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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81915完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 牟中原(Chung-Yuan Mou) | |
| dc.contributor.author | Li Xu | en |
| dc.contributor.author | 許立 | zh_TW |
| dc.date.accessioned | 2022-11-25T03:06:32Z | - |
| dc.date.available | 2027-01-01 | |
| dc.date.copyright | 2022-02-18 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-02-09 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/81915 | - |
| dc.description.abstract | "癌症是由快速生長的異常細胞所引起的一組導致身體失常的疾病的通稱，這些異常細胞可超越其通常邊界生長並侵襲擴散到其他器官。長久以來，癌症通常以結合手術、化療及放射療法的方式進行治療，但是這些傳統療法在臨床應用上始終有一定的侷限性。近年來，隨著科學研究的進步，基於人體自身免疫機制而開發的免疫治療及利用奈米科技開發的新型藥物和診斷試劑吸引了越來越多的目光，並已逐步進入臨床，諸如免疫檢查點抑制劑、脂質體藥物製劑等已在臨床上取得了矚目的成果。在本研究中，我們利用高生物相容性的中孔洞氧化矽奈米材料為主體，利用其具有的高比表面積、孔洞體積及表面官能修飾之特性，結合不同結構修飾及藥物負載，將其應用於腫瘤治療並取得了一定成效。本論文具體可分為以下三個主題： （1）如何克服腫瘤所建立的免疫抑制微環境，是腫瘤免疫治療一大挑戰。在此部份研究中，我們以正電荷修飾之中孔洞氧化矽奈米材料為載體，利用其攜帶干擾素基因刺激蛋白（STING）通路激動劑環二鳥苷酸（c-di-GMP, cdG）作為免疫佐劑，並通過腫瘤原位疫苗技術應用於小鼠乳癌腫瘤模型。實驗證明利用中孔洞氧化矽奈米製劑可以提升環二鳥苷酸療效，增加腫瘤微環境中樹突狀細胞、巨噬細胞及T細胞的比例，並最終有效抑制腫瘤生長。 （2）利用反相微乳系統及基於結構差異之選擇性蝕刻策略合成了具有中空結構的空心球狀中孔洞氧化矽奈米材料。將此材料應用於小鼠乳癌腫瘤模型，發現材料本身即具有佐劑特質，可以提高腫瘤微環境中巨噬細胞及細胞毒性T細胞的比例，並一定程度上抑制腫瘤生長。將其與免疫檢查點抑制劑anti-PD-1聯合使用，可達到進一步抑制腫瘤之效果。 （3）利用反相微乳系統及基於結構差異之選擇性蝕刻策略合成了具有雙層球殼結構的空心球狀中孔洞氧化矽奈米材料。我們結合腫瘤微環境通常具有酸性特質及較高濃度的過氧化氫之特性，進一步在雙層空心球狀中孔洞氧化矽奈米材料結構中引入一定含量的氧化錳（MnOx），主要利用二氧化錳與過氧化氫之反應性，從而得到了具有腫瘤微環境特異性的奈米載體。利用此載體攜帶化療藥物阿黴素應用於雞胚胎腫瘤模型，相同藥物劑量治療後，載體-阿黴素製劑具有更好之腫瘤抑制效果。 綜上所述，不同表面或者結構修飾之中孔洞氧化矽奈米材料，作為載體與其他生物試劑諸如免疫佐劑或者化療藥物組合，可用於動物腫瘤模型並展現出良好的腫瘤抑制效果。此外，具有中空結構之中孔洞氧化矽奈米材料本身亦具有免疫佐劑之潛力。在之後的研究中，我們希望進一步探究此類中孔洞氧化矽奈米材料的作用機制及應用，並評估其進一步往臨床實驗之可能。" | zh_TW |
| dc.description.provenance | Made available in DSpace on 2022-11-25T03:06:32Z (GMT). No. of bitstreams: 1 U0001-0802202204404700.pdf: 6146534 bytes, checksum: eca8ba2ab4bbebfe78108cb1f87d329e (MD5) Previous issue date: 2022 | en |
| dc.description.tableofcontents | "Contents 誌謝 I 中文摘要 II Abstract IV List of Figures XIII List of Tables XXI List of Abbreviations XXII Chapter 1 General introduction 1 1.1 Introduction of mesoporous silica nanoparticles 1 1.1.1 Synthesis of mesoporous silica nanoparticles (MSNs) 1 1.1.2 Synthesis of hollow silica nanospheres (HSNs) 4 1.1.3 Biomedical applications of mesoporous silica nanoparticles 8 1.2 Introduction of tumor microenvironment 10 1.3 Introduction of cancer immunotherapy 11 1.3.1 Mechanism of Cancer-Immunity Cycle for killing cancer 11 1.3.2 Therapeutic cancer vaccine 13 1.3.3 Immune checkpoint inhibitors 15 1.3.4 Adoptive cellular immunotherapy 18 Chapter 2 STING activator c-di-GMP-loaded mesoporous silica nanoparticles enhance immunotherapy against breast cancer 20 2.1 Abstract 20 2.2 Introduction 22 2.3 Materials and methods 28 2.3.1 Chemicals and reagents 28 2.3.2 Cell lines and animals 28 2.3.3 Synthesis of RMSN-PEG-TA 29 2.3.4 Characterizations of nanoparticles 30 2.3.5 Preparation of cdG-loaded RMSN-PEG-TA 30 2.3.6 Drug release profile 31 2.3.7 In vitro cellular uptake 31 2.3.8 Cell viability assay 32 2.3.9 Real-time PCR 32 2.3.10 Western Blot 33 2.3.11 Tumor growth and measurements 34 2.3.12 Leukocytes staining and flow cytometric analysis 35 2.3.13 Immunohistochemistry 36 2.3.14 Statistics 36 2.4 Results and discussion 38 2.4.1 Preparation and characterization of RMSN-PEG-TA 38 2.4.2 Treatment of cdG@RMSN-PEG-TA nanoparticles activates immune cytokine production in vitro 40 2.4.3 Injection of cdG@RMSN-PEG-TA nanoparticles is highly effective at reducing tumor growth in vivo 45 2.4.4 Administration of cdG@RMSN-PEG-TA nanoparticles triggers immune responses within the TME 50 2.5 Conclusion 53 Chapter 3 Hollow mesoporous silica nanospheres stimulate antitumor immunity in vivo 54 3.1 Abstract 54 3.2 Introduction 56 3.3 Materials and methods 60 3.3.1 Chemicals and reagents 60 3.3.2 Cell lines and animals 60 3.3.3 Synthesis of mesoporous silica nanospheres with different hollow cavities 60 3.3.4 Nanoparticle characterization 63 3.3.5 Cell viability assay 63 3.3.6 Tumor models and treatment 63 3.3.7 Leukocytes staining and flow cytometric analysis 65 3.3.8 Detection of IFN-γ production by CD8+ T cells 65 3.3.9 Statistics 66 3.4 Results and discussion 67 3.4.1 Preparation and characterization of hollow mesoporous silica nanospheres 67 3.4.2 Antitumor effects of mesoporous silica nanospheres with different hollow structure in vivo 69 3.4.3 In vivo and ex vivo immunogenic activity of hollow mesoporous silica nanospheres 73 3.4.4 Antitumor effects of HSN and its combination immunotherapy 80 3.5 Conclusion 84 Chapter 4 Manganese oxide (MnOx)-based hollow mesoporous silica nanospheres as tumor-microenvironment-responsive nanocarriers for cancer therapy 85 4.1 Abstract 85 4.2 Introduction 87 4.3 Materials and methods 90 4.3.1 Chemicals and reagents 90 4.3.2 Cell lines and animals 90 4.3.3 Synthesis of TA-modified/PEGylated/red fluorescent double-shell hollow mesoporous silica nanospheres (RHSN-PEG-TA) 91 4.3.4 Synthesis of MnOx-decorated RHSN-PEG-TA (RHSN-Mn-PEG-TA) 92 4.3.5 Nanoparticle characterization 93 4.3.6 Dissolved oxygen assay 94 4.3.7 In vitro nanoparticle degradation assay 94 4.3.8 Doxorubicin loading in hollow mesoporous silica nanospheres 94 4.3.9 Drug release profile characterization 95 4.3.10 Cell viability assay 96 4.3.11 Tumor models and treatment 96 4.3.12 Statistics 97 4.4 Results and discussion 98 4.4.1 Preparation and characterization of RHSN-PEG-TA and RHSN-Mn-PEG-TA 98 4.4.2 H2O2-dependent RHSN-Mn-PEG-TA decomposition and drug release of DOX@RHSN-Mn-PEG-TA 104 4.4.3 Cytotoxicity study with DOX@RHSN-Mn-PEG-TA in vitro 109 4.4.4 Antitumor effects of DOX@RHSN-Mn-PEG-TA in vivo 114 4.5 Conclusion 117 Reference 119 List of Figures Figure 1-1. Effects of pH value on the silica condensation rate, charge properties and charge density on the surface of the silica species.9 Reprinted with permission from reference 9. 2 Figure 1-2. Scheme of the formation mechanism of MCM-41.10 Reprinted with permission from reference 10. 3 Figure 1-3. The proposed mechanism of silica nanoparticles in W/O mircoemulsion system.20 Reprinted with permission from reference 20. 7 Figure 1-4. The Cancer-Immunity Cycle. Abbreviations are as follows: APCs, antigen presenting cells; CTLs, cytotoxic T lymphocytes.26 Reprinted with permission from reference 26. 12 Figure 1-5. Therapeutic cancer vaccine target types. Targets for tumor vaccines fall into two general classes: tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs).27 Reprinted with permission from reference 27. 14 Figure 1-6. Blockade of CTLA-4 and of PD-1 and PD-L1 to induce antitumor responses.36 Reprinted with permission from reference 36. 17 Figure 1-7. Schematic overview of the processes for adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), ACT with T cell receptor (TCR) gene therapy and ACT with chimeric antigen receptor (CAR)-modified T cells.45 Reprinted with permission from reference 45. 19 Figure 2-1. Schematic diagram of the STING activator cdG-loaded MSNs. 21 Figure 2-2. Model for STING-dependent pathway activation by cytosolic double-stranded (ds) DNA 60. Reprinted with permission from reference 60. 25 Figure 2-3. Characteristics of the RMSN-PEG-TA. (a) Transmission electron microscopy image of RMSN-PEG-TA (Inset: a magnification of image). (b) The particle size distribution was counted from TEM image and fitted with a normal function. (c) Zeta potential titration curve of RMSN-PEG-TA. (d) Nitrogen adsorption desorption isotherms and BJH pore size distributions (inset) of RMSN-PEG-TA. 39 Figure 2-4. The cellular uptake (a) and cytotoxicity (b) of RMSN-PEG-TA in RAW 264.7 cells were measured by flow cytometry and Cell Counting Kit-8, respectively. Data were shown as mean±SD (n=3). 41 Figure 2-5. Drug release profile of cdG@RMSN-PEG-TA. Data were shown as mean±SD (n=3). 42 Figure 2-6. cdG@RMSN-PEG-TA activated the RAW 264.7 cells in vitro. (a) The observation of the cell morphology changes with bright field microscope images in RAW 264.7 cells treated with PBS, LPS (200 ng/mL), RMSN-PEG-TA or cdG@RMSN-PEG-TA for 12 h (magnification: 400x). (b) RAW 264.7 cells were treated with 20 μM cdG, cdG@ RMSN-PEG-TA or RMSN-PEG-TA for 6 h. Quantitative PCR was performed for IL-1β, IFN-β and IL-6 gene expression analysis. The results were normalized to those of GAPDH. Data were shown as mean±SD (n=3). 44 Figure 2-7. RAW 264.7 cells were treated with 15 μM cdG, equivalent dose of cdG@ RMSN-PEG-TA or RMSN-PEG-TA for 24 h. Western bolt investigated the protein expression level of phospho-STING (Ser 365). 45 Figure 2-8. Antitumor activity of cdG@RMSN-PEG-TA in 4T1 tumor bearing Balb/c mice. (a) A schematic diagram of the therapeutic mice model. Balb/c mice were subcutaneously injected with 1×106 4T1 cells in the flank at day 0. Intratumoral injections of RMSN-PEG-TA, free cdG or cdG@RMSN-PEG-TA were started at day 8, 11, and 14. The tumor size (b) and body weight (c) were monitored. All mice were sacrificed at day 25. Representative tumors in each group (d) and the average tumor weight (e) were examined, respectively. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05, n=5). 48 Figure 2-9. Immunostaining of tumor tissues. At the end of the experiment, mice were euthanized and tumors were excised for tissue sections. (a) Overview of the immunohistochemistry staining of Ki-67 in tumor sections (scale bar: 6000 μm) and the (b) magnified images (scale bar: 50 μm). (c) Immunofluorescence staining of p-STING in tumor sections. Ki-67 (DAB, brown), Nuclei (DAPI, blue) and phospho-STING (Ser365) (Alexa-488 labeled, green) were stained (scale bar: 100 μm). 49 Figure 2-10. After 24 h intratumoral injections of RMSN-PEG-TA, cdG and cdG@RMSN-PEG-TA, the percentages of tumor-infiltrating myeloid and lymphoid cells within tumor were analysed by flow cytometry. Data were shown as mean±SD (****P≤0.0001, ***P≤0.001, **P≤0.01, *P≤0.05, n=3). 52 Figure 2-11. (a) Immunohistochemistry staining of tumor sections. Nuclei (DAPI, blue), cdG@RMSN-PEG-TA (RITC, red), and CD11c (Alexa-488 labeled, green) were observed (scale bar: 200 μm). (b) Percentages of nanoparticle-positive CD11c+ cells in tumor. Data were shown as mean±SD (n=3). 53 Figure 3-1. Schematic diagram of hollow mesoporous silica nanosphere as antitumor immune modulators 55 Figure 3-2. Flow chart of the synthetic process of different hollow mesoporous silica nanospheres. 62 Figure 3-3. TEM images of HSN, HSN-SS and HSN-CS (upper lane). The corresponding mean diameter and size distribution were calculated and fitted with a normal function, respectively (lower lane). 68 Figure 3-4. Antitumor activity of hollow mesoporous silica nanospheres in 4T1 tumor bearing Balb/c mice. (a) A schematic diagram of the therapeutic mice model. Balb/c mice were subcutaneously injected with 1×106 4T1 cells in the flank at day 0. Intravenous (iv) injection of PBS, HSN, HSN-SS or HSN-CS were started at days 4, 11, and 18. The tumor size (b, d, f) and body weight (c, e, g) were monitored, respectively. Data were shown as mean±SD (n=4). 71 Figure 3-5. Impacts of hollow mesoporous silica nanospheres in blood parameters in 4T1 tumor bearing Balb/c mice. (a) RBC, total number of erythrocytes; (b) HGB, hemoglobin concentration; (c) PLT, total number of platelets; (d) WBC, total number of leukocytes. Data were shown as mean±SD (n=4). 73 Figure 3-6. Intravenous injection of hollow mesoporous silica nanospheres enhanced leukocytes infiltration in 4T1 tumor bearing Balb/c mice. The population of various immune cells in spleen (a), lymph node (b) and tumor mass (c) were assayed by flow cytometry. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05). 76 Figure 3-7. Hollow mesoporous silica nanospheres induced potent CD8a+ T cells-mediated antitumor immunity. (a) Experimental treatment protocol; (b) Bright field images of cells after 20 h co-culture (magnification: 200X); (c) Cell viabilities of the PBMCs-treated 4T1 cells; (d) Percentages of CD8a+ IFN-γ+ T cells in PBMCs. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05). 79 Figure 3-8. Antitumor activity of HSNs in 4T1 tumor bearing Balb/c mice. (a) A schematic diagram of the therapeutic mice model. Balb/c mice were subcutaneously injected with 1×106 4T1 cells in the flank at day 0. Intravenous (iv) injection of PBS, HSNs were started at days 8, 12, and 16. The tumor size (b) and body weight (c) were monitored, respectively. All mice were sacrificed at day 22. Representative tumors in each group (d) and the average tumor weight (e) were measured, respectively. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05). 81 Figure 3-9. Antitumor activity of HSNs and anti-PD in 4T1 tumor bearing Balb/c mice. (a) A schematic diagram of the therapeutic mice model. Balb/c mice were subcutaneously injected with 1×106 4T1 cells in the flank on day 0. Intravenous (iv) injections of HSN were started on day 4, 11, and 18. While intraperitoneal (ip) injections of anti-PD-1 were started on day 4, 7, 11, and 14. The tumor size (b) and body weight (c) were monitored, respectively. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05). 83 Figure 4-1. Schematic illustration of DOX@RHSN-Mn-PEG-TA as a tumor-microenvironment-responsive antitumor agent. 86 Figure 4-2. TEM images of RHSN-PEG-TA (a) and RHSN-Mn-PEG-TA (c). The corresponding mean diameter and size distribution were calculated and fitted with a normal function, respectively (b, d). 100 Figure 4-3. Dark-field TEM image of RHSN-Mn-PEG-TA with EDX maps for Si, O and Mn (a) and the corresponding spectrum (b). 101 Figure 4-4. Nitrogen adsorption-desorption isotherms and BJH pore size distributions (inset) of RHSN-PEG-TA (a) and RHSN-Mn-PEG-TA (b). 102 Figure 4-5. Hydrodynamic diameter intensity distributions and Zeta potential titration curve of RHSN-PEG-TA (a, b) and RHSN-Mn-PEG-TA (c, d), respectively. Data were shown as mean±SD (n=3). 103 Figure 4-6. RHSN-PEG-TA and RHSN-Mn-PEG-TA were incubated with PBS or 100 μM H2O2 containing PBS solution for 24 h. The sizes of nanoparticles were measured by DLS (a) and then the nanoparticles were imaged by TEM (b). Data were shown as mean±SD (n=3). 105 Figure 4-7. The O2 generation of RHSN-Mn-PEG-TA in PBS solutions with various concentrations of c and pH values were evaluated by using a dissolved oxygen meter (Inset: bubbles were observed when 100 μL of 10 M H2O2 solution was added into 100 μL of 5 mg/mL RHSN-Mn-PEG-TA solution). 106 Figure 4-8. (a) Hydrodynamic diameters of DOX@RHSN-Mn-PEG-TA. (b) In vitro drug release profile of DOX@HSN-Mn-PEG-TA. Data were shown as mean±SD (n=3). 108 Figure 4-9. Intracellular distribution of RHSN-Mn-PEG-TA. RHSN-Mn-PEG-TA (75 μg/mL) were incubated with OVCAR-8 cells (a) and 4T1 cells (b) for 24h, and the images were recorded by fluorescence microscope, respectively. Nuclei (Hoechst 33342, blue) and nanoparticles (RITC, red) were stained (scale bar: 50 μm). 111 Figure 4-10. DOX@RHSN-Mn-PEG-TA exhibited enhanced cytotoxicity in vitro. DOX (2 μg/mL) and equivalent dose of nanoparticles were incubated with OVCAR-8 cells (a) and 4T1 cells (b) for 24h. Cytotoxicities were measured by Cell Counting Kit-8. Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05, n=3) 112 Figure 4-11. DOX (2 μg/mL) and equivalent dose of DOX@HSN-Mn-PEG-TA were incubated with OVCAR-8 cells (a) and 4T1 cells (b) for 24h and the images were recorded by fluorescence microscope, respectively. Nuclei (Hoechst 33342, blue) and DOX (red) were stained (scale bar: 50 μm). 113 Figure 4-12. Schematic diagram of the CAM assay.114 Reprinted with permission from reference 114. 115 Figure 4-13. Intravenous injection of DOX@RHSN-Mn-PEG-TA results in the elimination of tumor on chicken CAM membrane. (a) A schematic timeline of the experiment. (b) The sizes of representative tumors were recorded by bright field (magnification: 100x). 117 Figure 4-14. Antitumor effect of DOX@RHSN-Mn-PEG-TA in CAM assay. Representative tumors were recorded (a) and tumor weights were measured (b). Data were shown as mean±SD (***P≤0.001, **P≤0.01, *P≤0.05). 117 List of Tables Table 2-1. Primer sequences used for quantitative Real-time PCR amplification. 33 Table 2-2. Hydrodynamic size of nanoparticles in different solvent. 40 Table 3-1. Hydrodynamic size of nanoparticles in different solvent. 69 Table 4-1. Hydrodynamic size and isoelectric point of nanoparticles in different solvent. 103" | |
| dc.language.iso | en | |
| dc.subject | 中孔洞氧化矽奈米材料 | zh_TW |
| dc.subject | 腫瘤微環境 | zh_TW |
| dc.subject | 雙層空心球氧化矽奈米材料 | zh_TW |
| dc.subject | 腫瘤治療 | zh_TW |
| dc.subject | 腫瘤原位疫苗 | zh_TW |
| dc.subject | 佐劑 | zh_TW |
| dc.subject | Mesoporous silica nanoparticles | en |
| dc.subject | Adjuvant | en |
| dc.subject | In situ vaccination | en |
| dc.subject | Cancer therapy | en |
| dc.subject | Tumor microenvironment | en |
| dc.subject | Doule-shell hollow mesoporous silica nanospheres | en |
| dc.title | 功能性中孔洞氧化矽奈米材料於腫瘤治療之應用 | zh_TW |
| dc.title | Developing and Utilizing Functional Mesoporous Silica Nanoparticles for Cancer Therapy | en |
| dc.date.schoolyear | 110-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王宗興(Wen-Yu Hu),張煥正(Yen-Chun Lin),陳韻晶,陳奕平 | |
| dc.subject.keyword | 中孔洞氧化矽奈米材料,腫瘤微環境,腫瘤治療,腫瘤原位疫苗,佐劑,雙層空心球氧化矽奈米材料, | zh_TW |
| dc.subject.keyword | Mesoporous silica nanoparticles,Tumor microenvironment,Cancer therapy,In situ vaccination,Adjuvant,Doule-shell hollow mesoporous silica nanospheres, | en |
| dc.relation.page | 138 | |
| dc.identifier.doi | 10.6342/NTU202200356 | |
| dc.rights.note | 同意授權(全球公開) | |
| dc.date.accepted | 2022-02-11 | |
| dc.contributor.author-college | 理學院 | zh_TW |
| dc.contributor.author-dept | 化學研究所 | zh_TW |
| dc.date.embargo-lift | 2027-01-01 | - |
| 顯示於系所單位： | 化學系 | |
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| U0001-0802202204404700.pdf 此日期後於網路公開 2027-01-01 | 6 MB | Adobe PDF |
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