臺灣博碩士論文加值系統

近年來非侵入性治療越來越被接受且提倡，相對於侵入性治療來說有著較安全、副作用少、恢復快等優點。現今在治療如深腦刺激治療、腫瘤治療等等還難以達到功效，其原因當中有藥物傳遞不足、治療強度不足或是沒有達到患部位置等等。因此在此論文研究中以非侵入型療法為出發點，設計出結合藥物治療、標靶治療、能量傳遞的多功能載體。為了達到以上的目標，設計出多孔碳矽複合奈米片修飾脂雙層(lipid bilayer)作為傳導和高附載的載藥平台。功能性脂質DOPC (1,2-dioleoyl–sn-glycero-3-phosphocholine)和DPPC 1,2-dipalmitoyl-sn-glycero- 3-phosphocholine)包覆在多孔碳矽複合奈米片上，利用脂雙層的包覆提升細胞的相容性和攝取量。然而一但施加高頻磁場(HFMF)，此載體可透過冷次定律、厄斯特定律等電磁感應來產生感應電流用以刺激釋放藥物。
在此研究的第一部分，脂雙層修飾過的多孔碳矽複合奈米片包覆神經成長因子被應用在加強神經分化上，在高頻磁場刺激下此載體產生感應電流改變表面電位用以刺激釋放神經成長因子，此方法結合了電刺激和藥物治療。在結果的呈現上細胞分化百分比和神經突觸長度都有明顯的增加。在兩天內，神經突觸已成長到約90微米，約為對照組(未施加高頻磁場)的四倍。因此，有電磁感應的脂雙層多孔碳矽複合奈米片可被用來非侵入性的神經再生和組織工程修復上的應用。

研究的第二部分，將上述的載體應用在A549(肺癌細胞)的腫瘤治療上，透過封裝親水藥物Doxorubicin (Dox)和疏水藥物Docetaxel (DTX)兩種藥物來達到協同治療的效果。然而為了提升對腫瘤的針對性，標靶性蛋白藥物Erbitux被修飾在脂雙層表面，此複合性標靶-脂雙層-多孔碳矽複合奈米片被此腫瘤細胞的攝取有顯著的增加。接著施加高頻磁場誘導藥物釋放，在結果顯示確實有毒殺細胞和腫瘤抑制上的效果且在腫瘤以外器官沒有更一步的傷害。此具有標靶性的脂雙層多孔碳矽奈米片可做為一個優秀的藥物傳遞平台，結合了電磁感應控制釋放和搭載藥物可應用於腫瘤治療和其他生物上的應用。

Non-invasive treatment possessing the property of relatively safe, low side effect and rapid recovery has been increasingly advocated. However, many current treatments such as deep brain stimulus or tumor treatment are still difficult to achieve this goal because they suffer from the insufficient delivery of therapeutic molecules and weak energy transfer at the targeted site. In this thesis, therefore, the non-invasive therapy integrated local energy transfer, therapeutic agents, targeting and chemotherapy into a functional carrier was designed and fabricated. To meet these goals, the porous silica/carbon nanosheets (PSC) supported lipid bilayers with biocompatibility that doubles as a conducting and high cargo payload platforms were developed. The functional lipids (1,2-dioleoyl–sn-glycero-3-phosphocholine,DOPC+1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DPPC) coated on PSC (lipo-PSC) through lipid fusion not only improve the cell viability but also enhance the cell uptake. Furthermore, once applying high-frequency magnetic field (HFMF) to PSC, the electromagnetic induction is performed on the electrical conductor, i.e., PSC, through the production of an electromotive force or voltage across, which is also known as Oersted’s law and Lenz's law.
In our first project, the lipo-PSC encapsulating nerve growth factor (NGF) was developed to enhance neural-like cell (PC12) differentiation. During HFMF stimulus, the lipo-PSC as electroactive NGF-releasing electrodes that stimulate the differentiation of PC12 cells through the combination of electrically stimulated cellular differentiation and electrically controlled NGF release. Once electrical treatment is applied, NGF release and electrically enhanced cellular differentiation lead to an obvious increase both in the percentage of cells with neurites and in the neurite length. In the result, the neurite length of cells can reach nearly 90 µm within 2 days. The average neurite length is significantly increased (four-fold) compared with untreated group. The electromagnetic activate lipo-PSC may be used as potential protein carriers for neural regeneration and neural prosthetics in tissue engineering applications.
In the second project, by encapsulating both hydrophilic and hydrophobic drugs, Doxorubicin (Dox) and Docetaxel (DTX), cocktail therapy of PSC was achieved synergistic therapeutic effects. Further conjugating targeting protein, Erbitux, on lipo-PSC leads to significantly enhanced cancer cell uptake of nanocarriers. Intracellular drug release triggered by external HFMF has also been achieved to kill cancer cells efficiently. Furthermore, a combination of therapeutic agents (DOX and DTX) delivered by the transcytosis of lipo-PSC into tumors was released through electromagnetic induction and successfully suppressed xenograft tumors in 16 days without distal harm. This sophisticated lipo-PSC is an excellent delivery platform for electromagnetic-responsive, and combined cocktail chemotherapy to facilitate tumor treatment and for use in other biological applications.

中文摘要 i
Abstract iii
致謝 v
Contents vi
LIST OF SCHEMES viii
LIST OF FIGURE ix
Chapter 1 Literature Review and Theory 1
1.1 Nowadays brain stimulation approach 1
1.1.1 Introduction of several brain stimulation therapy 1
1.1.2 Repetitive trans-cranial magnetic stimulation (rTMS) 3
1.1.3 Nanoparticles in brain 4
1.2 Nanoparticles for cancer therapy 6
1.2.1 Nanoparticle size 7
1.2.2 Nanoparticle surface chemistry 8
1.2.3 Graphene oxide & mesoporous on cancer therapy 9
1.2.4 Liposome 11
1.3 Graphene-based nanocomposites for drugs and genes delivery 15
1.4 Carbon-based for magnetic stimulation therapy 17
Chapter 2 Materials and Methods 20
2.1 Material 20
2.2 Apparatus 23
2.3 Method 25
2.3.1 Synthesis of graphene oxide 25
2.3.2 Synthesis of porous Lipids@Silica/Carbon nanosheet 25
2.3.3 Characterization 27
2.3.4 Magnetic thermal heating effect of PSC 28
2.3.5 Drug loading and drug encapsulation efficiency 28
2.3.6 The Bradford method for nerve growth factor (NGF) quantitation 29
2.3.7 In vitro release 29
2.3.8 Cell culture 30
2.3.9 Cell vability assay 30
2.3.10 Cellular uptake of nanopea capsules 31
2.3.11 Targeting ability of the Erbitux-PLSC was quantified by flow cytometry 32
2.3.12 In vitro experiments – PC12 differentiate 32
2.3.13 In vivo experiments 32
Chapter 3 Results and Discussions 34
3.1 Synthesis and characterization of PSC and PLSC 34
3.2 PLSC is used in PC-12 cells differentiation 42
3.2.1 Drug loading capacity and HFMF-triggered drug release of PLSC/NGF 43
3.2.2 Cytotoxicity and cell uptake of PLSC 45
3.2.3 Neuronal changes of PC-12 cells cultured on NGF-loaded PLSC following magnetic stimulation 48
3.2.4 In vivo study- biocompatibility test in brain 51
3.3 Targeting PLSC is used in anticancer therapy 53
3.3.1 Property of Er-PLSC 54
3.3.2 Drug loading capacity and HFMF-triggered drug release of DOX and DTX 57
3.3.3 In vitro magnetic chemotherapy 59
3.3.4 In vivo study 60
Chapter 4 Conclusions 67
Reference 68

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