超音波治療以微氣泡為廣泛架構，然而其衰變期短、載藥量低且微米級大小限制了治療應用。本研究利用高孔隙率、高載藥量且可調孔隙大小的多孔性矽材料(MSNPs)，在表面修飾超疏水材料後可穩定的吸附氣泡增加載體內藥物穩定性並可重複激發產生穴蝕效應，搭配併發的活性氧化物種(ROS)及載體內的阿黴素(Dox)來達到加成治療的效果。最終本研究用超疏水架構做細胞及活體測試，藉超音波抗血管治療、聲動力治療及化學治療的加成效應來抑制腫瘤。
本研究使用MCM48多孔矽材料搭配全氟癸基三乙氧基矽烷(PFDTS)後得到超疏水的F48-ext，載入Dox後得F48-ext-dox。15 MHz探頭用以被動式測量納米材料在2 MHz超音波激勵下的穴蝕效應強度，用2,7-二氯螢光素二乙酸酯(DCFH-DA)定量ROS。後以Alamar Blue®應證細胞活性，以攝護腺癌為模型觀察其搭配超音波產生抗血管，ROS產生及抗腫瘤效果。
材料性質上，MCM48與F48-ext粒徑分別為253.1±92.5 nm及289.1±96.2 nm，其接觸角從10.9º上升至159º可確認具超疏水性質，孔隙內Dox的含量為0.5g/g sample。體外實驗發現，超疏水的F48-ext比起MCM48，在慣性穴蝕效應劑量(ICD)及ROS產生量上分別高出3.9±0.03倍及10.9±1.3倍。細胞活性中，穴蝕效應與藥物緩釋分別抑制40±4%與20±3%細胞增長。腫瘤治療上，F48-ext-dox + US灌注破壞了50% 的腫瘤血管，DHE染色顯示增加17倍的ROS產生。F48-ext-dox組別有25.7±9%治療效果。F48-ext-dox +US及F48-ext +US的組别，分別抑制58.2±3.0%及49.2±3.8%的腫瘤生長，並在活體存活度上皆有顯著差異。
本研究透過體外或是體內的實驗皆應證出超疏水材料產生顯著穴蝕效應，且在ROS及阿黴素的搭配下增進了活體治療上的成效。未來將與其他的釋藥架構進行結合，建立可被超音波響應的超疏水主動性釋藥架構。

Microbubbles have been widely used as ultrasound (US) contrast agents. However, their short lifetime, low drug payload and micron-sized restricted their applications. Mesoporous silica nanoparticles (MSNPs) have the properties of high porosity, high payload and tunable pore sizes. Thus, we proposed superhydrophobic MSNPs adsorbing air bubbles to prevent drug leakage from MSNPs and to be served as cavitation nuclei to initiate inertial cavitation (IC) repeatedly and efficiently by US sonication. In this study, anti-vascular therapy and reactive oxygen species (ROS) generated by means of IC (sonodynamic therapy) and chemotherapy were combined to achieve synthetic tumor therapeutics by applying the drug-loaded superhydrophobic MSNPs.
MCM-48 MSNPs were modified with perfluorodecyltriethoxysilane to obtain the F48-ext. F48-ext-dox were accomplished after loading DOX. A 15-MHz transducer was used as a passive cavitation detector to measure inertial cavitation dose (ICD) by MSNPs with HIFU sonications. Then, DCFH-DA assay was used to measure ROS caused by MSNPs under the same setup. Alamar Blue® assay was used to test the cell viability. The subcutaneous prostate tumor xenograft mice were established to evaluate the anti-vascular, ,ROS generation effect, and treatment efficiency.
The sizes of MCM48 and F48-ext were 253.1 ± 92.5 nm and 289.1 ± 96.2 nm, respectively. The contact angles were increased from 10.9° (hydrophilic) to 159º (superhydrophobic) after fluoridation. The amount of 0.5 g Dox can be loaded into 0.5 g F48-ext. The ICD of superhydrophobic F48-ext was 3.9±0.03 times larger than that of hydrophilic MCM48, and the amount of ROS also was increased 10.9±1.3 times accordingly. The cell viability results showed that the IC and Dox release inhibited 40±4 % and 20±3 % cell viability, respectively. Finally, ultrasound contrast-perfused imaging showed that F48-ext-dox combined with US decreased 50% of the tumor blood perfusion, and DHE staining showed that 17 times more ROS were produced than that of control group. The F48-ext and F48-ext-dox with US stimulus inhibited 58.2±3.0 % and 49.2±3.8 % tumor volume growth with respect to control group, respectively, while F48-ext-dox without ultrasound irradiation inhibited only 25.7±9 % tumor growth.
In this study, the occurrence of IC of superhydrophobic NPs both in vitro and vivo were observed, and the combination of anti-vascular, sonodynamic therapy by ROS, and chemotherapy obviously promoted the tumor treatment efficacy. Future work included to establish a superhydrophobic active drug-release system to improve the efficiency of chemotherapy.

第一章 緒論 1
1.1癌症(惡性腫瘤) 1
1.1.1 腫瘤的化學治療 2
1.1.2 抗腫瘤血管治療 3
1.1.3 外源驅動治療方式 3
1.2超音波效應及治療研究 5
1.2.1 熱效應 5
1.2.2 機械效應 6
1.2.3 化學效應 7
1.2.4 超音波的協同治療及安全性 8
1.3超音波響應材料與應用 9
1.3.1 微氣泡 9
1.3.2 相變液滴 10
1.3.3 聲敏劑 11
1.3.4 疏水材料 12
1.4多孔矽材料 16
1.4.1 多孔性矽材料之種類 17
1.4.2 多孔性矽材料之應用 18
1.5研究動機與目的 19
第二章 材料與方法 21
2.1概論 21
2.2多孔矽材料之合成與修飾 21
2.2.1 MCM48材料之合成 21
2.2.2 多孔矽材料之表面改質與藥物負載 22
2.2.3 材料表徵分析方法 23
2.3穴蝕效應與活性氧化物種量測分析 25
2.3.1 慣性穴蝕效應偵測架構及操作方法 25
2.3.2 數值分析 27
2.3.3 活性氧化物種測量與分析 28
2.4光聲系統觀測架構 29
2.5載藥與釋藥之測定方 30
2.5.1 載藥率測定方式 30
2.5.2 體外釋藥架構及操作 31
2.6細胞測試存活度測試 32
2.6.1 細胞測試架構及步驟 32
2.6.2 細胞活性分析方法 34
2.7活體測試及切片結果 34
2.7.1 窗型觀測腔架構及步驟 35
2.7.2 窗型觀測腔分析方法 37
2.7.3 活體內藥物衰變偵測架構及步驟 37
2.7.4 活體腫瘤治療架構及步驟 38
2.7.5 活體腫瘤治療結果分析與切片染色 40
2.7.6 活體腫瘤追蹤與活體存活度測試 41
2.7.7 活體內藥物分佈量測 41
第三章 實驗結果與討論 42
3.1多孔矽材料合成結果 42
3.1.1 外觀與粒徑分布結果 42
3.1.2 材料表徵 45
3.1.3 載藥效率結果 51
3.2體外穴蝕效應結果 53
3.3體外活性氧化物種測試 58
3.4體外穴蝕效應之高速觀測 60
3.5釋藥結果測試 60
3.6細胞存活測試 62
3.7活體測試 66
3.7.1 窗型觀測腔結果 66
3.7.2 體內穴蝕效應影像分析 71
3.7.3 活體腫瘤治療結果 72
3.7.4 腫瘤治療及存活度結果 81
3.7.5 活體內藥物分佈測試 85
第四章 結論與未來工作 87
4.1結論 87
4.2未來工作 88
4.2.1 釋藥成效之探討與優化 88
4.2.2 環糊精優化之詳細機制探討 89
4.2.3 主動釋藥架構之建構 89
參考文獻 90

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