Optical/Radionuclide Multimodal Molecular Imaging Applications On Hepatic/Gastric Cancer Tumor Models

Cancer,known as the leading cause of death,is a global major public health problem.Reducing the incidence and mortality of cancer has long been the goal for medical researchers all over the world.In China,hepatic cancer and gastric cancer hold the rankings among the cancer types with high incidence and cause the deaths of nearly one million patients each year.Early precise diagnose and effective treatment of metastatic lesions are major solution for improving survival of cancer patients.Optical/radionuclide multimodal molecular imaging can serve as a powerful tool for research of carcinogenesis mechanism,assessment of novel therapies,and development of cancer drugs with its ability of integrating anatomical,physiological,metabolic,pharmacokinetic,and pathologic information.This dissertation focused on applications of optical/radionuclide multimodal molecular imaging on hepatic/gastric cancer imaging,studied in vivo positron emission tomography（PET）/bioluminescencetomography（BLT）/fluorescencemoleculartomography（FMT）/Cerenkov luminescence tomography（CLT）/computed tomography（CT）pentamodal fusion imaging of murine orthotopic hepatic cancer xenografts and in vivo apoptosis imaging with CLI/PET of murine subcutaneous/orthotopic gastric cancer xenografts,assessed the value of optical/radionuclide multimodal molecular imaging applications on hepatic/gastric cancer imaging.The main contributions of the dissertation could be summarized as follows:1.In vivo PET/BLT/FMT/CLT/CT pentamodal fusion imaging of murine orthotopic hepatic cancer xenografts was studied.The self-developed optical molecular tomography（OMT）/PET/CT multimodal imaging system has not been applied in in vivo multimodal imaging yet.The system was upgraded to accommodate CLT imaging modality based on the original system.Resolution,sensitivity,and linearity of PET and OMT subsystems were tested.Then murine orthotopic hepatic cancer xenografts were constructed.In vivo PET/BLT/FMT/CLT/CT multimodal imaging data was acquired.Data of each modality were reconstructed and fused together for visualization.Acquisition and fusion of cell distribution information from luciferase reporter gene of hepatic cancer cells,biodistribuiton information of indocyanine green（ICG）,and metabolic information reflected by ¹⁸F-fluorodeoxyglucose(¹⁸F-FDG),validated the feasibility of performing in vivo PET/BLT/FMT/CLT/CT multimodal imaging with the OMT/PET/CT system,and further supported that optical/radionuclide multimodal molecular imaging can serve as a powerful tool for research of carcinogenesis mechanism,assessment of novel therapies,and development of cancer drugs with its ability of integrating anatomical,physiological,metabolic,pharmacokinetic,and pathologic information.The work provided exploration of feasibility and practical experience for further applications of PET/BLT/FMT/CLT/CT multimodal tumor imaging of the Special Fund for Basic Research on Scientific Instruments conducted by CAS key laboratory of molecular imaging,Chinese Academy of Sciences.2.In vivo apoptosis of CLI/PET of murine subcutaneous/orthotopic hepatic cancer xenografts was studied.There have been years of researches of in vivo apoptosis imaging with nuclear medicine imaging modalities,i.e.PET and single photon emission computed tomography（SPECT）,and several clinical trials with ^99mTc-HYNIC-Annexin V.There is still no such research with CLI.Furthermore,existed studies of in vivo apoptosis focused on the development of apoptosis probes.Rather simple xenografts used in these studies were unable to show the importance of in vivo apoptosis imaging in assessing tumor early-response to treatment.Hence,durg-resistant murine subcutaneous/orthotopic xenografts were constructed,vincristine and cisplatin treatments were applied to simulate the scenario of selection of treatment scheme,and in vivo apoptosis imaging of CLI was explored.Firstly,radionuclide apoptosis probe ⁶⁸Ga-DOTA-Annexin V was synthesized.Secondly,relative resistance to vincristine of SGC7901/VCR vs.SGC7901/WT was validated with MTT assays.In vitro apoptosis levels induced by cisplatin and vincristine on SGC7901/WT and SGC7901/VCR were confirmed with flow cytometry based on Annexin V-FITC/propidium iodide.In vitro apoptosis of CLI validated the targeting specificity of the apoptosis probe and the correlation between CLI radiance and apoptosis levels.These in vitro results proved the feasibility of apoptosis imaging of CLI.Thirdly,drug-resistant murine subcutaneous/orthotopic xenografts were constructed,in vivo apoptosis imaging of CLI/PET was performed,and subsequent changes of tumor volumes were monitored.Strong signals of apoptosis imaging of CLI/PET were detected in both cisplatin-treated subcutaneous and orthotopic SGC7901/VCR xenografts,and subsequent shrinkage of tumor volume confirmed strong signals of apoptosis imaging o CLI/PET were related to the effectiveness of treatment.These in vivo results proved the feasibility and effectiveness of in vivo apoptosis imaging of CLI.Finally,terminal deoxynucleotidyl transferase dUTP nick-end labeling（TUNEL）assays of tumor tissue slices were conducted to validate the apoptosis levels in the tumor tissues from in vivo imaging experiments.The work proved consistency of in vivo apoptosis imaging of CLI and PET and the correlation of its signal intensities and apoptosis levels.Correlation of signal intensities of in vivo apoptosis imaging of CLI/PET and effectiveness of treatment was shown by the application of apoptosis imaging on drug-resistant gastric cancer xenografts.In vivo apoptosis imaging of CLI was suggested to be a promising alternative method of in vivo apoptosis imaging for small animals.In vivo apoptosis imaging of CLI assessed in the dissertation expanded applications of CLI in tumor early-response to treatment,provided an alternative method for in vivo apoptosis imaging of small animals with the ability of enabling high throughput screening,which render it valuable for clinical translation.The dissertation researched on two sample applications of hepatic/gastric cancer imaging with optical/radionuclide multimodal molecular imaging.These imaging techniques could be easily migrated to cancer imaging of other types and imaging of other applicable diseases.