We are studying factors that govern in vivo transport of macromolecules such as growth hormones, ribonucleases, protein toxins, streptavidin, immunotoxins and monoclonal antibodies (MAb) in an effort to increase the delivery of such agents to targeted tissues. Three experimental studies, supported by mathematical models, are being conducted in cell culture and animal models. The first, low uptake of immunotoxins in solid tumors, prompted investigation of cotreatment with angiotensin II, which reportedly opens capillary beds of solid tumors selectively. In our tumor model, however, it had no effect on tumor uptake or spatial distribution of immunotoxin measured by quantitative autoradiography. In the second, spatially distributed pharmacokinetic models were developed to simulate the experimental characteristics of two-step protocols for imaging and treatment of metastatic cancer. These protocols involve combined use of a modified MAb and a rapidly diffusible radiolabeled substance that binds to the MAb. Model simulations suggested conditions under which such protocols would improve pharmacokinetic indices. Recent progress in expression of single-chain immunoglobulin fragments fused with streptavidin has furthered interest in this approach. Model simulations are being implemented to assist in the design of an experimental clinical protocol. The third involves pharmacokinetic studies of several members of the homologous RNase A superfamily and genetically engineered ribonuclease hybrids, and has provided information on molecular determinants of the uniquely high kidney retention of onconase, a frog ribonuclease being tested in clinical trials for the treatment of pancreatic cancer.
