隨著醫學領域技術的發展，腦癌作為最臭名昭著的癌症之一，其診斷和治療也取得了很大的進步。儘管如此，與其他癌症相比，用於腦腫瘤的藥物輸送系統仍有許多改進的空間。為了克服血腦屏障（BBB）的障礙及改善腦腫瘤標靶效率，我們首先合成了兩種具有潛力的奈米傳遞系統。一種是由BV2微膠細胞之細胞膜所包裹的PLGA納米顆粒。另一種是利用月桂酸沒食子酸酯搭載阿黴素（DOX）的奈米顆粒。
兩種奈米顆粒均顯示出直徑約200 nm並且在水溶液中穩定，與裸露的PLGA奈米顆粒和裝有DOX的脂質體LIPO-DOX相比，兩種奈米顆粒在小鼠星狀膠質細胞瘤細胞系ALTS1C1的攝取量更高。此外，這兩種奈米顆粒在腦腫瘤藥物輸送系統中表現出不同的優勢。例如BV2細胞膜包裹的奈米顆粒在小鼠腦中表現出潛在的高浸潤性，還有月桂酸沒食子酸酯搭載DOX的奈米顆粒不僅對正常細胞和癌細胞具有選擇性的細胞毒性，也具有潛在對抗P-gp高表達的抗藥性腦癌細胞系ALTS1C1。希望藉助奈米技術結合具有腦腫瘤靶向能力的高生物相容性材料，這些奈米遞送系統將來可以應用於腦腫瘤的診斷或治療。

With the development of technology in the medical field, the diagnosis and treatment of brain cancers, one of the most notorious cancer, have made much progress. The drug delivery system for brain tumors still has many rooms for improvement compared to other cancers. To overcome the hindrance of the blood-brain barrier (BBB) without affecting the homeostasis in the brain and increase the brain tumor targeting ability, we first synthesized two kinds of potential bio-friendly nano-delivery systems. One is BV2 microglia membrane-coated PLGA nanoparticles. The other is lauryl gallate-based nanoparticles loaded with doxorubicin (DOX), a chemo-drug.
Both nanoparticles showed a diameter of around 200 nm, stable in aqueous solution, and a higher uptake amount of ALTS1C1, a murine astrocytoma cell-line compared to bare PLGA nanoparticles and LIPO-DOX, a liposome loaded with DOX individually. Besides, each nanoparticle exhibited different advantages in delivering the drug to the target brain tumor. Examples include BV2 microglia membrane-coated nanoparticles seemed to show a higher infiltration in the murine brain, and lauryl gallate-based nanoparticles loaded with DOX exhibited not only selective cytotoxicity toward normal cell and the cancer cell, but the potential of anti-drug resistance in P-gp highly expressed brain cancer cell line, ALTS1C1. With nanotechnology combined with bio-friendly materials with brain tumor targeting ability, we hope that these nano-delivery systems can be applied in the diagnosis or treatment of brain tumors in the future.

中文摘要--------1
Abstract--------2
致謝--------4
Table of contents--------5
Chapter 1: Introduction--------8
1.1 Overviews of Brain Tumors--------8
1.2 Advantages of Nanomaterials for Treating Brain Tumors--------9
1.3 Cell Membrane-Coated Nanoparticles: A Potential Biomimetic Platform--------11
1.4 Lauryl Gallate, a Promising Natural Anticancer Product--------13
1.5 The Purpose of the Study--------15
Chapter 2: Materials and Methods--------16
2.1 Cells and animals--------16
2.1.1 Cell Lines--------16
2.1.2 Animals--------17
2.2 Cell Membrane Extraction--------17
2.3 Cell Membrane Characterization--------18
2.3.1 Size and zeta potential--------18
2.3.2 Protein Quantification--------19
2.3.3 Protein Qualification--------19
2.3.3.1 SDS-PAGE--------19
2.3.3.2 Western-Blot--------21
2.3.4 In Vitro Interaction of Cell Membrane with ALTS1C1--------22
2.3.4.1 Speed and Velocity Analysis of ALTS1C1-GFP Co-cultured with Cell Membrane--------22
2.3.4.2 Cell Membrane Localization Analysis Co-cultured with ALTS1C1-GFP--------23
2.3.4.3 Colony Size and Number Analysis Formed by ALTS1C1 and Cell Membrane--------24
2.3.4.4 ALTS1C1 Uptake and Granularity Analysis Co-cultured with Cell Membrane 24
2.3.4.5 Chemo Drug Uptake Ability of ALTS1C1 Co-cultured with Cell Membrane--------25
2.4 Synthesis of PLGA/SPIO/DiO NPs--------25
2.5 Preparation of Cell Membrane-Coated PLGA/SPIO/DiO NPs--------26
2.6 Characterization of Cell Membrane-Coated PLGA/SPIO/DiO NPs--------27
2.6.1 TEM Morphology of Nanoparticles--------27
2.6.2 Size and Zeta Potential--------28
2.6.3. Content Analysis in Nanoparticles--------28
2.6.3.1 Iron Content--------28
2.6.3.2 DiO Content--------29
2.6.3.3 Protein Content--------29
2.6.4 Cellular Uptake of Nanoparticles--------29
2.6.5 Cell Toxicity Test of Nanoparticles--------30
2.6.6 In Vivo Brain Distribution of Nanoparticles--------31
2.6.7 In Vivo Immune Modulation of Nanoparticles--------31
2.7 Synthesis of Lauryl Gallate-Based Nanoparticles--------32
2.8 Characterization of Lauryl Gallate-Based Nanoparticles--------33
2.8.1 Lauryl Gallate and Cholesterol Qualification of Lauryl Gallate-Based Nanoparticles--------33
2.8.2 Stability Examination of Lauryl Gallate-Based Nanoparticles--------33
2.8.3 DiO Content and DiO Release of DiO-loaded Lauryl Gallate-Based Nanoparticles--------33
2.8.4 TEM morphology of Lauryl Gallate-Based Nanoparticles--------34
2.9 Synthesis of DOX-loaded Lauryl Gallate-Based Nanoparticles--------34
2.10 Characterization of DOX-loaded Lauryl Gallate-Based Nanoparticles--------35
2.10.1 Size and Zeta Potential of DOX-loaded Lauryl Gallate-Based Nanoparticles--------35
2.10.2 DOX Content Analysis of DOX-loaded Lauryl Gallate-Based Nanoparticles--------36
2.10.3 Cellular Uptake of DOX-loaded Lauryl Gallate-Based Nanoparticles--------36
2.10.4 Cytotoxicity Analysis of DOX-loaded Lauryl Gallate-Based Nanoparticles--------36
2.11 Statistic Analysis--------37
Chapter 3: Results--------38
3.1 Cell Membrane Characterization--------38
3.2 In Vitro Interaction of ALTS1C1 with Cell Membrane--------39
3.2.1 Colony Formation of ALTS1C1 Treated with ALTS1C1@m, BV2@m, and RAW264.7@m--------39
3.2.2 Membrane Protein Amount and Co-cultured Time Are Related to Colony Formation of ALTS1C1 Treated with ALTS1C1@m, BV2@m, and RAW264.7@m--------40
3.2.3 ALTS1C1 has a different internalized pattern with the different cell membrane--------41
3.3 Physical Characterizations of Membrane-Coated Nanoparticles--------42
3.4 Biological Characterizations of Membrane-Coated Nanoparticles--------43
3.5 Characterization of Lauryl Gallate-Based Nanoparticles--------45
3.6 Characterization of DOX-loaded Lauryl Gallate-Based Nanoparticles --------46
Chapter 4: Discussion--------49
4.1 Promising Strong Affinity of Microglia Membrane Toward Astrocytoma--------49
4.2 In vivo Behaviors of Membrane-coated Nanoparticles--------51
4.3 Factors Affecting the Physical Characterization of Lauryl Gallate-based Nanoparticles--------54
4.4 Biological Interactions of LG/CHOL@DOX NPs--------55
4.5 Future Directions--------57
Chapter 5: Conclusion--------59
Chapter 6: Figures--------60
Chapter 7: References--------93

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