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Nanoparticle-Delivered Suicide Gene Therapy Effectively Reduces Ovarian Tumor Burden in Mice

¹ Lankenau Institute for Medical Research, Wynnewood, Pennsylvania; ² David H. Koch Institute for Integrative Cancer Research and ³ Chemical Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts; ⁴ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; ⁵ Department of Dermatology and Cutaneous Biology and ⁶ Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University, Philadelphia, Pennsylvania

Requests for reprints: Janet A. Sawicki, Lankenau Institute for Medical Research, 100 East Lancaster Avenue, Wynnewood, PA 19096. Phone: 610-645-3123; Fax: 610-645-2205; E-mail: sawickij{at}mlhs.org or Daniel G. Anderson, David H. Koch Institute for Integrative Cancer Research, 77 Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-258-6843; Fax: 617-258-8827; E-mail: dgander{at}mit.edu.

Key Words: ovarian cancer • diphtheria toxin • nanoparticles • poly(β-amino ester)s • mesothelin

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(β-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. [Cancer Res 2009;69(15):6184–91]