多功能超音波對比劑於腫瘤診斷與治療

Multifunctional Ultrasound Contrast Agents for Tumor Theranosis

王中信(Chung-Hsin Wang)

指導教授 ： 葉秩光

國立清華大學/原子科學院/生醫工程與環境科學系/博士(2012年)

摘要

本論文主要研究超音波對比劑於醫用超音波影像上的整合應用，同時包含了診斷與治療的面向。整體可以分為兩大主題：第一主題主要陳述於第二章，以研製一般對比劑與探討選用材料對其物化性質的影響為主軸。而第二部分則針對臨床應用進行加值技術的開發，其中包括了分子影像、藥物輸送與多模式影像等延伸應用，並陳述於三、四兩章。
第二章中，我們嘗試以調控對比劑製成材料的比例來控制氣泡粒徑的大小並用以增進微氣泡於特定聲頻下的振動響應。系統的研究證實了此一技術可在0.93 到2.86 微米的區間內調控氣泡的平均粒徑，並用作最佳化微氣泡造影穩定度的方式。而第三章，我們針對超音波分子影像的應用開發了一個共價鍵結的微氣泡修飾系統並進一步搭配了新一代的適合體標靶分子以提供對腫瘤較高的專一性與吸附力。另外，也針對流程所需時間與過程中可能的氣泡衰亡進行技術改良。相較於傳統的製程，使用此一優化的製程將能提高標的分子的修飾效率1.7倍。
最後在第四章的部分，我們為了將診斷與治療加以整合於超音波上，著手開發了新一代的超音波影像對比劑，相轉變液滴。在研究的過程中，前後結合適合體標的分子、小紅莓抗癌藥物以及超順磁奈米鐵粒子於同一液滴載體上。利用相轉變液滴於高能量聲場下能被氣化進而產生穴蝕效應與釋放包覆藥物的特性，提出能同時提供瞬時物理性治療與長效化學性治療的複合式腫瘤治療手段。

關鍵字

標靶微氣泡 ； 適合體修飾 ； 粒徑控制 ； 相轉變液滴 ； 超音波分子生物影像 ； 超音波診斷治療

並列摘要

The primary goal of this dissertation is to apply ultrasound contrast agents (UCAs) to the integrated applications of medical ultrasound imaging. The main topics can be divided to two certain parts. The first part which mainly described in chapter 2 includes the investigations on the fabrication of UCA and the influence of shell compositions on the physic-chemical properties of these agents. The second part focused on the developments of value-added techniques including ultrasound molecular imaging, drug delivery, and bi-model imaging applications that described in chapter 3 and 4.
In chapter 2, we described a size controlling technique that based on regulating the compositions of shell materials for improving the oscillation response of bubbles at specific ultrasound frequency. The systemic results indicate that we could use the regulation technique to control the mean sizes of bubbles from 0.93 to 2.86 μm and even to optimize the imaging stability of fabricated bubbles. In chapter 3, we developed a covalently conjugated bubble system coupling with the new class of targeting ligands, aptamers, for providing a high specific affinity for ultrasound targeting studies. Further technical improvements were also made to reduce the required time and avoid the degradation of bubbles during conjugation process. With the optimized process, the conjugation efficiency of targeted bubbles was up to 1.7-fold higher compared with traditional processes.
In chapter 4, we turned to the development of the new generation UCA, acoustic phase-change droplets, in the cause of integrating the diagnosis and therapy in one modality. Several ingredients were associated with the acoustic droplets, such as aptamer molecules, anti-cancer drug (doxorubicin) and superparamagnetic iron oxide nanoparticles. With ultrasound insonation, these droplets underwent an instant phase transition into gas bubbles called acoustic droplet vaporization. This instant vaporization process occurred with inertial cavitation while liberating the encapsulated therapeutic drugs in the same time. By utilizing these properties, we purposed a hybrid tumor treatment strategy that integrated both the instant mechanical and long-term chemical therapeutic effects.

並列關鍵字

targeted microbubbles ； aptamer conjugation ； size control ； acoustic phase-change droplets ； ultrasound molecular imaging ； ultrasound theranosis

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