奈米粒子與雙親水嵌段共聚物(DHBC)透過靜電絡合的自組裝，是一種用於開發刺激響應奈米藥物的新穎方法，提高以奈米粒子為基礎的治療劑之生物相容性、生物可用性、細胞內攝取和治療效果。在本研究中，開發以酸不穩定之聚乙二醇接枝聚乙烯亞胺(PEG-g-PEI)雙親水接枝共聚物(DHGC)與硼碳氮氧(BCNO)奈米粒子的自組裝，形成BCNO奈米組裝體作為硼中子捕獲療法(BNCT)的硼基奈米藥物輸送劑。首先，透過席夫鹼反應合成了一段帶電-中性的PEG-g-PEI DHGC，並與帶負電的BCNO奈米粒子在水溶液中混合，形成BCNO奈米組裝體，其尺寸、表面電荷和型態分別透過動態光散射(DLS)、ζ電位和穿透式電子顯微鏡(TEM)分析。
　　除了合成BCNO奈米組裝體，在此論文中還研究了混合比(VBCNO/VDHGC)對BCNO奈米組裝體之尺寸及表面電荷的影響。DLS的結果表明，於一個很大範圍的混合比下所製備的BCNO奈米組裝體，在水溶液中皆能保持穩定，而根據TEM圖像顯示，在較高混合比下製備之BCNO奈米組裝體的形狀較不規則且尺寸分布範圍較廣，在較低混合比下製備的BCNO奈米組裝體則呈現較規則的球形且尺寸分布較一致。此外，當DHGC上帶電的PEI嵌段分子量增加時，BCNO奈米組裝體的尺寸也會隨之增加。此研究還證明了BCNO奈米組裝體在不同離子強度溶液中的穩定性，結果顯示出其在0.1 M NaCl溶液中能夠維持穩定48小時以上。最後，本研究分別在pH 6.9、6.0和5.0下對BCNO奈米組裝體進行了pH刺激響應的測試，結果顯示在微酸性環境中席夫鹼鍵會裂解，從而促使BCNO奈米組裝體成功分解成較小的尺寸。總結上述，BCNO奈米組裝體的尺寸及表面電荷，可以透過改變混合比、DHGC帶電嵌段的分子量、溶液的離子強度和pH值等條件來控制。
　　體外細胞硼攝取量之研究結果顯示，與BCNO奈米組裝體共同培養的MDA-MB-231三陰性乳腺癌細胞中，每104個細胞中含有627 ng的硼，是與BCNO奈米粒子共同培養之細胞的大約5倍，且還是與富含硼-10的BPA共同培養之細胞的大約37倍。最後，此研究還進行了體外BNCT治療以評估所製備之BCNO奈米組裝體的治療效果，與用BCNO及富含硼-10的BPA共同培養之細胞相比，與BCNO奈米組裝體共同培養MDA-MB-231細胞顯示出較低的細胞存活率，這是由於BCNO奈米組裝體同時具有高含硼量以及pH刺激響應這兩個優勢，因此提高了細胞的硼攝取量，也增進了BNCT的治療效果。綜上所述，這項研究成功證明了BCNO奈米粒子在DHGC中的自組裝，是一種非常有潛力且能應用於BNCT的刺激響應硼基奈米藥物。

The self-assembly of nanoparticles within double hydrophilic block copolymers (DHBC) via electrostatic complexation is a novel approach that is used to develop a stimuli-responsive nanodrug to improve the biocompatibility, bioavailability, intracellular uptake, and therapeutic efficacy of the nanoparticle-based theranostic agent. In this study, self-assembly of boron carbon oxynitride (BCNO) nanoparticles within polyethylene glycol-graft-polyethyleneimine (PEG-g-PEI), an acid-labile double hydrophilic graft copolymer (DHGC), was developed as a boron-based drug delivery agent for boron neutron capture therapy (BNCT). The charged-neutral PEG-g-PEI DHGC was first synthesized via Schiff base reaction and mixed with the negatively charged BCNO in an aqueous solution to form BCNO nanoassemblies. Dynamic light scattering (DLS), zeta potential, and transmission electron microscopy (TEM) were used to analyze the hydrodynamic size, surface charge, and morphology of the complexes, respectively.
Besides, the effect of mixing ratios (VBCNO/VDHGC) on the hydrodynamic size and surface charge of the BCNO nanoassemblies were also investigated. The DLS results indicated that the as-prepared BCNO nanoassemblies remain stable in an aqueous solution over a wide range of mixing ratios. According to TEM images, the morphology of the BCNO nanoassemblies prepared at a higher mixing ratio exhibited ill-defined shapes with polydisperse sizes while the BCNO nanoassemblies prepared at a lower mixing ratio were observed to possess spherical shapes and more uniform sizes. Furthermore, when the molecular weight of the charged PEI block on DHGC increased, the size of the BCNO nanoassemblies increased accordingly. The investigation of the BCNO nanoassemblies stability in different ionic strength solutions was also demonstrated in this study. The results showed that the BCNO nanoassemblies were stable in 0.1 M NaCl (saline) solution over 48 hours. Lastly, the pH-responsive test was carried out at pH 6.9, 6.0, and 5.0. The BCNO nanoassemblies disassembled to a smaller size due to the cleavage of the Schiff base bond in the slightly acidic environment. In summary, the hydrodynamic size and surface charge of the BCNO nanoassemblies can be controlled by changing the mixing ratio, molecular weight of the charged block, ionic strength, and pH value of the solution.
For in vitro cellular boron uptake, the MDA-MB-231 triple-negative breast cancer cells treated with the BCNO nanoassemblies showed 627 ng-B/104 cells which are approximately 5 times higher than the cells treated with bare BCNO nanoparticles and about 37 times higher than 10B-rich BPA. At last, in vitro BNCT treatment was performed to evaluate the therapeutic efficacy of the as-prepared BCNO nanoassemblies. The MDA-MB-231 cells treated with the BCNO nanoassemblies showed lower cell viabilities compared to the cells treated with bare BCNO and 10B-rich BPA after neutron irradiation. Since the high boron content of BCNO nanoparticles and stimuli-responsive DHGC, the BCNO nanoassemblies enhance the intracellular uptake of boron and actually improve the therapeutic efficacy of BNCT. In conclusion, this study successfully demonstrated the self-assembly of the BCNO nanoparticles within DHGC as a promising approach for developing stimuli-responsive boron-based nanodrug for BNCT.

Abstract.....i
摘要.....iv
Acknowledgements.....vi
Table of Contents.....vii
Figures and Tables.....ix
Chapter 1 Introduction.....1
1.1 Executive summary.....1
Chapter 2 Literature Review.....5
2.1 Boron neutron capture therapy (BNCT).....5
2.2 Boron delivery agents.....9
2.2.1 Evolution of boron delivery agents for BNCT.....9
2.2.2 Nanoparticle-based boron delivery agents.....14
2.3 Challenges of nanoparticles in drug delivery.....19
2.4 Stimuli-responsive drug delivery.....22
2.4.1 Types of stimuli-responsive nanoassemblies.....22
2.4.2 Advantages of pH-responsive nanoassemblies.....26
2.4.3 Stimuli-responsive nanoparticles assemblies.....28
2.5 Self-assembly of double hydrophilic block copolymer (DHBC).....31
2.6 Electrostatic complexation of DHBC and nanoparticles.....36
2.6.1 Mechanism.....36
2.6.2 Factors that affect the formation of PIC.....38
Chapter 3 Materials, Instruments, and Experiments.....46
3.1 Materials and instruments.....47
3.2 Synthesis of PEG-g-PEI@BCNO nanoassemblies.....50
3.2.1 Preparation of BCNO nanoparticles.....50
3.2.2 Synthesis of benzaldehyde end-functionalized PEG (CHO-PEG-CHO).....51
3.2.3 Synthesis of PEG-g-PEI double hydrophilic graft copolymer (DHGC).....52
3.2.4 Preparation of PEG-g-PEI@BCNO nanoassemblies.....52
3.2.5 PEG-g-PEI@BCNO nanoassemblies in different ionic strength.....55
3.2.6 PEG-g-PEI@BCNO nanoassemblies in different pH value.....55
3.3 In vitro assays.....57
3.3.1 Cell viability.....57
3.3.2 Cell uptake.....57
3.3.3 In vitro BNCT treatment.....58
Chapter 4 Results and Discussion.....60
4.1 Synthesis of PEG-g-PEI@BCNO nanoassemblies.....60
4.1.1 Synthesis of benzaldehyde end-functionalized PEG (CHO-PEG-CHO).....61
4.1.2 Synthesis of PEG-g-PEI double hydrophilic graft copolymer (DHGC).....63
4.1.3 Preparation of PEG-g-PEI@BCNO nanoassemblies.....68
4.2 Self-assembly mechanism of PEG-g-PEI@BCNO.....73
4.2.1 Effect of mixing ratio.....73
4.2.2 Effect of PEI molecular weight.....83
4.2.3 Effect of ionic strength.....86
4.2.4 Effect of pH value.....91
4.3 In vitro assays.....98
4.3.1 Cell viability.....98
4.3.2 Cell uptake.....100
4.3.3 In vitro BNCT treatment.....102
Chapter 5 Conclusions.....105
Chapter 6 Prospective.....107
References.....110

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