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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-08, Vol.69 (15), p.6184-6191
• Main Authors: HUANG, Yu-Hung, ZUGATES, Gregory T, ANDERSON, Daniel G, SAWICKI, Janet A, WEIDAN PENG, HOLTZ, David, DUNTON, Charles, GREEN, Jordan J, HOSSAIN, Naushad, CHERNICK, Michael R, PADERA, Robert F, LANGER, Robert
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; beta-Defensins; Biological and medical sciences; DNA - administration & dosage; DNA - genetics; Epididymal Secretory Proteins - genetics; Female; Genetic Therapy - methods; Genetic Vectors - administration & dosage; GPI-Linked Proteins; Humans; Medical sciences; Membrane Glycoproteins - genetics; Mesothelin; Mice; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Pharmacology. Drug treatments; Polymers - administration & dosage; Polymers - chemistry; Promoter Regions, Genetic; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-09-0061

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.