硼中子治療(BNCT)是一種新穎的癌症治療方式，此種治療方式當含硼藥物經過低能的中子輻射激發後開始作用治療，可以破壞癌症細胞並不會傷害到正盛的細胞。個別來說，中子熱能和含硼藥物皆不會對任何細胞造成傷害，當兩種東西加在一起作用時，高能的線性能量游離轉換(LET)可以對癌症細胞的DNA造成不可逆的破壞。傳統的放射治療和化學治療，放射線治療不僅會對癌症細胞造成傷害也會對一般細胞造成影響，所以接受傳統化療/放射治療的癌症患者會遭受到很多的副作用，並且生活品質也會大幅下降。硼中子治療(BNCT)雖然已經被用於實驗性治療多種癌症像是頭頸癌，但是臨床前和臨床的研究都還沒有決定性的結論。硼中子治療藥物研發的困難點在於藥物需要具有高選擇性，並且能夠將含有足夠含量的 10B 送到癌症細胞內。為了克服硼中子治療(BNCT)的困難點，此論文希望能研究出用聰明，多功能性的奈米載體來輸送含硼藥物。這個奈米藥物載體具有高中子截面積使其具有治療癌症的功效。這個多功能性的癌症藥物不僅可以跨過生物屏障也可以將具有癌症治療功效的藥物輸送到癌症細胞，並最終提升癌症患者的治療指數。此次提出的可變化具有治療性的奈米藥物含有硼的奈米粒子可以自我組裝成100-200奈米大小且具有良好的表面電位以利於穿透癌症的微環境. 在癌症酸性的微環境當中，對酸性敏感的化學鍵結將會被打斷並釋出極小的，且帶有正電的硼奈米粒子。此轉換電性以及改變大小是為了提高對癌症細胞的穿透性以及提高在癌症細胞內的擴散速度，並加速進入到癌症區域進行治療。與此同時，含硼藥物會在癌症腫瘤位子釋放。在這個論文所提出的可變化含硼藥物可有效的將高含量的10B輸送到癌症的微環境，並且降低整體系統的毒性進而提升對癌症變換的治療效果，以防止病症的再次發生。

Boron neutron capture therapy (BNCT) is an emerging cancer treatment modality that allows selective destruction of individual cancer cells when a particular boron drug is administered without harming neighboring healthy cells upon low energy epithermal neutron irradiation. Individually, epithermal and boron medication do not create any harm to the cell. When combined, high linear energy transfer (LET) ionization resulted in irreversible damage to the DNA of the cancer cell. In contrast to conventional radiotherapy and chemotherapy, both cancer and healthy cells are affected by anticancer treatment. Consequently, cancer patients undergoing traditional radio- and chemotherapy suffer from many side effects and reduced quality of life during treatment. While BCNT has been used in an experimental treatment for several different tumors, including head and neck cancer, both preclinical and clinical studies are non-conclusive. One of the major challenges in BCNT is in developing a highly selective boron carrier that could deliver a sufficient concentration of 10B into every single cancer cell.
To overcome challenges associated with BNCT, this thesis aims to engineer a size and charge transformable nanocarrier, in which the nanocarrier itself is composed of materials with therapeutics properties, specifically with a large neutron cross-section. The size and charge transformable nanocarrier not only can overcome biological barriers but is also capable of delivering boron-containing therapeutics agents to the cancer site, and minimizing systemic toxicity, and ultimately improved the therapeutic index for cancer patients. The transformable nanotherapeutic is composed of ultrasmall boron nanoparticles that self-assembled into uniformly sized vesicles of optimal size range between 100-200 nm and with an optimal surface charge for infiltration into the tumor microenvironment. At the tumor microenvironment, the slightly acidic pH microenvironment triggers the disassembly of the boron vesicles into ultrasmall, positively charge boron nanoparticles. The size and charge transformation of the boron vesicles into ultrasmall, positively charged nanoparticles aims at enhancing cell internalization and diffusion into a solid tumor. Simultaneously, the boron vesicle releases boron containing BCNO at the tumor microenvironment. This research thesis aims to develop transformable boron vesicles that could effectively deliver both a high concentration of 10B in the tumor microenvironment with minimal systemic toxicity and thus increase therapeutic index for the patients and in preventing disease relapse after BNCT.

Table of Content

Chapter 1 Introduction
1.1 Executive summary 9
Chapter 2 Literature Review
2.1 Boron neutron capture therapy 13
2.2 Boron delivery agents 14
2.3 Boron carbon oxynitride (BCNO) 18
2.4 Challenge of in vivo drug delivery 21
2.5 Stimuli-responsive chemical linker for better drug delivery 24
Chapter 3 Preparation and Design of Experiments
3.1 Synthesis BCNO nanoparticle 29
3.2 Functionalized BCNO with polymer ligand (PEI, PEG, and PSMA-CRs) 31
3.3 Synthesis of aldehyde end-functionalized PEG 32
3.4 Preparation and characterization of PEG-b-PEI@BCNO nanoparticle 32
3.5 Preparation of PEI@BCNO-b-PEG aggregated nanoparticle 33
3.6 Material characterization 34
3.7 Cell viability assay of BCNO 35
3.8 In vitro cell uptake of BCNO containing solution 36
Chapter 4 Results and Discussion
4.1 Synthesis and characterization of BCNO 40
4.1.1 Microwave synthesis of BCNO 40
4.1.2 Thermal annealed BCNO and thermal cut synthesis BCNO 43
4.2 BCNO chemical structure investigation 50
4.2.1 Structural analysis of the thermal annealed BCNO nanoparticle 50
4.2.2 Structural analysis of the BCNO nanosheet 53
4.3 BCNO functionalization with polymer ligand (PEG, PEI, and PSMA-CRs) 59
4.3.1 Characterization of the PEG@BCNO and PEI@BCNO 60
4.3.2 Cytotoxicity and cell uptake study of the BCNO, polymer-coated BCNO 65
4.3.3 Characterization of PSMA-CRs@BCNO 69
4.4 Size and charge transformable self-assemble polymer-coated BCNO synthesis and characterization 72
4.4.1 Synthesis of aldehyde end-functionalized PEG 73
4.4.2 Characterization of self-assemble PEG-b-PEI@BCNO nanostructure 76
4.4.3 Self-assembly mechanism of the PEG-b-PEI@BCNO 81
4.5 Cytotoxicity and cell uptake of PEG-b-PEI@BCNO 89
Chapter 5 Conclusion 94
References 95

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