Abstract
Anti-vascular therapy disrupts tumor immature vessels to restrict oxygen and nutrient transport for tumor growth inhibition. However, tumor peripheral vessels with mature and stable structure show treatment resistance in current anti-vascular therapy, called the viable rim effect, to induce local tumor recurrence. Ultrasound stimulated microbubble can damage vascular endothelial cells to accomplish anti-vascular therapy by microbubble inertial cavitation. Since previous studies reported that the efficiency of vascular disruption was proportional to the microbubble inertial cavitation dose, which provided a potential way to disrupt tumor peripheral vessels by regulating ultrasound parameters. Furthermore, chemotherapy was applied to compensate the treatment resistance of anti-vascular therapy via drug accumulation in tumor periphery, the disrupted tumor vessels can also improve drug penetration in tumor center. Therefore, our study investigated the efficiency of anti-vascular effect and drug penetration to improve therapeutic efficacy by regulating ultrasound stimulated microbubbles. The in vitro inertial cavitation dose of home-made microbubbles (1.12±0.08 µm) was measured to evaluate the correlation in anti-vascular effect. Window chamber mice model was applied to define the optimal ultrasound parameters by assessing the efficiency of vascular disruption and drug penetration. The optimal parameters of ultrasound (2-MHz, 1000-cycle, pulse repetition frequency of 2 Hz, 7 MPa, and 2x107 microbubbles/mouse) and liposomal-doxorubicin (160 µg/mouse) were applied for combination therapy in solid tumor model. The efficiency of vascular disruption at 3, 5, 7, and 9 MPa showed 0, 33, 50, and 50% at the vessel size of 21-30 µm. The correlation coefficient was 0.931 between the in vitro inertial cavitation dose of microbubbles and disrupted vessel size. Comparison the treatment efficacy in tumor center and periphery, blood perfusion was reduced to 27±3% and 27±4% (p>0.05), and vessel density was decreased to 23±14% and 24±5% (p>0.05). The uniform treatment in both tumor center and periphery by combination therapy inhibited 74±2.4% of tumor growth relative to the control group (p<0.05). Therefore, our study confirmed that regulating ultrasound parameters can improve the efficiency of anti-vascular therapy and drug penetration to reduce the viable rim effect and inhibit tumor growth.