Orthotopic hepatocellular carcinoma: molecular imaging-monitored intratumoral hyperthermia-enhanced direct oncolytic virotherapy

Abstract Objective: To validate the feasibility of molecular imaging-monitored intratumoral radiofrequency hyperthermia (RFH) enhanced direct oncolytic virotherapy for hepatocellular carcinoma (HCC). Methods: This study included in vitro experiments using luciferase-labeled rat HCC cells and in vivo validation experiments on rat models with orthotopic HCCs. Both cells and HCCs in four groups (n？=？6/group) were treated by: (1) combination therapy of oncolytic virotherapy (T-VEC) plus RFH at 42？°C for 30？min; (2) oncolytic virotherapy alone; (3) RFH alone; and (4) saline. For in vitro confirmation, confocal microscopy and bioluminescence optical imaging were used to evaluate the cell viabilities. For in vivo validation, oncolytic viruses were directly infused into rat HCCs through a multi-functional perfusion-thermal RF electrode, followed by RFH. Ultrasound and optical imaging were used to follow up size and bioluminescence signal changes of tumors overtime, which were correlated with subsequent laboratory examinations. Results: For in vitro experiments, confocal microscopy showed the lowest number of viable cells, as well as a significant decrease of bioluminescence signal intensity of cells with combination therapy group, compared to other three groups (p？<？.001). For in vivo experiments, ultrasound and optical imaging showed the smallest tumor volume, and significantly decreased bioluminescence signal intensity in combination therapy group compared to other three groups (p？<？.05), which were well correlated with pathologic analysis. Conclusion: It is feasible of using molecular imaging to guide RFH-enhanced intratumoral oncolytic virotherapy of HCC, which may open new avenues to prevent residual or recurrent disease of thermally ablated intermediate-to-large HCCs