Deeper penetration into tumor tissues and enhanced in vivo antitumor activity of liposomal paclitaxel by pretreatment with angiogenesis inhibitor SU5416

Yuta Yoshizawa, Ken Ichi Ogawara, Aya Fushimi, Shigeki Abe, Keisuke Ishikawa, Tomoya Araki, Grietje Molema, Toshikiro Kimura, Kazutaka Higaki

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19 Citations (Scopus)

Abstract

The recently emerged concept of "vessel normalization" implies that judicious blockade of vascular endothelial growth factor (VEGF) signaling may transiently "normalize" the tumor vasculature, making it more suitable for tumor disposition of subsequently administered drugs. In this study, therefore, the effect of pretreatment with SU5416, a selective VEGF receptor-2 inhibitor, on tumor disposition and in vivo antitumor activity of polyethylene glycol (PEG)-modified liposomal paclitaxel (PL-PTX) was evaluated in Colon-26 solid tumor-bearing mice. To improve the solubility and in vivo disposition characteristics of SU5416, the inhibitor was formulated in PEGylated O/W emulsion (PE-SU5416). Pretreatment with PE-SU5416 significantly enhanced the in vivo antitumor effect of PL-PTX, although PE-SU5416 administration alone did not show any antitumor effect. Immunostaining for endothelial cells and pericytes demonstrated that the pretreatment with PE-SU5416 enhanced the pericyte coverage of the tumor vasculature. In addition, tumors treated with PE-SU5416 contained significantly smaller hypoxic regions compared with the nontreated control group, demonstrating that structural normalization of the tumor vasculature resulted in an improvement in tumor vessel functions, including oxygen supply. Furthermore, the pretreatment with PE-SU5416 increased the distribution of PEG liposomes and included PTX in the core region of the tumor, as well as conversely decreasing the ratio of their peripheral distribution. These results suggest that the structural and functional normalization of the tumor vasculature by the pretreatment with PE-SU5416 enabled liposomes to reach the deeper regions within tumor tissues, leading to more potent antitumor activity of PL-PTX.

Original languageEnglish
Pages (from-to)3486-3494
Number of pages9
JournalMolecular Pharmaceutics
Volume9
Issue number12
DOIs
Publication statusPublished - Dec 3 2012

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Keywords

  • PEG liposome
  • VEGF
  • angiogenesis
  • drug delivery
  • paclitaxel

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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