TARGETED IMMUNOSUPPRESSION USING DEXTRAN PRODRUGS

使用右旋糖酐前药进行靶向免疫抑制

• 批准号: 2603521
• 负责人: REZA MEHVAR
• 金额: $ 3.16万
• 依托单位: DRAKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2603521
• 关键词: artificial immunosuppression; chemical conjugate; dextrans; laboratory rat; liver metabolism; lymphocyte proliferation; methylprednisolone; pharmacokinetics; prodrugs

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.

描述（改编自研究者摘要）：长期目标 申请人的目的是使用葡聚糖聚合物作为大分子前药用于 药物治疗剂的靶向和/或持续递送。 这 本申请的具体目的是研究右旋糖酐的可行性 用于将免疫抑制剂靶向递送至肝脏的前药，使用 甲基强的松龙（MP）作为模型药物。 假设 MP 的右旋糖酐前药会积聚在肝脏中，并在那里释放游离 MP 逐渐产生，导致持续的局部免疫抑制，这将 有利于肝移植。 为了检验这个假设，首先， 右旋糖酐-甲基泼尼松龙琥珀酸酯 (DEX-MPS) 将通过以下方法制备 琥珀酸甲泼尼龙 (MPS) 与 70 kD 葡聚糖的缀合。 二、DEX-MPS优惠累积及后续释放 肝脏中的 MP 将通过大鼠血液、血清和血液中的体外研究进行测试 肝溶酶体，以及单剂量后大鼠体内实验 （相当于 5 mg/kg MP）DEX-MPS。 三、DEX-MPS对 全身和局部免疫系统将在体内测试后进行 施用类似剂量的前药。 对于系统性影响， 免疫抑制的时间进程将通过使用脾脏来定量 淋巴细胞增殖试验。 对于局部效应，时间过程 释放细胞因子（白细胞介素 1 和白细胞介素 6） 脂多糖攻击的离体灌注大鼠肝脏将 决定。 为了进行比较，类似的处置和药理学数据将 在施用等剂量的游离MP后收集。 这 生物样品中 MP、NOS 和 DEX-MPS 的浓度为 使用特定的色谱方法和适当的方法测定 将估计药代动力学和药效学参数。 这 这些研究的结果将用于评估潜在作用 右旋糖酐-免疫抑制剂缀合物在局部免疫抑制中的作用 肝。