Quantitative and Molecular Mechanism-Based Analysis of Factors Interfering with Macromolecular Drug Targeting

在大鼠的Kupffer细胞和肝实质细胞中，根据对马来化牛血清白蛋白（Mal-BSA）的敏感性，发现参与分离肝素摄取的清道夫受体可分为两种类型。虽然库普弗细胞对乙酰化低密度脂蛋白（Ac-LDL）敏感，但肝实质细胞对其不敏感。库普弗细胞中对mall - bsa敏感的可能属于A类清道夫受体，而其他的似乎不属于文献记载的任何一类清道夫受体。需要更详细地研究清除受体的多样性和组织和细胞分布，包括在腹膜巨噬细胞和脑毛细血管内皮细胞中发现的清除受体，以制定调节清除受体介导的分离肝素和其他阴离子大分子药物处置的策略。目前，我们正基于人、兔和大鼠库普弗细胞的cDNA信息，从大鼠库普弗细胞中克隆A类清道夫受体。克隆受体将有助于进一步研究摄取机制。此外，还在研究Mal-BSA对肝脏分离肝素摄取的定量体内外相关性，这在体内的研究更为深入。

It was found, in each of the Kupffer cell and the liver parenchymal cell of the rat, that scavenger receptors involved in the uptake of fractionated heparin can be classified into two types, in terms of sensitivity to maleylated bovine serum albumin (Mal-BSA). Although those in the Kupffer cell were sensitive to acetylated low density lipoprotein (Ac-LDL), those in the liver parenchymal cell were not The Mal-BSA sensitive one in the Kupffer cell may belong to class A scavenger receptors, while the others do not seem to belong any type of scavenger receptor documented in the literature. More detailed investigation should be required about multiplicity and tissue and cellular distributions of scavenger receptors, including those found in the peritoneal macrophage and the brain capillary endothelial cell, to devise strategies for regulating scavenger receptor-mediated disposition of fractionated heparin and some other anionic macromolecular drugs.We are currently working on cloning of class A scavenger receptors from the rat Kupffer cell, based on cDNA information of those in the human, rabbit and rat. Cloned receptors should be useful for further investigating into the uptake mechanism. Also under investigation is quantitative in vitro-in vivo correlation of the effect of Mal-BSA on fractionated heparin uptake by the liver, which was more profound in vivo.