Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated.
Targeting 15d-prostaglandin J2 to hepatic stellate cells: two options evaluated.
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DOI：
10.1007/s11095-006-9175-2
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发表时间：
2007-03
影响因子：
3.7
通讯作者：
Beljaars, Leonie
中科院分区：
文献类型：
--
作者：
Hagens, Werner I.;Mattos, Adriana;Greupink, Rick;de Jager-Krikken, Alie;Reker-Smit, Catharina;van Loenen-Weemaes, AnneMiek;Gouw, Annette S. H.;Poelstra, Klaas;Beljaars, Leonie
将凋亡诱导化合物递送至肝星状细胞（HSC）可能是逆转肝纤维化的有效策略。因此，本研究的目的是检查细胞凋亡诱导药物 15-脱氧-Δ12,14-前列腺素 J2 (15dPGJ2) 与两种不同 HSC 载体的选择性靶向：用糖甘露糖-6-磷酸 (M6PHSA) 修饰的人血清白蛋白或用 PDGF 受体识别肽 (pPBHSA) 修饰的白蛋白。 15dPGJ2 与载体化学缀合后，该构建体在体外表现出药理活性和特异性受体介导的与 HSC 的结合。与 15dPGJ2-pPBHSA 不同，15dPGJ2-M6PHSA 的细胞结合被清道夫受体拮抗剂减少。在体内，两种缀合物在纤维化肝脏中快速积累。肝内分析显示15dPGJ2-M6PHSA主要在HSC中积累，在Kupffer细胞中也有少量积累。 15dPGJ2-pPBHSA 也主要在 HSC 中积累，并在肝细胞中额外摄取。对人类肝硬化肝脏中靶受体的评估表明，M6P/IGFII 受体表达存在于纤维化区域。 PDGF-β受体表达在人成纤维细胞上大量表达。这些研究表明，与 M6PHSA 或 pPBHSA 偶联的 15dPGJ2 被 HSC 特异性吸收，并且在这些细胞内非常有效。两种载体的受体特异性不同，导致肝内分布存在差异。尽管如此，两种载体都可以用于在体内将细胞凋亡诱导药物15dPGJ2递送至HSC。
Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the sugar mannose-6-phosphate (M6PHSA) or albumin modified with PDGF-receptor recognizing peptides (pPBHSA). After chemical conjugation of 15dPGJ2 to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ2-pPBHSA, the cellular binding of 15dPGJ2-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ2-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ2-pPBHSA also predominantly accumulated in HSC with additional uptake in hepatocytes. Assessment of target receptors in human cirrhotic livers revealed that M6P/IGFII-receptor expression was present in fibrotic areas. PDGF-β receptor expression was abundantly expressed on human fibroblasts. These studies show that 15dPGJ2 coupled to either M6PHSA or pPBHSA is specifically taken up by HSC and is highly effective within these cells. Both carriers differ with respect to receptor specificity, leading to differences in intrahepatic distribution. Nevertheless, both carriers can be used to deliver the apoptosis-inducing drug 15dPGJ2 to HSC in vivo.
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影响因子：
25.7
作者：
Adrian, JE;Poelstra, K;Kamps, JAAM
通讯作者：
Kamps, JAAM
影响因子：
29.4
作者：
Issa, R;Zhou, XY;Iredale, JP
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Iredale, JP
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82.9
作者：
Gilroy, DW;Colville-Nash, PR;Willoughby, DA
通讯作者：
Willoughby, DA
影响因子：
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作者：
Greupink, Rick;Bakker, Hester I.;Poelstra, Klaas
通讯作者：
Poelstra, Klaas
影响因子：
3.6
作者：
HARMS, G;DIJKSTRA, CD;HARDONK, MJ
通讯作者：
HARDONK, MJ