Baxter L T, Jain R K
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890.
Microvasc Res. 1989 Jan;37(1):77-104. doi: 10.1016/0026-2862(89)90074-5.
A general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors is developed. The resulting equations are applied to the most simple case of a homogeneous, alymphatic tumor, with no extravascular binding. Numerical simulations show that in a uniformly perfused tumor the elevated interstitial pressure is a major cause for heterogeneous distribution of nonbinding macromolecules, because it (i) reduces the driving force for extravasation of fluid and macromolecules in tumors, (ii) results in nonuniform filtration of fluid and macromolecules from blood vessels, and (iii) leads to experimentally verifiable, radially outward convection which opposes the inward diffusion. The models are used to predict the interstitial pressure, interstitial fluid velocity, and concentration profiles as a function of radial position and tumor size. The model predictions agree with the following experimental data: (i) the interstitial pressure in a tumor is lowest at the periphery of the tumor and increases towards the center; (ii) the radially outward fluid velocity predicted by the fluid transport model is of the same order of magnitude as that measured in tissue-isolated tumors; and (iii) the concentration of macromolecules is higher in the periphery than in the center of tumors at short times postinjection; however, at later times the peripheral concentration is less than the concentration in the center. This work shows that in addition to the heterogeneous distribution of blood supply, hindered interstitial transport, and rapid extravascular binding of macromolecules (e.g., monoclonal antibodies), the elevated interstitial pressure plays an important role in determining the penetration of macromolecules into tumors. If the genetically engineered macromolecules are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers in tumors.
本文建立了一个关于肿瘤中液体和大分子经血管交换及血管外转运的通用理论框架。所得方程应用于均质、无淋巴管且无血管外结合的最简单肿瘤情况。数值模拟表明，在均匀灌注的肿瘤中，升高的间质压力是导致非结合大分子分布不均的主要原因，因为它（i）降低了肿瘤中液体和大分子外渗的驱动力，（ii）导致液体和大分子从血管的非均匀滤过，以及（iii）导致实验可验证的径向向外对流，该对流与向内扩散相反。这些模型用于预测间质压力、间质液速度以及作为径向位置和肿瘤大小函数的浓度分布。模型预测与以下实验数据相符：（i）肿瘤中的间质压力在肿瘤周边最低，并向中心增加；（ii）流体传输模型预测的径向向外流体速度与在组织分离肿瘤中测量的速度具有相同的数量级；以及（iii）在注射后短时间内，大分子在肿瘤周边的浓度高于中心；然而，在稍后时间，周边浓度低于中心浓度。这项工作表明，除了血液供应的异质性分布、间质运输受阻以及大分子（如单克隆抗体）的快速血管外结合外，升高的间质压力在决定大分子进入肿瘤的渗透方面也起着重要作用。如果基因工程大分子要实现其临床前景，必须开发方法来克服肿瘤中的这些生理屏障。
