硼中子捕獲治療(Boron neutron capture therapy, BNCT)已被廣泛研究在治療神經膠質瘤(Glioblastoma miltiforme, GBM)上，治療方式是靜脈注射含硼藥物後，等待藥物自然被腦腫瘤吸收至足夠治療之劑量後，再照射中子射束驅動含硼藥物釋放放射性元素，殺死腫瘤細胞。目前臨床上所使用的含硼藥物，如BSH (Sodium Borocaptate)，由於血腦障蔽(Blood-brain barrier, BBB)及血腫瘤障蔽(Blood-tumor barrier, BTB)的阻礙，僅能透過增強滲透滯留效應 (Enhanced permeability and retention effect, EPR effect)被動進入腫瘤中，需等待相當長的循環時間(~6小時)以達到治療所需的劑量，如此將提升其他健康組織額外吸收含硼藥物的風險；此外，此被動式藥物遞送方式將會因為個體差異所導致硼藥物在腦瘤累積量的不足、硼藥物的分布不均勻及達不到足夠的腫瘤正常組織比(Tumor/normal tissue ration, T/N ratio)進行治療。為改善上述問題，本研究提出利用含硼藥物負載之磷脂質微氣泡 (boron drug-loaded microbubbles, B-MBs)配合超音波激發之藥物遞送方法，利用超音波誘發微氣泡產生穴蝕效應，增加血腦障蔽通透性並同時將微氣泡負載的藥物遞送入腫瘤中，企圖在短時間內提升腫瘤組織比和腫瘤血液比(Tumor/Blood ratio, T/B ratio)。
本研究首先將含硼藥物(PEG-b-PMBSH)以靜電相吸的方式吸附在正電微氣泡(positive microbubble, pMBs)上，其濃度為5.5 ± 2.4 ppm，並且對其基本物理及聲學性質進行測量。後續在C57BL/6小鼠腦瘤模型上評估超音波與微氣泡對腦部之傷害，再以伊凡藍染色(Evans blue, EB)進行開啟血腦障蔽之可行性測試與最佳超音波參數評估，最後再以感應藕荷電漿質譜儀(Inductively couple plasma mass spectrometry, ICP-MS)和雷射剝蝕感應藕荷電漿質譜儀(Lasar ablation inductively couple plasma mass spectrometry, LA-ICP-MS)定量分析含硼藥物遞送後腫瘤、血液和對側腦組織之硼元素濃度和分布。
結果顯示B-MBs配合參數0.5 MPa、duty cycle 0.5 %、照射時間1分鐘的超音波的作用下，可在不傷害腦組織的情況下達到最佳的BTB通透性；腫瘤內部的硼藥物濃度在超音波照射結束後即達到最高的T/N ratio (4.4 ± 1.4)，而含硼藥物與微氣泡分開注射的組別則須等待60分鐘才可達到接近劑量(0.55 ppm)；此外，將藥物包覆之微氣泡中可大幅減少血液中的硼濃度，提供較高的T/B ratio (1.4 ± 0.6 v.s 0.08 ± 0.01)。
未來工作包括延長超音波照射的時間及提升微氣泡上的藥物負載量以增加腫瘤中的藥物累積量，達到治療劑量後將實際照射中子應用在硼中子捕獲治療上觀察其療效。

Boron neutron capture therapy (BNCT) is the mainstay radiotherapy for treating glioblastoma multiforme (GBM). However, the penetration of current clinical drug (i.e. BSH) for BNCT into brain tumor is limited by the cerebral vesicular protective structures, blood-brain barrier (BBB) and blood-tumor barrier (BTB). In order to achieve sufficient tumor/normal tissue (T/N) ratio of BSH for BNCT treatment, it is necessary to wait BSH natural diffusion into tumor for several hours (~6 h) via ERP effect, probably inducing greatly different deposition within tumor. This study proposed the boron drug (PEG-b-PMBSH) loaded cationic microbubbles (B-MBs). With focused ultrasound (FUS) sonication, B-MBs could simultaneously achieved BTB-opening and boron drug delivery into tumor tissue, improving the T/N ratio in 30 min. B-MBs (5.5 ± 2.4 ppm) were prepared by loading PEG-b-PMBSH (300 ± 9 nm) onto the lipid-shell of cationic MBs (1 ± 0.2 µm) by electrostatic force. FUS (frequency = 1 MHz, energy = 0.3-0.7 MPa, duty cycle = 0.5%, sonication = 1 min) was applied following B-MB IV injection. The permeability of BTB was estimated by Evans blue staining. The 10B deposition within tumor tissue were quantified and mapped by inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), respectively. B-MBs with FUS (0.5 MPa) provided sufficient BBB-opening area for enhanced Evans blue within tumor lesions without occurrence of brain damage. Compared with the group of MBs with PEG-b-PMBSH separately administration, the T/N ratio was immediately increase into the tumor by B-MBs (4.4 ± 1.4 vs 1.3 ± 0.001 ) within 30 min. In addition, the tumor/blood tissue (T/B ratio) were largely increase following the encapsulation of PEG-b-PMBSH into MBs (1.4 ± 0.6 vs 0.08 ± 0.01). The LA-ICP-MS also confirmed that the treatment of B-MBs with FUS not only enhanced the permeability of BBB, but also largely delivered 10B into the tumor.
The T/N ratio could be improved 3 fold by the proposed drug delivery platform within 30 min. The Boron concentration within blood could be decreased 20 fold by the encapsulation of MBs. Future work including: (1) increasing the amount of drug accumulation (elongating the FUS irradiation time and improving the amount of drug encapsulation); (2) combing with BNCT for brain tumor treatment with low side-effects.

第一章 緒論 1
1.1 神經膠質母細胞瘤 1
1.1.1 腦瘤治療與現今治療瓶頸 1
1.1.2 硼中子捕獲治療 (Boron neutron capture therapy, BNCT) 2
1.1.3 含硼藥物 3
1.2 血腦障蔽 (BLOOD BRAIN BARRIER, BBB) 4
1.2.1 增加血腦障蔽通透性的方法 5
1.3 聚焦式超音波 6
1.3.1 超音波對比劑微氣泡 7
1.3.2 超音波和生物組織之相互效應 7
1.3.2.1 熱效應 7
1.3.2.2 機械效應 8
1.3.2.3 穴蝕效應 8
1.3.2.4 微氣泡與超音波之協同作用 9
1.4 載藥微氣泡 10
1.5 BNCT藥物遞送方法 12
1.6 研究動機與目的 13
第二章 材料與方法 15
2.1 概論 15
2.2 包覆硼藥物微氣泡製備(B-MBS) 15
2.2.1 造影用微氣泡製作 16
2.2.2 光學定性分析 16
2.2.3 濃度、粒徑、表面電位量測分析 16
2.2.4 B-MBs 載藥量定量 17
2.2.5 仿體製備 17
2.2.6 聲學穩定度分析 17
2.3 體外聲學實驗 18
2.3.1 慣性穴蝕效應量測 19
2.3.2 擊破閥值量測 21
2.4 細胞實驗 23
2.4.1 細胞培養繼代 23
2.4.2 細胞存活率實驗 23
2.4.3 微氣泡配合超音波細胞傷害之測試 24
2.5 動物實驗架構 25
2.5.1 聚焦式超音波探頭校正與聲場掃描 26
2.5.2 實驗動物 28
2.5.3 體內存活率 28
2.5.4 腦瘤腫瘤模型 29
2.5.5 治療參數及開啟血腦障蔽之評估 30
2.5.5.1 組織切片與染色 31
2.5.5.2 H & E染色 31
2.5.5.3 傷害評估 32
2.5.5.4 血腦障蔽通透性量測 33
2.5.5.5 開啟血腫瘤障蔽之時效性 33
2.5.6 雷射剝蝕電漿耦合質譜儀-硼分布圖譜 34
2.5.7 藥物遞送評估 35
2.5.7.1 血液樣品及組織樣品消化與硼濃度量測 35
2.5.8 微氣泡代謝路徑分布評估 36
2.5.8.1 螢光微氣泡製備 36
2.5.8.2 非侵入式分子影像系統造影 36
2.6 統計分析 37
第三章 結果與討論 38
3.1 概述 38
3.2 B-MBS性質量測 38
3.2.1 B-MBs載藥量之量測 38
3.2.2 B-MBs光學性質 39
3.2.3 B-MBs粒徑分布 40
3.2.4 B-MBs聲學穩定性 41
3.3 聲學性質量測 42
3.3.1 慣性穴蝕效應量測 42
3.3.2 擊破閥值量測 43
3.4 細胞實驗 44
3.4.1 細胞毒性測試 44
3.4.2 超音波搭配B-MBs瞬間傷害評估 45
3.5 GL261腦腫瘤生長曲線 46
3.6 體內穩定性 47
3.7 超音波校正與聲場掃描 48
3.8 超音波治療參數評估 50
3.8.1 以B-MBs開啟血腫瘤障蔽之傷害評估 50
3.8.2 血腫瘤障蔽通透性量測 52
3.8.3 開啟血腫瘤障蔽之時效性 53
3.9 藥物動力學 54
3.10 雷射剝蝕電漿耦合質譜儀-硼分布圖譜 58
3.11 微氣泡之生物分佈評估 59
第四章 結論與未來展望 61
4.1 結論 61
4.2 未來工作 62
4.2.1 拉長超音波照射時間及多次注射 62
4.2.2 製程改善 63
4.2.3 微氣泡生物分佈與代謝途徑 64
第5章 參考文獻 66

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