Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats
Effects of interferon-gamma liposomes targeted to platelet-derived growth factor receptor-beta on hepatic fibrosis in rats
复制标题
靶向血小板源性生长因子受体-β的干扰素γ脂质体对大鼠肝纤维化的影响
DOI：
10.1016/j.jconrel.2011.12.023
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发表时间：
2012-04-30
影响因子：
10.8
通讯作者：
Lu, Wei-yue
中科院分区：
文献类型：
--
作者：
Li, Feng;Li, Qing-hua;Lu, Wei-yue
目前还没有药物被临床批准用于治疗肝纤维化。尽管干扰素-γ在体外和体内的一些动物模型中是一种高效的抗纤维化药物，但由于其不受欢迎的非靶点效应和较短的半衰期导致疗效不佳，其临床抗纤维化作用一直令人失望。本研究的目的是开发一种新的靶向给药系统，选择性地将干扰素-γ输送到肝星状细胞(HSCs)，并研究其是否能改善干扰素-γ的抗纤维化作用，减少其在肝纤维化中的副作用。用与血小板衍生生长因子受体-β(PDGFR-β)具有特异性亲和力的环肽(Ppb)修饰空间稳定的脂质体(SSLS)，然后将干扰素-γ包埋在靶向脂质体(ppb-SSl-IFN-Gamma)中。在体外，PPB-SSL被培养的活化的HSC摄取和内化。FITC标记的ppb-SSL与激活的HSC的结合呈时间和浓度依赖关系，过量的未标记ppb-SSL、PDGF-BB、苏拉明或莫能菌素可抑制这种结合。Ppb-sIL-干扰素-γ对活化的HSCs增殖的抑制作用分别是非靶向包裹的游离干扰素-γ和游离干扰素-γ的7.24倍和2.95倍。在健康大鼠体内的组织分布、活体示踪图像分析和药代动力学研究表明，ppb-sl-干扰素-γ主要在肝脏内蓄积，半衰期比游离干扰素-γ长(3.98+/-0.52h比0.21+/-0.03h)。此外，在硫代乙酰胺诱导的大鼠肝纤维化模型中，免疫荧光双标FITC和白蛋白或α-平滑肌肌动蛋白(α-SMA)发现FITC标记的ppb-SSL主要定位于激活的HSC。Ppb-sl-干扰素-γ治疗的抗纤维化作用增强，表现为肝纤维化的组织学Ishak分期、I型胶原染色阳性面积和α-SMA表达水平显著降低。此外，ppb-sl-干扰素-γ治疗改善了低剂量和高剂量游离干扰素-γ治疗引起的白细胞减少症。综上所述，以ppb-SSL为载体的干扰素-γ具有较长的循环半衰期，并选择性地输送到活化的HSC中，增强了干扰素-γ的抗纤维化作用，减少了其对肝纤维化的毒副作用。因此，ppb-sIL-干扰素-γ有可能成为治疗肝纤维化的有效药物。(C)2011爱思唯尔B.V.保留所有权利。
No drugs have been approved clinically for the therapy of hepatic fibrosis. Though interferon-gamma (IFN-gamma) is a highly effective anti-fibrotic agent in vitro and in some animal models in vivo, its anti-fibrotic potential in clinical trials has been disappointing, due to unwanted off-target effects and a short half-life period which results in poor efficacy. The aims of this study are to develop a new targeted drug delivery system to selectively deliver IFN-gamma to hepatic stellate cells (HSCs) and to investigate whether it will improve the anti-fibrotic effect of IFN-gamma and reduce its side effects in fibrotic livers. Sterically stable liposomes (SSLs) were modified by cyclic peptides (pPB) with a specific affinity for platelet-derived growth factor receptor-beta (PDGFR-beta), and then IFN-gamma was encapsulated in the targeted liposomes (pPB-SSL-IFN-gamma). In vitro, pPB-SSL was found to be taken up and internalized by cultured activated HSCs. The binding of FITC-labeled pPB-SSL to activated HSCs was in a time-dependent and concentration-dependent manner, which could be inhibited by excess unlabelled pPB-SSL, PDGF-BB, suramin or monensin. The inhibitory effect of pPB-SSL-IFN-gamma on the proliferation of activated HSCs was respectively 7.24-fold and 2.95-fold higher than that of free IFN-gamma and IFN-gamma encapsulated in untargeted SSLs. In healthy rats, the tissue distribution, living-body tracing image analyses and pharmacokinetics study showed that pPB-SSL-IFN-gamma accumulated mainly in the livers and had a longer half-life than free IFN-gamma (3.98 +/- 0.52 h vs. 0.21 +/- 0.03 h). Furthermore, in rats with hepatic fibrosis induced by thioacetamide injection, FITC-labeled pPB-SSL was found to predominantly localize in activated HSCs by immunofluorescent double staining for FITC and albumin or alpha-smooth muscle actin (alpha-SMA). The enhanced anti-fibrotic effect of pPB-SSL-IFN-gamma treatment was indicated by significant decreases in the histologic Ishak stage, collagen I-staining positive areas, and alpha-SMA expression levels in fibrotic livers. In addition, pPB-SSL-IFN-gamma treatment improved the leukopenia caused by low-and high-dosage free IFN-gamma treatments. In conclusion, IFN-gamma encapsulated in pPB-SSL had an extended circulation half-life and was selectively delivered to activated HSCs, which enhanced the anti-fibrotic effect of IFN-gamma and reduced its side-effects in rats with hepatic fibrosis. Thus, pPB-SSL-IFN-gamma may be an effective agent for the therapy of hepatic fibrosis. (C) 2011 Elsevier B.V. All rights reserved.