介孔性二氧化矽奈米粒子(mesoporous silica nanoparticles, MSNs)具有一些優秀的特性，如高比表面積與孔洞體積、獨特的介孔結構與可調孔徑大小、易於表面修飾，與優良的生物相容性等。然而，奈米粒子(NPs)在生物體內的血管中容易被免疫系統視為入侵者，而被網狀內皮系統(reticuloendothelial system, RES)/單核吞噬細胞系統(mononuclear phagocyte system, MPS)清除。因此本研究利用紅血球膜包覆MSNs的方式進行偽裝，延長在體內血液循環的壽命。
　　本研究第一部分先探討紅血球膜對不同大小的MSNs進行包覆的差異。改變styrene的濃度，合成出110-450 nm大小的MSNs，利用比表面積分析儀(surface area and porosimetry analyser, ASAP/BET)和熱重量分析儀(thermogravimetric Analyzer, TGA)分析MSNs的性質，孔洞大小為12 nm；再利用掃描式電子顯微鏡(scanning electron microscopy, SEM)、穿透式電子顯微鏡(transmission electron microscopy, TEM)、表面電位和膠體電泳(SDS-PAGE)去驗證紅血球膜包覆在MSNs的表面，得出包覆在不同大小MSNs上的紅血球膜厚度約9-10 nm。在細胞存活率結果顯示，紅血球膜包覆的MSNs無顯著毒性。在動物實驗中，紅血球膜包覆的大小MSNs的累積程度沒有差異，但大RBCm@MSNs的累積量較小的多4.5倍，顯示出延長血液循環並累積達四天的成果。
　　第二部分將MSNs同時裝載疏水性藥物歐洲紫杉醇(Docetaxel, DTX)和石墨烯量子點(graphene quantum dots, GQD)，裝載量(loading capacity, LC)和包覆率(encapsulation efficiency, EE)分別為72.3%和80.3%。透過近紅外光(808 nm)照射後，裝載GQD可在5分鐘內升溫至65 °C。利用化療與熱療的方式達到協同治療的效果。再利用標靶性蛋白藥物爾必得舒(Erbitux®)修飾在紅血球膜表面，增強對A549(人類肺癌細胞株)的治療效果，在治療後第三天抑制住腫瘤生長。

　　本研究開發出具標靶性紅血球膜包覆介孔性二氧化矽奈米粒子，同時裝載DTX和GQD，經由近紅外光照射，產生化療與熱療的協同治療效果，有效抑制老鼠身上A549腫瘤細胞的生長達19天以上。

Mesoporous silica nanoparticles (MSNs) have some excellent properties, such as high surface areas and large pore volumes, unique mesoporous structure and tunable pore sizes, ease of surface modification, and good biocompatibility. However, nanoparticles (NPs) are introduced to in vivo applications through the bloodstream; they are easily considered as intruders by the innate immune system and cleared by the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS). Therefore, this study utilizesd the approach of erythrocyte membranes (red blood cell membranes, RBCm) coated MSNs camouflage to prolong the circulation lifetime.
In the first study project, RBCm coated different sizes of MSNs were investigated. The sizes of MSNs synthesized were 110-450 nm in different concentration of styrene. The properties of MSNs were first analyzed with surface area and porosimetry analyser (ASAP/BET) and thermogravimetric analyzer (TGA). The pore size of MSNs was 12 nm. Then, we confirmed RBCm coated on the surface of MSNs with scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta potential, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The thickness of as-prepared RBCm coated MSNs (RBCm@MSNs) were 9-10 nm in different sizes. RBCm@MSNs showed no significant toxicity by cell viability. The accumulative level of RBCm@MSNs in different size were no difference, but amount of big RBCm@MSNs were accumulated 4.5 times more than small one. In vivo experiments, RBCm@MSNs prolonged the blood circulation and accumulated for 4 days.

In the second project, MSNs were loaded hydrophobic drug Docetaxel (DTX) and graphene quantum dots (GQD). The loading capacity (LC) and drug encapsulation efficiency (EE) were 72.3 % and 80.3 %, respectively. GQD loaded MSNs were heated to 65 °C in 5 minutes with near-infrared irradiation (808 nm). GQD loaded MSNs combined chemotherapy and thermal therapy to achieve synergistic therapeutic effects. Then, targeting protein drug, Erbitux, modified on the surface of RBCm to enhance treatment effects to A549 (a human lung carcinoma cell line) cancer cells and inhibited the tumor growth after treatments on the third day.
This study developed targeting RBCm coated MSNs loaded DTX and GQD produced synergistic therapeutic effect of chemotherapy and thermal therapy to inhibit A549 tumor cells on the mice growth with near-infrared irradiation up to 19 days.

摘要 I
Abstract III
致謝 V
List of Figures IX
List of Tables XIII
List of Schemes XIV
Chapter 1 Literature Review and Theory 1
1.1 Nanoparticles for Drug Delivery Systems 1
1.2 Erythrocyte Membrane-Camouflaged DDS 5
1.3 Tumor Penetration 12
Chapter 2 Experimental Section 16
2.1 Materials 16
2.2 Apparatus 18
2.3 Synthesis of mesoporous silica nanoparticles (MSNs) 19
2.4 Preparation of RBC-Membrane-Derived Vesicles 20
2.5 Fusion of RBCm-Derived Vesicles with MSNs. 20
2.6 Synthesis of graphene quantum dots (GQD) 21
2.7 Characterization 22
2.8 Photothermal heating effect of GQD and MSNs 22
2.9 Drug loading and drug encapsulation efficiency 22
2.10 In Vitro Release 23
2.11 Cell culture 23
2.12 Cell vability assay 24
2.13 Cellular uptake of MSNs 24
2.14Targeting ability of the Erbitux-RBCm@LPMSNs was quantified by flow cytometry 25
2.15In vivo experiments 25
Chapter 3 Results and Discussions 27
3.1 RBCm coating MSNs for circulation in size effects 27
3.1.1 Characterizations of MSNs 27
3.1.2 Characterizations of RBCm@MSNs 30
3.1.3 Cytotoxicity and cell uptake of MSNs 33
3.1.4 In Vivo Experiments 35
3.2 Targeting RBCm@LPMSNs in Cancer Therapy 37
3.2.1 Characterization of Erbitux-RBCm@LPMSNs 37
3.2.2 Characterization of LPMSNs@GQD 39
3.2.3 Drug loading capacity and NIR light-triggered drug release of LPMSNs 42
3.2.4 In Vitro Experiments 43
3.2.5 In Vivo Experiments 46
Chapter 4 Conclusions 51
Reference 52

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