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研究生:丁倩妤
研究生(外文):Ting, Chien-Yu
論文名稱:以聚焦式超音波驅動包覆化療藥物微氣泡之藥物遞送以及血腦屏障之開啟於大鼠腦瘤模型上研究與治療
論文名稱(外文):Delivery of drug-loaded microbubbles and disruption of blood-brain barrier by focused ultrasound in a xenograft rat glioma model
指導教授:葉秩光
指導教授(外文):Yeh, Chih-Kuang
口試委員:王士豪李夢麟劉浩澧葉秩光
口試日期:2011-6-28
學位類別:碩士
校院名稱:國立清華大學
系所名稱:生醫工程與環境科學系
學門:工程學門
學類:生醫工程學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:113
中文關鍵詞:多形性膠質母細胞瘤聚焦式超音波微氣泡化學治療血腦屏障
外文關鍵詞:glioblastoma multiforme (GBM)focused ultrasound (FUS)microbubble (MB)chemotherapyblood-brain barrier (BBB)
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多形性膠質母細胞瘤為常見之惡性腦瘤,目前臨床上常用的傳統化學治療對腫瘤的控制效果並不佳,主要來自於兩個限制因素:一為腦組織本身所具備的特殊保護構造-血腦屏障;二為化療藥物毒殺細胞的藥物毒性。使用傳統化療藥物投遞方式欲在腦瘤局部累積足夠的治療劑量,勢必須施予大劑量藥物治療,但同時會造成周遭腦組織或身體其他器官暴露於高劑量藥物中而引發極大副作用。近年來研究專注於提升血腦屏障的通透性,並證實以聚焦式超音波配合微氣泡確實可以非侵入式的將血腦屏障打開。另一方面文獻亦提出各式各樣的藥物載體,目的是包覆藥物並於體內運輸至目標區域,減少對整體的藥物暴露,另外配合對環境產生應答或是其他外界驅動方式,於局部大量釋放出藥物,提升治療的功效。
  本研究的目的是以自製微氣泡利用疏水作用力以及靜電吸引力包覆脂溶性的化療舊藥亞硝氮芥(BCNU)於微氣泡脂質殼層的疏水端,作為新型的藥物載體(BCNU-MB),配合聚焦式超音波探頭的驅動,局部開啟血腦屏障,同時將包覆藥物微氣泡擊破,大量釋放出BCNU達到局部治療的功效。
  研究工作首先是備置藥物載體,並且對BCNU-MB做完整的特性量測。以1-MHz 聚焦式超音波,配合最佳化的參數(0.5 MPa, duty cycle = 5 %, 照射2 min)驅動BCNU-MB的藥物釋放,於Sprague–Dawley大鼠C-6腦瘤模型上進行腫瘤治療,期望在對腦組織產生最少傷害的前提下釋放出最多的藥物。接著於正常大鼠(無腦瘤植入)上測試血腦屏障開啟的可行性,同時以高效液相層析儀配合UV偵檢器定量本研究提出之藥物釋放系統於腦組織中的藥物遞送量,並評估對正常組織的藥物毒性。最後在腫瘤細胞植入後第4天以及第5天,靜脈注射0.5 ml的BCNU-MB後施打聚焦式超音波,進行腫瘤治療,配合MRI T2-weighted影像追蹤治療效果。
結果顯示使用BCNU-MB在聚焦式超音波的協同作用下能夠提升血腦屏障通透性,並且在腦組織藥物定量分析中證實此新型藥物釋放系統比起傳統化療藥物遞送方式,確實可以在超音波照射的腦組織部位提升局部藥物的遞送量;此外,由肝臟藥物萃取實驗中反映出此藥物釋放系統可以減少5倍的肝臟藥物沉積量,顯示此系統具有降低對其他正常組織產生副作用的能力。最後在對腫瘤模型進行治療的部分,藉由MRI影像持續追蹤腫瘤的大小,結果發現此種藥物遞送方法不但可以抑制腫瘤的生長,甚至可以很顯著的使腫瘤體積縮小,達到驚人的腦瘤治療效果。
未來工作包括在包覆藥物微氣泡上修飾專一性標誌配位體,達到更精確的腫瘤標靶治療,將化療藥物更準確的遞送至病灶部位;抑或可以結合其他造影方式的對比劑例如SPIO,進一步將包覆藥物微氣泡提升成同時具備多功能的微氣泡。

Glioblastoma multiforme (GBM) is the most common and highly malignant primary brain tumor. Traditional chemotherapy for treating GBM has limitations such as systemic cytotoxic effects and poor blood-brain barrier (BBB) penetration. When sufficient amounts of chemotherapeutic agents were delivered to the tumor locations, severe systemic cytotoxic effects would be induced, and thus some studies recently focused on enhancing the permeability of BBB by using focused ultrasound (FUS) with microbubbles (MBs) to non-invasively and locally disrupt BBB. Moreover, several drug carriers and drug controlled release methods have been proposed as promising strategies to increase local drug concentrations meanwhile reducing systemic side effects.
The aim of this study is to develope a drug-loaded MB formulation (BCNU-MB) with a high loading capacity of 1,3-bis(2-chloroethyl)-1- nitrosourea (BCNU) drug, which was complexed to the lipid shell by both hydrophobic and electrostatic interactions. Note that the BCNU-MBs with FUS contained specific acoustic properties for delivering drug and locally disrupting BBB simultaneously.
BCNU-MBs were fabricated via the thin-film hydration method. The BCNU drug encapsulation efficiency was 68.01 ± 4.35 % estimated by an UV-visible spectrometer. Cultured C6 glioma cells implanted in Sprague-Dawley rats were established as tumor model. A 1-MHz FUS with 0.7 MPa pressure, 5% duty factor, and 2 min sonication were used to minimize the intracerebral hemorrhage while maximizing the drug delivery. On day 4 and 5 after the implantation of tumor cells, 0.5 ml BCNU-MBs were delivered intravenously, following the synergistic effect of FUS. BCNU accumulation in the brain and liver were analyzed by high performance liquid chromatography (HPLC) coupled with an UV detector. Tumor volumes were monitored by a series of MR T2-weighted images to follow outcomes of the treatment.
Results showed that BBB disruption could be achieved by BCNU-MB with FUS. The HPLC data showed that BCNU-MB delivery system indeed locally release more drugs at FUS-treated hemisphere brains than traditional intravenous chemotherapy drug delivery way. Besides, the BCNU-MB method performed 5-fold less deposition of BCNU in the liver compared to that in traditional chemotherapy, and the MRI images also revealed the significant changes in tumor growth between the two methods.
In the study, delivery of drug-loaded MBs and disruption of BBB by FUS in a xenograft rat glioma model can be achieved at the same time. Future works include modifying specific ligands and SPIO particles on BCNU-MBs surface for targeting therapy and as multimodality contrast agents, respectively.


第一章 緒論 1
1.1 腦瘤 1
1.1.1 多形性膠質母細胞瘤 2
1.1.2 腦瘤治療 2
1.1.3 腦瘤治療瓶頸 3
1.2傳統化療 3
1.2.1 亞硝氮芥(BCNU) 4
1.2.2 藥物載體 5
1.3 血腦屏障 7
1.3.1 增加血腦屏障通透性方法 9
1.3.2 聚焦式超音波 10
1.3.2.1 超音波與生物物質作用之相互效應 11
1.3.2.1.1 機械效應 11
1.3.2.1.2 熱效應 11
1.3.2.1.3 穴蝕效應 11
1.3.2.2 微氣泡 13
1.3.2.3 聚焦式超音波與微氣泡的協同作用 14
1.4 包覆藥物微氣泡 17
1.5 研究動機與目的 19
第二章 實驗材料與方法 20
2.1 概論 20
2.2 包覆藥物微氣泡(BCNU-MB)之製備方法 20
2.2.1 造影用微氣泡之製備 22
2.2.2 BCNU-MB之物理特性量測 22
2.2.2.1 光學定性分析 22
2.2.2.2 粒徑分析 22
2.2.2.3 聲學穩定性 23
2.2.3 BCNU-MB之藥物包覆量定量 23
2.2.4藥物由BCNU-MB中滲漏率量測 24
2.3 動物實驗架構 24
2.3.1 高頻超音波影像系統 26
2.3.2 聚焦式超音波 27
2.3.2.1 聚焦式超音波探頭校正 28
2.3.2.2 聚焦式超音波輸出 30
2.3.3 實驗動物 31
2.3.3.1 BCNU-MB於活體內之存活時間 32
2.4 仿體實驗 33
2.4.1 仿體製做 34
2.4.2 仿體實驗架構 34
2.4.3 仿體實驗釋藥定量 36
2.5 活體實驗治療流程 37
2.5.1 實驗組( (BCNU-MB)+FUS)治療流程 38
2.5.2 陽性控制組治療流程 39
2.5.3腦內藥量定量 40
2.5.4 體內藥物毒性評估 40
2.5.5 組織切片與染色 41
2.5.5.1 H&E染色 41
2.6 腦瘤治療 42
2.6.1 細胞培養 42
2.6.2 腦瘤動物模型 43
2.6.3 治療流程 44
2.6.4 控制組 45
2.6.5治療效果追蹤 45
2.7 數據統計 46
第三章 實驗結果與討論 47
3.1 BCNU穩定性測試 47
3.2 BCNU-MB製備及其性質量測 49
3.2.1 BCNU-MB粒徑分布 50
3.2.2 BCNU-MB物理穩定性 53
3.2.3 BCNU-MB聲學穩定性 54
3.2.4 BCNU-MB包藥量及包藥效率之量測 55
3.2.5 藥物由BCNU-MB中滲漏率量測 59
3.2.6 BCNU-MB於活體內之存活時間 61
3.3 BCNU-MB擊破釋藥之參數評估與選定 63
3.3.1 聲學方法 64
3.3.2 以HPLC直接定量釋出藥量 66
3.4 活體上以BCNU-MB增加血腦屏障通透性之測試 69
3.5 活體上BCNU-MB釋藥量之量測 70
3.5.1 改變聚焦式超音波聲壓 70
3.5.2 改變聚焦式超音波脈衝重複頻率 74
3.5.3 改變聚焦式超音波照射時間 77
3.6 活體上控制組釋藥量之量測 80
3.7 活體上藥物毒性之評估 83
3.8 腦瘤模型治療 86
3.8.1 聚焦式超音波穿頭骨測試 86
3.8.2 利用MRI評估治療效果 87
第四章 結論與未來展望 90
4.1 結論 90
4.2 未來展望 91
4.2.1腦瘤標靶治療 91
4.2.1.1 包覆藥物標靶微氣泡(VEGFR2-BCNU-MB)之製備 94
4.2.1.2 標靶微氣泡之物理特性及包藥量量測 96
4.2.1.3 標靶微氣泡之標誌配位體標定效率量測 97
4.2.1.4 離體細胞標定實驗 99
4.2.2多功能藥物載體 100
4.2.3晚期腫瘤治療 101
4.2.4結合10-MHz超音波與BCNU-MB之治療 101
4.2.4.1 配合10-MHz聚焦式超音波活體藥物定量 102
參考文獻 104


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