Mannose-6-phosphate/insulin-like growth Factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells
Mannose-6-phosphate/insulin-like growth Factor-II receptors may represent a target for the selective delivery of mycophenolic acid to fibrogenic cells
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DOI：
10.1007/s11095-006-9025-2
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发表时间：
2006-08-01
影响因子：
3.7
通讯作者：
Poelstra, Klaas
中科院分区：
文献类型：
--
作者：
Greupink, Rick;Bakker, Hester I.;Poelstra, Klaas
目的.胰岛素样生长因子轴在纤维形成中起重要作用。然而，关于纤维化过程中甘露糖-6-磷酸/胰岛素样生长因子-II受体（M6 P/IGF-IIR）的表达知之甚少。当在纤维化细胞上优先表达时，该受体可用于选择性地将药物递送至这些细胞。我们研究了M6 P/IGF-IIR在胆管结扎（BDL）大鼠肝脏和肾素转基因TGR（mRen 2）27大鼠肾血管壁中的表达。两种模型的特征在于纤维化过程。此外，我们还研究了通过M6 P/IGF-II受体介导的药物摄取在成纤维细胞中是否可行。在BDL后3、7和10天检测M6 P/IGF-IIRmRNA表达。在所有时间点，与健康对照相比，肝脏M6 P/IGF-IIR表达显著增加。此外，免疫组化染色显示α-sma阳性细胞为M6 P/IGF-IIR阳性。在TGR（mRen 2）27大鼠的肾脏中，每个显微镜视野的M6 P/IGF-IIR阳性动脉数量比健康对照增加5.5倍。为了检查M6 P/IGF-IIRs是否可以用作药物的进入端口，我们将霉酚酸（MPA）偶联到甘露糖-6-磷酸修饰的人血清白蛋白（M6 PHSA）。M6 PHSA-MPA呈剂量依赖性抑制3 T3成纤维细胞增殖，与过量的M6 PHSA共孵育可逆转M6 PHSA的抑制作用，但HSA不能逆转M6 PHSA的抑制作用。M6 P/IGF-IIRs由纤维化细胞表达，可用于受体介导的抗纤维化药物MPA的细胞内递送。
Purpose. The insulin-like growth factor axis plays an important role in fibrogenesis. However, little is known about mannose-6-phosphate/Insulin-like growth factor-II receptor (M6P/IGF-IIR) expression during fibrosis. When expressed preferentially on fibrogenic cells, this receptor may be used to selectively deliver drugs to these cells.Methods. We investigated M6P/IGF-IIR expression in livers of bile duct-ligated (BDL) rats and in renal vascular walls of renin transgenic TGR(mRen2)27 rats. Both models are characterized by fibrogenic processes. Furthermore, we studied whether drug delivery via M6P/IGF-II-receptor-mediated uptake is possible in fibroblasts.Results. M6P/IGF-IIR mRNA expression was investigated 3, 7 and 10 days after BDL. At all time-points hepatic M6P/IGF-IIR expression was significantly increased compared to healthy controls. Moreover, immunohistochemical staining revealed that alpha-sma-positive cells were M6P/IGF-IIR-positive. In kidneys of TGR(mRen2)27 rats, the number of M6P/IGF-IIR-positive arteries per microscopic field was increased 5.5 fold over healthy controls. To examine whether M6P/IGF-IIRs could be used as a port of entry for drugs, we coupled mycophenolic acid (MPA) to mannose-6-phosphate-modified human serum albumin (M6PHSA). M6PHSA-MPA inhibited 3T3-fibroblast proliferation dose-dependently, which was reversed by co-incubation with excess M6PHSA, but not by HSA.Conclusions. M6P/IGF-IIRs are expressed by fibrogenic cells and may be used for receptor-mediated intracellular delivery of the antifibrogenic drug MPA.