Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1

Makoto Oba, Yelena Vachutinsky, Kanjiro Miyata, Mitsunobu R. Kano, Sorato Ikeda, Nobuhiro Nishiyama, Keiji Itaka, Kohei Miyazono, Hiroyuki Koyama, Kazunori Kataoka

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

In this study, a polyplex micelle was developed as a potential formulation for antiangiogenic gene therapy of subcutaneous pancreatic tumor model. Poly(ethylene glycol)-poly(l-lysine) block copolymers (PEG-PLys) with thiol groups in the side chain of the PLys segment were synthesized and applied for preparation of disulfide cross-linked polyplex micelles through ion complexation with plasmid DNA (pDNA) encoding the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which is a potent antiangiogenic molecule. Antitumor activity and gene expression of polyplex micelles with various cross-linking rates were evaluated in mice bearing subcutaneously xenografted BxPC3 cell line, derived from human pancreatic adenocarcinoma, and polyplex micelles with optimal cross-linking rate achieved effective suppression of tumor growth. Significant gene expression of this micelle was detected selectively in tumor tissue, and its antiangiogenic effect was confirmed by decreased vascular density inside the tumor. Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application.

Original languageEnglish
Pages (from-to)501-509
Number of pages9
JournalMolecular Pharmaceutics
Volume7
Issue number2
DOIs
Publication statusPublished - Apr 5 2010
Externally publishedYes

Keywords

  • Antiangiogenic tumor gene therapy
  • Block copolymer
  • Polymeric micelle
  • SFlt-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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