The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue
The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue
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DOI：
10.1016/s0006-2952(03)00445-3
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发表时间：
2003-10-01
影响因子：
5.8
通讯作者：
Poelstra, K
中科院分区：
文献类型：
--
作者：
Beljaars, L;Weert, B;Poelstra, K
血小板源性生长因子（plateletderivedgrowthfactor，PDGF）是以活化的成纤维细胞为靶细胞的纤维化疾病诱导和进展的关键因子。以PDGF受体为靶点的药物被认为是治疗该疾病的新途径。因此，我们构建了一个大分子与PDGF-β受体的亲和力，通过修饰白蛋白与小肽，识别这种PDGF-β受体。肽修饰的白蛋白（pPB-HSA）与PDGF-β受体的结合在使用NIH/3 T3-成纤维细胞和活化的肝星状细胞的PDGF-BB的竞争研究中得到证实。此外，pPB-HSA能够减少PDGF-BB诱导的成纤维细胞增殖在体外，并证明是缺乏增殖诱导活性本身。我们评估了pPB-HSA在两种纤维化模型中的体内分布，并将pPB-HSA的分布与PDGF-β受体密度相关联。在肝纤维化大鼠（胆管结扎模型）中，pPB-HSA在肝内迅速蓄积，与未修饰的HSA相比有显著性差异（P < 0.001）。pPB-HSA在肝纤维化中主要定位于肝星状细胞。在肾纤维化大鼠（抗Thy 1.1模型）中，pPB-HSA也归巢于表达PDGF-P受体的细胞，即肾小球中的系膜细胞。这些结果表明，pPB-HSA可用作大分子药物载体，其在表达PDGF-β受体的细胞中特异性积累，从而允许抗纤维化剂选择性递送至这些细胞。(C)2003年爱思唯尔公司All rights reserved.
Platelet derived growth factor (PDGF) is a key factor in the induction and progression of fibrotic diseases with the activated fibroblast as its target cell. Drug targeting to the PDGF-receptor is explored as a new approach to treat this disease. Therefore, we constructed a macromolecule with affinity for the PDGF-beta receptor by modification of albumin with a small peptide that recognises this PDGF-beta receptor. The binding of the peptide-modified albumin (pPB-HSA) to the PDGF-beta receptor was confirmed in competition studies with PDGF-BB using NIH/3T3-fibroblasts and activated hepatic stellate cells. Furthermore, pPB-HSA was able to reduce PDGF-BB-induced fibroblast proliferation in vitro, and proved to be devoid of proliferation-inducing activity itself. We assessed the distribution of pPB-HSA in vivo in two models of fibrosis and related the distribution of pPB-HSA to PDGF-beta receptor density. In rats with liver fibrosis (bile duct ligation model), pPB-HSA quickly accumulated in the liver in contrast to unmodified HSA (P < 0.001). The major part of pPB-HSA in the fibrotic liver was localized in hepatic stellate cells. In rats with renal fibrosis (anti-Thy 1.1 model), pPB-HSA also homed to the cells that expressed the PDGF-P receptor, i.e. the mesangial cells in the glomeruli of the kidney. These results indicate that pPB-HSA may be applied as a macromolecular drug-carrier that accumulates specifically in cells expressing the PDGF-beta receptor, thus allowing a selective delivery of anti-fibrotic agents to these cells. (C) 2003 Elsevier Inc. All rights reserved.