A Novel Etanercept-loaded Nano-emulsion for Targeted Treatment of Inflammatory Arthritis via Draining Lymph Node.

IF 2.8 4区医学 Q2 PHARMACOLOGY & PHARMACY Current drug delivery Pub Date : 2024-01-01 DOI:10.2174/1567201821666230810115230

Chenglong Li, Guanting Lu, Yue Jiang, Huaiyu Su, Chen Li

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Abstract

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production.

Aim: The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG₂₀₀₀ and Ca(OH)₂.

Methods: A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG₂₀₀₀ and Ca(OH)₂ were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model.

Results: Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN.

Conclusion: NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.

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通过引流淋巴结靶向治疗炎症性关节炎的新型依那西普纳米乳剂

背景：类风湿性关节炎（RA）是一种全身性自身免疫性疾病，全球发病率为 0.5%~1%。现有药物可减轻症状，但目前尚无根治此病的方法。依那西普（Etanercept，EN）可竞争性抑制 TNF-α 与细胞表面 TNF 受体的结合，从而治疗 RA。然而，皮下注射游离的依那西普容易造成全身分布，并诱发免疫系统功能低下。引流淋巴结（LN）是异常免疫反应和炎性细胞因子产生的主要部位，因此在 RA 的发病、维持和发展过程中起着重要作用。该研究采用高压均质法制备了负载EN的纳米乳液，并用DSPE-MPEG2000和Ca(OH)2对其进行了修饰：方法：构建了一种新型纳米乳液（NE），用于将EN（NE/EN）输送到RA排水型LN。为了减少聚集和负载EN，DSPE-mPEG2000和Ca(OH)2先后被装饰在脂质注射乳剂的表面。利用激光粒度分析仪和透射电子显微镜分别研究了NAs/EN的流体力学直径和形态。体内荧光成像系统用于研究制剂的体内 LN 靶向能力。在治疗实验中，通过皮下注射 NEs/EN 来抑制小鼠关节炎模型的发展：结果：圆二色光谱和 L929 细胞实验证实，NEs 封装对EN 的生物活性没有影响。对胶原诱导的关节炎（CIA）小鼠模型的体内研究表明，NEs/EN具有良好的腹股沟淋巴结靶向能力，并对RA具有抗炎作用。与自由组相比，NEs/EN 组的爪子厚度和关节炎评分明显减轻。此外，经 NEs/EN 治疗的小鼠体内促炎细胞因子 TNF-α 和 IL-1β 的浓度也低于游离 EN 组：结论：NEs/EN 能有效提高 EN 治疗 RA 的疗效。我们的研究为扩大EN的临床应用提供了实验基础。

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来源期刊

Current drug delivery PHARMACOLOGY & PHARMACY-

CiteScore

5.10

自引率

4.20%

发文量

170

期刊介绍： Current Drug Delivery aims to publish peer-reviewed articles, research articles, short and in-depth reviews, and drug clinical trials studies in the rapidly developing field of drug delivery. Modern drug research aims to build delivery properties of a drug at the design phase, however in many cases this idea cannot be met and the development of delivery systems becomes as important as the development of the drugs themselves. The journal aims to cover the latest outstanding developments in drug and vaccine delivery employing physical, physico-chemical and chemical methods. The drugs include a wide range of bioactive compounds from simple pharmaceuticals to peptides, proteins, nucleotides, nucleosides and sugars. The journal will also report progress in the fields of transport routes and mechanisms including efflux proteins and multi-drug resistance. The journal is essential for all pharmaceutical scientists involved in drug design, development and delivery.