Oxaliplatin-resistant colorectal cancer models for nanoparticle hyperthermia

Abstract

Introduction: Metastatic colorectal cancer (CRC) is complicated by chemotherapy-resistant cell populations. Oxaliplatin is used in heated intraperitoneal hyperthermic chemoperfusion (HIPEC) for treatment of disseminated CRC. Photothermal nanoparticles can provide focal heating to improve the response of CRC cells to oxaliplatin, by confining heating near individual cells. Reduction in cellular luciferase signal may allow single-cell-resolution recording of thermal dosimetry. Methods: Oxaliplatin resistant (OxR) variants of luciferase-expressing CT26.WT-Fluc-Neo CRC cells were developed and their sensitivity to hyperthermia was evaluated. Polymer-based photothermal nanoparticles were developed, characterized and used to explore their potential for imparting a thermal dose to improve cell response to oxaliplatin. A correlation of thermal dose to intracellular luciferase activity was established using quantitative luminescence monitoring and microscopy. Results: Luciferase-based monitoring of thermal dose within CT26 cell lines was validated within the ranges of 0.04–8.33 CEM43 for parental cells and 0.05–9.74 CEM43 for OxR CT26 cells. This was further confirmed using nanoparticle-induced hyperthermia, where the single-cell resolution of the thermal dose can be achieved. The nanoparticles enhance cell killing of resistant cells when combined with oxaliplatin and stimulated to generate heat. Conclusion: Nanoparticle-based hyperthermia is effective for augmenting chemotherapy and can be coupled with reductions in CT26 luciferase expression to monitor thermal dose at single-cell resolution. The development of OxR CT26.WT-Fluc-Neo CRC cells sets the stage for pre-clinical evaluations to measure nanoparticle-induced hyperthermia to augment chemotherapy (Nano-HIPEC) in a chemotherapy-resistant model of disseminated CRC.