Tumor-targeted delivery of polyethylene glycol-conjugated D-amino acid oxidase for antitumor therapy via enzymatic generation of hydrogen peroxide

Jun Fang, Tomohiro Sawa, Takaaki Akaike, Hiroshi Maeda

Research output: Contribution to journalArticlepeer-review

96 Citations (Scopus)

Abstract

Hydrogen peroxide (H2O2) is a strong oxidant that induces apoptosis of tumor cells in vitro. Here, we investigated the antitumor activity of an H2O2-generating enzyme, D-amino acid oxidase (DAO), and its conjugate with polyethylene glycol (PEG; PEG-DAO). Compared with DAO, PEG-DAO showed improved pharmacokinetic parameters in mice after i.v. injection. PEG-DAO administered i.v. accumulated selectively in tumor tissue with insignificant accumulation in normal organs and tissues. To generate cytotoxic H2O2 at the tumor site, PEG-DAO was first administrated i.v. to tumor-bearing mice. After an adequate lag time, the substrate of DAO, D-proline, was injected i.p. This treatment resulted in significant suppression of tumor growth compared with tumor growth in control animals (not given treatment; P < 0.001). Similar treatment with native DAO showed no effect under the same conditions. Oxidative metabolites were significantly increased in solid tumors by administration of PEG-DAO followed by D-proline (P < 0.002, compared with the group receiving no treatment), as evidenced by thiobarbituric acid-reactive substance assay. This treatment did not affect results from the metabolites in the liver and kidney. These findings suggest that tumor-targeted delivery of DAO is accomplished by using pegylated enzyme and thereby taking advantage of the enhanced permeability and retention effect in solid tumor. PEG-DAO thus delivered together with D-proline produces remarkable antitumor activity via extensive generation of H2O2.

Original languageEnglish
Pages (from-to)3138-3143
Number of pages6
JournalCancer Research
Volume62
Issue number11
Publication statusPublished - 2002 Jun 1
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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