Department of Orthopedics, University Hospital Jena, Eisenberg, Germany.
Arthritis Res Ther. 2010;12(4):R147. doi: 10.1186/ar3089. Epub 2010 Jul 19.
The objective of this study was to evaluate the efficacy of intravenous (i.v.) injection of liposomally encapsulated dexamethasone phosphate (DxM-P) in comparison to free DxM-P in rats with established adjuvant arthritis (AA). This study focused on polyethylene glycol (PEG)-free liposomes, to minimize known allergic reactions caused by neutral PEG-modified (PEG-ylated) liposomes.
Efficacy was assessed clinically and histologically using standard scores. Non-specific and specific immune parameters were monitored. Activation of peritoneal macrophages was analyzed via cytokine profiling. Pharmacokinetics/biodistribution of DxM in plasma, synovial membrane, spleen and liver were assessed via mass spectrometry.
Liposomal DxM-P (3 × 1 mg/kg body weight; administered intravenously (i.v.) on Days 14, 15 and 16 of AA) suppressed established AA, including histological signs, erythrocyte sedimentation rate, white blood cell count, circulating anti-mycobacterial IgG, and production of interleukin-1beta (IL-1β) and IL-6 by peritoneal macrophages. The suppression was strong and long-lasting. The clinical effects of liposomal DxM-P were dose-dependent for dosages between 0.01 and 1.0 mg/kg. Single administration of 1 mg/kg liposomal DxM-P and 3 × 1 mg/kg of free DxM-P showed comparable effects consisting of a partial and transient suppression. Moreover, the effects of medium-dose liposomal DxM-P (3 × 0.1 mg/kg) were equal (in the short term) or superior (in the long term) to those of high-dose free DxM-P (3 × 1 mg/kg), suggesting a potential dose reduction by a factor between 3 and 10 by liposomal encapsulation. For at least 48 hours after the last injection, the liposomal drug achieved significantly higher levels in plasma, synovial membrane, spleen and liver than the free drug.
This new PEG-free formulation of macrophage-targeting liposomal DxM-P considerably reduces the dose and/or frequency required to treat AA, with a potential to enhance or prolong therapeutic efficacy and limit side-effects also in the therapy of rheumatoid arthritis. Depot and/or recirculation effects in plasma, inflamed joint, liver, and spleen may contribute to this superiority of liposomally encapsulated DxM-P.
本研究旨在评估脂囊化磷酸地塞米松（DxM-P）静脉注射（i.v.）与游离 DxM-P 在佐剂性关节炎（AA）大鼠模型中的疗效。本研究重点关注无聚乙二醇（PEG）的脂囊，以尽量减少由中性 PEG 修饰（PEG-化）的脂囊引起的已知过敏反应。
采用标准评分法进行临床和组织学评估。监测非特异性和特异性免疫参数。通过细胞因子谱分析来评估腹腔巨噬细胞的激活。通过质谱法评估 DxM 在血浆、滑膜、脾和肝中的药代动力学/分布。
脂囊化 DxM-P（3×1mg/kg 体重；于 AA 第 14、15 和 16 天静脉内（i.v.）给药）抑制了已建立的 AA，包括组织学迹象、红细胞沉降率、白细胞计数、循环抗分枝杆菌 IgG 以及腹腔巨噬细胞产生的白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）。抑制作用强烈且持久。脂囊化 DxM-P 的临床效果呈剂量依赖性，剂量范围为 0.01 至 1.0mg/kg。单次给予 1mg/kg 脂囊化 DxM-P 和 3×1mg/kg 游离 DxM-P 具有相似的效果，表现为部分和短暂的抑制。此外，中剂量脂囊化 DxM-P（3×0.1mg/kg）的效果（短期）与高剂量游离 DxM-P（3×1mg/kg）的效果相当（长期），提示通过脂囊化将剂量减少 3 至 10 倍的可能性。在最后一次注射后至少 48 小时内，脂囊化药物在血浆、滑膜、脾和肝中的水平明显高于游离药物。
这种新型无 PEG 的巨噬细胞靶向脂囊化 DxM-P 制剂显著减少了治疗 AA 所需的剂量和/或频率，有可能增强或延长治疗效果，并限制类风湿关节炎治疗中的副作用。在血浆、炎症关节、肝脏和脾脏中的储存和/或再循环效应可能是脂囊化 DxM-P 具有优势的原因。
