聚焦式超音波藉由其產生的熱效應與非熱效應能增進藥物傳輸的能力。此論文分為兩個部分：(1)利用聚焦式超音波搭配微氣泡傳送神經保護物質用於治療缺血後再灌流所造成傷害之腦部組織；(2)利用短時間聚焦式超音波熱治療增加化療藥物進入腦腫瘤區域。紅血球生成素是一種用於治療大腦缺血後再灌流傷害的神經保護物質，然而其通過血腦屏障的能力有限。聚焦式超音波搭配微氣泡震盪能有效開啟血腦屏障，增加血管之通透性。本研究利用聚焦式超音波搭配微氣泡用於延長紅血球生成素的神經保護治療期效。實驗設計為雄性大白鼠施以50分鐘局部腦缺血，於腦部血流再灌流後五小時施以以下幾種治療：I/R (Ischemia/reperfusion)、I/R+MBs (Microbubbles) /FUS (Focused ultrasound)、I/R+hEPO、I/R+hEPO (human recombinant erythropoietin)+MBs/FUS。動物於24小時後進行急性期之評估；長期療效評估包含步態分析及前肢使用頻率差別。由定量分析結果得知，聚焦式超音波搭配微氣泡可增加紅血球生成素累積於受損害之腦組織。急性期分析結果顯示I/R+hEPO+MBs/FUS組別其神經動作表現與損傷區域皆有明顯改善。更重要的是長期行為評估亦顯示I/R+hEPO+MBs/FUS的確對於其行動步態左右前肢使用協調有顯著的改善。此研究證實就算超過單獨使用紅血球生成素的治療效期，聚焦式超音波搭配微氣泡仍然可以傳送具有神經保護作用之物質進入受損腦區，並達到治療之效果。血腦屏障與血腫瘤屏障會抑制化療藥物在腦部之吸收與累積，而熱治療可增進化療藥物進入腫瘤區域。此研究探討短時間聚焦式超音波熱治療是否可增強pegylated liposomal doxorubicin (PLD)對於乳癌腦部轉移之化療效用。本實驗使用小鼠乳癌細胞4T1種植於小鼠腦部。利用活體影像系統(IVIS)追蹤腫瘤生長。治療時間點設定為細胞植入後六天，給予PLD (5 mg/kg)並施以10分鐘聚焦式超音波熱治療。由定量結果得知，短時間聚焦式超音波熱治療可增加PLD累積於腦瘤區域。化療藥物PLD加上短時間聚焦式超音波熱治療確實能有效抑制腫瘤之生長，而免疫染色及細胞凋亡測試亦可證實其效用。此研究證實應用短時間聚焦式超音波熱治療能促進化療藥物有效進入腦腫瘤組織並達到治療之效果。

Focused ultrasound is a promising modality to enhance drug delivery via its thermal and non-thermal effects. The study included two parts: part (1) using MBs/FUS to deliver a neuroprotective agent into ischemia/reperfusion (I/R)-induced injured brain; and part (2) using short-time FUS hyperthermia to enhance a chemotherapeutic agent into the brain tumor.
Erythropoietin (EPO) is a neuroprotective agent against cerebral I/R-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.
The blood–brain/tumor barrier (BBB/BTB) inhibits the uptake and accumulation of chemotherapeutic drugs. Hyperthermia can enhance the delivery of chemotherapeutic agent into tumors. In this study, we investigated the effects of short-time FUS hyperthermia on the delivery and therapeutic efficacy of pegylated liposomal doxorubicin (PLD) for brain metastasis of breast cancer. Murine breast cancer 4T1-luc2 cells expressing firefly luciferase were injected into female BALB/c mice striatum tissues and used as a brain metastasis model. The mice were intravenously injected with PLD (5 mg/kg) with/without 10 min transcranial FUS hyperthermia on Day-6 after tumor implantation. The amounts of doxorubicin accumulated in the normal brain tissues and tumor tissues with/without FUS hyperthermia were measured using fluorometry. The tumor growth for the control, hyperthermia, PLD, and PLD+Hyperthermia groups was measured using an IVIS system every other day from day 3 to day 11. Cell apoptosis and tumor characteristics were assessed using immunohistochemistry. Short-time FUS hyperthermia was able to significantly enhance the PLD delivery into brain tumors. The tumor growth was effectively inhibited by a single treatment of PLD+Hyperthermia, compared with both PLD alone and short-time FUS hyperthermia alone. Immunohistochemical examination further demonstrated the therapeutic efficacy of PLD plus short-time FUS hyperthermia for brain metastasis of breast cancer. The application of short-time FUS hyperthermia after nanodrug injection may be an effective approach to enhance nanodrug delivery and improve the treatment of metastatic cancers.

口試委員會審定書 I
中文摘要 III
Abstract V
Contents VIII
List of Figures XI
Chapter 1 Introduction 1
1-1 Ultrasound 1
1-1-1 General Properties of Ultrasound 1
1-1-2 Bio-effects of Ultrasound 1
1-1-3 Hyperthermia (HT) 2
1-1-4 Microbubbles (MBs) 3
1-2 Ultrasound Drug Delivery 4
1-2-1 Blood-Brain Barrier Opening by Focused Ultrasound with Microbubbles 4
1-2-2 Ultrasound Hyperthermia 4
1-3 Blood-Brain / Blood-Tumor Barriers 5
1-3-1 Blood-Brain Barrier 5
1-3-2 Blood-Tumor Barrier 6
1-4 Purposes 6
1-5 Overview 7
Chapter 2 Targeted Delivery of Erythropoietin by Transcranial Focused Ultrasound for Neuroprotection against Ischemia/reperfusion-induced Neuronal Injury: A Long-term and Short-term Study 10
2-1 Introduction 10
2-2 Materials and Methods 12
2-2-1 Three Vessels Occlusion (3VO) Model 13
2-2-2Experimental Grouping 13
2-2-3 Focused Ultrasound (FUS) Sonication 14
2-2-4 Quantification of hEPO Entering the Brain Tissue 15
2-2-5 Infarct Volume and Residual Brain Volume Evaluation 16
2-2-6 Behavioral Evaluation 16
2-2-7 Immunohistochemistry 17
2-2-8 Statistical Analysis 19
2-3 Results 19
2-3-1 Amount of hEPO Delivered into Brain and CSF by MBs/FUS 19
2-3-2 Reduction of Infarct Volume by hEPO+MBs/FUS 20
2-3-3 Improvement of Neurological Behavior 20
2-3-4 Neuroprotective Effect of hEPO+MBs/FUS 21
2-3-5 Increase of Residual Brain Volume by hEPO+MBs/FUS in Chronic Phase 21
2-3-6 Improvement of Asymmetric Limb-Use and Recovery of Gait Deficits by hEPO+MBs/FUS in Chronic Phase 22
2-4 Discussion 23
Chapter 3 Short-time Focused Ultrasound Hyperthermia Enhances Liposomal Doxorubicin Delivery and Anti-tumor Efficacy for Brain Metastasis of Breast Cancer 34
3-1 Introduction 34
3-2 Materials and Methods 36
3-2-1 Preparations of Cells and the Intracranial Tumor Model 36
3-2-2 Focused Ultrasound (FUS) System and Short-time FUS Hyperthermia 37
3-2-3 Experimental Grouping 39
3-2-4 Quantification of PLD Entering the Brain Tissue 39
3-2-5 Measurement of Tumor Growth by In vivo Imaging 40
3-2-6 Histology and Immunohistochemistry 41
3-2-7 TUNEL Assay 42
3-2-8 Statistical Analysis 43
3-3 Results 43
3-3-1 Enhancement of PLD Delivery to Normal Brain and Tumor Tissues by FUS Hyperthermia 43
3-3-2 Short-time FUS Hyperthermia Enhances the Cytotoxic Action of PLD in Tumor 44
3-3-3 Inhibition of Proliferation in Tumors by FUS Hyperthermia plus PLD 45
3-3-4 Enhancement of TUNEL Staining by Short-time FUS Hyperthermia plus PLD 46
3-4 Discussion 46
Chapter 4 Conclusions 60
Chapter 5 Future Work 63
References 65

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