Human Serum Albumin-TRAIL Conjugate for the Treatment of Rheumatoid Arthritis
Human Serum Albumin-TRAIL Conjugate for the Treatment of Rheumatoid Arthritis
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DOI：
10.1021/bc500427g
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发表时间：
2014-12-01
影响因子：
4.7
通讯作者：
Youn, Yu Seok
中科院分区：
文献类型：
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作者：
Byeon, Hyeong Jun;Min, Sun Young;Youn, Yu Seok
白蛋白偶联被认为是延长蛋白质短的体内寿命和靶向类风湿性关节炎（RA）的有效手段。在这项研究中，我们提出了一种人血清白蛋白（HSA）通过双功能PEG衍生物（HSA-TRAIL）与肿瘤坏死因子相关的凋亡诱导配体（TRAIL）结合。制备的HSA-TRAIL分子大小（约240 kDa， 15.4 nm）大于TRAIL（约66 kDa， 6.2 nm），在Mia Paca-2细胞和小鼠脾细胞中保持了良好的生物活性（凋亡、细胞毒性和抗增殖）。HSA-TRAIL在胶原诱导关节炎（CIA）小鼠中具有增强的治疗效果。hsa - trail治疗小鼠的发病率和临床评分（以红斑和肿胀程度表示）明显低于trail治疗小鼠。hsa - trail处理小鼠血清中促炎因子ifn - γ、tnf - α、IL-1 β和IL-2水平显著低于trail处理小鼠。此外，HSA-TRAIL在CIA小鼠的后爪中积累，而在幼稚的TRAIL小鼠中没有。与TRAIL相比，HSA-TRAIL的药代动力学特征显著改善(AUC(inf): 844.1 +/- 130.0 vs 36.0 +/- 1.2 ng /mL；T（1/2:）分别为6.20 +/- 0.72 vs 0.23 +/- 0.01 h)。HSA-TRAIL偶联物具有HSA靶向类风湿性关节炎和长体循环的明显优势和TRAIL独特的抗炎功效，有望成为治疗类风湿性关节炎的新方法。
Albumin conjugation is viewed as an effective means of protracting short in vivo lifespans of proteins and targeting rheumatoid arthritis (RA). In this study, we present a human serum albumin (HSA) conjugate linked with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a bifunctional PEG derivative (HSA-TRAIL). Prepared HSA-TRAIL was found to have a larger molecular size (similar to 240 kDa, 15.4 nm) than TRAIL (similar to 66 kDa, 6.2 nm), and its bioactivity (apoptosis, cytotoxicity, and antiproliferation) was well preserved in Mia Paca-2 cells and mouse splenocytes. The enhanced therapeutic efficacy of HSA-TRAIL was demonstrated in collagen-induced arthritis (CIA) mice. The incidence and clinical scores, expressed as degree of erythema and swelling in HSA-TRAIL-treated mice, were remarkably lower than those of TRAIL-treated mice. The serum levels of pro-inflammatory cytokines IFN-gamma, TNF-alpha, IL-1 beta, and IL-2 in HSA-TRAIL-treated mice were significantly lower than those of TRAIL-treated mice. Furthermore, HSA-TRAIL accumulated in the hind paws of CIA mice, not in naive TRAIL mice. Pharmacokinetic profiles of HSA-TRAIL were greatly improved in comparison to those of TRAIL (AUC(inf): 844.1 +/- 130.0 vs 36.0 +/- 1.2 ngh/mL; t(1/2:) 6.20 +/- 0.72 vs 0.23 +/- 0.01 h, respectively). The HSA-TRAIL conjugate, which presents clear advantages of targeting RA and long systemic circulation by HSA and unique anti-inflammatory efficacy by TRAIL, has potential as a novel treatment for rheumatoid arthritis.