Interstitial transport of rabbit and sheep antibodies in normal and neoplastic tissues.
Interstitial transport of fluorescein isothiocyanate-conjugated nonspecific polyclonal rabbit and sheep IgG was studied in normal (mature granulation) and neoplastic (VX2 carcinoma) tissues grown in a rabbit ear chamber. The interstitial concentration gradients after i.v. injection were analyzed to yield effective interstitial diffusion coefficients, Deff. The one-dimensional diffusion model underestimated Deff by a factor of up to 3 when compared with a two-dimensional model. Despite marked heterogeneities in Deff, the average values of Deff were higher in tumors than in normal tissue. Rabbit IgG moved faster in tumors than the sheep IgG by a factor of 2. When compared with the dextran of same molecular weight, the ratio of Deff between neoplastic and normal tissue decreased from 33 (dextran) to between 2 and 5 (sheep IgG and rabbit IgG, respectively). When compared with dextran of the same Stokes-Einstein radius, IgGs had a lower Deff in both tissue types. These results are consistent with the size, charge, and configuration of antibodies and the structure and charge of the interstitial matrix and suggest that the delivery of antibodies to tumors may be improved by modulating their charge, hydrophilicity, and antigenicity. The molecular weight dependence of Deff also provides a rational basis for the use of bifunctional antibodies and antibody-enzyme conjugates to increase the delivery of low molecular weight anticancer agents to solid tumors.
Clauss
M A
MA
Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213-3890.
Jain
R K
RK
D000818:Animals; D001692:Biological Transport; D002463:Cell Membrane Permeability; D007074:Immunoglobulin G / Q000493:pharmacokinetics*; D008297:Male; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism*; D011817:Rabbits; D012756:Sheep
D007074:Immunoglobulin G