Therapeutic Efficacies Of Combination Hifu With Paclitaxel Thermosensitive Liposomes On Lewis Lung Carcinomar In Mice

At present, cancer is still one of the diseases with the highest fatality, which threaten the life of human beings seriously. There are a great deal of studies on anti-tumor methods.Using the peculiar capability of penetration, orientation and focusing of the ultrasound, High Intensity Focused Ultrasound(HIFU) can build high intensity focus in deep tissue and cause acute cell death with high temperature. Because HIFU can produce small necrosis area in a short time, it may promote treatment precision, efficiency and effectiveness. HIFU as a thermal therapy has become a kind of new cancer therapy after operation therapy, radiopharmaceutical therapy and biology therapy.At the same time, in recent years scientists have paid close attention to liposome, as it has the advantages of increasing the therapeutic effect, reducing toxicity, notoxic and having no immunosuppression. However, the common liposome did not have the ideal targeting effect. It was instability in vivo and there existed some questions upon the store. These disadvantages limited its industrialization and application in clinical treatment. The thermo-sensitive liposome was a new kind of liposome that has a targeting for heat.The therapeutic efficacies of combination HIFU with paclitaxel thermosensitive liposomes on Lewis lung carcinoma(LLC) have been investigated in the thesis. Target therapy would come true. Target therapy is to improve the drug concentration, reduce the negative reactions, reduce the drug amount and improve the safety and the effect of medication. During the tumour target therapy process, the target tissue needs to be heated to a stated temperature and the heat-susceptivity carrier will release the inner drug immediately. High drug concentration in the target turnout can perish the tumor cell without destroying the normal cells.Paclitaxel is thus far one of the most effective anticancer drugs available on the market. It has shown substantial clinical efficacy for ovarian, breast, colon, head and neck and non-small cell lung cancers. However, paclitaxel is poorly soluble in water and therefore, clinical administration is currently formulated in a1:1mixture of Cremophor EL, apolyethoxylated castor oil, and ethanol. This formulation is associated with a series of significant vehicle related toxicity in the clinic.This causes the patients much pain and limits its application in clinical. In this study, The anti-tumor agent paclitaxel is selected as the model drug, and the paclitaxel thermosensitive liposome(PTL) is prepared. It is expected to change the release characteristic of liposome in vivo, increase the therapeutic effect, reduce the toxic and side effects in the whole body, so as to ease the pain that the cancer patients are suffering to a certain extent.Whether HIFU can heat paclitaxel thermosensitive liposome is observed. Firstly, the model of Lewis lung carcinoma by subcutaneous transplantation in mice has been established. Secondly, the HIFU therapeutic system is started and Lewis lung carcinoma is allocated. Then different powers(90W、100W、HOW) of HIFU are adopted to irradiate Lewis lung carcinoma. At the same time acupuncture of warmed needle is used to monitor tumor inner temperature for30min and observe changes of tumor inner temperature at different power. Finally the results of experiment show that when the tumor inner temperature reaches42℃, power of HIFU is100W. This temperature keeps stable and the skin of mice is not ambustion. That temperature of mice has not changed obviously.Lewis carcinoma models are established in80Kunmin mice. Mice are stratified by volume and randomly assigned to one of the eight groups: control(Con), HIFU along(HIFU), free paclitaxel along(PTX), paclitaxel liposomes(PL), paclitaxel themosensitive liposomes(PTL), free paclitaxel with HIFU(PTX+HIFU), paclitaxel liposomes with HIFU(PL+HIFU), paclitaxel themosensitive liposomes with HIFU(PTL+HIFU). Saline, free paclitaxel, paclitaxel liposomes, paclitaxel themosensitive liposomes are injected i.v. in mice followed by30min HIFU exposure with the temperature maintained at42-43℃in tumor. And treatments were repeated on the4th day and the7th day. The mice are monitored, and tumors are measured every day posttreatment. The mice are sacrificed on10th day and pathologic examination is performed. The apoptotic indices(AI) in tumor tissues are tested using TdT mediated dUTP nick end labeling(TUNEL) respectively.All mice have well tolerated the treatment. The tumor inhibition rate in PTL+HIFU group is71.6%, which is significantly higher than these of PTX+HIFU group(50.0%, P<0.05) and PL+HIFU group(59.4%, P<0.05). The tumor inhibition rate in PTX groups PL group and PTL group are21.3%、18.8%and23.4%, and there is not evident discrepancy in three groups(P>0.05). Pathologic study shows obvious tumor cells necrosis in PTX group, and mild tumor cells necrosis in other paclitaxel groups. However, there are a few tumor cells necrosis observed in Con and HIFU groups. AI in PTL+HIFU group is47.83%, which is more obviously than PL+HIFU group(41.46%) and PTX+HIFU group(36.07%).The differences are significant(P<0.05).While AI in PTL+HIFU group、PL+HIFU group and PTX+HIFU goup are more than other groups without HIFU heated treatment(PTX group is26.82%、PL group is28.53%、PTL group is31.45%). The differences are also significant(P<0.05). AI changes are more significant in HIFU group、paclitaxel group and HIFU with paclitaxel group than those of the control group(P<0.05).Combined with paclitaxel themosensitive liposomes, HIFU enhanced antitumor effects on Lewis lung carcinoma(LLC). These results imply that HIFU can be used as a target heating device for tumor target in paclitacel thermosensitive liposome therapy.