開發應答性奈米複合療法傳輸系統於癌症治療之應用

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研究生：	盧廷瑜 Lu, Ting-Yu
論文名稱：	開發應答性奈米複合療法傳輸系統於癌症治療之應用 Development of functionized nanoparticle delivery of multiple modality therapies for cancer treatments
指導教授：	邱信程 Chiu, Hsin-Cheng
口試委員:	王先知駱俊良許源宏
學位類別：	碩士 Master
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2018
畢業學年度：	106
語文別：	中文
論文頁數：	181
中文關鍵詞：	藥物傳輸系統、酸鹼應答、氧化應答
外文關鍵詞：	Drug delivery system, pH responsive, ROS responsive
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本研究目的為開發具增加腫瘤組織累積能力具有雙標靶之固態脂質奈米粒子 (Solid lipid nanoparticles, SLNs)，可於腫瘤微環境中轉換奈米載體表面電性與藉由磁導引來增加藥物於腫瘤內累積；同時結合化療藥物Doxorubicin(DOX)及奈米氧化鐵粒子(SPIONs)的熱療效果能有效抑制腫瘤生長。
首先利用二次乳化法製備搭載DOX/SPIONs的固態脂質奈米粒子，並於過程中嵌插具腫瘤微環境應答特性之雙性分子(Histamine derivative dodecanol, HDD) 於奈米粒子表面能賦予SLNs 腫瘤環境辨別能力，並強化載藥SLNs 滯留於腫瘤組織間之效果此外，藉由控制HDD 之導入數量可調控SLNs 之等電點，使載體能於pH 值6~7 環境中進行電性變化。當表面電性轉為正電時，會因正負電相吸引而易於吸附在癌症細胞膜上增強載體進入細胞之效率，強化化療效果。包覆油酸氧化鐵之SLNs 具有磁導引及磁生熱之特性，藉由高頻交流磁場的施予產生磁熱效應可達到熱殺癌細胞的功效。
此載藥奈米微粒直徑約114 nm， DOX 及 SPIONs 含量分別為10.94 %與1.6 %。帶有 HDD 之奈米載體於表面電性量測上成功證實其於微酸環境中之電性轉化能力，於細胞吞噬實驗中亦證實具有電性轉換能力之奈米載體相較於控制組於微酸環境中被癌細胞攝取數量有顯著提升。此外藉由磁導引可使奈米載體大量累積於腫瘤區，大幅提升癌細胞內藥物濃度。
於動物腫瘤抑制實驗結果亦可證實經給予腫瘤雙標靶奈米載體確實能有效累積於腫瘤處，並給予化學/熱雙重治療能有效抑制腫瘤生長。綜觀以上成果，本研究開發出具雙標靶特性之固態脂質奈米傳輸系統並同時具有化學/磁熱雙重療法並成功驗證其抑制腫瘤之功效。
本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射本研究旨在開發能藉由近紅外光雷射 (NIR)照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠照射光敏藥物靛氰綠 (Indocyanine green, ICG)後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基後大量產生活性氧自由基 (reactive oxygen species, ROS)進行應答以釋放化療 /輻射增敏藥物之智慧型奈米載體系統，同時產生局部升溫以進行光熱治療，並搭配放射有效抑制腫瘤生長與復發。
本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子本研究成功開發出對活性氧物質具應答能力之高分子 poly(thiodiethylene malonate) (PSDEM)與其三團聯高分子與其三團聯高分子 PEG-PSDEM-PEG，並利用此高分子材料製備出搭載化療 /輻射增敏藥物 Vorinostat (suberoylanilide hydroxamic acid, SAHA)
與光敏藥物靛氰綠 (Indocyanine green, ICG)。此高分子透過。此高分子透過 thiodiethylene glycol 內硫醚 (sulfides)在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（在高氧化力環境中會被為亞碸（ sulfoxide）的特性，賦）的特性，賦）的特性，賦予其疏水 /親水性間轉換能力。一旦構築奈米粒子之高分被氧化變成特性時，即會導致奈米粒子瓦解並釋放出所搭載之藥物。此徑大小約為性時，即會導致奈米粒子瓦解並釋放出所搭載之藥物。此徑大小約為性時，即會導致奈米粒子瓦解並釋放出所搭載之藥物。此徑大小約為性時，即會導致奈米粒子瓦解並釋放出所搭載之藥物。此徑大小約為性時，即會導致奈米粒子瓦解並釋放出所搭載之藥物。此徑大小約為 126 nm，並具有良好藥物搭載效率 (ICG : 9.1 wt%, SAHA : 4.5 wt% )。藉由近紅外。藉由近紅外光雷射照產生 ROS之氧化應答能力評估顯示，經過後的奈米粒子形態會產生瓦解現象，且藥物累積釋放量經氧化後亦會明顯提升。細胞實驗中證藉由產生瓦解現象，且藥物累積釋放量經氧化後亦會明顯提升。細胞實驗中證藉由產生瓦解現象，且藥物累積釋放量經氧化後亦會明顯提升。細胞實驗中證藉由產生瓦解現象，且藥物累積釋放量經氧化後亦會明顯提升。細胞實驗中證藉由產生瓦解現象，且藥物累積釋放量經氧化後亦會明顯提升。細胞實驗中證藉由 NIR照射所產生的 ROS破壞而釋放出藥物與產生光熱治療，並搭配射能導致 4T1癌細胞 DNA嚴重損傷而使細胞凋亡。在腫瘤抑制實驗中，當給予具應嚴重損傷而使細胞凋亡。在腫瘤抑制實驗中，當給予具應嚴重損傷而使細胞凋亡。在腫瘤抑制實驗中，當給予具應嚴重損傷而使細胞凋亡。在腫瘤抑制實驗中，當給予具應嚴重損傷而使細胞凋亡。在腫瘤抑制實驗中，當給予具應答性奈米粒子并照射 NIR與搭配放射治療後確實有最佳抑制效果，證明載體可與搭配放射治療後確實有最佳抑制效果，證明載體可受 NIR照射觸發輻增敏藥物釋放強化治療效果與產生光熱，搭配上照射觸發輻增敏藥物釋放強化治療效果與產生光熱，搭配上放射治療可成功抑制腫瘤生長並減少復發情形。綜觀上述果，本研究開之搭載治療可成功抑制腫瘤生長並減少復發情形。綜觀上述果，本研究開之搭載治療可成功抑制腫瘤生長並減少復發情形。綜觀上述果，本研究開之搭載治療可成功抑制腫瘤生長並減少復發情形。綜觀上述果，本研究開之搭載治療可成功抑制腫瘤生長並減少復發情形。綜觀上述果，本研究開之搭載 ICG/SAHA之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與之氧化應答奈米粒子，具有提升現今放射治療功效利用光熱與射

In this study, a versatile chemodrug/magnetite delivery system based on solid lipid nanoparticles (SLNs) has been developed to enhance cancer therapeutic efficacy via surface charge conversion and magnetic guidance. To endow the SLNs with pH-inducible surface charge conversion, a pH-responsive lipid derivative (HDD) was first synthesized via the covalent conjugation between histamine and 1-dodecanal. In addition, the cationic anticancer drug, doxorubicin (DOX), was complexed with the anionic lipids through electrostatic interaction to facilitate the encapsulation of DOX within the hydrophobic core of SLNs.
The drug/magnetite-loaded SLNs (DSLNs) modified with HDD on the surface (DSLNs-H) are 115 nm in diameter. In acidic tumor microenviroment (pH 6.6 ~ 6.0), the surface charge conversion (-7 to +5 mv) of the DSLNs-H was observed due to the extensive protonation of histamine groups. The DOX can be released by the disruption of nanocarriers in lysosomes by lipolytic enzymes.
In vitro and In vivo data demonstrates that the cellular uptake of DSLNs-H by cancer cells was obviously enhanced through electrostatic association between positively charged HDD and negatively charged cell membrane in culture medium at acidic environment under magnetic guidance. Owing to the pronounced cellular uptake, the DSLNs-H show the superior chemotherapy and hyperthermia effect against cancer cells under alternative magnetic field treatment, which also demonstrates great potential of thermos/chemo combination therapy in cancer treatment.
This work aims to develop a novel nanoparticle delivery system capable of liberating therapeutic paylods in response to the dramatic increase of the external reactive oxygen species (ROS) level upon Near-infrared and radiation therapy for improving the overall anti-cancer efficacy. Herein, the ROS-responsive poly(thiodiethylene malonate) (PSDEM) have been successfully prepared by stepwise polymerization approach and employed as the major materials in developing the novel nanotherapeutics. Through the ROS-mediated oxidation reaction, the non polar sulfide groups on the main chains of polyesters are chemically converted to the polar sulfoxide group, thus resulting in the hydrophobic-hydrophilic transition of the ROS-sensitive polymers. This inevitably leads to the structural disruption of nanotherapeutics comprising mainly the ROS-sensitive polyester upon the irradiation and thus activates drug liberation for chemotherapy in combination with the NIR and radiation against breast cancer. The nanotherapeutics with a particle size of ca 126 nm in diameter demonstrate an excellent radiosensitizer comfinement of HDAC inhibitor, SAHA. In vitro cytotoxic analysis data demonstrates that the viability of 4T1 cells co-incubated with NIR pretreated nanoparticles was reduced proportionally with the increase of the SAHA dose, while that of cancer cells incubated with the nanoparticles in the absence of ROS activation remained relatively high, indicating the strong dependence of drug release from the smart nanoparticles on the production of ROS. Importantly, in vivo tumor growth inhibition study strongly illustrates that the incorporation of photothermal therapy and radiation therapy with the smart nanoparticles exhibit potent antitumor efficacy . Based on the above results, this study provides a promising strategy for the development of ROS responsive drug delivery nanotherapeutics for tumor therapy.

Abstract ......................................................... 12
摘要 ............................................................. 13
致謝 ............................................................. 14
一、 研究動機 ................................................. 15
二、 文獻回顧 ................................................. 17
1 惡性腫瘤 ...................................................................................................................... 17
2 腫瘤微環境 .................................................................................................................. 17
2.1 Enhanced Permeation and Retention effect (EPR effect) ................................. 19
2.2 腫瘤微環境 pH 值 .............................................................................................. 20
3 奈米載藥現況 .............................................................................................................. 21
3.1 奈米藥物載體傳遞系統 ....................................................................................... 21
3.2 固態脂質奈米微粒 ............................................................................................... 23
4 D-alpha-tocopheryl poly(ethylene glycol) succinate (TPGS)簡介 ........................... 24
5 Histamine與Imidazole contain polymer 於藥物傳遞系統之應用 ........................ 25
6 化療藥物阿黴素(Doxorubicin) .................................................................................. 26
7 奈米氧化鐵粒子藥物傳遞應用 .................................................................................. 27
7.1 磁性奈米氧化鐵粒子特性 ................................................................................... 28
7.2 奈米氧化鐵粒子的磁熱效應 ............................................................................... 29
三、實驗方法 ..................................................... 30
1 材料合成與鑑定 .......................................................................................................... 30
1.1 Histamine derivative dodecanol (HDD)分子製備方法 ...................................... 30
1.2 奈米氧化鐵(SPIONs)製備及鑑定 ....................................................................... 30
2 奈米微粒製備與性質探討 .......................................................................................... 31
2.1 搭載DOX之具酸鹼應答固態脂質奈米微粒製備 ............................................ 31
2.2固態脂質奈米微粒的粒徑分布 ............................................................................ 32
2.3固態脂質奈米微粒的藥物裝載量 ........................................................................ 34
2.4 固態脂質奈米微粒藥物釋放分析 ....................................................................... 34
3
3 體外細胞實驗 .............................................................................................................. 35
3.1細胞來源 ................................................................................................................ 35
3.2 細胞繼代 ............................................................................................................... 35
3.3細胞計數 ................................................................................................................ 36
3.4 模擬腫瘤微酸環境之細胞培養液pH值調整 .................................................... 36
3.5細胞對DOX及奈米微粒吞噬情形 ..................................................................... 37
3.6 共軛焦雷射掃描螢光顯微鏡(CLSM)觀察細胞對奈米微粒吞噬 ..................... 38
3.7細胞毒性分析 ........................................................................................................ 39
4動物實驗 ....................................................................................................................... 40
4.1動物來源 ................................................................................................................ 40
4.2 腫瘤模型建立 ....................................................................................................... 40
4.3 腫瘤內載體累積時間分布 ................................................................................... 41
4.4 動物體內奈米載體累積分布 ............................................................................... 41
4.5腫瘤抑制評估 ........................................................................................................ 41
4.6 動物犧牲與組織包埋 ........................................................................................... 42
4.7 組織切片 ............................................................................................................... 42 3.4.8 組織切片Hematoxylin and eosin (H&E)染色 .................................................. 43 3.4.9 組織切片免疫螢光染色 ....................................................................................... 43
5 數據統計 ...................................................................................................................... 44
四、 結果與討論 .................................................. 45
1 材料鑑定與分析 .......................................................................................................... 45
1.1 Histamine derivative dodecanol (HDD)組成分析與鑑定 .................................. 45
1.2 奈米氧化鐵粒子分析 ........................................................................................... 46
2 奈米微粒特性分析 ...................................................................................................... 47
2.1 固態脂質奈米微粒特性分析 ............................................................................... 47
2.2 固態脂質奈米微粒之表面電荷轉換能力分析 ................................................... 49
2.3固態脂質奈米微粒穩定度分析 ............................................................................ 50
2.4 固態脂質奈米微粒體外藥物釋放評估 ............................................................... 51
4
2.5 固態脂質奈米微粒之升溫效率評估 ................................................................... 52
3 細胞實驗 ...................................................................................................................... 53
3.1 微酸環境與外加磁場下細胞吞噬評估 ............................................................... 53
3.2 固態脂質奈米微粒之細胞毒性 ........................................................................... 55
4 小鼠動物實驗 .............................................................................................................. 60
4.1 固態脂質奈米微粒於動物體內累積分布 ........................................................... 60
4.2 腫瘤抑制評估 ....................................................................................................... 62
4.3 組織切片觀察 ....................................................................................................... 69
五、 結論 ........................................................ 73
六、 參考文獻 .................................................... 74
Abstract ......................................................... 87
摘要 ............................................................. 88
一、 研究動機 ................................................. 89
二 文獻探討 ...................................................... 91
1 惡性腫瘤 ...................................................................................................................... 91
1.1 乳癌 ....................................................................................................................... 91
1.2 乳癌分期 ............................................................................................................... 92
1.3 乳癌治療現況 ....................................................................................................... 95
2 腫瘤微環境 .................................................................................................................. 96
2.1放療後腫瘤微環境與腫瘤復發機制 .................................................................... 98
3 癌症治療 ...................................................................................................................... 99
3.1放射線治療 ............................................................................................................ 99
3.2放射線增敏劑 ...................................................................................................... 101
3.3 Vorinostat (suberoylanilide hydroxamic acid, SAHA)介紹 ............................ 104
3.4光熱治療(Photothermal therapy, PTT) ............................................................ 105 2.3.5靛氰綠(Indocyanine green, ICG) ...................................................................... 106
4 奈米載藥現況 ............................................................................................................ 106
4.1 奈米藥物載體傳遞系統 ..................................................................................... 106
5
4.2高分子微粒 .......................................................................................................... 108
4.3氧化應答於藥物傳遞系統的應用 ...................................................................... 110
4.4 放射線療法與藥物傳輸系統之應用 ................................................................. 114
三、實驗方法與步驟 .............................................. 116
1 高分子合成與鑑定 .................................................................................................... 116
1.1 PSDEM和PHMA合成 ..................................................................................... 116
1.2 PEG-PSDEM-PEG 和 PEG-PHDEA-PEG合成 ........................................... 117
1.3 高分子氧化應答特性測試 ................................................................................. 118 3.2奈米微粒製備與性質探討 ......................................................................................... 118 3.2.1 奈米微粒置備 ..................................................................................................... 118 3.2.2 奈米微粒之粒徑分布 ......................................................................................... 119
2.3 奈米微粒之藥物裝載量 ..................................................................................... 120
2.4奈米微粒膠體穩定性與冷凍乾燥保存測試 ...................................................... 121
2.5搭載光熱藥物ICG之奈米粒子升溫能力評估 ................................................. 121
2.6 活性氧物質生成測定(ROS treatment) ............................................................ 121
2.7活性氧物質對奈米載體氧化應答能力之評估 .................................................. 122
3.8奈米微粒體外藥物釋放實驗與分析 .................................................................. 123
3 體外細胞實驗 ............................................................................................................ 123
3.1細胞來源 .............................................................................................................. 123
3.2 細胞繼代 ............................................................................................................. 124
3.3細胞計數 .............................................................................................................. 124
3.4細胞對奈米微粒吞噬情形分析 .......................................................................... 125
3.5 共軛焦雷射掃描螢光顯微鏡(CLSM)與流式細胞儀(Flow)觀察細胞內ROS生成情形 ........................................................................................................................... 125
3.6細胞毒性分析 ...................................................................................................... 127
3.7近紅外光雷射作用下之細胞毒性分析 .............................................................. 129
3.8合併治療之細胞毒性 .......................................................................................... 129
3.9 γ-H2AX antibody測量細胞DNA損傷情形 .................................................... 130
3.10 Clonogenic survival assays 探討放射線治療對細胞分裂之影響 ................. 131
6
3.11 Live/Dead Fixable Dead Cell Stain Kits 測量細胞存活率 ........................... 132
4動物實驗 ..................................................................................................................... 132
4.1動物來源 .............................................................................................................. 132
4.2 原位乳癌模型建立 ............................................................................................. 133
4.3 腫瘤內載體累積時間分布 ................................................................................. 134
4.4 動物體內奈米載體累積分布 ............................................................................. 134
4.5 奈米載體於小鼠腫瘤內之升溫能力測試 ......................................................... 134
4.6腫瘤抑制評估 ...................................................................................................... 135
4.7 動物犧牲與組織包埋 ......................................................................................... 136
4.8 組織切片 ............................................................................................................. 136 3.4.9 組織切片Hematoxylin and eosin (H&E)染色 ................................................ 136 3.4.10 組織切片免疫螢光染色 ................................................................................... 137
5 數據統計 .................................................................................................................... 137
四、 結果與討論 ................................................. 138
1 高分子合成與鑑定 .............................................................................................. 138
1.1 Poly(thiodiethylene malonate) (PSDEM)與Poly(hexamethylene adipate) (PHMA) 合成與組成鑑定 .......................................................................................... 138
1.2 PEG-PSDEM-PEG 和 PEG-PHMA-PEG合成與組成鑑定 .................... 139
2高分子氧化應答能力 ................................................................................................. 141
3 奈米粒子特性分析 .................................................................................................... 142
3.1奈米微粒性質分析 .............................................................................................. 142
3.2奈米微粒穩定度分析 .......................................................................................... 144
3.3奈米微粒升溫能力測試 ...................................................................................... 145
3.4奈米微粒氧化應答能力評估 .............................................................................. 146
3.5 奈米微粒體外藥物釋放 ..................................................................................... 148
4 細胞實驗 .................................................................................................................... 149
4.1 奈米微粒於NIR treatment後生物相容性測試 .............................................. 149
4.2 奈米微粒之細胞吞噬評估 ................................................................................. 150
4.3 奈米微粒ROS產生能力測試 ........................................................................... 151
7
4.4 奈米微粒之細胞毒性分析 ................................................................................. 153
4.5 癌細胞DNA損傷程度分析 .............................................................................. 156
4.6 癌細胞之細胞分裂能力評估 ............................................................................. 159
4.7 放射線結合光熱治療/化療之細胞毒性分析 .................................................... 161
5動物實驗 ..................................................................................................................... 163
5.1藥物載體於動物體內累積分布 .......................................................................... 163
5.2 腫瘤區升溫能力測試 ......................................................................................... 165
5.3 經熱治療後腫瘤缺氧區表現評估 ..................................................................... 166
5.4 腫瘤抑制評估 ..................................................................................................... 169
5.5 肺轉移情形評估 ................................................................................................. 174
五、結論 ........................................................ 176
六、 參考資料 ................................................ 177
                                

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