Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer

• Published in: Molecular cancer therapeutics Vol. 13; no. 7; pp. 1750 - 1757
• Main Authors: Gharpure, Kshipra M, Chu, Kevin S, Bowerman, Charles J, Miyake, Takahito, Pradeep, Sunila, Mangala, Selanere L, Han, Hee-Dong, Rupaimoole, Rajesha, Armaiz-Pena, Guillermo N, Rahhal, Tojan B, Wu, Sherry Y, Luft, J Christopher, Napier, Mary E, Lopez-Berestein, Gabriel, DeSimone, Joseph M, Sood, Anil K
• Format: Journal Article
• Language: English
• Published: United States 01-07-2014
• Subjects: Administration, Metronomic; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Female; Gene Silencing - drug effects; Humans; Mice; Mice, Nude; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Polycomb Repressive Complex 2 - antagonists & inhibitors; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Randomized Controlled Trials as Topic; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Taxoids - administration & dosage; Taxoids - chemistry
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0930

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.