腫瘤會出現缺氧是因為其不正常的細胞生長和血管給給不足而導致供氧不足，這樣的缺氧環境直接導致了化療抗藥性的產生，也間接導致了血管新生及蛋白質組/基因組的變化。因此本研究的目的是透過帶氧微氣泡來恢復缺氧環境及提升化療藥物的吸收效率，進而改善化療的治療效果。在體外實驗測試中，帶氧微氣泡在高能量聚焦式超音波 (High-intensity focused ultrasound, HIFU) 的作用下會破裂而提升環境的氧分壓。為了證明超音波搭配帶氧微氣泡在體外模型中改善化療的治療效果，本研究建立了套缺氧的細胞模型。本研究以Image-iT作為判斷缺氧程度的指示劑，在經過4個小時的培養後，細胞出現抗藥性。體外實驗根據降低缺氧程度及細胞活力的相關性來調整OMB的最佳劑量，在這個劑量下，本研究證明了超音波搭配帶氧微氣泡的組別降低了70%的缺氧程度並增加20%的細胞通透性。若是搭配阿黴素 (Dox) 化療藥物一同使用時，超音波搭配帶氧微氣泡的組別更能增加14±5%的阿黴素藥物攝取量。在細胞活力的表現上，相較於只有使用阿黴素藥物的組別高達88±5%，超音波搭配帶氧微氣泡的組別細胞活力降低至45±10%，足見其發展潛力。

Hypoxia develops in solid tumors because of insufficient oxygen delivery caused by exponential cellular growth and poor vascular supply. Chemotherapeutic resistance occurs in hypoxic region as a direct result of a shortage of oxygen in the tumor, as well as indirectly a response to angiogenesis and changes of proteome/genome. In this study, we propose a hypothesis of promoting chemotherapy by using oxygen microbubbles (OMB) to recover hypoxic condition and enhance drug uptake. Under the effect of high intensity focused ultrasound (HIFU), OMB are disrupted and directly boost the oxygen pressure in vitro. To illustrate the performance of OMB+US (oxygen microbubbles and high intensity focused ultrasound) in modulating chemotherapy outcomes in vitro, a hypoxic TRAMP cell model was created. The hypoxic degree was indicated by hypoxic reagent Image-iT, the drug resistance occurred after 4 hours hypoxic incubation. To cope with the in vitro created hypoxia, an optimal dose of OMB was determined depending on the correlation of hypoxic level reduction and cell viability. With this dose, OMB+US was proved to decay approximately 70% hypoxic degree, increase about 20% cell permeability. In combination with Doxorubicin (Dox), Dox+OMB+US enhances Dox uptake 14±5%, results in decrease cell viability down to 45±10%, while the cell viability is 88±5% in Dox only and 72±6% in Dox+CMB+US in hypoxic condition.

CONTENTS

ABSTRACT I
摘要 II
ACKNOWLEDGMENT III
CONTENTS IV
LIST OF FIGURES VI
LIST OF TABLES VII
ABBREVIATIONS VIII
CHAPTER 1. INTRODUCTION 1
1.1. Tumor hypoxia 1
1.2. Relation of Hypoxia and chemotherapy resistance 2
1.3. Overcoming drug resistance 5
1.4. Ultrasound with microbubbles 7
1.5. Reoxygenation by OMB cavitation 9
1.6. The aim of this study 11
CHAPTER 2. MATERIALS AND METHODS 13
2.1. Preparing microbubbles 13
2.1.1. Manufacture Oxygen microbubbles 13
2.1.2. Microbubble’s characteristics 14
2.2. OMB improve chemotherapy in hypoxic condition 17
2.2.1. Cell line 17
2.2.2. Creating and testing the Hypoxic conditions 18
2.2.3. US parameters examination on cells and Optimize OMB dose 20
2.2.4. Doxorubicin toxicity in normal condition and hypoxic condition 22
2.2.5. Cell uptake Dox and chemotherapy sensitivity via cell viability 23
2.3. Statistical Analysis 26
CHAPTER 3. RESULTS 27
3.1. MBs characteristics 27
3.1.1. Concentration and size distribution of MBs 27
3.1.2. The stability of MBs 28
3.1.3. Released oxygen pressure in vitro measurement 29
3.2. OMB with chemotherapy effect on cell viability 31
3.2.1. US parameters examination on cells 31
3.2.2. Creating and testing the Hypoxic conditions 33
3.2.3. Drug resistance in hypoxic condition 34
3.2.4. OMB+US improve hypoxic condition: optimize OMB dose 35
3.2.5. OMB+US enhances Cell permeability 36
3.2.6. Cell uptake Dox and chemotherapy modulating by OMB+US co-treatment 38
CHAPTER 4. DISCUSSION 41
4.1. Discussion 41
4.2. Future works and application 42
CHAPTER 5. CONCLUSION 44
REFERENCE 45

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