Effect of cell arrangement and interstitial volume fraction on the diffusivity of monoclonal antibodies in tissue.
We present theoretical calculations relating the effective diffusivity of monoclonal antibodies in tissue (Deff) to the actual diffusivity in the interstitium (Dint) and the interstitial volume fraction phi. Measured diffusivity values are effective values, deduced from concentration profiles with the tissue treated as a continuum. By using homogenization theory, the ratio Deff/Dint is calculated for a range of interstitial volume fractions from 10 to 65%. It is assumed that only diffusion in the interstitial spaces between cells contributes to the effective diffusivity. The geometries considered have cuboidal cells arranged periodically, with uniform gaps between cells. Deff/Dint is found to generally be between (2/3) phi and phi for these geometries. In general, the pathways for diffusion between cells are not straight. The effect of winding pathways on Deff/Dint is examined by varying the arrangement of the cells, and found to be slight. Also, the estimates of Deff/Dint are shown to be insensitive to typical nonuniformities in the widths of gaps between cells. From our calculations and from published experimental measurements of the effective diffusivity of an IgG polyclonal antibody both in water and in tumor tissue, we deduce that the diffusivity of this molecule in the interstitium is one-tenth to one-twentieth its diffusivity in water. We also conclude that exclusion of molecules from cells (an effect independent of molecular weight) contributes as much as interstitial hindrance to the reduction of effective diffusivity, for small interstitial volume fractions (around 20%). This suggests that the increase in the rate of delivery to tissues resulting from the use of smaller molecular-weight molecules (such as antibody fragments or bifunctional antibodies) may be less than expected.
el-Kareh
A W
AW
Department of Physiology, University of Arizona, Tucson 85724.
Braunstein
S L
SL
Secomb
T W
TW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000627:therapeutic use; D055592:Biophysical Phenomena; D001703:Biophysics; D048429:Cell Size; D004058:Diffusion; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal