臺灣博碩士論文加值系統

臨床上，能夠診斷治療兼具的奈米藥物載體，不但可以大幅減少療程，也可以增加療效，因此成為奈米藥物領域上熱門研究主題。此外，若診療載體結合超音波與磁場導引，可局部累積在病灶位置同時作控制藥物快速釋放，將會為奈米生醫領域帶來革命性的發展。在此論文中，我們設計並製作出三種智慧型診療載體。首先，我們製作出對溫度敏感的藥物載體，此載體不需要透過交聯劑來穩定，而是透過微乳化的技術，我們將超順磁性奈米氧化鐵與藥物包覆進高分子的載體球中。其中此高分子為普朗尼克(Pluronic F127)與聚乙烯醇(PVA)的混和，透過控制高分子的比例的搭配，我們可以製作出不同程度的溫度敏感載體，進而可以具有不同形式的藥物釋放行為。在診斷能力方面，此溫度敏感載體為優良的磁振造影對比劑。在癲癇大鼠(Long Evans)體內實驗中，溫度敏感載體在接受體外磁場刺激之後，可以快速釋放抗癲癇藥物，達到抑制癲癇的效果。在第二部分，我們將溫度敏感的藥物載體，設計成中空的結構(奈米微泡)使之可以反饋超音波的刺激，同時再包覆全氟化碳氣體(perfluoropentane)，可以大幅增加超音波對比訊號，成為一個優良的超音波對比劑。此外，奈米微泡是透過簡單的一步合成來製作，而且超順磁性氧化鐵扮演一個穩定殼層結構的角色，不僅增加超音波背向散射訊號，更讓奈米微泡成為一個優良的磁振造影對比劑，因此，此奈米微泡成為具有雙重顯影的診療利器。我們進一步包覆腦瘤藥物，在動物的異位腫瘤實驗中，利用外加磁場引導奈米微泡到腫瘤位置聚集，接著開啟聚焦超音波釋放奈米微泡內的腦瘤藥物，這樣不僅增加了局部的治療效果，還利用聚焦超音波開啟局度的細胞通透性，達成絕佳的腫瘤治療效率。但是在治療腦部疾病方面，奈米微泡若無法克服血腦阻障層(brain blood barrier)，便無法傳輸藥物到病灶位置進行治療，因此在第三部分，我們設計一個較為硬性無機的矽基奈米微泡，此新型的矽基奈米微泡同樣包覆著全氟化物，在殼層中也有超順磁性氧化鐵嵌合在其中。透過控制合成時三種不同矽烷類濃度，我們可以作出不同類型的殼層，進而研究開啟血腦阻障層需要的殼層特性與機制。在此部分中，磁導引扮演一個很重要的角色，他不僅可以導引矽基奈米微泡大量累積到病灶部位，還可以增加病灶部位的超音波與磁振造影的對比度。在開啟聚焦超音波來刺激矽基奈米微泡後，大量的矽基奈米微泡爆炸所產生的微剪切氣流，可使局部的細胞通透性增加，達成開啟血腦阻障層的效果。在此研究顯示，矽基奈米微泡時為跨時代的診療利器，針對腦部疾病治療具有前瞻性，同時可以達到多重顯影的功能。

Magneto-guidable-theranosis nanocarriers can serve as a simple one pot therapy agent through the combination of magnetic guidance (MG) and Focus ultrasound (FUS), and it may be a revolutionary step in the nanomedical platforms recently. In this thesis, three kinds of quickly stimuli-responsive magneto-carriers would be designed and fabricated. In the first part, self-assembling, crosslinker-free, highly thermosensitive nanocarriers (TSNCs) were synthesized by the incorporation of iron oxide nanoparticles and hydrophobic drug molecules into a thermosensitive matrix composed of PEO-PPO-PEO (F127) triblock-copolymer and polyvinyl alcohol (PVA) using a microemulsion process. Depending on the PVA/F127 ratios, the TSNCs can act as a remotely triggered drug delivery platform with a tunable burst drug release profiles through the structure deformation by an external magnetic field. Furthermore, the TSNCs also presented ultrasensitive magnetic resonance imaging (MRI), as demonstrated by a relatively high r2/r1 ratio (430). A preliminary in vivo study using the Long-Evans rat model has demonstrated a significant quickly reduction in the spike-wave discharge after the anti-epilepsy drug, Ethosuximide (ETX), was burst released from the TSNCs. Using a well-controlled burst release, TSNCs may provide significant advantages as highly temperature-responsive nanocarriers for the treatment of acute diseases. In the second part, thermosensitive nanocarrier has been designed to hollow structure in order to multifunctionalize. This bubble-like nanocarrier (nanobubble) encapsulated with perfluoropentane and stabilized with superparamagnetic iron oxide nanoparticles has been synthesized through a single-step emulsion process. Nanobubbles can serve as theranostic platforms for ultrasound (US) and magnetic resonance (MR) imaging, and combined MG and high-intensity focused ultrasound (FUS)-triggered drug release for tumor therapy. Both US and MR imaging contrast can be optimized by varying the shell thickness and SPIO-embedded concentration. The US contrast can be enhanced from a mean grey value of 62 to 115, and the MR r2 value can be enhanced from 164 to 208 (s-1mM-1 Fe) by increasing the SPIO concentration from 14.1 to 28.2 mg/mL, respectively. In vivo investigations of SPIO-embedded nanobubbles in excised tumors under external MG revealed that the US and MR signals change quantitatively compared to the same site without MG. This combined strategy enables the nanobubbles to enhance both passive targeting (increasing the permeability by FUS) and physical MT of chemotherapeutic drugs to tumors. The integration of functionalities makes this system to achieve simultaneous in vivo tumor imaging and efficacious cancer therapy, but the challenge has been difficult and significant to overcome brain blood barrier (BBB) in the brain disease treatment. Finally, we proposed a novel adjustable shell of monodispersed MNBs which comprises of three kinds of silane and superparamagnetic iron oxide (SPIO) to adjust shell porosity (octyltriethoxysilane), hardness (tetraethyl orthosilicate), hydrophility (3-Aminopropyl triethoxysilane), and magnetization to further investigate the mechanism of BBB opening efficiency. Most importantly, MG also acts as a key factor that can not only increase ultrasound (US) contrast but also induce BBB opening in vivo. The novel MNBs can intrinsically serve as diagnostic ultrasound and magnetic resonance imaging contrast agents, and after optimizing shell hardness and embedded SPIO content, can concurrently serve as a catalyst for BBB opening. Therefore, integrating these multifunctional properties makes MNBs a powerful noninvasive platform to achieve BBB opening and brain diagnosing without any cumbersome process of brain slices.

摘要 II
Abstrast IV
致謝 VII
Contents VIII
Figure Captions XI
Chapter 1 Introduction 1
Chapter 2 Literature Review and Theory 6
2.1 Introduction of Multimodal Diagnosis and Therapy 6
2.2 Magneto-Nanoparticles for Theranostic Applications 9
2.2.1 Synthesis of Superparamagnetic Iron Oxide Nanoparticles 10
2.2.2 SPIOs for high performance imaging 13
2.2.3 Surface Modification of SPIOs 15
2.2.4 SPIOs for drug delivery as drug carriers 17
2.2.5 SPIOs for hyperthermia treatment 19
2.3 Ultrasono-nanoparticles for theranostic applications 21
2.3.1 Ultrasound contrast agents 22
2.3.2 UBs for controlled drug/gene release 27
2.3.3 UBs for high intensity focus ultrasound (HIFU) surgery 29
Chapter 3 Experimental Procedures 32
3.1 Experimental overviews 32
3.2 Synthesis of SPIOs 33
3.3 Characterization 33
3.4 High intensity focus ultrasound system 35
3.5 In vivo high frequency magnetic field triggered TSNC-2 drug release 35
3.6 In vivo US-MR tumor imaging and HIFU-triggered nanobubbles drug release 37
3.7 In-vivo nanobubbles Biodistribution with/without magnetic guidance 39
3.8 In vivo MNB-facilitated HIFU-BBB Opening with Magnetic Guidance 39
Chapter 4 Self-assembling PVA-F127 thermosensitive nanocarriers with highly sensitive magnetically-triggered drug release for epilepsy therapy in vivo 41
4.1 Introduction 41
4.2 Synthesis and drug release of Ethosuximide-loaded TSNC-2 45
4.3 Characterization of TSNCs 48
4.4 Drug release behavior of TSNCs 51
4.5 Magnetic characterization and contrast agent relaxivity 54
4.6 Comparison of ETX@TSNC-2 vs. ETX@PVA in the treatment of epilepsy in vivo 57
4.7 Summary 59
Chapter 5 61
SPIO nanoparticle-stabilized PAA-F127 thermosensitive nanobubbles with MR/US dual-modality imaging and HIFU-triggered drug release for magnetically guided in-vivo tumor therapy 61
5.1 Introduction 61
5.2 Preparation of BCNU-loaded nanobubbles 64
5.3 Interpolymer Hydrogen-Bonding Complexes 66
5.4 Characterization of the nanobubble synthetic process 69
5.5 Morphology of the nanobubbles 71
5.6 Ultrasonic contrast as a function of polymer ratio and SPIO concentration 74
5.7 MR contrast as a function of SPIO concentration 76
5.8 In vitro evaluation of drug release with exposure to HIFU 78
5.9 In-vivo Biodistribution with and without MT 80
5.10 Therapeutic efficacy 81
5.11 Summary 84
Chapter 6 85
Magnetic-guided monodispersed SPIO-stabilized silica nanobubbles coorperate with focused ultrasound in blood-brain barrier disruption 85
6.1 Introduction 85
6.2 Preparation of MNBs 90
6.3 Characterization of the MNBs in synthetic process 92
6.4 MNB shell morphology changing with the concentration of OTES 94
6.5 Morphological changes of MNBs following pulsed-mode FUS exposure 96
6.6 Comparison of the enhancement of US contrast between MNB without/with MG 99
6.7 MNB-facilitated FUS-induced BBB opening with magnetic guidance in vivo 102
6.8 The safety and evaluation of FUS- induced BBB disruption by the size-dependence MNB 106
6.9 Summary 108
Chapter 7 Conclusion 109
7.1 Self-assembling PVA-F127 thermosensitive nanocarriers with highly sensitive magnetically-triggered drug release for epilepsy therapy in vivo 109
7.2 SPIO nanoparticle-stabilized PAA-F127 thermosensitive nanobubbles with MR/US dual-modality imaging and HIFU-triggered drug release for magnetically guided in-vivo tumor therapy 109
7.3 Magnetic-guided monodispersed SPIO-stabilized silica nanobubbles coorperate with focused ultrasound in blood-brain barrier disruption 110
Reference 111
Curriculum Vitae 125
Publications 126

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