A Cell-Delivered and Cell-Activated SN38-Dextran Prodrug Increases Survival in a Murine Disseminated Pancreatic Cancer Model

作者：Basel Matthew T^*; Balivada Sivasai; Shrestha Tej B; Seo Gwi Moon; Pyle Marla M; Tamura Masaaki; Bossmann Stefan H; Troyer Deryl L

来源：Small, 2012, 8(6): 913-920.

DOI：10.1002/smll.201101879

• prodrug therapy
• cytotherapy
• pancreatic cancer
• cancer targeting

Enzyme-activated prodrugs have been investigated and sought after as highly specific, low-side-effect treatments, especially for cancer therapy. Unfortunately, excellent targets for enzyme-activated therapy are rare. Here a system based on cell delivery that can carry both a prodrug and an activating enzyme to the cancer site is demonstrated. Raw264.7 cells (mouse monocyte/macrophage-like cells, Mo/Ma) are engineered to express intracellular rabbit carboxylesterase (InCE), which is a potent activator of the prodrug irinotecan to SN38. InCE expression is regulated by the TetOn (R) system, which silences the gene unless a tetracycline, such as doxycycline, is present. Concurrently, an irinotecan-like prodrug, which is conjugated to dextran and can be loaded into the cytoplasm of Mo/Ma, is synthesized. To test the system, a murine pancreatic cancer model is generated by intraperitoneal (i.p.) injection of Pan02 cells. Engineered Mo/Ma are loaded with the prodrug and are injected i.p. Two days later, doxycycline was given i.p. to activate InCE, which activated the prodrug. A survival study demonstrates that this system significantly increased survival in a murine pancreatic cancer model. Thus, for the first time, a prodrug/activating enzyme system, which is self-contained within tumor-homing cells and can prolong the life of i.p. pancreatic tumor bearing mice, is demonstrated.

• 出版日期2012-3