Department of Pharmacy, Deyang People's Hospital, Deyang 618000, China.
Laboratory of Translational Medicine Research, Department of Pathology, Deyang People's Hospital, Deyang 618000, China.
Curr Drug Deliv. 2024;21(8):1106-1113. doi: 10.2174/1567201821666230810115230.
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.
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-mPEG and Ca(OH).
A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG and Ca(OH) 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 fluorescence imaging system was used to study the LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model.
Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. 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.
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.
类风湿性关节炎（RA）是一种系统性自身免疫性疾病（AD），全球发病率为 0.5%~1%。现有的药物可以减轻症状，但这种疾病尚无已知的治愈方法。依那西普（EN）可以竞争性抑制 TNF-α与细胞表面 TNF 受体的结合，从而治疗 RA。然而，游离 EN 的皮下注射容易导致全身分布，并引起免疫系统功能低下。引流淋巴结（LNs）在 RA 的发病、维持和进展中起着重要作用，因为它们是异常免疫反应和炎症细胞因子产生的主要部位。
本研究旨在通过将依那西普（EN）包封在纳米乳液（NEs/EN）中，并将其特异性递送至引流 LNs，成功治疗 RA。采用高压匀化法制备 EN 载药纳米乳液，并对其进行 DSPE-mPEG 和 Ca(OH)修饰。
构建了一种新型纳米乳液（NE），将依那西普（EN）递送至 RA 引流 LNs。为了减少聚集并负载 EN，我们成功地在脂质注射乳液的表面依次修饰了 DSPE-mPEG 和 Ca(OH)。采用激光粒度分析仪和透射电子显微镜分别考察了 NEs/EN 的水动力学粒径和形态。采用荧光成像系统研究了该制剂对 LNs 的靶向能力。在治疗实验中，通过皮下给予 NEs/EN 抑制小鼠关节炎模型的发展。
圆二色光谱和 L929 细胞实验证实 NEs 包封对 EN 的生物学活性没有影响。胶原诱导性关节炎（CIA）小鼠模型研究表明，NEs/EN 具有良好的腹股沟淋巴结靶向能力，对 RA 具有抗炎作用。与游离组相比，NEs/EN 组的爪厚和关节炎评分明显减轻。此外，NEs/EN 治疗组小鼠促炎细胞因子 TNF-α和 IL-1β的浓度低于游离 EN 组。
NEs/EN 有效提高了 EN 治疗 RA 的疗效。我们的工作为扩大 EN 的临床应用提供了实验基础。
