Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells

E. Cocco, Y Deng, EM Shapiro, I Bortolomai, S Lopez, K Lin, Stefania Bellone, J Cui, G Menderes, JD Black, CL Schwab, E Bonazzoli, F Yang, F Predolini, L Zammataro, G Altwerger, C De Haydu, M Clark, J Alvarenga, E RatnerM Azodi, DA Silasi, PE Schwartz, B Litkouhi, WM Saltzman, AD Santin

Research output: Contribution to journalArticlepeer-review

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 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. © 2016 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)323-333
Number of pages11
JournalMolecular Cancer Therapeutics
Volume16
Issue number2
DOIs
Publication statusPublished - 2017

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