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.
