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Mechanisms of Heterogeneous Distribution of Monoclonal Antibodies and Other Macromolecules in Tumors: Significance of Elevated Interstitial Pressure¹

Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890

The therapeutic efficacy of monoclonal antibodies (MAbs), bound to radionuclides, chemotherapeutic agents, toxins, growth factors, or effector antibodies, depends upon their ability to reach their target in vivo in adequate quantities. Despite the high vascular permeability and interstitial transport coefficients in tumor tissue compared to several normal tissues, MAbs and their fragments do not distribute homogeneously in a tumor. Heterogeneity of tumor-associated antigen expression alone cannot explain this maldistribution of MAbs in tumors. We propose that in addition to the heterogeneous blood perfusion, hindered diffusion in the interstititum, and extravascular binding of MAbs, elevated interstitial pressure is responsible for the poor penetration of MAbs into tumors. Elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and also leads to an experimentally verifiable, radially outward convection which opposes the inward fiffusion. We present here mathematical models for transport of fluid and macromolecules in a tumor. To illustrate the significance of elevated interstitial pressure, these models are used to describe the interstitial pressure, interstitial fluid velocity, and concentration of non-binding macromolecules as a function of radial position in a uniformly perfused tumor.

The key result of these models is that the filtration of fluid from blood vessels in a uniformly perfused tumor is (a) spatially heterogeneous, (b) a result of elevated interstitial pressure, and (c) sufficient to explain the heterogeneous distribution of macromolecules in tumors. Nonuniform blood flow, and extravascular binding would enhance this heterogeneity in the solute distribution considerably. The results of the models also agree with the following experimental data: (a) tumor interstitial pressure is low in the periphery and it increases toward the center of the tumor; (b) the radially outward fluid velocity at the tumor periphery predicted by the model is of the same order of magnitude as measured in tissue-isolated tumors; and (c) immediately after bolus injection, the concentration of macromolecules is higher in the periphery than in the center; however, at later time periods the peripheral concentration is lower than in the center. These results have significant implications not only for MAbs and their fragments, but for other biologically useful macromolecules (e.g., cytokines) produced by genetic engineering for cancer diagnosis and treatment.

¹ Supported by the National Cancer Institute (CA-36902). This work was presented at the Radiation Research Society Annual Meeting in Philadelphia, April 16–21, 1988, and at the Annual Meetings of the Microcirculation Society and the Biomedical Engineering Society in Las Vegas, April 30 to May 5, 1988.

² To whom requests for reprints should be addressed.

³ Recipient of NSF Predoctoral Fellowship.

Received 4/ 8/88. Revised 6/14/88. Revised 8/ 8/88. Accepted 9/21/88.