Research On Dual-modal Contrast Agent And X-ray Excited Simultaneous Dual-modal Imaging Technique For CT/Fluorescence

Medical imaging is the technique and process of creating visual representations of the interior of a body for clinical analysis and medical intervention,as well as visual representation of the function of some organs or tissues.As a discipline and in its widest sense,it is part of biological imaging and consists of many kinds of modalities such as X-ray radiography,X-ray computed tomography(CT),magnetic resonance imaging(MRI),single-photon emission computed tomography(SPECT),positron emission tomography(PET),fluorescence imaging,infrared imaging,ultrasound imaging,and so on.All these imaging modalities demonstrate their individual characteristics in spatial resolution,penetration capabilities,imaging time,security and other factors when they have been contributed to diverse science research fields and clinical practice.For achieving a better image quality and tissue structure details,a corresponding variety of contrast agents for a variety of imaging modalities have been developed.Recently,researchers focus on the nanoscale contrast agents which provide new technical methods for medical imaging and diagnosis.The newly developed nanomaterials like magnetic iron oxide nanoparticles,gold nanoparticles and fluorescence quantum dots(QDs),have extraordinary features such as long blood circulation time,target specificity and biocompatibility,as well as excellent contrast enhancement capabilities for some of modalities like magnetic resonance imaging(MRI),X-ray computed tomography(CT)and optical imaging etc.The multimodal imaging contrast agent synthesized by two or more contrast agents,which are originally for single modality imaging,will facilitate to obtain two or more enhanced images of a patient at one time through single injection.By registration and fusion techniques,the images from different modalities could give full play to their unique advantages and demonstrate a more comprehensive and more accurate diagnostic information.Nowadays,with the development of molecular imaging and nanotechnology,many dual-modal or tri-modal contrast agents based on different nanomaterial-based platforms have attracted increasing attention,which have broad prospects in biomedical research and clinical applications.Specifically,the dual-modal contrast agent for CT/fluorescence can take use of the advantages of CT and fluorescence imaging mutually to achieve more specific relevant information.Since CT imaging presents some qualities like high spatial resolution,unabridged three-dimensional information,fast scanning and fast image reconstruction,meanwhile,the fluorescence imaging possesses high sensitivity,high safety performance,high reliability and quick response,the fusion of dual-modal imaging will integrate the anatomical structure with the metabolizing results,and bring out very broad applications in medical diagnosis and scientific research.Of the CT/fluorescence dual-modal contrast agent imaging,this paper presents the following aspects of the materials,imaging conditions and instrument methods in details:1.Preparation and characterization of CT/Fluorescence dual-modal imaging contrast agentThe iodinated oil injection is used as the CT contrast agent and the oil soluble ICG-Der-01 fluorescent dye is used as the near-infrared fluorescent probe.The ICG-Der-01 fluorescent dye-iodinated oil nanoemulsion were prepared by the means of ultrasonic cleaning after stirring under the effect of mixed emulsifier PEG(25)monostearate and lecithin.Electron microscopy and hydrodynamic size measurements shows that dual-modal iodinated oil nanoemulsion with 3 different average sizes of 25nm,60nm and 100nm could be obtained by adjusting the amount of Iodinated Oil and surfactant,and the ultrasonic power.With the increase of nanoemulsion concentration,the fluorescence signal and the value of CT number of them increase significantly,which demonstrate that the dual-modal iodinated oil nanoemulsion can be used as a dual-modal contrast agent on research.2.Research on size-dependent tissue distribution and targeting organs of CT/Fluorescence dual-modal imaging nanoemulsionThe imaging ability,tissue distribution and target organ location of CT/fluorescent dual-modal nanoemulsion were studied by means of fluorescence imaging,clinical CT imaging,in vivo Micro CT imaging and high-resolution Micro CT imaging respectively from different levels and resolution of tissue and in vivo.The distribution of contrast agents in main organs of small animals was studied by histopathology method,which could be as a reference for the CT/fluorescence dual-modal image enhancement experiment.The visible target organ of rat for the dual-modal nanoemulsion is the liver,which could be observed by Fluorescence imaging characterized by its high sensitivity.However,due to limited resolution of imaging,some small distribution of nanoemulsion cannot be observed in it.Thus the clinical CT scans were employed to compare the imaging enhanced results of the different organs by injecting into the contrast agents with different hydrodynamic sizes.The results show that the main targeting organs by the iodinated oil nanoemulsions are rat's liver and spleen,and there was also a significant dose-dependence between the increased size of nanoemulsions and their cumulative effects in the liver and the spleen.It follows that the enhanced permeability and retention(EPR)effect decreases along with the size of the nanoemulsion reduces.In the arterial phase,the CT number reaches the peak value in the inferior vena cava after the contrast agent injection;while in the late arterial phase,when the contrast agent is spreading throughout the whole body as well as accumulating and metabolizing on the liver and the spleen,the CT numberof the same place shows a rapid decline at firstand recovers slightly at final.Furthermore,by using in vivo small animal Micro CT imaging system,the cumulative distribution of targeting organs(liver,spleen)in rats with different sizes of dual-modal iodinated oil nanoemulsion has been studied,which is also coincidence with the clinical CT imaging results.The high-resolution Micro CT is then employed to screen the rat's liver and spleen tissues in vitro.Since its resolution is up to 1.7 micron,the particle distribution of the contrast agent in the tissue can be revealed by the high-resolution Micro CT.The result indicates that the contrast agent enriched on the liver and the spleen has formed some local spot-like patterns,the smallest region with high density discernable in the images is about 0.01-2mm2.Meanwhile,the tissue and cellular distribution of the iodinated oil nanoemulsion based contrast agent has also been studied by the histopathological method,and the effects of targeting and aggregation of which were testified on the liver and the spleen at tissue and cellular level.Moreover,it also indicates that this kind effects occur occasionally in the heart tissue and but never aggregate in the lung tissue.3.Preparation of the folate-decorated iodinated oil nanoemulsion probe and imaging on its targeting tumors by clinical CTIn this part,some HeLa cell-implanted mouse models of cervical cancer were set up,the cumulative effects of the folate-targeted iodinated oil nanoemulsion in the tumor have been studied.The results demonstrated that,after injection of the nanoemulsion,the average value of CT number in both the livers and the Hela cervical tumors all increases slightly at the beginning,and then gradually enhances as time goes by,finally reaches the peak over 120min-180min.Hence we may consider the folate-targeted iodinated oil nanoemulsion as a long-circulating and tumor-specific targeting contrast agent.4.X-ray excited simultaneous dual-modal imaging for CT/fluorescence and further image processingIn the X-ray excitation dual-modal imaging experiment,the BaPt(CN)4 is chosen as the fluorescence material for its high luminous intensity and no activators.Then a new single-source X-ray Micro CT/fluorescence dual-modal tomography system is designed,which cooperates with the chosen material,to screen the biological samples.The system consists of an X-ray Micro CT imaging subsystem and a fluorescence molecular tomography subsystem.As the two models are highly coupled,the fusion images can be simultaneously obtained by the dual-modal CT/fluorescence imaging with only a single X-ray source and single scan.The results indicate that the structural and functional information of the mouse cadaver can be achieved by single X-ray excitation in the dual-modal imaging.In conclusion,the single-source X-ray CT/fluorescence dual-modal tomography system can acquire abundant diagnostic information efficiently and accurately in low-dose radiation by X-ray Micro CT and fluorescence dual-modal imaging.