In its journey from the blood stream to cancer cells, a therapeutic agent encounters two barriers: the microvascular wall and the interstitium. The overall goal of our research is to develop a quantitative understanding of these two barriers to transport in tumors, and to develop novel strategies to overcome these barriers for improved cancer detection and treatment. More specifically, the aims for this renewal project are (1) to characterize binding kinetics in vivo between monoclonal antibodies and tumor-associated antigens and (2) to optimize two-step approaches for antibody-mediated delivery. Transport of fluorescently labelled molecules of interest will be measured in normal tissue and human tumors grown in the dorsal chamber in immunodeficient mice using two techniques developed in our laboratory: dual-fluorescence intravital microscopy (DFIM) and fluorescence recovery after photobleaching (FRAP). We will analyze these data using appropriate mathematical models. These models will also be used to develop guidelines for optimal dose and schedule of therapeutic agents. The proposed investigation is a logical extension of our previous research on the transport of nonspecific molecules in the rabbit ear chamber preparation. This renewal project will provide novel and -crucial data on the movement of anti-tumor monoclonal antibodies in human tumor xenografts. It not only represents a major step towards a fundamental understanding of transport and binding in tumors, but is also essential to improve the delivery of novel as well as conventional anti-tumor agents.
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