Macromolecular agents are increasingly being used to treat residual disease on the peritoneum arising from intra-abdominal carcinomas. Therapies such as antibodies conjugated to radionuclides, however, may fail to eliminate small tumor nodules (diameter approximately 5 mm) because the penetration of the agent is limited by slow diffusion through the tumor, by local binding to the tumor parenchyma, or because the solution containing the agent does not have sufficient contact with the tumor. To overcome these problems, a research program is proposed: a) to investigate hydrostatic pressure-driven convection as a means to enhance penetration of a monoclonal antibody (MAb) through the tumor, b) to study the in vivo binding properties of the MAb to specific and nonspecific sites in the tumor in order to optimize the MAb dose delivered, and c) to test a specialized dialysis solution to insure that all surfaces in the cavity receive adequate therapy. A mathematical model of MAb transport through tumor has been formulated to include diffusion, convection, transcapillary transport, and binding. To determine the parameters required for the model, including the tissue hydraulic conductivity, interstitial volume, interstitial pressures, and binding properties of the MAb to tumor, a human xenograft will be transplanted into the abdominal wall of athymic rats, and peritoneal dialysis will be used to deliver MAb. The tumor position permits control of the intraperitoneal (i.p.) pressure that drives convection into tissues surrounding the cavity, and dual-label quantitative autoradiography can be used to measure concentration profiles of markers in the tumor. With the experimentally derived parameters, the mathematical model will be used to predict the intraperitoneal pressure, MAb concentration in the dialysis solution, and the duration of treatment that result in effective penetration of the tumor. The model predictions will be tested with additional in vivo experiments. After experimental validation, these delivery conditions will be further studied in rats bearing tumors at multiple peritoneal sites with a special dialysis solution designed to bathe the entire peritoneum. Efficacy of antibody distribution and penetration into all tumors will be determined and compared with transport into normal tissue. The long-term goals of the program include: development of the capability to predict macromolecular transport through tumors located in tissue surrounding the peritoneal cavity and the delineation of effective strategies for the regional treatment of peritoneal tumors with macromolecular agents.
