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不同的单抗运输机制在肿瘤中的相对贡献。实验将包括直接测量肿瘤注射后不同时间的(I)血液灌注率、(Ii)间质压力、(Iii)抗原和(Iv)抗体的空间分布。肿瘤将作为标准的植入物在皮下种植，并作为通过一条动脉和一条静脉与宿主相连的“孤立肿瘤”生长。后一种制剂可以直接测量肿瘤周围的间质液体速度。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。结果数据将通过开发两个基于生理的分布参数模型进行分析：(I)流体传输模型和(Ii)溶质传输模型。前者允许计算肿瘤中的间质压力和间质速度，而后者将允许计算单抗在肿瘤中的空间和时间分布。将进行广泛的模拟和敏感性分析，以建议改善单抗在肿瘤中的传递和分布的方法。如果单抗要实现它们的承诺，就必须开发方法，有选择地、足量地将它们输送到它们体内的目标位置。不幸的是，单抗在癌症治疗中显示出有限的成功或没有成功，主要是因为它们不能均匀地穿透实体肿瘤。特别是，当单抗被注射到血液中时，非常低的量积累在实体肿瘤的中心。单抗优先分布在离功能血管最近的区域，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放射成像技术检测肿瘤，但对中心细胞没有治疗作用。在外层细胞被杀死后，残留的肿瘤又会重新生长。用于识别和理解肿瘤中异质性分布机制的工程学方法可能会提出新的方法，将抗体和其他大分子输送到肿瘤的所有区域。

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.