Mechanisms of Heterogeneous Transport of Monoclonal Antibodies in Tumors

这项工作的总体目标是通过实验测量， 用数学方法分析各种因素的相对贡献 单克隆抗体（MAb）在肿瘤中的转运机制。 实验将涉及直接测量空间分布 （i）血液灌注率，（ii）间质压，（iii） 抗原，和（iv）肿瘤注射后不同时间的抗体。 肿瘤将作为标准植入物皮下生长， 一个“孤立的肿瘤”连接到主机与一个单一的动脉和 单一静脉。 后者的制备将允许直接测量 肿瘤周边的间质液流速。 辨别 结合作用，将使用两种类型的抗体：非特异性抗体 抗体和肝癌特异性抗体。 产生的数据将是 通过开发两个基于生理学的分布参数 模型：（i）流体传输模型和（ii）溶质传输模型 模型 前者将允许计算间隙压力 和肿瘤间质速度，后者将允许 计算MAb在一个细胞中的时空分布， 肿瘤 将进行广泛的模拟和敏感性分析 提出了改善MAb交付和分配的方法， 肿瘤的 如果单克隆抗体要实现其承诺，必须开发方法， 有选择地将它们以足够的数量提供给他们， 目标在体内。 不幸的是，单克隆抗体显示有限或没有 癌症治疗的成功主要是由于他们无法 均匀地穿透实体肿瘤。 特别是，当MAb被 注射到血液中，非常少量的积累在 实体瘤的中心 有优惠 MAb在最接近功能性血液区域的分布 血管，在许多情况下，在肿瘤周边。 丰富 在肿瘤周围的抗体可能有助于肿瘤 检测使用放射成像技术，但它没有 对中心细胞的治疗效果。 在外部 细胞被杀死后，残留的肿瘤又长出来了。 的 工程方法用于识别和理解 控制肿瘤中不均匀分布的机制可能 提出了递送抗体和其它 大分子扩散到肿瘤的所有区域。

The overall objective of this work is to measure experimentally and to analyze mathematically the relative contributions of various mechanisms of transport of monoclonal antibodies (MAbs) in a tumor. Experiments will involve direct measurement of spatial distributions of (i) blood perfusion rate, (ii) interstitial pressure, (iii) antigen, and (iv) antibody at various times post-injection in a tumor. The tumor will be grown as a standard implant subcutantously, and as an "isolated-tumor" connected to the host with a single artery and a single vein. The latter preparation will permit direct measurement of interstitial fluid velocity at the tumor periphery. To discern the role of binding, two types of antibodies will be used: a non-specific antibody and a hepatoma specific antibody. The resulting data will be analyzed by developing two physiologically-based distributed parameter models: (i) a fluid transport model and (ii) a solute transport model. The former will permit calculations of interstitial pressure and interstitial velocity in a tumor, and the latter will permit calculations of the spatial and temporal distribution of MAbs in a tumor. Extensive simulations and sensitivity analyses will be carried out to suggest ways of improving MAb delivery and distribution in tumors. If MAbs are to fulfill their promise, methods must be developed to deliver them selectively and in adequate quantities to their target in the body. Unfortunately, MAbs have shown limited or no success in cancer treatment primarily due to their inability to penetrate solid tumors uniformly. In particular, when MAbs are injected into the blood stream, very low amounts accumulate in the center of a solid tumor. There is a preferential distribution of MAbs in areas closest to the functional blood vessels and, in many cases, on the tumor periphery. An abundance of antibody at the tumor periphery may be helpful in the tumor detection using radioimaging techniques, but it has no therapeutic effect against cells in the center. After the outer cells have been killed, the residual tumor grows back again. The engineering approach used for identifying and understanding the mechanisms governing the heterogeneous distribution in tumors may suggest novel approaches to deliver antibodies and other macromolecules to all regions of a tumor.