Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin

Importance of vascular permeability within tumors

Ken ichi Ogawara, Keita Un, Keiko Minato, Ken ichi Tanaka, Kazutaka Higaki, Toshikiro Kimura

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon-26 (C26) and B16BL6 melanoma (B16)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radiolabelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX.

Original languageEnglish
Pages (from-to)234-240
Number of pages7
JournalInternational Journal of Pharmaceutics
Volume359
Issue number1-2
DOIs
Publication statusPublished - Jul 9 2008

Fingerprint

Capillary Permeability
Neoplasms
Colon
Liposomes
Lung Neoplasms
liposomal doxorubicin
Evans Blue
Experimental Melanomas
Tumor Cell Line
Intravenous Injections
Doxorubicin
Colonic Neoplasms
Vascular Endothelial Growth Factor A
Permeability

Keywords

  • Doxorubicin
  • EPR effect
  • Liposome
  • Tumor vasculature
  • VEGF

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin : Importance of vascular permeability within tumors. / Ogawara, Ken ichi; Un, Keita; Minato, Keiko; Tanaka, Ken ichi; Higaki, Kazutaka; Kimura, Toshikiro.

In: International Journal of Pharmaceutics, Vol. 359, No. 1-2, 09.07.2008, p. 234-240.

Research output: Contribution to journalArticle

Ogawara, Ken ichi ; Un, Keita ; Minato, Keiko ; Tanaka, Ken ichi ; Higaki, Kazutaka ; Kimura, Toshikiro. / Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin : Importance of vascular permeability within tumors. In: International Journal of Pharmaceutics. 2008 ; Vol. 359, No. 1-2. pp. 234-240.
@article{3238308182324ddc9c008a4e2d262f14,
title = "Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin: Importance of vascular permeability within tumors",
abstract = "To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon-26 (C26) and B16BL6 melanoma (B16)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radiolabelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX.",
keywords = "Doxorubicin, EPR effect, Liposome, Tumor vasculature, VEGF",
author = "Ogawara, {Ken ichi} and Keita Un and Keiko Minato and Tanaka, {Ken ichi} and Kazutaka Higaki and Toshikiro Kimura",
year = "2008",
month = "7",
day = "9",
doi = "10.1016/j.ijpharm.2008.03.025",
language = "English",
volume = "359",
pages = "234--240",
journal = "International Journal of Pharmaceutics",
issn = "0378-5173",
publisher = "Elsevier",
number = "1-2",

}

TY - JOUR

T1 - Determinants for in vivo anti-tumor effects of PEG liposomal doxorubicin

T2 - Importance of vascular permeability within tumors

AU - Ogawara, Ken ichi

AU - Un, Keita

AU - Minato, Keiko

AU - Tanaka, Ken ichi

AU - Higaki, Kazutaka

AU - Kimura, Toshikiro

PY - 2008/7/9

Y1 - 2008/7/9

N2 - To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon-26 (C26) and B16BL6 melanoma (B16)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radiolabelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX.

AB - To elucidate the determinants of the in vivo anti-tumor efficacy of polyethylene glycol (PEG)-modified liposomal doxorubicin (DOX), we examined its anti-tumor effect against three different tumor cell lines (Lewis lung cancer (LLC), Colon-26 (C26) and B16BL6 melanoma (B16)) in vitro and in vivo. In vitro, LLC was the most sensitive tumor to DOX and liposomal DOX based on the MTT assay. However, the strongest in vivo anti-tumor effect was observed in the C26 tumor-bearing mice. The in vivo accumulation of radiolabelled PEG liposome in the C26 tumor after intravenous injection was significantly larger than in other tumors. The extent of vascularity assessed by immunohistochemical staining of CD31 was not directly related with the tumor accumulation of PEG liposome. On the other hand, Evans blue extravasation and secretion of VEGF in C26 tumors were higher than in LLC tumors, clearly demonstrating that the vasculature permeability was higher within C26 tumors. These results indicated that the vascular permeability within the tumor substantially affects the tumor accumulation of PEG liposome and may be one of the important determinants in the in vivo anti-tumor efficacy of PEG liposomal DOX.

KW - Doxorubicin

KW - EPR effect

KW - Liposome

KW - Tumor vasculature

KW - VEGF

UR - http://www.scopus.com/inward/record.url?scp=44749086570&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=44749086570&partnerID=8YFLogxK

U2 - 10.1016/j.ijpharm.2008.03.025

DO - 10.1016/j.ijpharm.2008.03.025

M3 - Article

VL - 359

SP - 234

EP - 240

JO - International Journal of Pharmaceutics

JF - International Journal of Pharmaceutics

SN - 0378-5173

IS - 1-2

ER -