以Integrin為目標之標靶鐵蛋白應用於腫瘤分子影像與藥物載體之可行性研究

王栩沅

doi:10.6342/NTU201703622

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以Integrin为目标之标靶铁蛋白应用於肿瘤分子影像与药物载体之可行性研究

Integrin-targeting ferritin nanoparticles for tumor imaging and drug delivery

王栩沅 , 硕士　　导师：黄枫婷　　

繁体中文 DOI： 10.6342/NTU201703622

铁蛋白； RGD胜肽； DGEA胜肽；阿霉素；药物载体；分子影像； ferritin ； RGD peptide ； DGEA peptide ； doxorubicin ； drug delivery ； molecular imaging

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摘要 │ 参考文献 (37) │ 国际计量

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In tradition, drugs for cancer treatment always belong to a dump release system. Furthermore, people are devoted to developing the new drug delivery for cancer therapy. Recently, liposomes, primarily composed of phospholipids, are the major drug delivery system. However, liposomes still have some disadvantages as follows. In recent years, there are many research for find new drug delivery, and the ferritin is the one of them. 
Ferritin is composed of 24 subunits and able to self-assemble to form a nanocage structure with external and internal diameters of 12 and 8 nm, respectively. Ferritin can be easily modified and conjugated with various molecules onto the surface, including dye, peptides, siRNA or antibodies etc. the cavity of ferritin can be loaded drugs. 
Recent studies demonstrated RGD-modified ferritin had potential in cancer diagnosis and therapy. The RGD peptide has high affinity to integrin αVβ3, a tumor angiogenesis biomarker, and is currently applied to clinical cancer imaging. However, the RGD peptide has disadvantages that the peptide also targets to endothelial cells, leading to stimulation of tumor growth and angiogenesis. 
Hence, in this study, we wanted to construct a new drug delivery and applied on molecular imaging and cancer therapy. We intended to set up the integrin-targeted ferritin with the DGEA (Asp-Gly-Glu-Ala) peptide which has high affinity to integrin α2β1. In the thesis, we not only made the construct of DGEA-ferritin but also tried the 2xDGEA-ferritin to assess the effect of increasing the copy number of DGEA on the surface of ferritins. Next, we estimated the tumor targeting ability of DGEA-ferritin and 2xDGEA-ferritin on U-87 MG, glioblastoma cell line, or PC-3, human prostate cancer cell line, by incubating cells with FITC-labeled protein. After confirming that proteins could recognize cancer cells through the DGEA peptide, we loaded the doxorubicin into 2xDGEA-ferritin. Through the MTT assay, we demonstrated that the 2xDGEA-ferritin could kill cancer cells and improved drug efficiency, which could use less amount of doxorubicin than free doxorubicin to achieve the same cellular toxicity effect. In the future, we will do in vivo experiments to confirm the potential of developing this drug delivery. If the system succeeds, it will be a new, safe and efficient technology and has great potential in clinical application. Furthermore, multiple peptides could be constructed on the ferritin or other drugs be loaded into the ferritin, and apply these modified-ferritins on molecular imaging and cancer therapy.

参考文献 ( 37 ) 〈TOP〉

[1] Kinam Park. (2014). Controlled drug delivery systems: Past forward and future back. Journal of Controlled Release, 190, 3-8. doi: 10.1016/j.jconrel.2014.03.054.
连结：
[2] L Hendeles, M Weinberger, G Milavetz, M Hill 3d and L Vaughan. (1985). Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity. Chest, 87(6), 758-765.
连结：
[3] Gaurav Tiwari, Ruchi Tiwari, Birendra Sriwastawa, L Bhati, S Pandey, P Pandey, Saurabh K Bannerjee. (2012). Drug delivery systems: An updated review. Int J Pharm Investig, 2(1), 2–11. doi: 10.4103/2230-973X.96920
连结：
[4] Hyo Jin Kang, Young Ji Kang, Young-Mi Lee, Hyun-Hee Shin, Sang J. Chung, Sebyung Kang. (2012). Developing an antibody-binding protein cage as a molecular recognition drug modular nanoplatform. Biomaterials, 33(21), 5423-5430. doi: 10.1016/j.biomaterials.2012.03.055.
连结：
[5] Marta Truffi, Luisa Fiandra, Luca Sorrentino, Matteo Monieri, Fabio Corsi, Serena Mazzucchelli. (2016). Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer. Pharmacological Research. 107, 57-65. doi: 10.1016/j.phrs.2016.03.002.
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引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。