Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes
Complete remission of experimental arthritis by joint targeting of glucocorticoids with long-circulating liposomes
复制标题
DOI：
10.1002/art.11140
复制
发表时间：
2003-07-01
影响因子：
--
通讯作者：
Storm, G
中科院分区：
文献类型：
--
作者：
Metselaar, JM;Wauben, MHM;Storm, G
Objective.为了增加糖皮质激素在实验性关节炎中的治疗活性，通过封装在长循环聚乙二醇脂质体中，其显示出在静脉内给药后优先在发炎关节中积累的能力。在首次出现疾病体征后几天，用脂质体和游离磷酸泼尼松龙（PLP）静脉内治疗了患有类固醇诱导的关节炎（AIA）的大鼠。评估了治疗后几周内对爪子炎症评分的影响。用放射性In-111-oxine标记脂质体，观察脂质体的生物分布和关节定位。通过研究包封在其他类型脂质体中的PLP，其显示出独特的组织分布模式和减少在发炎关节中的积累，说明了靶向递送到发炎关节以实现增加的治疗效果的重要性。脂质体PLP在大鼠AIA模型中被证明是高度有效的。单次注射10 mg/kg导致炎症反应完全缓解近一周。相比之下，相同剂量的未包封的PLP没有减少炎症，并且在每天重复注射后仅观察到轻微的效果。有证据表明，优先将糖皮质激素输送到炎症关节是解释脂质体制剂所观察到的强大治疗益处的关键因素，而排除了其他可能的机制，如脾脏蓄积或泼尼松龙在循环中的延长释放。使用长循环脂质体的靶向递送是一种有前途的、成功地用糖皮质激素治疗干预关节炎的新手段。
Objective. To increase the therapeutic activity of glucocorticoids in experimental arthritis by encapsulation in long-circulating polyethylene glycol liposomes, which have shown the ability to preferentially accumulate in inflamed joints after intravenous administration.Methods. Rats with adjuvant-induced arthritis (AIA) were treated intravenously with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of disease. The effect on paw inflammation scores during the weeks after treatment was evaluated. Liposome biodistribution and joint localization were investigated by labeling the preparation with radioactive In-111-oxine. By studying PLP encapsulated in other types of liposomes, which show a distinctive tissue distribution pattern and reduced accumulation in inflamed joints, the importance of targeted delivery to inflamed joints for achieving an increased therapeutic effect was illustrated.Results. Liposomal PLP proved to be highly effective in the rat AIA model. A single injection of 10 mg/kg resulted in complete remission of the inflammatory response for almost a week. In contrast, the same dose of unencapsulated PLP did not reduce inflammation, and only a slight effect was observed after repeated daily injections. Evidence was found that preferential glucocorticoid delivery to the inflamed joint was the key factor explaining the observed strong therapeutic benefit obtained with the liposomal preparation, while other possible mechanisms, such as splenic accumulation or prolonged release of prednisolone in the circulation, were excluded.Conclusion. Targeted delivery using long-circulating liposomes is a promising, novel means to successfully intervene in arthritis with glucocorticoid therapy.