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 Ratner & 6 others Masoud Azodi, Dan Arin Silasi, Peter E. Schwartz, Babak Litkouhi, W. Mark Saltzman, Alessandro D. Santin

    Research output: Contribution to journalArticle

    • 1 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 1 2017

    Profile

    Ovarian Neoplasms
    Nanoparticles
    Suicide
    Drug Therapy
    Genes
    Clostridium perfringens
    Enterotoxins
    Diphtheria Toxin
    Cytomegalovirus
    Neoplasms
    Intraperitoneal Injections
    Genetic Therapy
    Plasmids
    In Vitro Techniques
    Claudin-3
    Claudin-4
    Tumor Cell Line
    Heterografts
    Fluorescent Antibody Technique
    Transfection

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells. / 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.; Bonazzoli, Elena; Yang, Fan; Predolini, Federica; Zammataro, Luca; Altwerger, Gary; De Haydu, Christopher; Clark, Mitchell; Alvarenga, Julio; Ratner, Elena; Azodi, Masoud; Silasi, Dan Arin; Schwartz, Peter E.; Litkouhi, Babak; Saltzman, W. Mark; Santin, Alessandro D.

    In: Molecular Cancer Therapeutics, Vol. 16, No. 2, 01.02.2017, p. 323-333.

    Research output: Contribution to journalArticle

    Cocco, E, Deng, Y, Shapiro, EM, Bortolomai, I, Lopez, S, Lin, K, Bellone, S, Cui, J, Menderes, G, Black, JD, Schwab, CL, Bonazzoli, E, Yang, F, Predolini, F, Zammataro, L, Altwerger, G, De Haydu, C, Clark, M, Alvarenga, J, Ratner, E, Azodi, M, Silasi, DA, Schwartz, PE, Litkouhi, B, Saltzman, WM & Santin, AD 2017, 'Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells' Molecular Cancer Therapeutics, vol 16, no. 2, pp. 323-333. DOI: 10.1158/1535-7163.MCT-16-0501

    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.; Bonazzoli, Elena; Yang, Fan; Predolini, Federica; Zammataro, Luca; Altwerger, Gary; De Haydu, Christopher; Clark, Mitchell; Alvarenga, Julio; Ratner, Elena; Azodi, Masoud; Silasi, Dan Arin; Schwartz, Peter E.; Litkouhi, Babak; Saltzman, W. Mark; Santin, Alessandro D. / Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells.

    In: Molecular Cancer Therapeutics, Vol. 16, No. 2, 01.02.2017, p. 323-333.

    Research output: Contribution to journalArticle

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    AU - Lopez,Salvatore

    AU - Lin,Ken

    AU - Bellone,Stefania

    AU - Cui,Jiajia

    AU - Menderes,Gulden

    AU - Black,Jonathan D.

    AU - Schwab,Carlton L.

    AU - Bonazzoli,Elena

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    AU - Predolini,Federica

    AU - Zammataro,Luca

    AU - Altwerger,Gary

    AU - De Haydu,Christopher

    AU - Clark,Mitchell

    AU - Alvarenga,Julio

    AU - Ratner,Elena

    AU - Azodi,Masoud

    AU - Silasi,Dan Arin

    AU - Schwartz,Peter E.

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