TARGETED IMMUNOSUPPRESSION USING DEXTRAN PRODRUGS

描述（改编自研究者摘要）：长期目的 本申请人的另一个目的是使用葡聚糖聚合物作为大分子前药， 靶向和/或持续递送药剂。 的 本申请的具体目的是研究右旋糖酐 用于将免疫抑制剂靶向递送至肝脏的前药， 甲基强的松龙（MP）作为模型药物。 据推测， MP的葡聚糖前药会在肝脏中积累，在那里它释放游离的 MP逐渐，导致持续的局部免疫抑制， 有利于肝移植。 为了验证这个假设，首先， 葡聚糖-琥珀酸甲泼尼龙（DEX-MPS）将通过以下方法制备： 琥珀酸甲泼尼龙（MPS）与70 kD葡聚糖的偶联。 第二，DEX-MPS的优先积累和随后的释放， 肝脏中的MP将通过大鼠血液、血清和 肝溶酶体，以及大鼠单次给药后的体内实验 （相当于5 mg/kg MP）。 第三，DEX-MPS对 将在体内试验后测试全身和局部免疫系统 给予相似剂量的前药。 对于全身效应， 免疫抑制的时间过程将通过使用脾来定量 淋巴细胞增殖试验 对于局部效应， 细胞因子（白细胞介素-1和白细胞介素-6）的释放 将脂多糖激发的离体灌注大鼠肝脏 测定 为了进行比较，相似的分布和药理学数据将 在给予等效剂量的游离MP后采集。 的 生物样品中MP、NOS和DEX-MPS的浓度将被 使用特定的色谱方法测定，以及适当的 将估计药代动力学和药效学参数。 的 这些研究的结果将被用来评估潜在的作用， 葡聚糖-免疫抑制剂偶联物在局部免疫抑制中的应用 肝脏

DESCRIPTION (Adapted from Investigator's Abstract): The long-term objective of the applicant is to use dextran polymers as macromolecular prodrugs for targeted and/or sustained delivery of pharmacotherapeutic agents. The specific purpose of this application is to study the feasibility of dextran prodrugs for targeted delivery of immunosuppressants to the liver, using methylprednisolone (MP) as a model drug. It is hypothesized that the dextran prodrug of MP would accumulate in the liver, where it releases free MP gradually, resulting in a sustained, local immunosuppression which would be beneficial in liver transplantation. To test this hypothesis, first, dextran-methylprednisolone succinate (DEX-MPS) will be prepared by conjugation of methylprednisolone succinate (MPS) with a 70 kD dextran. Second, the preferential accumulation of DEX-MPS and subsequent release of MP in the liver will be tested by in vitro studies in rat blood, serum, and liver lysosomes, and by in vivo experiments in rats after single doses (equivalent to 5 mg/kg MP) of DEX-MPS. Third, the effects of DEX-MPS on the systemic and local immune systems will be tested after in vivo administration of a similar dose of the prodrug. For systemic effects, the time course of immunosuppression will be quantitated by using the spleen lymphocyte proliferation test. For local effects, the time course of the release of cytokines (interleukin-1 and interleukin-6) from lipopolysaccharide-challenged isolated perfused rat livers will be determined. For comparison, similar disposition and pharmacologic data will be collected after the administration of equivalent doses of free MP. The concentrations of MP, NOS, and DEX-MPS in biological samples will be determined using specific chromatographic methods, and appropriate pharmacokinetic and pharmacodynamic parameters will be estimated. The results of these studies will be used to assess the potential role of dextran-immunosuppressant conjugates in local immunosuppression of the liver.