrane-coated nanoparticle (RNP). Compared with bare NP and RNP, MNP showed a significantly enhanced targeting effect in vivo in a collagen-induced arthritis (CIA) mouse model. The targeting mechanism was subsequently revealed according to the proteomic analysis, indicating that Mac-1 and CD44 contributed to the outstanding targeting effect of the MNP. A model drug, tacrolimus, was encapsulated in MNP (T-RNP) and significantly suppressed the progression of RA in mice. The present study demonstrates MMV as a promising and rich material, with which to mimic macrophages, and demonstrates that MNP is an efficient biomimetic vehicle for RA targeting and treatment.
靶向递送至类风湿关节炎 (RA) 部位一直是一个长期存在的挑战。受巨噬细胞固有炎症靶向能力的启发，开发了一种巨噬细胞衍生的微泡 (MMV) 涂层纳米颗粒 (MNP) 用于靶向 RA。通过一种新方法高效地产生了 MMV。细胞松弛素 B (CB) 被应用于放松细胞骨架与巨噬细胞膜之间的相互作用，从而刺激 MMV 的分泌。通过 iTRAQ（相对和绝对定量的同重同位素标记）分析 MMV 的蛋白质组学图谱。MMV 的膜蛋白与巨噬细胞的膜蛋白相似，表明 MMV 可以表现出与 RA 靶向巨噬细胞相似的生物活性。随后，用 MMV 涂层聚乳酸-共-羟基乙酸 (PLGA) 纳米颗粒，并在体外和体内评估 MNP 的炎症介导靶向能力。MNP 与炎症 HUVECs 的体外结合明显强于红细胞膜涂层纳米颗粒 (RNP) 的结合。与裸 NP 和 RNP 相比，MNP 在胶原诱导关节炎 (CIA) 小鼠模型中表现出明显增强的体内靶向效果。随后根据蛋白质组学分析揭示了靶向机制，表明 Mac-1 和 CD44 有助于 MNP 的出色靶向效果。将模型药物他克莫司封装在 MNP 中（T-RNP），可显著抑制小鼠 RA 的进展。本研究表明 MMV 是一种很有前途且丰富的材料，可用于模拟巨噬细胞，并表明 MNP 是一种用于 RA 靶向治疗的高效仿生载体。
