Enhanced viral activity in tumors using focused ultrasound and microbubbles-A long term study.

Oncolytic viruses target and kill cancer cells and self-amplify through replication. However, viral therapy in vivo is limited by insufficient systemic delivery. Here, focused ultrasound (FUS) was used in conjunction with microbubbles to produce cavitation and enhance tumor viral delivery. Human breast cancer cells (ZR75.1) were injected subcutaneously in mice (n = 8), which grew to a tumor volume of at least 30 mm(3). The tumors were then exposed to FUS (frequency: 0.5 MHz, pulse duration: 50 000 cycles, pulse repetition frequency: 0.5 Hz) for 4 min following injection of 100 μl of SonoVue microbubbles (SVM) with polymer-coated adenovirus encoding luciferase (pc-Ad-Luc). Experiments were repeated for three controls: pc-Ad-luc with neither FUS nor SVMs, FUS and SVM without pc-Ad-Luc, and buffer alone. Acoustic emissions were recorded with a passive detector, which validated the presence of inertial cavitation and ensured good SVM reperfusion kinetics. Tumor viral expression was then imaged using IVIS following luciferin injection. At 1, 2, 3, and 7 days post-injection, 3, 20.3, 30.2, and 22.9-fold increases in photons/s/cm(2) were observed when pc-Ad-Luc was used with FUS and SVM compared to pc-Ad-Luc alone. In conclusion, FUS and SVM enhanced oncolytic virus delivery resulting in amplified viral expression over time