Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis
Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis
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DOI：
10.4049/jimmunol.170.9.4793
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发表时间：
2003-05-01
影响因子：
4.4
通讯作者：
Fiehn, C
中科院分区：
文献类型：
--
作者：
Wunder, A;Müller-Ladner, U;Fiehn, C
我们最近报道，白蛋白是一种合适的药物载体，甲氨蝶呤（MTX）的肿瘤靶向输送。由于肿瘤组织中的病理生理条件，大量白蛋白在肿瘤中蓄积并被恶性细胞代谢。MTX，共价偶联到人血清白蛋白（MTX-HSA）用于癌症治疗，目前正在进行II期临床试验评估。由于类风湿性关节炎（RA）患者的滑膜具有在肿瘤中也观察到的各种特征，因此基于白蛋白的药物靶向炎症关节可能是一种有吸引力的治疗方法。因此，检查了白蛋白和MTX在关节炎小鼠模型中的药代动力学。此外，研究了RA患者滑膜成纤维细胞对白蛋白的摄取以及MTX和MTX-HSA在关节炎小鼠中的疗效。结果表明，与MTX相比，在发炎的爪子中积累了显著更高量的白蛋白，在肝脏和肾脏中发现了显著更低量的白蛋白。该蛋白质在体外和体内由人滑膜成纤维细胞代谢。MTX-HSA在抑制小鼠关节炎发作方面比MTX显著更有效。总之，白蛋白似乎是RA中合适的药物载体，最可能是由于对滑膜成纤维细胞的影响，这可能会增加MTX的疗效并减少副作用。
We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX.