Abstract
Phase-change droplets (PCDs) encapsulated liquid perfluorocarbon (PFC) by lipid shell are more stable than microbubbles in the circulation. PCDs have potentials for theranostics applications due to their ability of converting from liquid to gas phase under ultrasound excitations (referred to acoustic droplet vaporization, ADV). In order to predict the region of PCDs drug release by ADV and alter the aspect of treatment immediately, we established an integrated ultrasound system to monitor and control the drug release and utilized acoustic-based temperature map to predict the occurrence of ADV. The transmitting pulse was comprised of long pulsing for local tumor heating and short pulsing for vaporizing the thermal sensitive PCDs. The overlapping area between temperature map and ultrasound B-mode image was calculated. The thermal sensitive PCDs were composed of C5F12 and C6F14. The stability, ADV efficiency and cell toxicity of PCDs were estimated. The optimization of ADV threshold (including mixture ratio, temperature, and ultrasound parameters) was also estimated and discussed. We quantified the overlapping area of the ADV region and the temperature map by means of performing different parameters, and established the ultrasound contrast image database to evaluate the relationship between temperature profile and pressure distribution. Then the optimized conditions were applied in mouse tumor model and confirmed the feasibility of prediction ADV location in vivo. The ratio of C5F12 and C6F14 was 7: 3 and the corresponding PCDs were with average size of 1.1 μm and the concentration of 20×109/mL. In the ADV threshold conditions of 8.6 MPa and a 3-cycle pulse, the ADV efficiencies were 29% and 63%, at 37˚C and 41˚C (p<0.01), respectively. By comparisons at 37 ˚C, the cell viability decreased 21% at 41 ˚C (p<0.05), showing heating could enhance the cell membrane permeability and drug uptaken. In vitro phantom testing at 41 ˚C, the overlapping image ratios were 40% and 87%, at 8 and 8.6 MPa (p<0.01), respectively, confirming that the pressure of 8.6 MPa performed higher precision of ADV location. At the same condition, the overlapping image ratio in tumor model was 83%, with no significant difference (p>0.05). In conclusion, our proposed imaging technique provided a useful tool with the thermal sensitive PCDs to monitor the prediction of ADV. Operating ultrasound can monitor the ADV region guided by the temperature map. The heating with ADV process enhanced the cell permeability and precisely released drugs within tumor. Future work is to apply the proposed system to cancer therapy with a real-time monitoring drug delivery/release, and enhancing the efficiency of treatment.