Nanoparticle-delivered suicide gene therapy effectively reduces ovarian tumor burden in mice.
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.
Huang
Yu-Hung
YH
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Zugates
Gregory T
GT
Peng
Weidan
W
Holtz
David
D
Dunton
Charles
C
Green
Jordan J
JJ
Hossain
Naushad
N
Chernick
Michael R
MR
Padera
Robert F
RF
Langer
Robert
R
Anderson
Daniel G
DG
Sawicki
Janet A
JA
D000818:Animals; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics; D030501:Epididymal Secretory Proteins / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D000090204:Mesothelin; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays; D023083:beta-Defensins
C426184:DEFB126 protein, human; D030501:Epididymal Secretory Proteins; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; D011108:Polymers; D023083:beta-Defensins; C507253:poly(beta-amino ester); D004247:DNA; D000090204:Mesothelin