硼中子捕獲治療(BNCT)是具有潛力的癌症治療法。與傳統放射治療不同，BNCT有高線性能量（LET），可以在短距離內（< 10微米）釋放所有能量。高 LET 粒子能夠精確殺死腫瘤細胞，同時不會損害鄰近的正常細胞。硼藥物輸送的主要困難在於藥物的腫瘤選擇性能力。有效的 BNCT 治療需要對腫瘤細胞有高選擇性並含有足夠濃度的硼-10（約 20-50 微克 10B/g 腫瘤）。此外，硼藥物必須在腫瘤細胞中維持足夠的時間，且在腫瘤組織和正常組織之間的分佈存在顯著差異（T/N，T/B比值 > 3）。近年來，第三代硼藥物被開發出來以克服小分子藥物的限制。在這些第三代硼藥物中，硼基底奈米粒子藥物因其每個奈米粒子具有高硼含量而引起關注。然而，目前的硼基底奈米粒子藥物面臨一些挑戰，包括需要增加在生理環境中的穩定性、提高藥物的細胞通透性、降低毒性以確保長期的血液循環。為了克服這些挑戰，此碩士論文透過非共價或共價鍵結將硼碳氮氧化物 (BCNO) 奈米粒子與聚乙二醇 (PEG) 和聚丙烯酸 (PAA) 進行表面功能化，並分析這些奈米顆粒的高分子含量、尺寸、表面電荷、形態和穩定性。根據熱重分析儀（TGA）、動態光散射（DLS）和穿透式電子顯微鏡（TEM）的結果，最佳的表面功能化方式為非共價鍵結PEG於BCNO奈米粒子，具有高達40%的功能化效率、球形形貌及適當的尺寸範圍(直徑為50至200奈米)。因此，我們選擇了非共價功能化方法進行主動靶向功能化。
主動靶向方法在提升腫瘤細胞中的藥物濃度和增強腫瘤選擇性方面顯示出潛力。由於葉酸能選擇性地結合過度表現於乳腺癌細胞上的葉酸受體，葉酸作為癌症治療中的活性靶向劑備受關注。透過將葉酸與抗癌藥物、奈米顆粒或其他藥物結合，可以增強遞送效果並減少對正常細胞的毒性。在本篇研究中，我們合成了含有葉酸配體的PEG功能化BCNO奈米粒子（BCNO@PEG-FA）作為主動靶向硼奈米藥物。使用雷射掃描共軛焦顯微鏡 (LSCM) 和感應耦合電漿質譜 (ICP-MS) 分析了 BCNO@PEG-FA 的體外細胞攝取，結果顯示硼的細胞攝取量增加了近兩倍。此外，與BCNO@PEG相比，BCNO@PEG-FA在體外 BNCT 治療後顯示腫瘤細胞存活率降低了10%。這些結果證明了主動靶向藥物傳輸和 BNCT 治療相結合用於癌症治療的潛力。

Boron neutron capture therapy (BNCT) holds great potential in cancer treatment. Unlike traditional radiation therapy, BNCT has high linear energy transfer (LET), which deposit a large amount of energy over a short distance (< 10 μm). The high LET radiation can cause significant damage to cell death in the targeted tumor cells while sparing the normal tissues. The main difficulty in boron drug delivery is the selectively ability of boron delivery agents. An effective BNCT treatment requires high tumor cell targeting and sufficient concentration of boron atoms delivered to tumor cells (~ 20-50 µg 10B/g of tumor). Furthermore, boron agents must persist in the tumor cells for a sufficient time, with greatly different distribution of boron between tumor tissue and normal tissue (T/N, T/B ratio > 3). The third generation of boron agents is currently being developed to overcome the limitations of small molecule drugs. Among the third generation of boron agents, boron-based nanoparticle drugs have shown promise due to their high boron composition per nanoparticle. However, current boron-based nanoparticle drugs face several challenges, including the need to increase stability in the physiological environment, improve cell permeability, and reduce toxicity to ensure long-term blood circulation. To address these challenges, this master's thesis demonstrates the functionalization of boron carbon oxynitride (BCNO) nanoparticles with polyethylene glycol (PEG) and polyacrylic acid (PAA) via non-covalent or covalent conjugation. The polymer content, size, surface charge, morphology, and stability of these nanoparticles were investigated. According to the results from thermogravimetric analysis (TGA), dynamic light scattering (DLS) and transmission electron microscopy (TEM), the BCNO nanoparticles functionalized PEG via non-covalent coupling demonstrated optimal functionalization, with a high 40% functionalization efficiency, spherical morphology, and a suitable size range of 50 to 200 nm in diameter. Consequently, we selected the non-covalent functionalization approach for forward active targeting functionalization.
An active targeting approach has shown promise in increasing drug concentration in tumor cells and enhancing tumor selectivity. Folic acid has gained attention as an active targeting agent in cancer therapy due to its ability to selectively bind to the overexpression of folate receptors on breast cancer cells. By conjugating folic acid to anticancer drugs, nanoparticles, or other drug agents, it is possible to enhance delivery efficacy and reduce toxicity to normal cells. In this work, we have synthesized a PEG-functionalized boron carbon oxynitride (BCNO) nanoparticles with folic acid ligand (BCNO@PEG-FA) as an active targeting boron nanodrug. The in vitro cellular uptake of the BCNO@PEG-FA was analyzed using laser scanning confocal microscope (LSCM) and inductively coupled plasma mass spectrometry (ICP-MS), revealing nearly 2-fold higher boron cellular uptake. Moreover, the BCNO@PEG-FA showed a 10% reduction in tumor cell viability after in vitro BNCT treatment compared to BCNO@PEG. These results demonstrated the potential of combining active targeting drug delivery and BNCT treatment for enhance therapeutic outcomes for cancer treatment.

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