The parameters that limit supply of photosensitizer to the cancer cells in a solid tumor were systematically analyzed with the use of microvascular transport modeling and histology data from frozen sections. In particular, the vascular permeability transport coefficient and the effective interstitial diffusion coefficient were quantified for Verteporfin-for-Injection delivery of benzoporphyrin derivative (BPD). Orthotopic tumors had higher permeability and diffusion coefficients (Pd = 0.036 μm/s and D = 1.6 μm2/s, respectively) as compared to subcutaneously grown tumors (Pd = 0.025 μm/s and D = 0.9 μm2/s, respectively), likely due to the fact that the vessel patterns are more homogeneous orthotopically. In general, large intersubject and intratumor variability exist in the verteporfin concentration, in the range of 25% in plasma concentration and in the range of 20% for tissue concentrations, predominantly due to these microregional variations in transport. However, the average individual uptake of photosensitizer in tumor tissue was only correlated to the total vascular area within the tumor (R2 = 64.1%, P < 0.001). The data are consistent with a view that microregional variation in the vascular permeability and interstitial diffusion rate contribute the spatial heterogeneity observed in verteporfin uptake, but that average supply to the tissue is limited by the total area of perfused blood vessels. This study presents a method to systematically analyze microheterogeneity as well as possible methods to increase delivery and homogeneity of photosensitizer within tumor tissue.
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Vol. 82 • No. 5