Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 323-333 |
| Number of pages | 11 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 16 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2017 |
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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 journal › Article
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TY - JOUR
T1 - Dual-targeting nanoparticles for in vivo delivery of suicide genes to chemotherapy-resistant ovarian cancer cells
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
PY - 2017
Y1 - 2017
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. © 2016 American Association for Cancer Research.
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. © 2016 American Association for Cancer Research.
U2 - 10.1158/1535-7163.MCT-16-0501
DO - 10.1158/1535-7163.MCT-16-0501
M3 - Article
VL - 16
SP - 323
EP - 333
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 2
ER -