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

发现在大鼠的枯否细胞和肝实质细胞中，根据对马来酰化牛血清白蛋白（Mal-BSA）的敏感性，参与分级肝素摄取的清道夫受体可分为两种类型。Kupffer细胞中对乙酰化低密度脂蛋白（Ac-LDL）敏感的受体可能属于A类清道夫受体，而肝实质细胞中对Mal-BSA敏感的受体可能不属于文献报道的任何清道夫受体。为研究清道夫受体介导的肝素及其他阴离子大分子药物的处置，需要对清道夫受体的多样性、组织和细胞分布（包括在腹腔巨噬细胞和脑毛细血管内皮细胞中的清道夫受体）进行更详细的研究。根据人、兔和大鼠的cDNA信息，克隆的受体应该是有用的，为进一步研究的摄取机制。还在研究Mal-BSA对肝脏分级肝素摄取的影响的体外-体内定量相关性，这在体内更为深刻。

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.