目前臨床上利用奈米藥物輸送系統來提升化療藥物的治療效果與降低副作用，奈米藥物載體可藉由腫瘤血管通透效應達到累積效果以治療腫瘤，然而，載體於腫瘤的穿透能力依然有限，無法直接進入腫瘤深部的位置，使腫瘤局部無法到達藥物有效濃度，而導致深部腫瘤治療效果有限。所以在本研究中，我們結合了標靶 (targeting) 和磁導引 (magnetic guiding) 的特性，製備出「高均一性的多孔洞氧化矽包覆桿狀奈米氧化鐵」平台，攜帶載運大量疏水性藥物-歐洲紫杉醇(Docetaxel, DTX)的「次奈米藥物載體-樹枝狀聚合物 (dendrimer)」，利用外部磁場高週波的刺激操控藥物穿透，驅使次奈米藥物載體進入腫瘤，達到藥物腫瘤穿透及治療目的。並在於載體最外層包覆脂雙層(lipid bilayer)，及修飾「標靶性蛋白藥物爾必得舒 (Erbitux®)」和「腫瘤壞死因子 (Tumor Necrosis Factor)」，以提升細胞的相容性和攝取量，和達到專一性標靶、破壞腫瘤的血管新生和緻密的細胞層，增加藥物的通透效果。此外，載體桿狀的設計，可以減少其在血液的流動中被巨噬細胞吞噬的機會，也有助於載體貼齊血管壁運動、載體上的抗體有效黏附在標靶細胞表面，進而累積至腫瘤位置。
論文第一部分為多孔磁性奈米載體的合成與特性的研究。首先，氯化鐵水解反應過程中，經由控制升溫速率、聚乙烯亞胺 (polyethyleneimine, PEI)的濃度，可得到不同粒徑的四方纖鐵礦 (β-FeOOH)，外層再包覆二氧化矽 (mesoporous silica)，通過還原氣氛中煅燒除去有機組分，產生中孔氧化鐵，具有高比表面積與孔洞體積、獨特的介孔結構、易於表面修飾，與優良的生物相容性等優點，利用比表面積分析儀(surface area and porosimetry analyser, ASAP/BET)分析MSIR的性質，得到表面積和總孔體積分別為523 m2/g 和1.119 cm3/g，透過電子顯微鏡 (SEM, TEM)、X 光繞射分析儀及超導量子干涉儀磁性分析可以得知該奈米粒子具有超順磁性，粒徑長度約160奈米及寬度約70奈米，可被磁場吸引並穩定分布於水相中。此外，多孔磁性奈米棒裝載化療藥物/次級載體的裝載量 (loading capacity, LC) 和包覆率 (encapsulation efficiency, EE) 分別為1.49 %和99.36 %，並且在高週波的刺激之下造成藥物釋放。
論文第二部分在細胞實驗、微流道生成腫瘤微球的平台、以及老鼠皮下腫瘤模式中，以A549 (人類肺癌細胞株) 做為模型，評估載體生物相容性、抑制癌細胞能力、穿透深部腫瘤與動物療效。在細胞實驗結果中可以發現相較於單獨磁場生熱及單獨化學治療的組別，結合標靶性、熱療與免疫化學協同治療的組別對於癌細胞的毒殺能力最佳；在微流道生成腫瘤微球的平台觀察腫瘤屏壁變化，結果顯示給予外部磁場高週波後，會驅使小於5奈米的次級藥物載體穿透至腫瘤微球內部，以增加腫瘤微球攝取藥物載體的量，達到階段性釋放的目的；然而，文獻指出腫瘤壞死因子會增強癌細胞對熱治療敏感程度，所以腫瘤壞死因子結合高週波後，更能使腫瘤微球瓦解，有效毒殺癌細胞；而在老鼠腫瘤模式中，有標靶性蛋白藥物Erbitux與腫瘤壞死因子修飾在脂雙層表面上的奈米載體，能有效累積於腫瘤位置，接著施加高頻磁場誘導攜帶化療藥物的次級載體釋放與穿透至腫瘤深部，同時磁場生熱溫度達攝氏 43 度以上，產生化療與熱療的協同治療效果，有效抑制腫瘤生長達20天以上，且沒有造成遠端器官的傷害。
因此，此多功能藥物標靶載體是一個有潛力的藥物傳輸平台，能有效提升腫瘤累積、藥物腫瘤穿透、有效毒殺癌細胞及抑制腫瘤生長，期許能在腫瘤治療或其他生醫領域有更多方面性的運用。

Nowadays delivery of drug within responsive carriers that with high stability during long circulation in the body and effectively target and accumulate in cancer cells is demanded in personalized medicine. However, the physiological barrier of the tumor restrict drug penetration delivery, and impedes drug carriers to release their therapeutic agents into cancerous cells at the center of tumors. Therefore, engineering particles that can transport therapeutic agents deep into tumors is a key factor for tumor therapy.
In this study, we report a mesoporous silica layer on iron rod that doubles as a magneto-thermal agent and high cargo payload platform, which releases a burst of drug-incorporated second-nanocarriers and intense heat upon high-frequency magnetic field (HFMF). To form this ultrasmall second-nanocarriers (less than 5 nm), docetaxel was loaded in the core of PAMAM dendrimers (DTX/Den), and then encapsulated into mesoporous silica to prolonged drug circulation in vivo and facilitating the penetration into the deep tumor tissue. Subsequent, coating lipid bilayers outside the mesoporous silica iron rods (MSIR) not only capable of concealing drug-incorporated second-nanocarriers but also improve biocompatibility and enhance the cell uptake.
Furthermore, targeting protein Erbitux® (Cetuximab) and tumor necrosis factor α (TNF α) were modified on Lipo-MSIR by Sulfo-SMCC linker (an amine-to-sulfhydryl crosslinker), could significantly enhance the accumulation of MSIR in A549 cells (2D monolayers and 3D spheroids) and successfully deliver drugs into targeted cancer cells. The experiment of in vitro, targeted chemo-thermal therapy by DTX/Den@Er-T-Lipo-MSIR +HFMF 10 min performs 1.4-fold and 1.3-fold higher therapeutic efficacy than single chemotherapy (DTX/Den@Er-T-Lipo-MSIR) and thermal therapy (MSIR +HFMF 10 min), respectively. The results in 3D spheroids show that delivery of dendrimer-FITC to the tumor site is actuated by HFMF, which ruptures the Liop-MSIR as well as releases nanosized dendrimer. This trigger also results in thermal damage to the tumor and increase the drug penetration into the deep tumor tissue far from blood vessels, as well as having good repression in tumor growth of the BALB/c female nude mice model with A549 tumor in 20 days without distal harm.
This sophisticated Lipo-MSIR is an excellent delivery platform for targeted and penetrated delivery of drugs to deep tumor, MF-responsive, and combined chemo-thermotherapy to facilitate tumor treatment and for use in other biological applications.

中文摘要 I
Abstract III
致謝 V
List of Figures IX
List of Schemes XVI
Chapter 1 Literature Review and Theory 1
1.1 Nanoparticles for Drug Delivery Systems 1
1.1.1 The particle size effect 3
1.1.2 The particle shape effect 5
1.1.3 The surface chemistry effect 8
1.2 Porous silica for drug delivery 10
1.3 Combination therapy of porous silica/IO 13
1.4 Nanocomposites for penetration drug delivery 17
1.4.1 Tumor-on-a-chip 19
1.4.2 Tumor necrosis factor  (TNF) 22
1.4.3 Dendrimer 25
Chapter 2 Experimental Section 29
2.1 Materials 29
2.2 Apparatus 32
2.3 Method 34
2.3.1 Synthesis of -FeOOH nanorods 34
2.3.2 Synthesis of mesoporous silica iron rods (MSIR) 35
2.3.3 Synthesis of DTX/Den@ MSIR 36
2.3.4 Synthesis of DTX/Den@Er-T-Lipo-MSIR 37
2.3.5 Characterizations 38
2.3.5 Magnetic Thermal Heating Effect of MSIR 39
2.3.6 Drug Loading Efficiency and Encapsulation Efficiency 40
2.3.7 In Vitro Release 40
2.3.8 Cell culture 41
2.3.9 Cellular Uptake 42
2.3.10 Cell viability assay 43
2.3.11 Targeting ability of the Den@Er-Lipo-MSIR was quantified by flow cytometry 44
2.3.12 Microfluidic device design and fabrication 45
2.3.13 Poly-HEMA coating process. 46
2.3.14 Cell loading for spheroid formation 47
2.3.15 Penetration of the nanoparticles in A549 spheroids 49
2.3.16 In vivo experiments 51
Chapter 3 Results and Discussions 52
3.1 Synthesis and morphology of -FeOOH, silica/-FeOOH, MSIR and Lipo-MSIR 54
3.2 Characterization of -FeOOH, silica/-FeOOH, MSIR and Lipo-MSIR 66
3.3 Thermal effect, drug loading capacity and HFMF-triggered drug release of MSIR 68
3.4 Cytotoxicity and cell uptake of MSIR 71
3.5 Characterization of polyHEMA-coated surface and sphere formation assays 78
3.6 A microfluidic platform for tumor penetration and drug-release testing of multicellular lung cancer spheroids 82
3.7 In vitro chemo-HFMF trigger therapy of MSIR and Er-T-Lipo-MSIR 85
3.8 In vivo animal experiment 86
Chapter 4 Conclusions 99
Reference 100

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