Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-beta receptor inhibitor on extravasation of nanoparticles from neovasculature.
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.
Kano
Mitsunobu R
MR
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Komuta
Yukari
Y
Iwata
Caname
C
Oka
Masako
M
Shirai
Yo-taro
YT
Morishita
Yasuyuki
Y
Ouchi
Yasuyoshi
Y
Kataoka
Kazunori
K
Miyazono
Kohei
K
D000818:Animals; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles; D009369:Neoplasms / Q000098:blood supply*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D011804:Quinolines
D001549:Benzamides; D001557:Benzenesulfonates; D000068877:Imatinib Mesylate; D009536:Niacinamide; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D018125:Receptors, Transforming Growth Factor beta; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A; C506615:HTS 466284; D011804:Quinolines