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 journalArticle

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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Ovarian Neoplasms
Nanoparticles
Suicide
Drug Therapy
Diphtheria Toxin
Genes
Cytomegalovirus
Intraperitoneal Injections
Genetic Therapy
Neoplasms
Claudin-3
Plasmids
Claudin-4
Clostridium enterotoxin
Tumor Cell Line
Heterografts
Fluorescent Antibody Technique
Transfection
Flow Cytometry
Cell Death

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Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells. / Cocco, E.; Deng, Y; Shapiro, EM; Bortolomai, I; Lopez, S; Lin, K; Bellone, Stefania; 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.

In: Molecular Cancer Therapeutics, Vol. 16, No. 2, 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. https://doi.org/10.1158/1535-7163.MCT-16-0501
Cocco, E. ; Deng, Y ; Shapiro, EM ; Bortolomai, I ; Lopez, S ; Lin, K ; Bellone, Stefania ; 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. / Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 2. pp. 323-333.
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AU - Cocco, E.

AU - Deng, Y

AU - Shapiro, EM

AU - Bortolomai, I

AU - Lopez, S

AU - Lin, K

AU - Bellone, Stefania

AU - Cui, J

AU - Menderes, G

AU - Black, JD

AU - Schwab, CL

AU - Bonazzoli, E

AU - Yang, F

AU - Predolini, F

AU - Zammataro, L

AU - Altwerger, G

AU - De Haydu, C

AU - Clark, M

AU - Alvarenga, J

AU - Ratner, E

AU - Azodi, M

AU - Silasi, DA

AU - Schwartz, PE

AU - Litkouhi, B

AU - Saltzman, WM

AU - Santin, AD

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