膠質母細胞瘤（Glioblastoma, GBM）是一種侵襲性極強的癌症，會影響中樞神經系統。 儘管醫療技術取得了進步，GBM仍然難以治療且預後較差。 目前治療 GBM 的臨床方法包括手術切除，然後進行放療和化療，但這些治療的成功率往往有限。 GBM 治療的一大挑戰是血腦屏障 (blood-brain barrier, BBB)，它阻礙藥物輸送到腫瘤部位。 為了克服這一障礙，研究人員制定了創新策略。
在本研究中我們開發出聚穀胱甘肽結合三苯基膦修飾的金奈米粒子(poly-glutathione conjugated triphenylphosphine gold nanoparticles, 簡稱pGSH-TPP@GNP) 聚穀胱甘肽具有可以修飾不同化學物質的官能團，三苯基膦可以特異性靶向腫瘤細胞內的線粒體。在奈米粒子搭載的化療藥物ONC201是一種TRAIL (TNF-related apoptosis-inducing ligand) 激活劑，並可滲透血腦屏障，透通過誘導Akt和ERK的失活誘導Foxo3a去磷酸化，導致癌細胞凋亡。
經三苯基膦修飾的金奈米粒子帶正電，粒線體膜電位帶負電，且癌細胞的線粒體膜電位比正常細胞高 60 mV。兩者之間的差異導致癌症線粒體中帶正電物質的濃度增加十倍。因此，正電的金奈米粒子得以優先標靶腫瘤細胞。
此外，我們在細胞實驗中對標靶粒線體的癌細胞給予高頻磁場 (high-frequency magnetic field, HFMF)刺激，發現癌細胞會因電刺激導致粒線體去極化而死亡，在給腫瘤球體高頻磁場刺激後，可見腫瘤球體的結構鬆散與破碎，標明標靶粒線體結合高頻磁場的抗腫瘤能力。
將金奈米粒子與高頻磁場 (high-frequency magnetic field, HFMF) 療法相結合已被證明是有效的。 使用對流增強遞送系統 (convection-enhanced delivery, CED) 繞過血腦屏障，將奈米顆粒直接遞送至腫瘤部位。 在腫瘤部位，pGSH-TPP@GNP 奈米顆粒會誘導癌細胞線粒體中的氧化壓力，導致癌細胞功能障礙並隨後死亡。由此產生的細胞死亡會釋放損傷相關分子模式 (damage-associated molecular pattern, DAMP)，並轉移至淋巴結活化樹突狀細胞並訓練 T 細胞，從而增強免疫系統及T細胞浸潤腫瘤。 通過與免疫檢查點療法相結合，可以進一步增強這種方法，從而產生抑制腫瘤生長的全面抗腫瘤作用，在實驗的結果中也表明對腫瘤的抑制及對生存時長的提升。
總體而言，標靶治療和創新遞送系統的開發，以及基於免疫的方法的整合，有望改善 GBM 患者的病情及未來展望。

Glioblastoma (GBM) is an extremely aggressive cancer that affects the central nervous system. Despite advances in medical technology, GBM remains difficult to treat and has a poor prognosis. Current clinical approaches to treating GBM include surgical resection followed by radiation and chemotherapy, but these treatments often have limited success. A major challenge in GBM treatment is the blood-brain barrier (BBB), which impedes drug delivery to the tumor site. To overcome this obstacle, the researchers developed innovative strategies.
In this study, we developed poly-glutathione conjugated triphenylphosphine gold nanoparticles (poly-glutathione conjugated triphenylphosphine gold nanoparticles, referred to as pGSH-TPP@GNP). Poly-glutathione has the ability to modify different chemical substances The functional group of triphenylphosphine can specifically target the mitochondria in tumor cells. The chemotherapeutic drug ONC201 carried on nanoparticles is a TRAIL (TNF-related apoptosis-inducing ligand) activator, which can penetrate the blood-brain barrier and induce Foxo3a dephosphorylation by inducing the inactivation of Akt and ERK, leading to cancer cell apoptosis death.
The gold nanoparticles modified with triphenylphosphine are positively charged, and the mitochondrial membrane potential is negatively charged, and the mitochondrial membrane potential of cancer cells is 60 mV higher than that of normal cells. The difference between the two resulted in a tenfold increase in the concentration of positively charged species in cancer mitochondria. Therefore, positively charged gold nanoparticles can preferentially target tumor cells.
In addition, we gave high-frequency magnetic field (high-frequency magnetic field, HFMF) stimulation to cancer cells targeting mitochondria in cell experiments, and found that cancer cells would die due to the depolarization of mitochondria due to electrical stimulation. After the tumor spheroids were stimulated by a high-frequency magnetic field, the structure of the tumor spheroids was loose and broken, indicating the anti-tumor ability of the target mitochondria combined with high-frequency magnetic fields.
Combining gold nanoparticles with high-frequency magnetic field (HFMF) therapy has been shown to be effective. Convection-enhanced delivery (CED) bypasses the blood-brain barrier and delivers nanoparticles directly to tumor sites. At the tumor site, pGSH-TPP@GNP nanoparticles induce oxidative stress in the mitochondria of cancer cells, leading to cancer cell dysfunction and subsequent death. The resulting cell death releases damage-associated molecular patterns (DAMPs) that travel to lymph nodes to activate dendritic cells and train T cells, thereby enhancing the immune system and T cell infiltration of tumors. This approach can be further enhanced by combining it with immune checkpoint therapy, resulting in a comprehensive anti-tumor effect that inhibits tumor growth, and the results of the experiment also show tumor suppression and improved survival time.
Overall, the development of targeted therapies and innovative delivery systems, as well as the integration of immune-based approaches hold promise for improving outcomes and future prospects for GBM patients.

Table of contents
中文摘要 II
Abstract IV
Table of contents VIII
List of Figure XI
Chapter 1 Introduction 1
Chapter 2 Literature review and theory 3
2.1 Glioblastoma brain cancer 3
2.1.1 Blood-brain barrier (BBB) 5
2.2 Convection- enhanced delivery (CED) system 7
2.2.1 Convection-enhanced delivery (CED) system mechanism 8
2.2.2 Convection-enhanced delivery system applied in glioblastoma treatment 10
2.2.3 The convection-enhanced delivery of nanocarriers 12
2.3 Nanomaterials for mitochondria-targeted therapeutics 14
2.3.1 Mitochondria structure and function 14
2.3.2 Mitochondria targeting 17
2.3.3 Targeting mitochondria for cancer therapy 19
2.3.4 Different strategies for mitochondria-targeted nanotherapy 21
2.4 Gold nanoparticles combined with magnetoelectric effect 24
2.4.1 Nanoporous gold nanoparticles 24
2.4.2 Magneto-electric effect 26
2.4.3 Magnetoelectric effect for cancer treatment and drug delivery 29
2.5 Immunotherapy in brain tumor 32
2.5.1 The understanding of brain immunity 32
2.5.2 CNS tumour microenvironment 35
2.5.3 Immune checkpoint inhibitors 38
2.5.4 Immunotherapy of adoptive T cells 41
Chapter 3 Experimental section 44
3.1 Materials 44
3.2 Apparatus 47
3.3 Method 48
3.3.1 Synthesis of gold nanoparticles (GNPs) 48
3.3.2 Synthesis of pGSH-TPP@GNP 48
3.3.3 Characterization 49
3.3.4 Cell culture 50
3.3.5 Cell viability assay 51
3.3.6 Cellular Uptake 52
3.3.7 Mitochondrial membrane potential (MMP) depolarization 53
3.3.8 Mitochondrial ROS detection 54
3.3.9 Penetration of the nanoparticles in ALTS1C1 spheroid 55
3.3.10 Preparation of nanoparticles with BSA and drug loading 57
3.3.11 In vitro antigen capturing test 57
3.3.12 In vivo experiments 59
Chapter 4 Results and Discussions 62
4.1 Synthesis and characterization of nanoparticles 62
4.2 In vitro experiments 71
4.2.1 Cell cytotoxicity 71
4.2.2 Cellular uptake 72
4.2.3 Targeting mitochondria experiment 73
4.2.4 pGSH-TPP@GNP combined with HFMF treatment 75
4.2.5 Mitochondrial ROS AFM enhanced 77
4.2.6 JC-1 staining 79
4.2.7 3D tumor spheroid model 81
4.2.8 Antigen captrue 83
4.3 In vivo experiment 85
4.3.1 CED in vitro model 86
4.3.2 Animal model and biodistribution 87
4.3.3 Tumor elimination and inhibition 90
4.3.4 Dendritic cell activation induces immune infiltration 94
4.3.5 In vivo animal therapeutic efficacy and metabolism 100
Chapter 5 Conclusions 105
Reference 106

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