Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells

Authors

Emiliano Cocco, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Yang Deng, Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
Erik M. Shapiro, Department of Radiology, Michigan State University, East Lansing, Michigan.
Ileana Bortolomai, San Raffaele Research Institute, Milan, Italy.
Salvatore Lopez, Division of Gynecologic Oncology, University Campus Bio-Medico of Rome, Rome, Italy.
Ken Lin, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Jiajia Cui, Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
Gulden Menderes, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Jonathan D. Black, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Carlton L. Schwab, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Elena Bonazzoli, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.

Document Type

Article

Publication Title

Molecular cancer therapeutics

Abstract

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 chemotherapy-resistant 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 chemotherapy-resistant ovarian tumor cell lines in vitro (P = 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 tumor-bearing 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. Mol Cancer Ther; 16(2); 323-33. ©2016 AACR.

First Page

323

Last Page

333

DOI

10.1158/1535-7163.MCT-16-0501

Publication Date

2-1-2017

Recommended Citation

Cocco, Emiliano; Deng, Yang; Shapiro, Erik M.; Bortolomai, Ileana; Lopez, Salvatore; Lin, Ken; Bellone, Stefania; Cui, Jiajia; Menderes, Gulden; Black, Jonathan D.; Schwab, Carlton L.; and Bonazzoli, Elena, "Dual-Targeting Nanoparticles for In Vivo Delivery of Suicide Genes to Chemotherapy-Resistant Ovarian Cancer Cells" (2017). MIGs. 3.
https://scholar.bridgeporthospital.org/migs/3

Identifier

27956521 (pubmed); NIHMS834819 (mid); PMC5292071 (pmc); 10.1158/1535-7163.MCT-16-0501 (doi); 1535-7163.MCT-16-0501 (pii)