Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature

Mitsunobu Kano, Yukari Komuta, Caname Iwata, Masako Oka, Yo Taro Shirai, Yasuyuki Morishita, Yasuyoshi Ouchi, Kazunori Kataoka, Kohei Miyazono

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-β 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-β 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-β 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-β 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-β 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.

Original languageEnglish
Pages (from-to)173-180
Number of pages8
JournalCancer Science
Volume100
Issue number1
DOIs
Publication statusPublished - 2009
Externally publishedYes

Fingerprint

Growth Inhibitors
Growth Factor Receptors
Transforming Growth Factors
Nanoparticles
Phosphotransferases
Pericytes
Dextrans
Neoplasms
Pancreatic Neoplasms
Colonic Neoplasms
Endothelium
Imatinib Mesylate
sorafenib
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature. / Kano, Mitsunobu; Komuta, Yukari; Iwata, Caname; Oka, Masako; Shirai, Yo Taro; Morishita, Yasuyuki; Ouchi, Yasuyoshi; Kataoka, Kazunori; Miyazono, Kohei.

In: Cancer Science, Vol. 100, No. 1, 2009, p. 173-180.

Research output: Contribution to journalArticle

Kano, Mitsunobu ; Komuta, Yukari ; Iwata, Caname ; Oka, Masako ; Shirai, Yo Taro ; Morishita, Yasuyuki ; Ouchi, Yasuyoshi ; Kataoka, Kazunori ; Miyazono, Kohei. / Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature. In: Cancer Science. 2009 ; Vol. 100, No. 1. pp. 173-180.
@article{9931bb42fe11475e860fc605cd6deb0a,
title = "Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature",
abstract = "There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-β 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-β 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-β 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-β 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-β 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.",
author = "Mitsunobu Kano and Yukari Komuta and Caname Iwata and Masako Oka and Shirai, {Yo Taro} and Yasuyuki Morishita and Yasuyoshi Ouchi and Kazunori Kataoka and Kohei Miyazono",
year = "2009",
doi = "10.1111/j.1349-7006.2008.01003.x",
language = "English",
volume = "100",
pages = "173--180",
journal = "Cancer Science",
issn = "1347-9032",
publisher = "Wiley-Blackwell",
number = "1",

}

TY - JOUR

T1 - Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature

AU - Kano, Mitsunobu

AU - Komuta, Yukari

AU - Iwata, Caname

AU - Oka, Masako

AU - Shirai, Yo Taro

AU - Morishita, Yasuyuki

AU - Ouchi, Yasuyoshi

AU - Kataoka, Kazunori

AU - Miyazono, Kohei

PY - 2009

Y1 - 2009

N2 - There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-β 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-β 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-β 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-β 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-β 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.

AB - There are a number of kinase inhibitors that regulate components of the neovasculature. We previously reported the use of transforming growth factor (TGF)-β 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-β 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-β 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-β 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-β 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.

UR - http://www.scopus.com/inward/record.url?scp=58149284060&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149284060&partnerID=8YFLogxK

U2 - 10.1111/j.1349-7006.2008.01003.x

DO - 10.1111/j.1349-7006.2008.01003.x

M3 - Article

C2 - 19037999

AN - SCOPUS:58149284060

VL - 100

SP - 173

EP - 180

JO - Cancer Science

JF - Cancer Science

SN - 1347-9032

IS - 1

ER -