Department of Pharmaceutics, School of Pharmacy , Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education , Shanghai 201203 , China.
School of Pharmacy , Minzu University of China , Beijing 100081 , China.
ACS Appl Mater Interfaces. 2019 Jun 5;11(22):20304-20315. doi: 10.1021/acsami.8b22693. Epub 2019 May 22.
Rheumatoid arthritis (RA) is a chronic, systemic, progressive autoimmune disease. The vascular permeability of inflamed joints in RA makes it a natural candidate for passive targeting, similar to the enhanced permeability and retention (EPR) effect in solid tumors. Thus, various therapeutic drugs have been encapsulated in nanocarriers to achieve longer in vivo circulation times and improve RA targeting. Although liposomes are the most widely used nanocarriers for RA treatment, the effects of physical and chemical characteristics of liposomes, such as particle sizes, surface charge, polyethylene glycol (PEG) chain length, and PEG concentration, on their passive RA targeting effect have not been fully elucidated. Here, we systematically investigated the effects of physical and chemical properties of liposomes on circulation time and conducted preliminary studies on their passive targeting mechanisms. A series of liposomes with different particle sizes (70, 100, 200, and 350 nm), surface charges (positive, negative, slight positive, and slight negative), PEG chain lengths (1, 2, and 5 kDa), and concentrations (5, 10, and 20% w/w of total lipid) were prepared by lipid film dispersion and extrusion. The pharmacokinetics of liposomes with different formulas were evaluated with a fluorescence microplate reader. A collagen-induced arthritis (CIA) mouse model was utilized to mimic RA pathological conditions and to evaluate the targeting and efficacy of liposomes with different properties using a near-infrared fluorescence imaging system. Uptake of fluorescent liposomes by various synovial cells was measured by flow cytometry. The results indicated that liposomes with 100 nm diameter, a slight negative charge, and 10% incorporation of 5 kDa PEG had better in vivo circulation time and inflamed joint targeting than did other liposomes. Dexamethasone (Dex) was encapsulated into optimized liposomes as an active ingredient for RA treatment. Pharmacodynamic studies demonstrated that Dex liposomes could significantly improve the antiarthritic efficacy of Dex in a CIA mouse model of RA. This study also found that the retention mechanism of RA was mainly increased because of the uptake of liposomes by fibroblasts and macrophages in inflamed joints. This study provides a persuasive explanation for passive RA targeting by liposomes and advances our ability to treat RA with nanomedicine.
类风湿关节炎（RA）是一种慢性、系统性、进行性自身免疫性疾病。RA 炎症关节的血管通透性使其成为被动靶向的理想候选者，类似于实体瘤中的增强通透性和滞留（EPR）效应。因此，各种治疗药物已被包裹在纳米载体中，以实现更长的体内循环时间并改善 RA 靶向性。尽管脂质体是治疗 RA 最广泛使用的纳米载体，但脂质体的物理和化学特性，如粒径、表面电荷、聚乙二醇（PEG）链长和 PEG 浓度，对其被动 RA 靶向效果的影响尚未得到充分阐明。在这里，我们系统地研究了脂质体的物理和化学性质对循环时间的影响，并对其被动靶向机制进行了初步研究。通过脂质膜分散和挤出法制备了一系列具有不同粒径（70、100、200 和 350nm）、表面电荷（正、负、轻微正和轻微负）、PEG 链长（1、2 和 5kDa）和浓度（5、10 和 20%w/w 总脂质）的脂质体。用荧光微孔板读数器评估不同配方脂质体的药代动力学。利用胶原诱导性关节炎（CIA）小鼠模型模拟 RA 病理条件，并用近红外荧光成像系统评估具有不同性质的脂质体的靶向性和疗效。通过流式细胞术测量各种滑膜细胞对荧光脂质体的摄取。结果表明，粒径为 100nm、带轻微负电荷且 PEG 含量为 10%（分子量为 5kDa）的脂质体具有更好的体内循环时间和炎症关节靶向性。地塞米松（Dex）被包裹在优化的脂质体中作为 RA 治疗的活性成分。药效学研究表明，Dex 脂质体可显著改善 RA CIA 小鼠模型中 Dex 的抗关节炎疗效。该研究还发现，RA 的保留机制主要是由于炎症关节中的成纤维细胞和巨噬细胞摄取了脂质体。这项研究为脂质体对 RA 的被动靶向提供了有说服力的解释，并提高了我们用纳米医学治疗 RA 的能力。
