李百祺Li, Pai-Chi臺灣大學:電機工程學研究所阮嘉翎Ruan, Jia-LingJia-LingRuan2010-07-012018-07-062010-07-012018-07-062008U0001-2707200823523400http://ntur.lib.ntu.edu.tw//handle/246246/187943具有分子靶向性的對比劑除了具有將傳統醫學影像更進一步推向分子層次外，也對臨床的診斷和治療開啟了新的契機。靶向性對比劑的製作取決於對比劑本身的性質與所探討的生醫議題相對應的分子。透過新興生物技術的發展，超音波靶向性對比劑可以被應用在癌症血管新生及血栓生成的診療上。本文的目的即在於發展靶向性對比劑應用在此兩議題上。血管新生提供癌細胞成長及轉移所需的養分和路徑，因此被視為癌症治療上不可或缺之標的。而利用各種藥物抑制癌症血管新生則被視為臨床癌症治療的曙光，但如何有效的評估新生血管被抑制的狀況，仍是目前一大研究課題。本研究即利用在癌症部位新生血管表面過度表現的蛋白質Molecularly targeted contrast agents will not only broadly extend conventional anatomical imaging into molecular imaging, but also create new opportunities on therapy. Preparation of targeted contrast agents depends on both physical properties of contrast agents and the conjugated biological molecules. Ultrasonic molecular imaging of angiogenesis in cancer and thrombosis has been intensively studied thanks to the rapid discovery of novel biomarkers and affinity ligands. The purpose of this study therefore is to develop targeted ultrasound contrast agents able to recognize thrombi and tumor angiogenesis. Angiogenesis recently has been extensively studied because it is the source of nutrition and metastasis for tumor cells.　Anti-angiogenic therapy, which makes use of angiogenic inhibitors to suppress this mechanism, provides a new way for cancer treatment. However, the lack of effective techniques to assess angiogenesis efficiency impedes fundamental researches and clinical diagnoses. Ultrasonic molecular imaging of tumor angiogenesis may be a potential solution. To construct an ultrasonic imaging system for angiogenesis, endothelial surface proteins中文摘要 i文摘要 iiicknowledgement vIntroduction .1 Medical Ultrasound………………………………………………..…………1.2 Ultrasound Contrast Agents …………………….……………………………7.2.1 Size……………………………………………………………………11.2.2 Core Gas………………………………………………………………14.2.3 Shell…………………………………………………………………...16.2.4 Acoustic Cavitation…………………………………………………...17.3 Targeted Ultrasound Contrast Agents……………………………………….21.3.1 Biomarker Discovery………………………………………………….22.3.2 Targeting………………………………………………………………231.3.2.1 Passive Targeting……………………………………………..23.3.2.2 Active Targeting………………………………………………24.3.3 Biomedical Applications of Targeted Ultrasound Contrast Agents…...27.3.3.1 Ultrasonic Molecular Imaging………………………………...27.3.3.2 Therapeutic Applications ……………………………………..30.4 Aim of Research……………………………………………………………..31.5 Thesis Overview……………………………………………………………..32 Assessment of Tumor Angiogenesis by Ultrasonic Molecular Imaging 33.1 Biology of Tumor Angiogenesis…………………………………………….33.2 Anti-Angiogenic Therapy...………………………………………………….35.3 Assessment of Tumor Angiogenesis………………………………………...38.4 Materials and Methods………………………………………………………39.4.1 Ultrasound Contrast Agents……………………………………………41 2.4.2 Animal Model for Angiogenesis………………………………………43.4.3 High Frequency Ultrasonic System……………………………………43.4.4 Imaging Processing and Data Analysis………………………………..46.5 Results………………………………………………………………………...47.5.1 in vivo Imaging for Commercial Contrast Agents……………………..48.5.2 Homemade Targeted Microbubbles and Subcutaneous Breast Tumor..49 .6 Summary and Discussion..…………………………………………………..54 Thrombus-Targeted Ultrasound Contrast Agents and Sonothrombolysis 55.1 Biology of Thrombosis………………………………………………………..56.2 Thrombolysis………………………………………………………………….58.3 Diagnosis and Treatment……………………………………………………...60.4 Materials and Methods………………………………………………………..62.4.1 Ultrasound Contrast Agents……………………………………………64.4.2 Preparation of Clots……………………………………………………64.4.3 Microbubble Concentration Measurement.……………………………64.4.4 Fixed Plate Assay…………………………………………………… ..65.4.5 in vitro High Frequency Imaging……………………………………...65.4.6 Cavitation Effect Detection……………………………………………66.4.7 Thrombolysis in Flow and Static System……..……………………….66.4.8 Quantification of Inertial Cavitation Dose…………………………….68.4.9 Evaluation of Thrombolytic Efficiency………………………………..68.5 Results and Discussion………………………………………………………..69.5.1 Characterization of Thrombus-Targeted Microbubbles……………….69.5.1.1 Size Distribution………………………………………………..70.5.1.2 Inertial Cavitation………………………………………………71.5.2 Fixed Plate Assay……………………………………………………...72 .5.3 Thrombus Detection with Targeted Microbubbles…………………….72.5.4 Ultrasound-Aided Thrombolysis………………………………………73 .6 Summary……………………………………………………………………80Conclusion and Future Works 80.1 Contributions of This Thesis…………………………………………………80.2 Future Works………………………………………………………………81Bibliography 853402959 bytesapplication/pdfen-US靶向性對比劑分子影像癌症腫瘤血管新生血栓生成超音波輔助血栓溶解穴蝕效應Targeted ultrasound contrast agentMolecular imagingCancerAngiogenesisThrombosisUltrasound-assisted thrombolysis[SDGs]SDG3thesishttp://ntur.lib.ntu.edu.tw/bitstream/246246/187943/1/ntu-97-R95921055-1.pdf