Journal
MOLECULAR CANCER THERAPEUTICS
Volume 16, Issue 2, Pages 323-333Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-16-0501
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Funding
- NIH [R01 CA154460-01, U01 CA176067-01A1]
- Deborah Bunn Alley Foundation
- Tina Brozman Foundation
- Women's Health Research at Yale - The Ethel F. Donaghue Women's Health Investigator Program at Yale
- Yale Cancer Center
- Discovery to Cure Foundation
- Guido Berlucchi Foundation
- Italian Ministry of Health [RF-2010-2313497]
- NIH from NCI [CA-16359]
- Michigan State University Foundation
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Ovarian cancer is the most lethal gynecologic cancer. Claudin-3 and -4, the receptors for Clostridium perfringens enterotoxin (CPE), are overexpressed in more than 70% of these tumors. Here, we synthesized and characterized poly (lactic-co-glycolic-acid) (PLGA) nanoparticles (NPs) modified with the carboxy-terminal-binding domain of CPE (c-CPE-NP) for the delivery of suicide gene therapy to chemotherapyresistant ovarian cancer cells. As a therapeutic payload, we generated a plasmid encoding for the diphtheria toxin subunit-A (DT-A) under the transcriptional control of the p16 promoter, a gene highly differentially expressed in ovarian cancer cells. Flow cytometry and immunofluorescence demonstrated that c-CPE-NPs encapsulating the cytomegalovirus (CMV) GFP plasmid (CMV GFP c-CPE-NP) were significantly more efficient than control NPs modified with a scrambled peptide (CMV GFP scr-NP) in transfecting primary chemother-apy-resistant ovarian tumor cell lines in vitro (P similar to 0.03). Importantly, c-CPE-NPs encapsulating the p16 DT-A vector (p16 DT-A c-CPE-NP) were significantly more effective than control p16 DT-A scr-NP in inducing ovarian cancer cell death in vitro (% cytotoxicity: mean + SD = 32.9 +/- 0.15 and 7.45 +/- 7.93, respectively, P = 0.03). In vivo biodistribution studies demonstrated efficient transfection of tumor cells within 12 hours after intraperitoneal injection of CMV GFP c-CPE-NP in mice harboring chemotherapy-resistant ovarian cancer xenografts. Finally, multiple intraperitoneal injections of p16 DT-A c-CPE-NP resulted in a significant inhibition of tumor growth compared with control NP in chemotherapy-resistant tumorbearing mice (P = 0.041). p16 DT-A c-CPE-NP may represent a novel dual-targeting therapeutic approach for the selective delivery of gene therapy to chemotherapy-resistant ovarian cancer cells.
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