Enhanced Tumor Uptake and Penetration of Virotherapy Using Polymer Stealthing and Focused Ultrasound
Menée à l'aide de xénogreffes de cancer du sein sur un modèle murin, cette étude évalue l'intérêt d'une stratégie reposant, d'une part, sur l'injection simultanée par voie intraveineuse de microbulles de gaz et d'un adénovirus enrobé par un polymère puis, d'autre part, sur l'exposition de la tumeur à des ultrasons focalisés, pour augmenter la pénétration du virus dans la tumeur et améliorer l'efficacité de la virothérapie
Background : Oncolytic viruses are among the most powerful and selective cancer therapeutics under development and are showing robust activity in clinical trials, particularly when administered directly into tumor nodules. However, their intravenous administration to treat metastatic disease has been stymied by unfavorable pharmacokinetics and inefficient accumulation in and penetration through tumors. Methods : Adenovirus (Ad) was “stealthed” with a new N-(2-hydroxypropyl)methacrylamide polymer, and circulation kinetics were characterized in Balb/C SCID mice (n = 8 per group) bearing human ZR-75-1 xenograft tumors. Then, to noninvasively increase extravasation of the circulating polymer-coated Ad into the tumor, it was coinjected with gas microbubbles and the tumor was exposed to 0.5 MHz focused ultrasound at peak rarefactional pressure of 1.2MPa. These ultrasound exposure conditions were designed to trigger inertial cavitation, an acoustic phenomenon that produces shock waves and can be remotely monitored in real-time. Groups were compared with Student t test or one-way analysis of variance with Tukey correction where groups were greater than two. All statistical tests were two-sided. Results : Polymer-coating of Ad reduced hepatic sequestration, infection (>8000-fold; P < .001), and toxicity and improved circulation half-life (>50-fold; P = .001). Combination of polymer-coated Ad, gas bubbles, and focused ultrasound enhanced tumor infection >30-fold; (4×106 photons/sec/cm2; standard deviation = 3×106 with ultrasound vs 1.3×105; standard deviation = 1×105 without ultrasound; P = .03) and penetration, enabling kill of cells more than 100 microns from the nearest blood vessel. This led to substantial and statistically significant retardation of tumor growth and increased survival. Conclusions : Combining drug stealthing and ultrasound-induced cavitation may ultimately enhance the efficacy of a range of powerful therapeutics, thereby improving the treatment of metastatic cancer.