The advent of hybridoma technology has led to the large scale production of tumor-associated monoclonal antibodies (MAbs) and other biologically useful macromolecules. Realization of the clinical promise of these macromolecules will depend upon the ability to deliver them uniformly and in adequate quantities to tumors. Unfortunately, the use of MAbs in cancer treatment has had limited success to date due to their inability to reach all regions of a tumor. Heterogeneity of tumor-associated antigen expression alone can not explain this maldistribution of antibodies into tumors. We propose that the following three mechanisms are responsible for the poor distribution of antibodies in tumors: (i) heterogeneous blood supply; (ii) elevated interstitial pressure; and (iii) antibody-antigen binding. The objective of the work proposed here is to estimate the relative contribution of each of three mechanisms with the ultimate goal of improving the delivery of MAbs to tumors. Experiments will involve measurements of (i) blood perfusion rate, (ii) interstitial pressure, (iii) antigen density, and (iv) antibody concentration at various positions in tumors and liver. Theoretical work will involve development of two interrelated physiologically-based distributed parameter models -- (i) a fluid transport model to describe pressure and velocity distributions in the tumor interstitium, and (ii) a solute transport model to describe spatial and temporal distribution of MAbs in tumors. Comparison between models and data should provide novel insights into the transport and binding of MAbs in tumors, and ultimately suggest ways for improving the delivery and distribution of MAbs in tumors.
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