Targeted Therapy Effect Of Z_HER2:V2-pemetrexed For HER2-positive Lung Adenocarcinoma And It's Molecular Imaging Evaluation

Purpose:Lung cancer is one of the most common malignant tumors,the incidence of non-small cell lung cancer is as high as 80%or more,and the proportion of lung adenocarcinoma increased significantly in recent years.Targeted therapy is the first choice of treatment for advanced lung adenocarcinoma with treatable gene mutation.However,for patients with advancedlungadenocarcinomawithouttreatablegenemutations,platinum-based chemotherapy is one of the main treatment options.But the efficacy of chemotherapy drugs is poor meanwhile the side effects do exist.The study of targeted chemotherapy based on conjugation of receptor or antibody with chemotherapeutic drugs do have important clinical significance.The purpose of this study is to investigate the therapeutic effect of Z_HER2:V2-pemetrexed for HER2-positive lung adenocarcinoma and evaluate its therapeutic effect by ⁹⁹Tc^m-Z_HER2:V2-Pemetrexed molecular imaging.Methods:Fifteen nude mice bearing HER2-positive A549 xenografts were randomly divided into three groups.Z_HER2:V2-pemetrexed-treated group,pemetrexed-treatedgrouporsalinecontrolgroup.Micein Z_HER2:V2-pemetrexed-treated group and Pemetrexed-treated group were given Z_HER2:V2-pemetrexed or pemetrexed intraperiotoneally 200mg/kg?100?l?on day 1 and day 8;Mice in control group were given 100?l physiological saline on day 1 and 8.Mice body weights and tumour volume were monitored every three days during treatment.In vivo SPECT imaging was performed in mice of the three groups using ⁹⁹Tc^m-Z_HER2:V2-Pemetrexed before treatment,on day7 and 14 after treatment.Radiolabel probe uptake in tumours was measured as the ratio of radioactive counts in the tumour to that in the contralateral equivalent region?T/NT?.After SPECT imaging on day 14,all the mice were euthanized,Studies of the A549 xenografts were carried out to validate the imaging results and HER2 expression of the transplanted tumours was analyzed by immunohistochemistry?IHC?.Correlation analysis was performed between T/N ratios acquired by in vivo SPECT imaging on day 14and the HER2 level of tumours.All experimental data were expressed with x±s.P<0.05 can indicate that the difference is significant.Results:Though volumes of A549 xenografts gradually increased in eachgroupduringthetreatment,thetransplantedtumoursin Z_HER2:V2-pemetrexed-treated group and Pemetrexed-treated group had a slower growth than those in control group?F=113.27,365.69;P=0.00,0.00?.Meanwhile,15 mice body weight in the three groups gradually increased during treatment,which indicated that Z_HER2:V2-pemetrexed and pemetrexed treatment had no significant effect on the growth of tumor-bearing nude mice.Before the treatment,the T/NT ratios of ⁹⁹Tc^m-Z_HER2:V2-pemetrexed imaging in Z_HER2:V2-pemetrexed-treatedgroup,pemetrexed-treatedgroupand saline-treated control group were 2.63±0.04,2.65±0.02 and 2.68±0.11respectively.There is no significant statistical difference among three groups?F=0.65;P=0.54?;7 days after treatment,the T/NT ratios of tumor uptaken by⁹⁹Tc^m-Z_HER2:V2-pemetrexed imaging in Z_HER2:V2-pemetrexed treatment group,pemetrexed-treated group and normal saline treatment control group were1.90±0.06,1.67±0.06 and 2.67±0.05 respectively,which showed a significant decrease comparing with the control group?t=22.08,28.76;P=0.00,0.00?.The T/NT ratio of the two drug treatment groups was significantly lower than baseline?t=42.81,34.03;P=0.00,0.00?.The T/NT ratio of tumor uptake⁹⁹Tc^m-Z_HER2:V2-pemetrexedintheZ_HER2:V2-pemetrexed-treatedgroup,pemetrexed-treated group and saline-treated control group was 1.72±0.04,1.50±0.02 and 2.65±0.07 respectively after 14 days of treatment,and treatment grops is significantly lower than the control group?t=26.42,36.31;P=0.00,0.00?.The two drug treatment groups had a significant decrease again on the 7th day after their individual treatment?t=7.00,5.46;P=0.00,0.01?.At the 14th day,there was an obviously positive correlation between the T/NT ratio and HER2 expression level in its corresponding tumor tissue?rs=0.91,P=0.00?.Conclusion:Treatment with Z_HER2:V2-pemetrexed and pemetrexed had a clear inhibition on tumor growth.Z_HER2:V2-pemetrexed has significant targeted therapeutic effect on lung adenocarcinoma with high expression of HER2.The⁹⁹Tc^mZ_HER2:V2-pemetrexedmolecularimagingshowsthat⁹⁹Tc^mZ_HER2:V2-pemetrexed is markedly uptaken by HER2-positive lung adenocarcinoma tumor sites.⁹⁹Tc^mZ_HER2:V2-pemetrexed may be valuble in monitoring the therapeutic efficacy of HER2 high-expression lung adenocarcinoma.