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

Emiliano Cocco, Yang Deng, Erik M. Shapiro, Ileana Bortolomai, Salvatore Lopez, Ken Lin, Stefania Bellone, Jiajia Cui, Gulden Menderes, Jonathan D. Black, Carlton L. Schwab, Elena Bonazzoli, Fan Yang, Federica Predolini, Luca Zammataro, Gary Altwerger, Christopher De Haydu, Mitchell Clark, Julio Alvarenga, Elena RatnerMasoud Azodi, Dan Arin Silasi, Peter E. Schwartz, Babak Litkouhi, W. Mark Saltzman, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)323-333
Number of pages11
JournalMolecular cancer therapeutics
Volume16
Issue number2
DOIs
StatePublished - Feb 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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