近十年來，癌症的發病率預計還會持續一直增加，且癌症是人類死亡的第二大原因。因此，大量的研究致力於為不同類型的癌症開發更有效的治療和診斷方法。硼中子俘獲療法 (BNCT) 是一種新興的癌症治療方法，因為它可以在熱中子照射時通過施用具有腫瘤靶向特性的硼藥物選擇性地殺死癌細胞。基於BNCT的放射生物學，高線性能量(LET)將其所有能量消散在5 - 10 μm的距離內，大約是單個細胞的大小。因此，高LET粒子不會損害鄰近的健康細胞。與傳統放射治療相比，BNCT治療可以成為治療無效腫瘤和復發性癌症的一種替代和有效的治療方法，其治療指數高，對患者的副作用最小。雖然用於癌症治療的BNCT是一種很有前途的靶向放射治療，但在成為癌症的標準治療方法之前仍存在一些挑戰。BNCT的一個缺點是BNCT治療後癌症的復發。在BNCT治療後，有幾個挑戰會導致癌症復發。一個主要挑戰是將高負載的10B藥物專門輸送到靶向腫瘤部位。 BPA-果糖已被日本及美國食品藥品監督管理 (FDA) 批准用於臨床治療。此外，由於細胞膜外的BPA濃度梯度的降低，BPA的小分子大小很容易透過L型氨基酸轉運蛋白 (LAT-1) 轉運到細胞內，從而導致血液和其他重要器官中的10B高積累。因此，迫切需要開發一種更有效的BNCT硼藥物。另一方面，對治療性造影劑和影像造影劑的多功能癌症藥物的研究是癌症治療的重要技術進步，使癌症患者的治療、診斷和預後成為可能。在此，我們研究了硼碳氮氧納米粒子 (BCNO NPs) 的合成和功能化，該納米粒子之前由我們的實驗室開發為一種含硼藥物。在本碩士論文中，開發了一種模塊化的合成方案，將大環螯合劑（例如：DOTA）綴合到生物相容性聚合物上，然後在BCNO NPs表面進行功能化。生物相容性聚合物塗層顯著降低了由BCNO納米顆粒引起的生物毒性。此外，DOTA共軛聚合物能夠螯合各種放射性同位素，用於放射治療和成像。例如，可以通過正電子發射斷層掃描 (PET) 或單光子發射計算機斷層掃描 (SPECT) 系統地跟踪標記有 DOTA/放射性金屬複合物的納米藥物。腫瘤和器官內的生物分佈或放射性核素標記的BCNO納米顆粒可用於評估新硼藥物在體內應用的藥代動力學和潛在毒性。因此，非侵入性分子成像可以幫助研究人員研究藥物積累、生物分佈和腫瘤的靶向特異性，從而有效地將新的硼藥物應用於臨床。

The incidence of cancer has been increasing for around near a decade and is projected to continue. Cancer is the second cause of human death [1]. Therefore, significant research effort is devoted to the development of more effective therapies and diagnostics for different types of cancer. Boron neutron capture therapy (BNCT) is an emerging cancer treatment method because it can selectively kill cancer cells by administering a boron drug with tumor-targeting properties when exposed to thermal neutron irradiation. Based on the radiobiology of BNCT, the high linear energy (LET) dissipates all its energy within 5 - 10 μm in distance, which is about the size of a single cell. As a result, the high LET particles will not damage the neighboring healthy cells. Thus, BNCT treatment could be an alternative and effective treatment for inoperative tumors and recurrent cancer with high therapeutic indexes and minimal side effects for the patients compared to conventional radiation therapy. While BNCT for cancer treatment is a promising targeted radiation therapy, several challenges remained before it can become a standard treatment for a few selected cancers. The first downfall of BNCT is cancer recurrent after BNCT treatment. There are several challenges leading to cancer recurrent after BNCT treatment. One of major challenges is delivering a high loading of 10B drug specifically to the targeted tumor site. BPA-fructose has been approved by Japan and the Food and Drug Administration (FDA) and for clinical treatment. Because of the small molecular size of BPA readily transported across the cell membrane by L-type amino acid transporter (LAT-1) in response to a reduction in the concentration gradient of BPA across the extracellular membrane, resulting in a high 10B accumulation in the blood and other vital organs. Thus, there is an immense need to develop a more effective boron drug for BNCT. On the other hand, research in cancer drugs that carries both therapeutic and imaging contrast agents, which enable treatment, diagnosis, and prognosis in cancer patients, is an important technological progress in cancer treatment. Herein, we investigate the synthesis and functionalization of boron carbon oxynitride nanoparticles (BCNO NPs) which were previously developed by our laboratory as a potent boron drug. In this Master thesis, a modular synthetic protocol was developed in conjugating a macrocyclic chelator (ex: DOTA) onto a biocompatible polymer, followed by functionalizing onto the surface of the BCNO NPs. The biocompatible polymer coating significantly reduces the biological toxicity caused by the BCNO nanoparticles. Moreover, the DOTA-conjugated polymer enabled the chelation of a variety of radioisotopes for both radiotherapy and imaging. For example, nanodrugs tagged with DOTA/radiometal complex can be systematically tracked via positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Bio-distribution or radionuclide-tagged BCNO nanoparticles within tumors and organs can be used to evaluate the pharmacokinetics and potential toxicity of the new boron drug for in vivo application. As a result, non-invasive molecular imaging could facilitate researchers to first investigate the drug accumulation at the disease site, the biodistribution, and the tumor targeting specificity towards translating a new boron drugs to the clinic more effectively.

Table of Content
Abstract i
摘要 iv
Acknowledgment vi
Table of Content vii
Figure and Table 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 Drug delivery of BNCT 10
2.2.1 Evolution of BNCT boron agent 10
2.2.2 Cellular uptake of nanoparticles 15
2.2.3 Boron carbon oxynitride nanoparticles (BCNO NPs) 19
2.3 Medical imaging 23
Chapter 3 Materials, Instruments, and Experiments 30
3.1 Materials and instruments 31
3.2 PEG-DOTA@BCNO preparation 33
3.2.1 BCNO preparation 33
3.2.2 PEG-CCA & PEG-EDA synthesis 33
3.3.3 PEG-DOTA synthesis 34
3.3.4 Functionalized BCNO with PEG-DOTA 34
3.3 In vitro assay 35
3.3.1 Cell viability 35
3.3.2 Cell uptake 37
3.3.3 Cellular BNCT treatment 37
Chapter 4 Results and Discussion 40
4.1 Polymer Synthesis and Characterization 40
4.1.1 Polyethylene glycol - chloro acetyl chloride (PEG-CCA) & Polyethylene glycol - ethylene diamine (PEG-EDA) characterization 40
4.1.2 DOTA quantitation 44
4.2 Ligand exchange BCNO with PEG-DOTA 47
4.2.1 bare BCNO characterization 47
4.2.2 PEG-DOTA@BCNO characterization 54
4.3 In vitro assay against triple negative breast cancer cell 57
4.3.1 Cell viability 57
4.3.2 Boron uptake 59
4.3.2 In vitro BNCT treatment 63
Chapter 5 Conclusion 65
Chapter 6 Prospective 68
Reference 71

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