Triblock Pluronic Copolymer F127 as a Potential Enhancer of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in HT-29 Colorectal Cells
Authors:Alyssa Barriga, Eileen Brantley
- Christopher Perry, Assistant Professor of Basic and Pharmaceutical Sciences, Loma Linda University
- Eileen Brantley, Assistant Professor of Basic and Pharmaceutical Sciences, Loma Linda University
- Maheswari Senthil, Surgical Oncologist , Loma Linda University Medical Center
Peritoneal carcinomatosis is cancer that has spread to the lining of the abdomen and the abdominal viscera. Cytoreductive surgery and HIPEC have been shown to improve survival in patients with colorectal peritoneal carcinomatosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) involves infusing the abdominal cavity with heated chemotherapeutic agents such as Mitomycin C. Mitomycin C works by binding to DNA resulting in cross-linking and inhibition of DNA synthesis in cancer cells. However, multidrug resistance genes within cancer cells promote the efflux of Mitomycin C and undermine the effectiveness of HIPEC. Triblock pluronic copolymers are surfactants that frequently sensitize cancer cells to chemotherapeutic agents by inhibiting multidrug resistant gene action. These polymers contain amphiphilic properties enabling chemotherapeutic drugs to incorporate within their hydrophobic composition. Therefore, we hypothesize that coupling Pluronic F127 with Mitomycin C, as part of HIPEC will increase its therapeutic effectiveness in HT-29 colorectal cells. We determined the concentration of surfactants at which micelles (aggregates of molecules in a colloidal solution) form for Pluronic F127 at 42°C and at 37°C. Using the AlamarBlue ™assay, we evaluated the cytotoxicity of Mitomycin C alone and in combination with pluronic F127 at both 37°C and 42°C for 90 min followed by 72 h of exposure to plain media (37°C) to mimic clinical administration of HIPEC. Pluronic F127 used in combination with Mitomycin C at 42°C caused a slight enhancement in Mitomycin C-mediated cytotoxicity at concentrations ranging from 0.1-1μM. We synthesized and characterized a modified version of Pluronic F127 chemically conjugated to the fatty acid stearic acid for use in future studies that will incorporate Mitomycin C via electrostatic interactions. We will determine whether the resulting steric acid linked-F127 coupled with Mitomycin C will further enhance the effectiveness of HIPEC therapy in animal models of peritoneal carcinomatosis.