THE MICROPHARMACOLOGY OF BIOLOGICAL LIGANDS

生物配体的微观药理学

• 批准号: 6289196
• 负责人: JOHN N WEINSTEIN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289196
• 关键词: antigen antibody reaction; antineoplastics; chemical models; cytokine; drug delivery systems; drug screening /evaluation; guinea pigs; immunoglobulins; ligands; mathematical model; membrane permeability; model design /development; neoplasm /cancer pharmacology; neoplastic cell; pharmacokinetics; receptor binding; tissue /cell culture; tumor antigens; vascular endothelium permeability

For a number of years, we have been exploring ways to integrate macroscopic and microscopic aspects of the pharmacology of biologically interesting ligands, in particular immunoglobulins and cytokines. The principal aim has been to understand what limits effective access of these ligands to various regions of a tumor. The project has involved a combination of theoretical and experimental studies. Theoretical: we developed a program package (PERC) that integrates the ordinary differential equations for kinetic modeling of compartmental pharmacokinetics with the partial differential equations that govern convection, diffusion, binding, and reaction of ligands in tissues and tumors. The ensuing analyses led us to formulate the "binding site barrier" hypothesis - i.e., that the very fact of successful binding to a target antigen or receptor can limit penetration into the substance of a tumor. Calculations suggested that (1) the barrier effect could prevent penetration even 100-200 microns from a blood vessel; (2) paradoxically, high affinity and high binding site density could produce lower concentrations of ligand as little as 100 microns from a vessel. Experimental: We validated the binding site barrier hypothesis experimentally in bulk tumors and micrometastases of L10 carcinoma in guinea pigs. To do this it was necessary to combine double-label autoradiography with double-chromophore immunohistochemistry to detect simultaneously the distributions of antibody, control IgG, antigen, and blood vessels. We have proposed that the "binding site barrier" has been a factor in the evolution of autocrine-paracrine molecules and other biological ligands. As a corollary, this micropharmacological barrier must be considered when designing ligands for exogenous administration or for secretion in vivo by genetically modified cells. AIDS Title: The Micropharmacology of Biological Ligands: Cytokines in AIDS Pathogenesis.

多年来，我们一直在探索如何将 生物学药理学的宏观和微观方面 感兴趣的配体，特别是免疫球蛋白和细胞因子。的 主要目的是了解是什么限制了有效获取 这些配体与肿瘤的不同区域结合。该项目涉及 理论研究和实验研究相结合。理论：我们 开发了一个程序包（PERC），它集成了普通的 动力学模型的微分方程 药代动力学的偏微分方程， 组织中配体的对流、扩散、结合和反应， 肿瘤的随后的分析使我们形成了“结合位点 屏障”假设-即，成功绑定到 靶抗原或受体可以限制渗透到物质中 一个肿瘤。计算表明：（1）势垒效应可以 防止从血管渗透甚至100-200微米;（2） 矛盾的是，高亲和力和高结合位点密度可以产生 低浓度的配体小至100微米。 实验：我们验证了结合位点屏障假说 在L10癌的大块肿瘤和微转移中， 豚鼠要做到这一点，有必要将联合收割机的双标签 双发色团免疫组化放射自显影检测 同时测定抗体、对照IgG、抗原和 血管我们已经提出，“结合位点屏障”已经被 自分泌-旁分泌分子和其他 生物配体作为一个推论，这种微药理学屏障 在设计外源性给药的配体时必须考虑 或用于遗传修饰细胞的体内分泌。标签：The AIDS 生物配体的微观药理学：艾滋病发病机制中的细胞因子。