肺癌治療分為四種類型，包括手術治療，放射治療，化療和標靶治療。手術治療在肺癌早期使用效果良好，而在肺癌晚期只能以化療和標靶治療並輔以放射治療作為主要治療方法，而治療效果皆相當有限。因此，本研究設計出一種偽裝外泌體(Exosome)的多孔性氧化鐵，其可以攜帶大量的化療藥物並有效地遞送到腫瘤位置。而本多孔性氧化鐵具備高度的磁性，在高週波磁場(high-frequency magnetic field)的刺激下，可以快速生熱，進而有效釋放包覆的藥物，達到熱療與化療的效果。外吐小體是生物體的天然物質，它們擁有特定的蛋白質以幫助它們在細胞之間傳遞，可以迅速進入受體細胞並且可以避免其修飾的載體遭受免疫系統的攻擊。在細胞實驗中發現修飾過外泌體的氧化鐵在第1小時其被B16F10攝取的效率與未修飾之氧化鐵第12小時的效率相似。另外，我們發現外泌體修飾的氧化鐵在不到2個小時的時間就幾乎被B16F10黑色素瘤細胞攝入至細胞核中。另外本實驗也使用B16F10黑色素瘤細胞於C57BL6小鼠中建立了肺癌模型，在經過靜脈注射修飾過外吐小體的氧化鐵的24小時候，我們發現此載體在肺中的累積明顯多於肝臟說明本載體具有傑出的標靶腫瘤功效。修飾有外吐小體的奈米氧化鐵在經過注射後的1天至3天於肺癌部位的累積量可達15-25%，而在標靶藥物爾必得舒的幫助下於肺癌部位的累積量可高達35-60%。此外，在動物生存率實驗中，不做任何治療的肺癌小鼠約存活20天，使用修飾有外泌體的奈米氧化鐵並裝載阿黴素的載體來做治療的肺癌小鼠至少可存活30天，如果與爾必得舒結合，存活時間將增加至超過40天。此外，肺癌小鼠如果使用修飾有外泌體和爾必得舒的奈米氧化鐵且裝載有阿黴素的載體且搭配高週波做治療，則其存活時間將從不做治療組的20天增加至超過50天。未來希望能將此技術運用在其它癌症治療上。

關鍵字：轉移型肺癌、多孔性奈米氧化鐵、外泌體、阿黴素、爾必得舒

Lung cancer ranks second in the proportion of cancer in Taiwan in 2018. The lung is a common location for other tumors in the body. One of the lung metastasis tumor is melanoma cells. To research for the treatment of metastasis lung cancer, the B16F10 melanoma cells which is the one kind of cancer cells tend to metastasis to lung were adopted and the model of lung cancer was founded in C57BL/6 mice. The treatment of lung cancer is divided into four types involving surgical treatment, radiation therapy, chemotherapy and target treatment. At the beginning of lung cancer, surgical and radiation therapy are superior treatment to lung cancer. Nevertheless, surgery therapy is impressive to lung cancer and radiation therapy fallen as auxiliary treatment in the late stages of cancer, the treatment is replaced with chemotherapy and target treatment. For the purpose that developing a effective treatment for metastasis lung cancer in the late stages, the chemotherapy with the target drug which is called Erbitux were applied for the treatment. Exosome-camouflaged porous iron oxide nanoparticles can carry a large amount of chemotherapeutic drugs and be effectively delivered to tumor sites. The porous iron oxide has high magnetic properties, and can stimulate heat under the stimulation of a high-frequency magnetic field. The vehicles can effectively release the coated drug in order to achieve the effects of hyperthermia and chemotherapy. Exosomes are natural substances of organisms that possess specific proteins to facilitate their transfer between cells, Further to explain for the superiority, exosomes can rapidly enter the recipient cells and can prevent their modified vectors from being attacked by the immune system. In the cell experiments, it was found that the cellular uptake efficiency of exosome-camouflaged iron oxide for the B16F10 melanoma cells at the first hour was similar to the one of the unmodified iron oxide at the 12th hour. In addition, exosome-camouflaged iron oxide was almost ingested into the nucleus by B16F10 melanoma cells in less than 2 hours. Moreover, B16F10 melanoma cells were used to establish a lung cancer model in C57BL6 mice. The time which had passed for 24 hours after intravenous injection of exosome-camouflaged iron oxide. The amount of carriers accumulated in the lung more than in the liver. These vectors had outstanding target tumor efficacy. The accumulation of exosome-camouflaged iron oxide in the lung cancer area could reach 15-25% from 1 day to 3 days after injection, and the accumulation in the lung cancer area could reach 35-60% with the auxiliary of the target drug Erbitux. Furthermore, in the animal survival rate experiment, lung cancer mice that did not undergo any treatment survived for about 20 days, and the lung cancer suffered mice that were treated with exosome-camouflaged iron oxide which was loaded with Doxorubicin survived for more than 30 days, the survival time of the lung cancer suffered mice will increase to more than 40 days if combined with Erbitux. Eventually, the survival time of the lung cnacer suffered mice would be promoted to more than 50 days after the treatment which applying the exosome-camouflaged iron oxide which bound Erbitux and loaded with Doxorubicin combined with the application of HFMF. In the future, I hope to apply this technology to other cancer treatments.

Key words：Metastasis lung cancer, Mesoporous nano iron oxide, Exosome, Doxorubicin, Erbitux

中文摘要 ---------------------------------------------------------I
Abstract-------------------------------------------------------III
誌謝-------------------------------------------------------------V
Table of contents-----------------------------------------------VI
List of tables--------------------------------------------------IX
List of figures--------------------------------------------------X
Chapter 1 Introduction-------------------------------------------1
Chapter 2 Literature review--------------------------------------2
2.1 Introduction of lung cancer----------------------------------2
2.2 The comment about the cancer cell development from the primary tumor to the metastatic disease----------------------------------4
2.3 The characteristics of melanoma cells and the therapy for it to date----------------------------------------------------------6
2.4 The properties of magnetic nanoparticles and their applications-----------------------------------------------------9
2.5 The characteristic of exosomes and their operation mode between cells---------------------------------------------------10
2.7 The development of drug delivery----------------------------15
2.8 The applications and potential of exosomes in the drug delivery--------------------------------------------------------18
2.9 The application of serum exosomes in cancer therapy---------21
Chapter 3. Experiment section-----------------------------------24
3.1 Materials---------------------------------------------------24
3.2 Apparatus---------------------------------------------------26
3.3 Synthesis of mesoporous iron oxide nanoparticles------------27
3.4 The preparation of serum and its purification---------------27
3.5 Synthesis of mesoporous iron oxide nanopaticles which bind with exosomes originated from mice serum------------------------28
3.6.1 Drug loading efficiency and encapsulation efficiency------29
3.6.2 In vitro release------------------------------------------29
3.6.3 Cell culture----------------------------------------------29
3.6.4 Cell viability assay--------------------------------------30
3.6.5 Cellular uptake of Fe3O4, Fe3O4-Tf-Exo and Fe3O4-Tf-Exos-Dox ----------------------------------------------------------------30
3.6.6 Flow cytometry--------------------------------------------31
3.7 SDS PAGE experiments----------------------------------------32
3.8 Western Blot------------------------------------------------32
3.9 In vivo experiments-----------------------------------------33
Chapter 4. Results and Discussions------------------------------34
4.1 Synthesis and characterization of mesoporous iron oxide and mesoporous iron oxide which bind with exosomes from serum-------34
4.2 Cytotoxicity and cellular uptake of Dox, Fe3O4-Tf-Exo,
Fe3O4-Tf-Exo-Dox, Fe3O4-Tf-Exo-Er, Fe3O4-Exo-Er-Dox-------------43
4.3 Flow cytometry of Fe3O4-Tf-Exo------------------------------47
4.4 Dox release from Fe3O4-Tf-Exo and Fe3O4-Tf-Exo-Er-----------48
4.5 IVIS images and biodistribution of organs-------------------50
4.6 Liver and kidney function analysis of mice after they were injected with Fe3O4-Tf-Exo, Fe3O4-Tf-Exo-Er---------------------52
4.7 In vivo therapy and histochemistry analysis-----------------53
Chapter 5 Conclusions-------------------------------------------58
Reference-------------------------------------------------------59

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