相變液滴(phase-changed droplets, PCDs)主要由磷脂殼層包覆低沸點的氟碳化合物所構成，可於超音波刺激下汽化膨脹成氣泡(acoustic droplet vaporization, ADV)提供超音波對比影像並釋放藥物，達到診斷與治療並進的應用。為了預判藥物釋放的區域好即時調整治療計畫提升腫瘤治療效率，本研究欲使用溫度影像預判ADV產生的區域，以長脈衝超音波進行腫瘤局部加熱，並以短脈衝汽化溫度應答性PCDs，於後續評估溫度影像與超音波對比影像之相關性，建立超音波加熱、汽化以及溫度成像的整合系統。
溫度應答性PCDs內部由C5F12和C6F14混合而成，於體外量測穩定性、汽化效率與細胞毒性，決定最佳化之氟碳化合物混合比例、加熱溫度與超音波汽化參數。仿體實驗以熱耦器量測超音波加熱之升溫曲線並收集ADV影像，建立溫度與超音波對比影像資料庫，評估不同聲壓下之影像疊合率。最後以腫瘤小鼠靜脈注射溫度應答性PCDs，驗證超音波溫度影像於活體預判ADV位置之可行性。
本研究使用C5F12:C6F14體積比7:3之溫度應答性PCDs，其平均粒徑為1.1 μm，濃度為20×109/mL。於8.6 MPa、3-cycle汽化參數下，汽化效率在37˚C與41˚C分別為29%與63%（p<0.01）。細胞活度於41˚C下降21％相較於37˚C（p<0.05），證實加熱可提升細胞膜通透性與藥物遞送。仿體溫度與超音波影像在41˚C下，影像疊合率為70 %、96 %於8.0、8.6 MPa下，可知8.6 MPa之溫度影像預判汽化位置有較高的準確率（p<0.05）。活體實驗可於加熱至41˚C後，看見腫瘤中的ADV影像，其與溫度影像之疊合率為80％，與仿體結果沒有統計差異（p>0.05）。
本研究建立可同時加熱、汽化以及溫度成像之超音波整合系統，搭配溫度應答性PCDs，利用超音波加熱之溫度影像，以視覺化定位ADV區域，並提升腫瘤細胞膜通透性，可有效預測藥物釋放位置。未來期望運用在腫瘤治療上，即時調整藥物遞送區域，提升腫瘤治療效率。

Phase-change droplets (PCDs) encapsulated liquid perfluorocarbon (PFC) by lipid shell are more stable than microbubbles in the circulation. PCDs have potentials for theranostics applications due to their ability of converting from liquid to gas phase under ultrasound excitations (referred to acoustic droplet vaporization, ADV). In order to predict the region of PCDs drug release by ADV and alter the aspect of treatment immediately, we established an integrated ultrasound system to monitor and control the drug release and utilized acoustic-based temperature map to predict the occurrence of ADV. The transmitting pulse was comprised of long pulsing for local tumor heating and short pulsing for vaporizing the thermal sensitive PCDs. The overlapping area between temperature map and ultrasound B-mode image was calculated.
The thermal sensitive PCDs were composed of C5F12 and C6F14. The stability, ADV efficiency and cell toxicity of PCDs were estimated. The optimization of ADV threshold (including mixture ratio, temperature, and ultrasound parameters) was also estimated and discussed. We quantified the overlapping area of the ADV region and the temperature map by means of performing different parameters, and established the ultrasound contrast image database to evaluate the relationship between temperature profile and pressure distribution. Then the optimized conditions were applied in mouse tumor model and confirmed the feasibility of prediction ADV location in vivo.
The ratio of C5F12 and C6F14 was 7: 3 and the corresponding PCDs were with average size of 1.1 μm and the concentration of 20×109/mL. In the ADV threshold conditions of 8.6 MPa and a 3-cycle pulse, the ADV efficiencies were 29% and 63%, at 37˚C and 41˚C (p<0.01), respectively. By comparisons at 37 ˚C, the cell viability decreased 21% at 41 ˚C (p<0.05), showing heating could enhance the cell membrane permeability and drug uptaken. In vitro phantom testing at 41 ˚C, the overlapping image ratios were 40% and 87%, at 8 and 8.6 MPa (p<0.01), respectively, confirming that the pressure of 8.6 MPa performed higher precision of ADV location. At the same condition, the overlapping image ratio in tumor model was 83%, with no significant difference (p>0.05).
In conclusion, our proposed imaging technique provided a useful tool with the thermal sensitive PCDs to monitor the prediction of ADV. Operating ultrasound can monitor the ADV region guided by the temperature map. The heating with ADV process enhanced the cell permeability and precisely released drugs within tumor. Future work is to apply the proposed system to cancer therapy with a real-time monitoring drug delivery/release, and enhancing the efficiency of treatment.

第一章 緒論 1
1.1 惡性腫瘤 1
1.1.1 治療方式 2
1.1.2 藥物釋放 3
1.1.2.1 控制釋放時機 5
1.1.2.2 控制釋放範圍 5
1.2 超音波觸發熱效應 6
1.2.1 超音波測溫技術 7
1.3 一般超音波對比劑：微氣泡 9
1.4 新式超音波對比劑：相變液滴 11
1.4.1 汽化影像偵測 13
1.4.2 汽化閾值 14
1.4.3 相變材料 15
1.4.4 汽化控制 17
1.4.5 操作環境 17
1.5 升溫邊際效用 18
1.6 研究動機 20
第二章 實驗方法 23
2.1 概論 23
2.2 溫度應答性材料製作 23
2.2.1 微液滴對比劑之物理特性測量 24
2.3 聲場掃描與校正 24
2.4 溫度應答性微液滴測試 25
2.4.1 定義汽化效率 26
2.4.2 溫度應答性液滴 28
2.4.3 聲學參數測試 29
2.5 細胞膜通透性測試 29
2.5.1 細胞準備 29
2.5.2 測試架構 30
2.6 超音波溫度影像 30
2.6.1 程式擬合 30
2.6.2 溫度演算法 31
2.6.2.1 位移累積和位移修正 32
2.6.2.2 平滑化和應變處理 34
2.6.2.3 數值校正 34
2.6.2.4 疊圖顯示 34
2.7 加熱影像同步系統 35
2.7.1 系統架構 35
2.7.2 脈衝時序整合 36
2.7.3 同步系統參數選擇 38
2.8 體內外實驗 39
2.8.1 仿體準備 39
2.8.2 體內準備 40
2.8.3 儀器架構 41
2.8.4 資料分析 42
第三章 結果討論 45
3.1 微液滴的性質測定 45
3.2 掃描聲場 47
3.3 溫度應答性微液滴 49
3.3.1 溫度應答性材料選擇 49
3.3.2 溫度應答性材料汽化閾值之測試 52
3.4 細胞通透性探討 54
3.5 超音波溫度影像 57
3.5.1 模擬影像 58
3.5.2 位移計算窗格 58
3.5.3 累積位移和動作修正 61
3.5.4 平滑化和計算熱應變 64
3.5.5 比對結果 66
3.5.6 溫度影像和疊圖顯示 67
3.6 體內外實驗 71
3.6.1 仿體測試 71
3.6.2 體內結果 77
3.6.3 統計分析 80
3.6.3.1 溫度梯度和汽化相關性 80
3.6.3.2 汽化亮度分布對於溫度邊界 82
第四章 結論 85
參考文獻 87

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