Endocytic Relay as a Potential Means for Enhancing Ligand Transport through Cellular Tissue Matrices: Analysis and Possible Implications for Drug Delivery

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Abstract
The transport of peptide ligands, such as cytokines, through tissue is complicated by resistances due to cell multilayers and holdup in extracellular matrix. To determine whether it is possible for receptor-mediated endocytic trafficking to enhance ligand transport, we have developed a mathematical model of ligand flux through tissue containing cells possessing complementary receptors. Tissue is considered as two phases: the cell phase and the matrix phase; thus tissue is modeled as analogous to a packed bed reactor. This model allows calculation of steady-state flux of intact and degraded peptide through a one-dimensional cell/tissue matrix. Both environmental and molecular parameters were considered in this study. Results predict that three quantities should have a major influence on growth factor flux: the ratio of matrix diffusivity to intracellular "diffusivity" (D(m)/D(i)), the extracellular matrix proteolysis rate constant (k (prot)), and the fraction of internalized growth factor degraded (f(1)). For basal levels of intracellular degradation (0 < f(1) >/= 0.05) but no extracellular proteolysis, significant enhancement is possible only for D(m)/D(i) >/=1. f(1) increases, enhancement is only possible up to f(1)= 0.07 even for D(m)/D(i) < 1. For significant levels of extracellular proteolysis (k (prot) > 0), the requirements for D(m)/D(i) and f(1) to permit transport enhancement encompass a broader range with the exact values dependent on k (prot). These insights may be helpful for delivery of ligands generated from controlled-release devices or genetically modified autocrine cells, and may also provide better understanding of cytokine transport in embryonic development.