Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice

Cancer Res. 2009 Aug 1;69(15):6184-91. doi: 10.1158/0008-5472.CAN-09-0061.

Abstract

There is currently no effective therapy for patients with advanced ovarian cancer. To address the need for a more effective treatment for this deadly disease, we conducted preclinical tests in ovarian tumor-bearing mice to evaluate the therapeutic efficacy of using a cationic biodegradable poly(beta-amino ester) polymer as a vector for nanoparticulate delivery of DNA encoding a diphtheria toxin suicide protein (DT-A). The promoter sequences of two genes that are highly active in ovarian tumor cells, MSLN and HE4, were used to target DT-A expression to tumor cells. Administration of DT-A nanoparticles directly to s.c. xenograft tumors and to the peritoneal cavity of mice bearing primary and metastatic ovarian tumors resulted in a significant reduction in tumor mass and a prolonged life span compared to control mice. Minimal nonspecific tissue and blood chemistry toxicity was observed following extended treatment with nanoparticles. DT-A nanoparticle therapy suppressed tumor growth more effectively than treatment with clinically relevant doses of cisplatin and paclitaxel. Our findings suggest that i.p. administration of polymeric nanoparticles to deliver DT-A encoding DNA, combined with transcriptional regulation to target gene expression to ovarian tumor cells, holds promise as an effective therapy for advanced-stage ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • DNA / administration & dosage*
  • DNA / genetics
  • Epididymal Secretory Proteins / genetics
  • Female
  • GPI-Linked Proteins
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Humans
  • Membrane Glycoproteins / genetics
  • Mesothelin
  • Mice
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / therapy*
  • Polymers / administration & dosage*
  • Polymers / chemistry
  • Promoter Regions, Genetic
  • Xenograft Model Antitumor Assays
  • beta-Defensins

Substances

  • DEFB126 protein, human
  • Epididymal Secretory Proteins
  • GPI-Linked Proteins
  • MSLN protein, human
  • Membrane Glycoproteins
  • Msln protein, mouse
  • Polymers
  • beta-Defensins
  • poly(beta-amino ester)
  • DNA
  • Mesothelin