Figure 1.
Example molecules and model structure.
(A) Space filling models of oxygen, FDG, doxorubicin, and an IgG for size comparison. (B) Diagram of a Krogh cylinder labeled with the four fundamental steps in tumor localization.
Table 1.
Pharmacokinetic Classes.
Table 2.
Parameters and Groups.
Figure 2.
Simulation results for different class agents.
(A) Oxygen simulation in region with closely space vessels (50 µm Krogh radius) showing decreasing axial concentration due to poor blood flow (top). With the Krogh radius increased to 200 µm, the radial gradients show diffusion limited uptake for oxygen (bottom). (B) Antibody uptake is heterogeneous due to rapid binding relative to diffusion, and the lack of axial gradients indicates blood flow is not limiting (top). An epifluorescence image of an A431 tumor xenograft slice 24 hrs after 30 µg of cetuximab-VivoTag 680 was injected intravenously shows the perivascular distribution of the antibody (bottom). (C) The blood flow, extravasation, and diffusion are faster than cellular uptake for the class IV agent FDG resulting in homogenous distribution in the interstitium (top). This occurs even with heterogeneous cellular uptake as demonstrated by the intracellular FDG-6-phosphate in the same simulation (bottom).
Figure 3.
Class variation with antibodies.
Mice with HT-29 tumor on the left side and A431 tumors on the right side were injected with 30 µg (left) or 300 µg (right) of cetuximab-VT680. The lower dose is subsaturating, so uptake is limited by delivery from the vasculature with similar uptake in both tumors. At saturating doses, the uptake is limited by the number of binding sites, and uptake is statistically higher in the A431 xenografts, which express EGFR at a much higher level. The reported p values are from a two-tailed t-test.
Figure 4.
Class variation in time and multi-agent simulations.
The plasma profile along the length of the vessel is shown for the first 12 minutes for FDG (A) and an antibody (B). The axial gradients indicate a transient blood flow limitation (class I) for FDG while the antibody evenly fills the blood volume. (C) A joint simulation of oxygen (color scale) and a monoclonal antibody (z-axis) show differential uptake. The antibody is delivered to regions not reached by the blood flow limited oxygen, and other regions are well oxygenated with no antibody. (D) Similarly, a pretargeting simulation with higher antibody dose (z-axis) and reacting secondary agent (color scale) shows some regions targeted by the primary antibody may be missed by the rapidly cleared and blood flow limited small molecule secondary agent.