TY - JOUR
T1 - Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells
AU - Cocco, Emiliano
AU - Deng, Yang
AU - Shapiro, Erik M.
AU - Bortolomai, Ileana
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
AU - Yang, Fan
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.
AU - Litkouhi, Babak
AU - Saltzman, W. Mark
AU - Santin, Alessandro D.
N1 - Funding Information:
This work was supported in part by R01 CA154460-01 and U01 CA176067- 01A1 grants from the NIH, the Deborah Bunn Alley Foundation, the Tina Brozman Foundation, the Women's Health Research at Yale - The Ethel F. Donaghue Women's Health Investigator Program at Yale, the Yale Cancer Center, the Discovery to Cure Foundation, the Guido Berlucchi Foundation, and The Italian Ministry of Health grant RF-2010-2313497 (to A.D. Santin). This investigation was also supported by NIH research grant CA-16359 from the NCI (to A.D. Santino) and a Strategic Partnership grant from the Michigan State University Foundation (to E.M. Shapiro).
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/2
Y1 - 2017/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85011632718&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0501
DO - 10.1158/1535-7163.MCT-16-0501
M3 - Article
C2 - 27956521
AN - SCOPUS:85011632718
SN - 1535-7163
VL - 16
SP - 323
EP - 333
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -
