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和数学分析单克隆抗体（mab）在肿瘤中的各种运输机制的相对贡献。实验将包括直接测量(i)血液灌注率、（ii）间质压力、（iii）抗原和（iv）抗体在肿瘤注射后不同时间的空间分布。肿瘤将作为一个标准的皮下植入物生长，并作为一个“孤立的肿瘤”，通过一条动脉和一条静脉与宿主相连。后一种制备将允许直接测量肿瘤周围的间质液速度。为了辨别结合的作用，将使用两种类型的抗体：非特异性抗体和肝癌特异性抗体。将通过开发两种基于生理学的分布参数模型来分析所得数据：(i)流体输送模型和（ii）溶质输送模型。前者可以计算肿瘤组织间质压力和组织间质速度，后者可以计算单克隆抗体在肿瘤中的时空分布。将进行广泛的模拟和敏感性分析，以提出改善单克隆抗体在肿瘤中的传递和分布的方法。如果单克隆抗体要实现它们的承诺，就必须开发出有选择性地将它们以足够的量输送到体内目标的方法。不幸的是，单克隆抗体在癌症治疗中表现出有限或没有成功，主要是因为它们无法均匀穿透实体肿瘤。特别是，当单克隆抗体注射到血液中时，在实体肿瘤中心积聚的数量非常低。单克隆抗体优先分布在最靠近功能血管的区域，在许多情况下，在肿瘤周围。肿瘤周围丰富的抗体可能有助于使用放射成像技术检测肿瘤，但它对中心细胞没有治疗作用。在外部细胞被杀死后，残留的肿瘤又长出来了。用于识别和理解肿瘤中控制异质性分布的机制的工程方法可能为将抗体和其他大分子输送到肿瘤的所有区域提供新方法。

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.