腫瘤現為人類第二大死因之疾病，臨床上常用的治療方式為手術治療結合化學治療，但具有侵入式傷害與系統性細胞毒性等缺點。近年來，藉由超音波啟動聲敏劑(sonosensitizer)生成活性氧物質的聲動力治療(sonodynamic therapy)被認為是極具潛力之新型腫瘤治療模式，可達到非侵入式、細胞層級精準度的毒殺腫瘤細胞成效。但現有文獻所使用之聲敏劑需要相當高的超音波能量才能產生足夠毒殺腫瘤細胞之活性氧物質；將聲敏劑鍵結至微氣泡雖可降低聲動力治療所需的超音波能量，但聲敏劑與微氣泡間的鍵結材料卻可能引發宿主的免疫反應。此外，上述兩種方式僅會產生羥基自由基、單線態氧兩種不同形式之活性氧物質，然而此兩種存在時間極短，作用距離極短之活性氧物質，腫瘤治療成效因而受到限制。碳量子點因具有聲敏性以及光催化特性，因此.被認為是相當有潛力的聲敏劑，但當前研究表明驅動碳量子點生成活性氧物質所需要之超音波能量極高。為解決目前聲動力治療面臨之困境，本研究將開發新式聲敏劑微氣泡。本研究利用兩親性碳量子點自組裝形成微氣泡作為聲敏劑，一方面微氣泡特性可以降低啟動碳量子點聲動力效應之超音波能量閾值，另一方面通過兩親性碳量子點自組裝形成微氣泡之方式可以避免鍵結導致的免疫反應。通過這一方式可以同時達到安全且高效之聲動力效應。除此之外，本研究所使用之碳量子點可以在超音波啟動下生成多種活性氧物質，這進一步增強了超音波介導的聲動力治療。本研究希望藉由碳量子點微氣泡達成多種活性氧物質共同介導的聲動力治療可以在生物安全之超音波刺激下高效誘導腫瘤凋亡。
實驗共分為三大部分：(1)碳量子點微氣泡之聲學表徵測試，以評估碳量子點是否可作為微氣泡之殼層、具有超音波響應特性、可產生活性氧物質；(2)細胞實驗，驗證碳量子點微氣泡與超音波產生之活性氧物質是否可毒殺攝護腺腫瘤細胞，及細胞死亡機制是否與活性氧物質相關；(3)動物實驗，驗證碳量子點微氣泡與超音波是否可在活體實體腫瘤內產生活性氧物質、促進腫瘤細胞死亡，以及治療後碳量子點之生物分佈。實驗結果顯示在超音波啟動下，碳量子點微氣泡相較傳統方式僅需0.33倍之超音波能量即可產生活性氧物質。與一般磷脂質殼層組裝之微氣泡相比，可產生1.9倍之活性氧物質，包含羥基自由基、單線態氧、過氧化氫。細胞實驗顯示碳量子點微氣泡與超音波產生之活性氧物質可導致細胞膜的過氧化，進而誘導細胞凋亡，可毒殺42.9%之細胞。動物實驗結果證實碳量子點微氣泡與超音波可使腫瘤細胞之活性氧物質增加，促進腫瘤細胞凋亡。未來工作包含開發功能化修飾之碳量子點微氣泡與調控微氣泡內包覆之治療氣體，以進一步提升癌症治療成效與應用於標靶治療等多種腫瘤治療需求情境。

Tumors are now the second leading cause of death in humans and are commonly treated clinically by surgery combined with chemotherapy, but have the disadvantages of being invasive and systemically cytotoxic. In recent years, sonodynamic therapy, in which sonosensitizers are activated by ultrasound to generate reactive oxygen species, has been recognised as a promising new modality for the treatment of tumours, achieving non-invasive, and cellular-level precision in the killing of tumour cells. However, the sonosensitizers used in the current literature require high ultrasound energy to generate enough reactive oxygen species to kill tumour cells; while bonding the sonosensitizers to microbubbles reduces the ultrasound energy required for sonodynamic therapy, the bonding material between the sonodynamic agents and microbubbles may trigger an immune response in the host. In addition, these two approaches could generate only two different forms of reactive oxygen species, hydroxyl radicals and singlet oxygen, which are limited in their effectiveness in treating tumors due to their extremely short duration and distance of action. Carbon quantum dots （C-Dots）have acoustic and photocatalytic properties and are therefore. However, current studies have shown that the ultrasound energy required to drive carbon quantum dots to generate reactive oxygen species is extremely high. In order to solve the current dilemma of acoustic therapy, this study will develop a new type of acoustic sensitiser microbubble. This study uses self-assembled microbubbles of amphiphilic C-Dots as the sonosensitiser. In this way, a safe and efficient sonodynamic effect can be achieved at the same time. In addition, the C-Dots used in this study can generate a variety of reactive oxygen species when activated by ultrasound, which further enhances sonodynamic therapy. It is hoped that by using C-Dots MBs to achieve a combination of reactive oxygen species, sonodynamic therapy can be highly effective in inducing apoptosis under biosafe ultrasound stimulation.
The experiments are divided into three main parts: (1) characterization of C-Dots MBs to assess whether C-Dots can be used as the shell layer of microbubbles with ultrasound response and can produce reactive oxygen species; (2) cellular experiments to verify whether C-Dots MBs and reactive oxygen species produced by ultrasound can poison regenerative tumor cells and whether the cell death mechanism is related to reactive oxygen species; (3) animal experiments to verify whether C-Dots MBs and reactive oxygen species produced by ultrasound can kill regenerative tumor cells. The experimental results show that under ultrasound activation, the C-Dots MBs require only 33% more ultrasound energy than conventional methods to produce reactive oxygen species. Compared to lipid shell assembled microbubbles, 1.9 times more reactive oxygen species, including hydroxyl radicals, singlet oxygen and hydrogen peroxide, can be produced. Cellular experiments have shown that reactive oxygen species generated by C-Dots MBs combined with ultrasound caused peroxidation of cell membranes and induce apoptosis, which can kill 42.9% of cells. Animal experiments have demonstrated that C-Dots MBs combined with ultrasound can increase reactive oxygen species in tumour cells and promote apoptosis. Future work includes the development of functionally modified C-Dots MBs and the modulation of the therapeutic gases encapsulated within the microbubbles to further enhance the efficacy of cancer therapy and its application to a variety of oncology therapeutic needs such as targeted therapy.

第一章 緒論 1
1.1 腫瘤 1
1.2動態療法 2
1.2.1 活性氧物質 2
1.2.2 化學動力學治療 3
1.2.3 光動力治療 4
1.2.4 聲動力治療 4
1.3聲動力療法機制討論 5
1.3.1聲空化效應 6
1.3.2聲致發光 6
1.3.3熱解 7
1.3.4 ROS效應： 8
1.4 聲敏劑 10
1.5 碳量子點之開發應用 12
1.6研究目的與內容 13
第二章 實驗材料與方法 14
概論 14
2.1 C-Dots性質表徵 14
2.1.1材料表徵分析方法： 15
2.1.2螢光分析： 15
2.1.3臨界膠束濃度與主要相轉變溫度量測 16
2.1.4 超音波參數安全性： 16
2.1.5聲動力效應量測 17
2.1.6聲動力效應造成細胞損傷評估 18
2.2 C-Dots MBs之製備 20
2.2.1粒徑量測 22
2.2.2形態測量 23
2.2.3 光學成像分析 23
2.2.4穩定度量測 24
2.2.5超音波擊破量測 25
2.3 活性氧之量測 25
2.3.1聲動力效應量測 25
2.3.2 活性氧物種之電子自旋共振譜儀量測 26
2.3.3 ROS特異性探針 26
2.3.4 H2O2之量測 27
2.4 C-Dots MBs 之體外細胞毒性測定 28
2.4.1細胞培養與繼代 28
2.4.2細胞毒性量測 28
2.4.3 評估超音波結合 C-Dots MBs 介導的聲動力效應之細胞損傷效果： 29
2.4.4 評估聲動力治療細胞過程中ROS生成情況： 30
2.4.5 探討聲動力效應造成細胞死亡之機制 31
2.5 C-Dots MBs介導的聲動力治療之活體測試 32
2.5.1皮下腫瘤模型 32
2.5.2 紅細胞溶血測試 32
2.5.3 活體超音波影像分析 33
2.5.4 活體腫瘤治療架構以及流程 34
2.5.5腫瘤組織切片染色 35
2.5.6 腫瘤內C-Dots的分佈與累積 36
第三章 結果與討論 37
3.1碳量子點之特性分析 37
3.1.1材料表徵： 37
3.1.2 超音波參數安全性 40
3.1.3 活性氧之體外量測 41
3.1.4 超音波傷害測試： 42
3.1.5聲動力效應之細胞損傷量測 43
3.2微氣泡之物化分析 44
3.2.1配方最佳化 44
3.2.2微氣泡之形態測量 46
3.2.3 光學成像分析 48
3.2.4微氣泡之體外穩定性量測 49
3.2.5微氣泡擊破量測 51
3.3 微氣泡之活性氧量測： 52
3.3.1 微氣泡之活性氧效率量測 52
3.3.2 ESR量測活性氧種類： 53
3.3.3 特定類型活性氧探針量測： 56
3.4 細胞實驗 59
3.4.1 藥物毒性測試： 59
3.4.2 聲動力治療腫瘤細胞死亡率之實驗 61
3.4.3 細胞膜過氧化 63
3.4.4 細胞生成ROS之量測 64
3.4.5 細胞凋亡 66
3.5 活體腫瘤測試 67
3.5.1 微氣泡溶血實驗 68
3.5.2 活體影像 69
3.5.2瘤內分佈與累積 70
3.5.3組織切片之HE染色分析 72
3.5.5組織切片之細胞凋亡染色分析 75
第四章 結論與未來工作 77
參考文獻 80

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