Abstract
Abstract Purpose: The purpose of this study was to investigate the combined antitumor effects of metronomic docetaxel-containing PLGA-PRINT nanoparticles and antiangiogenic mEZH2 siRNA incorporated into chitosan nanoparticles (CH-mEZH2 siRNA). Method: In vivo dose-finding studies and therapeutic experiments with PLGA-PRINT-docetaxel and CH-mEZH2 siRNA were conducted in well-established orthotopic mouse models of ovarian cancer (HeyA8 and SKOV3ip1). Antitumor effects were quantified through mean tumor weight and tumor nodule counts. Tumor tissues from these studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase-3), and microvessel density (CD31). Result: Dose-finding studies for PLGA-PRINT-docetaxel revealed all doses (0.5, 1.5, 2 mg/kg for metronomic and 20mg/kg for MTD) significantly reduced tumor burden (p<0.05 for MTD; p<0.01 for metronomic doses). The lowest dose (0.5 mg/kg) reduced tumor weight by ∼80% and was selected for subsequent therapeutic studies. We then tested whether combining PLGA-PRINT-docetaxel particles with CH-mEZH2 siRNA would enhance antitumor effect. CH-mEZH2 siRNA alone reduced tumor weight by ∼70% in both models (p<0.01 for HeyA8; p<0.05 for SKOV3ip1). PLGA-PRINT-docetaxel treatment reduced tumor weight by ∼80% (p<0.01). Combination therapy showed the greatest therapeutic benefit with ∼95% reduction in tumor weight in both models (p<0.001 in HeyA8; p<0.01 in SKOV3ip1). In both the models, the combination therapy resulted in the greatest reduction of tumor nodules. Individual as well as combination therapies showed a significant reduction in proliferation (p<0.001). Metronomic PLGA-PRINT-docetaxel and CH-mEZH2 siRNA monotherapy increased the apoptotic index significantly (p<0.05), whereas the combination therapy had an additive effect (p<0.001). CH-mEZH2 siRNA as well as metronomic PLGA-PRINT-docetaxel therapy resulted in significant reduction in MVD (p<0.01). Conclusion: Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA is an attractive therapeutic strategy. Citation Format: Kshipra M. Gharpure, Kevin S. Chu, Charles Bowerman, Takahito Miyake, Sunila Pradeep, Lingegowda S. Mangala, Hee-Dong Han, Rajesha Rupaimoole, Sherry Y. Wu, Heather J. Dalton, Mary E. Napier, Gabriel Lopez-Berestein, Joseph M. DeSimone, Anil K. Sood. Metronomic docetaxel in PRINT nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5403. doi:10.1158/1538-7445.AM2014-5403
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