Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone
Attenuation of acute rejection in a rat liver transplantation model by a liver-targeted dextran prodrug of methylprednisolone
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DOI：
10.1097/01.tp.0000177654.48112.b6
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发表时间：
2006-03-15
期刊：
影响因子：
6.2
通讯作者：
Mehvar, R
中科院分区：
文献类型：
--
作者：
Chimalakonda, AP;Montgomery, DL;Mehvar, R
背景使用甲基强的松龙（MP）和其他皮质类固醇治疗急性肝移植排斥反应与严重的非靶组织毒性有关。因此，选择性地将NIP递送至肝脏可以提高其功效并减轻其副作用。我们研究了MP（MP）的一种新型肝靶向葡聚糖前体药物在大鼠原位肝移植（OLT）模型中的作用。该模型由高应答排斥菌株组合（深色琼脂供体和刘易斯受体）组成。肝脏受体静脉内给予生理盐水或单次亚治疗剂量的MP（5 mg/kg）作为母体药物（MP）或其前药（PGEX）。然后监测不同组的移植物存活或在移植后5或9天实施安乐死。测定血浆化学，包括碱性磷酸酶和胆红素，同种异体移植物组织学和存活时间。未经治疗的受体表现出肝损伤标志物的血浆水平升高，肝移植物中进行性门静脉和静脉炎症和细胞浸润，平均移植物存活时间（MST）为10.5天。MP治疗未改变任何这些参数。相反，单剂量的顺铂导致肝损伤标志物的血浆水平降低，第5天排斥反应的组织学分级降低，MST显著增加（27.5天）。这些结果表明，局部（同种异体移植物）免疫抑制后的急性排斥反应的衰减与单一的亚治疗剂量的NIP作为肝脏靶向前药交付。右旋糖酐前体药物可用于肝移植后免疫抑制剂向肝脏的选择性递送。
Background. The use of methylprednisolone (MP) and other corticosteroids for the treatment of acute liver allograft rejection is associated with severe toxicities in nontarget tissues. Therefore, selective delivery of NIP to the liver may improve its efficacy and alleviate its side effects. We investigated the effects of a novel liver-targeted dextran prodrug of MP (DMP) in an orthotopic rat liver transplantation (OLT) model.Methods. The model consisted of a high responder rejection strain combination (Dark Agouti donors and Lewis recipients). Liver recipients were intravenously administered saline or a single subtherapeutic dose of MP (5 mg/kg) as the parent drug (MP) or its prodrug (DMP). Different groups were then monitored for graft survival or euthanized 5 or 9 days posttransplantation. Plasma chemistry, including alkaline phosphatase and bilirubin, allograft histology, and survival duration were determined.Results. Untreated recipients exhibited elevated plasma levels of liver injury markers, progressive portal and venous inflammation and cellular infiltration in liver allografts, and a mean graft survival time (MST) of 10.5 days. MP treatment did not alter any of these parameters. In contrast, a single dose of DMP resulted in a decrease in plasma levels of liver injury markers, a decrease in histological grade of rejection on day 5, and a substantial increase in MST (27.5 days).Conclusions. These results demonstrate attenuation of acute rejection following local (allograft) immunosuppression with a single subtherapeutic dose of NIP delivered as a liver-targeted prodrug. Dextran prodrugs may be useful for selective delivery of immunosuppressants to the liver following liver transplantation.