There are a number of
kinase inhibitors that regulate components of the neovasculature. We previously reported the use of
transforming growth factor (
TGF)-beta inhibitor on neovasculature in stroma-rich
tumor models to increase the intratumoral distribution of nanoparticles. Here, we compared the effects of two other
kinase inhibitors,
imatinib and
sorafenib, with
TGF-beta inhibitor (LY364947) on extravasation of a modeled nanoparticle, 2 MDa
dextran. We first used a mouse model of neoangiogenesis, the
Matrigel plug assay, to compare neovasculature formed inside of and around
Matrigel plugs (intraplug and periplug regions, respectively). Intraplug vasculature was more strongly pericyte covered, whereas periplug vasculature was less covered. In this model,
TGF-beta inhibitor exhibited the most potent effect on intraplug vasculature in increasing the extravasation of
dextran, whereas
sorafenib had the strongest effect on periplug vasculature. Although
imatinib and
TGF-beta inhibitor each reduced pericyte coverage,
imatinib also reduced the density of endothelium, resulting in a decrease in overall delivery of nanoparticles. These findings were confirmed in two
tumor models, the CT26
colon cancer model and the BxPC3
pancreatic cancer model. The vasculature phenotype in the CT26 model resembled that in the periplug region, whereas the latter resembled that in the intraplug region. Consistent with this,
sorafenib most potently enhanced the accumulation of nanoparticles in the CT26 model, whereas
TGF-beta inhibitor did in the BxPC3 model. In conclusion, the appropriate strategy for optimization of
tumor vasculature for nanoparticles may differ depending on
tumor type, and in particular on the degree of pericyte coverage around the vasculature.