INTERSTITIAL DIFFUSION AND CAPILLARY PERMEABILITY IN NORMAL AND NEOPLASTIC TISSUES (MICROCIRCULATION, FLUORESCENCE MEASUREMENT, MACROMOLECULE TRANSPORT, IN VIVO, MASS TRANSFER, MODELLING).

摘要

A quantitative study of mass transfer characteristics of macromolecules in normal and tumor microvessels has been performed using the rabbit ear chamber. The probe macromolecule (150,000 MW dextran) was advantageous for this study for two reasons; (i) it is representative in size of monoclonal antibodies, and (ii) it is a stable, inert, and non-reactive when used in vivo. Visual observations of the fluorescent tagged dextran did not show any intense regions of preferential uptake (e.g. by endothelial cells along the microvessel wall). The diffusion of 150,000 molecular weight dextran was found to occur much more rapidly in tumors than in normal tissues (D(,T) = 3.157 x 10('-8) cm('2)/s and D(,N) = 4.77 x 10('-10) cm('2)/s). The permeability of the microvascular wall was also determined to be much greater in tumor tissues than normal tissue (P(,T) = 57.3 x 10('-8) cm/s and P(,N) = 7.2 x 10('-8) cm/s). The permeability measurements indicated that the rate limiting step to uptake of macromolecule was permeation across the vessel wall (i.e., the results were insensitive to changes in diffusion coefficient). Permeability studies were also performed under mild (43(DEGREES)C) and extreme hyperthermia (50(DEGREES)C) conditions, and following injections of glucose (0.2 gm/kg and 2.0 gm/kg) and galactose (0.2 gm/kg and 2.0 gm/kg). No preferential mass transfer alterations were found in the tumor over normal tissues due to any stimulus. A two-dimensional time dependent mathematical model was able to show that the tumor microvasculature contained more endothelial leakage sites than the corresponding normal microvasculature. These results provide a fundamental rationale for the current trends in cancer treatment and detection towards the use of macromolecules (e.g., monoclonal antibodies).