TY - JOUR
T1 - Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer
AU - Gharpure, Kshipra M.
AU - Chu, Kevin S.
AU - Bowerman, Charles J.
AU - Miyake, Takahito
AU - Pradeep, Sunila
AU - Mangala, Selanere L.
AU - Han, Hee Dong
AU - Rupaimoole, Rajesha
AU - Armaiz-Pena, Guillermo N.
AU - Rahhal, Tojan B.
AU - Wu, Sherry Y.
AU - Luft, J. Christopher
AU - Napier, Mary E.
AU - Lopez-Berestein, Gabriel
AU - DeSimone, Joseph M.
AU - Sood, Anil K.
PY - 2014/7
Y1 - 2014/7
N2 - The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models ( P < 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer.
AB - The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models ( P < 0.05). Individual as well as combination therapies showed significant antiangiogenic, antiproliferative, and proapoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer.
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UR - http://www.scopus.com/inward/citedby.url?scp=84904164280&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-13-0930
DO - 10.1158/1535-7163.MCT-13-0930
M3 - Article
C2 - 24755199
AN - SCOPUS:84904164280
SN - 1535-7163
VL - 13
SP - 1750
EP - 1757
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 7
ER -