Vascular targeted photodynamic therapy (VTP) is based on in-situ photosensitization of a circulating drug leading to intravascular reactive oxygen species (ROS) generation and the subsequent tumors’ blood vessel occlusion that lead to the tumor necrosis. We have developed a series of bacteriochlorophyll derivatives, among them WST11 (TOOKAD®-Soluble) a water-soluble agent that has just been granted approval by the European community (EMA) for the treatment of early/intermediate prostate cancer. Application to other cancers, specifically to pancreatic ductal adenocarcinoma (PDAC) is being evaluated and may require adjustments of the treatment conditions. The following work presents the first pre-clinical results using WST11-VTP to treat syngeneic PDAC in mice.
We utilize KPC cells derived from genetically engineered mouse model of spontaneous pancreatic adenocarcinoma to induce orthotopic PDAC tumor in C57B mice. Cells are injected in the mouse pancreas and are treated 7 days post-implantation. WST11 is injected i.v. by constant rate infusion followed by illumination of the exposed tumor at 755nm. Tumor growth is monitored using a Vevo 3100 US imaging apparatus. In parallel experiments, a window exposing the pancreas blood vasculature through a glass coverslip is positioned in a few mice. This allows live monitoring of the new angiogenic blood vessels during treatment using a fluorescent microscope and speckle imaging techniques.
WST11-VTP of orthotopic KPC tumors was tested using different drug/light doses. Two doses produced 75-80% tumor necrosis with minimal toxicity, namely 5/7 mg/kg WST11 combined with 100/120mW light. One month post-VTP, the surviving mice were sacrificed histopathological evaluations revealed dramatic tumor shrinkage and necrosis in the treated animals. Moreover, the combination of VTP with Gemcitabine seemed to further improve the treatment success.
WST11-VTP showed good safety/efficacy profile while applied to orthotopic KPC tumors in syngeneic mice. The combination with Gemcitabine seem to be beneficial and is being further evaluated. These results might in the future rationalize early clinical trials in PDAC patients.
Weizmann Institute of Science
Robert and Yaddle Sklare Professiorail Chair in Biochemistry and the Wade Thompson Family foundation.
All authors have declared no conflicts of interest.