Small Molecule Therapeutics Metronomic Docetaxel in PRINT Nanoparticles and EZH 2 Silencing Have Synergistic Antitumor Effect in Ovarian Cancer

The purpose of this studywas to investigate the antitumor effects of a combination ofmetronomic 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), andmicrovessel 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-PRINTdocetaxel combinedwithCH-mEZH2 siRNAhas significant antitumor activity in preclinicalmodels of ovarian cancer. Mol Cancer Ther; 13(7); 1750–7. 2014 AACR.