Abstract 4517: Differential cellular response to nanoparticle docetaxel and docetaxel at sub-therapeutic dose range.
Authors: Wang Edina C. , Sinnott Rebecca , Werner Michael E. , Sethi Manish , Tepper Joel E. , Whitehurst Angelique W. , Wang Andrew Z. 
Published: August 2014

Abstract
Nanoparticle (NP) formulations of taxanes overcome the need for excipients and improve the delivery of taxane therapeutics to tumors. These advantages have resulted in rapid clinical translation of NP taxanes and high interest in preclinical and clinical development of novel NP taxanes. However, the effects of NP taxanes on tumor cells compared to their small molecule counterparts have not been evaluated. Existing NP taxanes are polymeric NPs and release their cargo in a slow and controlled fashion. Due to this controlled release, the taxane concentration level and exposure time to a cell at any given time from NP taxanes are different from that of small molecule taxanes. We have utilized two distinct polymeric NP docetaxel formulations to study the influence of NP drug delivery of taxanes on tumor cells in vitro. We hypothesize that the cellular response to polymeric NP taxanes is different from that of small molecule taxanes due to the controlled release property.
We used docetaxel (Dtxl) as a model taxane therapeutic and studied tumor cell response to Docetaxel-PNP, a commercial polymeric NP formulation of Dtxl currently under clinical investigation, and folate-targeted nanoparticle docetaxel (FT-NP Dtxl), a targeted lipid-polymer NP formulation of Dtxl that was developed by our laboratory. The taxane formulations were evaluated using KB head and neck carcinoma. We performed liquid chromatography/mass spectrometry and determined that using the Dtxl equivalent dose of the Dtxl formulations provided the same intracellular concentration of Dtxl after 1 h exposure in KB cells. We demonstrated by fluorescence-activated cell sorting of the cell cycle distribution that NP Dtxl formulations and small molecule Dtxl have similar effects on KB tumor cells at therapeutic concentrations. However, cells treated with a sub-therapeutic concentration of NP Dtxl undergo a different progression through the cell cycle compared to cells treated with small molecule Dtxl, which suggests a difference in the cellular response between the Dtxl formulations. We validated the differential cellular response to sub-therapeutic doses of NP Dtxl and Dtxl by live cell imaging analysis of KB green fluorescent protein-histone 2B (GFP-H2B) expressing cells after treatment. We found that the cellular response of tumor cells to NP Dtxl is different from that of Dtxl at sub-therapeutic doses. In this dose range, we also found that the cellular response of cells to NP Dtxl is similar to that of Dtxl at a much lower dose, suggesting that controlled release property of NP Dtxl is responsible for the difference in the cellular response.
In conclusion, we have demonstrated that the cellular response of tumor cells to NP Dtxl is different from that to Dtxl at sub-therapeutic doses. We speculate that this difference is due to the controlled release property, which causes cells to be exposed to a lower concentration of Dtxl.
Citation Format: Edina C. Wang, Rebecca Sinnott, Michael E. Werner, Manish Sethi, Joel E. Tepper, Angelique W. Whitehurst, Andrew Z. Wang. Differential cellular response to nanoparticle docetaxel and docetaxel at sub-therapeutic dose range. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4517. doi:10.1158/1538-7445.AM2013-4517