Antibody transport in cultured tumor cell layers.
This review summarizes our recent in vitro studies of the factors affecting the tumor penetration of immunoconjugates. The studies were designed to probe the mechanisms of diffusion and convection, using a cultured layer of mouse melanoma cells as a model tumor cell layer and an antibody to the murine transferrin receptor as a model ligand. Transport of the binding antibody was observed to be slower than that of a non-binding control, a result that is consistent with the "binding site barrier" hypothesis (Fujimori et al., J. Nucl. Med., 31: 1191-1198, 1990). Internalization of the antibody/receptor complex was necessary for this effect to be observed, implying that intracellular trafficking is a determinant of net tumor transport rates. Convective fluid flow exhibited a dependence on cell density that is consistent with a Poiseuille flow model, suggesting that convective transport occurs as laminar flow in tortuous channels. Implications for immunoconjugate therapy, limitations of the approach, and future directions of the research program are discussed.
Topp
E M
EM
Department of Pharmaceutical Chemistry, The University of Kansas, Simons Laboratories, Lawrence 66047, USA. topp@kuhub.cc.ukans.edu
Kitos
P A
PA
Vijaykumar
V
V
DeSilva
B S
BS
Hendrickson
T L
TL
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000276:immunology; D001666:Binding Sites, Antibody; D004058:Diffusion; D004306:Dose-Response Relationship, Immunologic; D004705:Endocytosis; D051379:Mice; D011990:Receptors, Transferrin / Q000276:immunology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D011990:Receptors, Transferrin