癌症是目前全球人口的主要死因之一。癌症疫苗是藉由打入腫瘤的抗原來引起長效性的T細胞反應，破壞腫瘤細胞並防止癌症復發的一種治療方式。然而全腫瘤疫苗的製造不僅成本高也很費時，因此近來的研究提出了結合其他傳統治療方式，例如放射線治療、化學治療或是熱治療，直接在患者身上將腫瘤做成原位疫苗引起抗腫瘤免疫反應的新觀點。在第一部分的研究中，我們利用聚苯胺共軛乙二醇幾丁聚醣（polyaniline-conjugated glycol chitosan, PANI-GCS）奈米微粒做為載體包覆一疏水性的免疫佐劑(R848)，來進行癌症的光熱及免疫複合治療。疏水性的聚苯胺（PANI）可以經由氧化聚合接枝在親水性的乙二醇幾丁聚醣（GCS）上，形成一個兩性的高分子，並且在水相環境中自組裝行成奈米微粒。當接枝上的聚苯胺照射近遠紅外光雷射時，可以做為一個局部的奈米熱源，破壞腫瘤細胞；同時，我們所包覆的R848可以促使樹突細胞釋放出發炎相關的細胞激素，進而活化下游的專一性T細胞免疫反應。在動物實驗中我們發現，將PANI-GCS奈米微粒以腫瘤內注射的方式打入腫瘤並且照射近遠紅外光雷射後，可以在局部進行升溫進而抑制腫瘤的生長。此外，當我們打入包覆有R848的奈米微粒進行治療時，可以產生一個長效性的系統性抗腫瘤免疫反應，並且能有效防止我們二次接種的腫瘤生長。利用細菌來進行腫瘤治療（bacteria-mediated tumor therapy, BMTT）被認為是一種有效的治療方式，並且已經被研究了數十年。然而由於細菌本身潛在的感染風險，使得此種治療方法在臨床上的應用受到阻礙。為了解決此一問題，在第二部分的研究中我們提出了一種能夠仿造BMTT的功效，但不會引起不良副作用的尖刺狀類細菌金屬有機框架（metal-organic framework, MOF）用於癌症的免疫治療。我們藉由將硫酸鋁、氯化釕水合物和2-氨基對苯二甲酸的溶劑混和後進行熱反應來合成MOFs。取決於反應溫度的不同，它們的表面可能會呈現平滑球狀或是長出許多奈米等級的尖刺，而無論是球狀或是尖刺狀的MOFs都可做為光敏劑將所吸收的光能轉換成局部熱能。由於尖刺狀的MOFs與細胞接觸的表面積比球狀的MOFs更大，所以它們會更容易被巨噬細胞給吞噬，而它們所引起的細胞免疫反應也會更強。儘管單純利用尖刺狀的MOFs來進行光熱治療時可以有效將腫瘤轉化為原位疫苗，若再結合上免疫檢查點阻斷劑aPD-1的施打，它們治療癌症的能力將會再進一步提升，不僅能夠抑制原位腫瘤的生長，還能有效降低癌症復發和轉移的機率。在自然界當中，花粉顆粒的外殼由於具有多變的表面型態，因此能有效的促進其與花柱間的專一性辨認以及吸附作用，此特性也被認為有助於作為疫苗抗原的載體。然而即便透過繁複的化學處理，也無法完全去除花粉中的過敏物質。為了克服此一問題，在第三部分的研究當中我們合成了一種仿花粉型態的鋁MOFs作為抗原遞送的載體，並且吸附上模式抗原－卵清蛋白（Ovalbumin, OVA），使其在作為抗原載體的同時，也具有免疫佐劑的功效。實驗結果顯示具有較長尖刺的鋁MOFs擁有較好的細胞附著能力並且能更快速有效的被巨噬細胞給吞噬，引起更強烈的促發炎細胞激素的分泌，進而能增強抗原特異性的抗體免疫反應。

Cancer is one of the leading causes of death globally. Most cancer vaccines use defined antigens rather than whole tumor cells. Whole tumor cells can generate a strong anti-tumor immunologic memory against multiple tumor antigens but the preparation of whole-tumor vaccines can be costly and time-consuming. Recent studies have demonstrated that a combination of immunotherapy with other conventional treatment modalities can convert a tumor into an in situ vaccine that can reduce cancer metastasis and improve survival. In the first study, an insoluble adjuvant, R848, was encapsulated in polyaniline-conjugated glycol chitosan (PANI-GCS) nanoparticles (R848@NPs) for combination therapy. PANI-GCS NPs, which can absorb near-infrared (NIR) light, are utilized as nano-localized heat sources for tumor ablation, and R848 is used to induce potent inflammatory cytokine secretion by dendritic cells, which may subsequently enhance the T cell responses. In vivo study revealed that an intratumoral injection of R848@NPs generated localized heat upon exposure to NIR and partially suppressed the growth of CT26 tumor cells in a mouse model. Moreover, the injected R848@NPs successfully triggered long-term systemic antitumor immunity and rejected the rechallenged CT26 tumors. Bacteria-mediated tumor therapy (BMTT) is regarded as an effective therapeutic strategy. The injection of patients with bacteria can induce the infiltration of immune cells to exhibit numerous immune-mediated characteristics that modulate the tumor microenvironment. However, the clinical use of this method is inhibited by the risk of accompanying infections. In the second study, a bioinspired bacterium-like, spiky, aluminum (Al)-ruthenium (Ru) metal–organic framework (MOF) is proposed to replicate the function of BMTT without its adverse side-effects. These MOFs are synthesized in a solvothermal reaction of aluminum sulfate, ruthenium chloride hydrate, and 2-aminoterephthalic acid. Experimental results indicate that MOFs that are covered with numerous nanospikes are more easily phagocytosed by macrophages than are their spherical counterparts, improving subsequent immune responses. The checkpoint blockade of aPD-1 has been used in synergy with the in situ vaccination of intratumorally injected bacterium-like MOFs under NIR laser exposure to remove completely primary tumors and protect mice from tumor metastasis and recurrence. In nature, pollen particles have several unique surface morphologies that are thought to be responsible for their efficient recognition and strong adherence to stigma. Inspired by this natural pollination process, an ovalbumin (OVA)-loaded pollen-mimetic Al-MOF (OVA@Al-MOFs) with tunable spike-like nanostructures is proposed in the third study. These OVA@Al-MOFs act as not only an antigen delivery system but also an adjuvant. Analytical results demonstrate that the unique nanospikes on the surfaces of MOFs can cause them to interact effectively with the macrophages, leading to a stronger antigen-specific antibody response.

Abstract-----------------------------------------------------------I
Contents-----------------------------------------------------------V
List of Figures----------------------------------------------------XI
List of Tables-----------------------------------------------------XVII
Chapter 1 Introduction---------------------------------------------1
Chapter 2 Modulation of Tumor Microenvironment Using a TLR-7/8 Agonist-Loaded Nanoparticle System that Exerts Low-Temperature Hyperthermia and Immunotherapy for In Situ Cancer Vaccination
2-1. Introduction--------------------------------------------------6
2-2. Results and discussion----------------------------------------9
2-2.1. Characteristics of R848@NPs---------------------------------9
2-2.2. Cytotoxicity of R848@NPs------------------------------------11
2-2.3. In vitro photothermal ability of R848@NPs-------------------12
2-2.4. Hyperthermia-induced expression of HSP70--------------------13
2-2.5. In vitro immune activation by R848@NPs----------------------15
2-2.6. Thermoablative ability of empty NPs at high temperatures----17
2-2.7. Synergistic effects of low-temperature hyperthermia and immunotherapy------------------------------------------------------19
2-2.8. Systemic memory immunity------------------------------------21
2-2.9. Modulation of tumor microenvironment------------------------24
2-3. Conclusions---------------------------------------------------26
2-4. Materials and methods-----------------------------------------27
2-4.1. Materials---------------------------------------------------27
2-4.2. Preparation and characterization of R848@NPs----------------27
2-4.3. Optical and photothermal properties of R848@NPs-------------28
2-4.4. In vitro cytotoxicity study---------------------------------28
2-4.5. Cellular expression of HSP70--------------------------------29
2-4.6. Animal studies----------------------------------------------29
2-4.7. Uptake of R848@NPs by BMDCs---------------------------------29
2-4.8. Maturation of BMDCs-----------------------------------------30
2-4.9. In vivo photothermal ability of test NPs--------------------31
2-4.10. Anti-tumor treatments--------------------------------------31
2-4.11. Tumor rechallenge------------------------------------------31
2-4.12. ELISPOT assay----------------------------------------------32
2-4.13. Histological examination-----------------------------------32
2-4.14. Analysis of tumor microenvironment-------------------------32
2-4.15. Statistical analysis---------------------------------------33
Chapter 3 Bioinspired Engineering of a Bacterium-Like Metal–Organic Framework for Cancer Immunotherapy
3-1. Introduction--------------------------------------------------35
3-2. Results and discussion----------------------------------------38
3-2.1. Characteristics of MOFs-------------------------------------38
3-2.2. In vitro photothermal ability of MOFs-----------------------39
3-2.3. Cytotoxicity of MOFs----------------------------------------40
3-2.4. Hyperthermia-induced expression of HSP70--------------------42
3-2.5. Uptake of MOFs by macrophages-------------------------------43
3-2.6. In vitro immune activation by MOFs--------------------------43
3-2.7. In vitro degradability of MOFs------------------------------44
3-2.8. In vivo retention of MOFs-----------------------------------46
3-2.9. Synergistic antitumor effects of in situ vaccination and checkpoint blockade------------------------------------------------48
3-2.10. Systemic memory immunity-----------------------------------49
3-2.11. Modulation of tumor microenvironment-----------------------51
3-2.12. In vivo toxicity-------------------------------------------52
3-3. Conclusions---------------------------------------------------54
3-4. Materials and methods-----------------------------------------54
3-4.1. Materials---------------------------------------------------54
3-4.2. Synthesis and characterization of test MOFs-----------------54
3-4.3. Optical and photothermal properties of test MOFs------------55
3-4.4. In vitro cytotoxicity assay---------------------------------55
3-4.5. Cellular expression of HSP70--------------------------------56
3-4.6. Cellular uptake of test MOFs--------------------------------56
3-4.7. In vitro degradability of test MOFs-------------------------56
3-4.8. In vitro activation of macrophages--------------------------57
3-4.9. Experimental animals----------------------------------------57
3-4.10. Intratumoral retention of test MOFs------------------------57
3-4.11. In vivo photothermal effect--------------------------------58
3-4.12. In vivo cellular uptake of test MOFs-----------------------58
3-4.13. In vivo antitumor studies----------------------------------59
3-4.14. IFN-γ-secreting CD8+ T-cell ELISPOT assay-----------------59
3-4.15. Histological analysis--------------------------------------60
3-4.16. Analysis of tumor microenvironment-------------------------60
3-4.17. Blood biochemistry-----------------------------------------61
3-4.18. Statistics-------------------------------------------------61
Chapter 4 Pollen-Mimetic MOFs with Tunable Spike-Like Nanostructures that Promote Cell Interactions to Improve Antigen-Specific Humoral Immunity
4-1. Introduction--------------------------------------------------63
4-2. Results and discussion----------------------------------------65
4-2.1. Characteristics of MOFs-------------------------------------65
4-2.2. Cytotoxicity of MOFs----------------------------------------69
4-2.3. Uptake of MOFs by macrophages-------------------------------69
4-2.4. Characteristics of OVA@MOFs---------------------------------71
4-2.5. Uptake of OVA@MOFs by macrophages---------------------------74
4-2.6. In vitro disintegration of OVA@MOFs-------------------------75
4-2.7. In vitro immune activation by OVA@MOFs----------------------76
4-2.8. In vivo humoral immune response-----------------------------78
4-2.9. Biosafety of OVA@MOFs---------------------------------------78
4-3. Conclusions---------------------------------------------------80
4-4. Materials and methods-----------------------------------------81
4-4.1. Materials---------------------------------------------------81
4-4.2. Preparation and characterization of MOFs--------------------81
4-4.3. Preparation and characterization of OVA@MOFs----------------81
4-4.4. Cell viability assay----------------------------------------82
4-4.5. Attachment of MOFs to macrophages, their uptake and activation---------------------------------------------------------83
4-4.6. Experimental animals----------------------------------------83
4-4.7. In vivo OVA-specific humoral immune responses---------------84
4-4.8. Histological analysis and blood biochemistry----------------84
4-4.9. Statistical analysis----------------------------------------84
Chapter 5 References-----------------------------------------------86
Publications-------------------------------------------------------105

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