Vascular Effect Of Rabbit VX₂ Tumor Induced By Diagnostic Ultrasound With Microbubbles

Background:The number of deaths caused by malignant tumors kept increasing year by year,which has become the serious problem threatening human's health.Chemotherapy is the main treatment for most cancer patients.Due to the lack of blood supply and local hypoxia,the low efficiency of chemotherapy is quite low.It is difficult to achieve the effective dose of the drug in tumor,and the duration of action is short,which reduced the killing effect of chemotherapy on tumor cells.Therefore,finding an approach to improving curing effect of chemotherapy by increasing the blood perfusion of tumor to rich the the local drug concentration and expand the lasting time is of great importance.With the further research on the ultrasonic cavitation,great progress has been made in promoting the drug release.Our previous studies showed that high peak negative pressure?2.6-4.8MPa?ultrasound combined with microbubbles will produce damaging effects on the animal tumor angiogenesis,and develop the formation of local hematoma and edema,blocking tumor blood circulation.The 1.0MPa low pressure ultrasound could make rabbit VX₂ tumor perfusion increase in contrary.In order to increase the local drug concentration in the tumor tissue,we tried to employ the effects of ultrasound combined with microbubbles on tumor blood flow which showed no obvious side effects.We use of three different mechanical index?MI?in the experiment of ultrasonic microbubble cavitation to identify its effect on blood flow and basic pathology rabbit VX₂ tumor perfusion.And the doxorubicin was intravenously injected after ultrasonic treatment to measure the drug concentration in the tumor tissue.vascular effect judging ultrasound combined with microbubbles may produce to chemotherapeutic drug concentration,so as to improve the efficiency of clinical tumor chemotherapy provides a new idea.Objective:1.To investigate the different vascular effects of diagnostic ultrasound combined with microbubbles?MB?on rabbit VX₂ tumor.2.To evaluate the effect of different ultrasound combined with microbubbles on the vascular effects of VX₂ tumor in rabbits and the concentration of doxorubicin?Dox?in tumor tissues.Materials and Methods:1.Materials:?1?Diagnostic ultrasound imaging system: VINNO 70 ultrasound system with innovative microbubble ultrasonic cavitation control function?Vflash function?.The X4-12 L high frequency linear array probe with the frequency range from 4 to 12 MHz.?2?Animals: 62 healthy male New Zealand white rabbits?average weight of 2.3 2.5kg?were used.which were provided by the laboratory animal center of Xinqiao Hospital,the Third Military Medical University,?3?Microbubbles: Zhifuxian,a lipid-encapsulated microbubbles and the core gas is perfluoropropane,with a bubble concentration of?4-9?×109 / mL,was designed by Xinqiao Hospital,the Third Military Medical University.The MBs had a mean diameter of 2 ?m and 98% of them less than 8 ?m.2.Methods:?1?Forty rabbit with VX₂ tumors were treated by diagnostic ultrasound with different strengths of Mechanical index?MI?0.3,0.7,1.4 with MB as experiment group?n=10,n=10,n=10?and negative control?n=10?for 5 minutes.0.2ml microbubbles in 5 ml normal saline was used as a therapeutic dose.The tumor blood perfusion was imaged with contrast-enhanced US?CEUS?before and after treatment which were analyzed by the contrast analysis software of VINNO 70.After the treatment,the tumor samples were sent for pathological examination.?2?22 healthy male New Zealand rabbits were randomly divided into MI=0.3 group?n=8?,MI=1.4 group?n=8?and control group?n=6?,The contrast method and microbubble dose are as described above.30mg/kg of Dox was injected slowly through the ear vein.Ultrasound treatment were given 30 minutes later,and the blank control group was only injected with Dox.Ultrasound imaging was performed immediately after treatment,and the tumor samples were measured by liquid chromatography and analyzed the concentration of Dox.Results:?1?There are significant differences in PI values before and after the treatment in experiment group 1 and 3?P=0.028,0.018?,while PI in experiment group 2 and control group showed no difference?P=0.994,0.978?.The AUC in the experiment group 3 are significantly different before and after the treatment?P=0.009?,while no difference existed in experiment group 1,2 and control group?P=0.099,0.497,0.898?.HE staining showed no obvious pathological changes.?2?Data analysis showed that only group 1?MI = 0.3?had significant differences?P = 0.042?with the blank control group.No difference between the group 1 and 2 or the group 2 and the blank control group were observed.Conclusions:1.Low-intensity diagnostic ultrasound?MI=0.3?combined with microbubbles could enrich the blood perfusion of VX₂ tumor in rabbits,and high-intensity diagnostic ultrasound?MI=1.4?would decrease the blood perfusion.2.The drug concentration of VX₂ tumor increased due to the change of blood perfusion in rabbits,especially in the case of enrich the blood perfusion.