Abstract LB-199: SN38-dextran prodrug synthesis and cell delivery in a murine metastatic pancreatic cancer model

Abstract

Abstract Enzyme activated prodrugs have been investigated and sought after as highly-specific, low side effect treatments, especially for cancer therapy. We synthesized an SN38-dextran prodrug and utilized it in a cell delivery system that can carry both the prodrug and an activating enzyme to the cancer site. For delivery of our prodrug, we engineered Raw264.7 cells (mouse monocyte/macrophage like cells, Mo/Ma) to express intracellular rabbit carboxylesterase (InCE), which cleaves the prodrug to activate SN38. InCE expression was regulated by the TetOn® system, which silences the gene unless a tetracycline, such as doxycycline is present. To test the system, a murine pancreatic cancer model was generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma cells were loaded with the SN38-dextran prodrug and were injected i.p. into the mice. Two days following injection, doxycycline was given i.p. to activate the InCE, which in turn activates the prodrug into active SN38. A survival study demonstrated that this system significantly increased survival in a murine pancreatic cancer model, with an average post-diagnosis life expectancy increase of 20%. Thus, for the first time, a prodrug/activating enzyme system self-contained within tumor-homing cells has been demonstrated that can significantly prolong the life of i.p. pancreatic tumor bearing mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-199. doi:10.1158/1538-7445.AM2011-LB-199