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標題: | 去鐵鐵蛋白奈米載體應用於癌症診斷與治療 Apoferritin as Nanocarriers for Cancer Diagnosis and Treatment |
作者: | Chun-Yen Lin 林君彥 |
指導教授: | 謝銘鈞(Ming-Jium Shieh) |
關鍵字: | 去鐵鐵蛋白,益樂鉑,維必施,表皮生長因子受體,艾黴素,光感藥物,大腸直腸癌, apoferritin,oxaliplatin,panitumumab,EGFR,doxorubicin,photosensitizer,colorectal cancer, |
出版年 : | 2018 |
學位: | 博士 |
摘要: | 發展多功能奈米載體可應用於工程、材料、環境及醫學多方面領域上,尤其將奈米載體應用於癌症治療更是眾多研究學者所關注的議題。多功能性奈米載體可依照其製作的材料特性而賦予不同的功能性角色。現階段常用的多功能性奈米載體主要有微脂體、微胞、樹枝狀聚合物、金奈米粒子、碳管及蛋白質。其中蛋白質載體具有高穩定性、高生物相容性、可降解姓、低毒性及低免疫性的優點,是進一步應用於人體上相對好的奈體載體。
本論文共分成兩個部分進行研究,主要以去鐵鐵蛋白作為藥物運輸的載體,對於癌症的診斷或治療。第一部分為以去鐵鐵蛋白包覆鉑類金屬藥物益樂鉑(oxaliplatin),同時在去鐵鐵蛋白表面接上抗體維必施(panitumumab),用於大腸直腸癌的治療研究。益樂鉑及維必施為對抗轉移性大腸直腸癌病人的第一線用藥。維必施抗體可辨識癌細胞表面的表皮生長因子受體,達到準確的毒殺癌細胞及降低副作用的產生。當蛋白質載體在辨識癌細胞表面時,去鐵鐵蛋白會藉由受體媒介胞吞作用,吞噬入細胞內的溶酶體系統,當去鐵鐵蛋白遇酸性環境時會自然瓦解成次單元,使得鉑類藥物釋放出來。在實驗療效結果顯示,包覆益樂鉑的標靶蛋白質載體能有效的抑制腫瘤的生長並降低其副作用的產生。 第二部分為研究去鐵鐵蛋白結合化療藥物及光感藥物的合併治療。利用去鐵鐵蛋白包覆速溶艾黴素(doxorubicin)後,在其外圍搭載光感藥物ADS-780近紅外光染劑形成顆粒型奈米結構。此顆粒型奈米結構經由光照射後會瓦解進而釋放出蛋白質內部包覆的艾黴素,以此增加腫瘤細胞的毒殺。最後,若將此顆粒型結構藉由尾靜脈注射進入老鼠體內,待24小時腫瘤大量累積蛋白質顆粒後,藉由照射近紅外光可進行熱診斷及治療。實驗結果顯示,在有照光的區域下,腫瘤體積會有效地被抑制且縮小且不造成正常組織的損傷。 整體而言,我們希望建立一個以去鐵鐵蛋白為主,依其中空的特殊結構搭載藥物分子或修飾在其外圍修飾上抗體或胜肽片段作為標靶分子,甚至可以搭載光感藥物,完成後的多功能蛋白質奈米載體可應用於癌症的診斷及標靶治療。 The development of multiple functional nanoparticles can be applied in engineering, materials, the environment and medical fields. In particular, nanomedicine has attracted many researchers focusing on cancer treatment. Versatile nanocarriers are given different functional roles depending on the properties of the materials. Commonly used multi-functional nanocarriers mainly include liposomes, micelles, dendrimers, gold nanoparticles, carbon nanotubes, and proteins. Protein carriers have the advantages of high stability, high biocompatibility, biodegradability, low cytotoxicity, and low immunogenicity. Therefore, protein carriers are valuable carriers for further applications in humans. This dissertation is separated into two parts with the principal research focusing on a drug carrier based on an apoferritin nanocage for cancer diagnosis or treatment. The first part is apoferritin (AF) encapsulated with oxaliplatin and conjugated with panitumumab for the treatment of colorectal cancer. Oxaliplatin and panitumumab have been used as a first-line therapy for metastasis in the treatment of colorectal cancer. Panitumumab has the capability to recognize a tumor cell surface marker called epidermal growth factor receptor (EGFR) and can accurately kill tumor cells and reduce side effects. When protein nanocarriers were targeted the cell surface marker, AF was internalized into the endosome and lysosome through receptor-mediated endocytosis. Then, AF was disassembled into subunits, and the containing drugs were released into acidic environments. The results showed that the oxaliplatin-loaded AF conjugated with panitumumab (AFPO) could inhibit tumor growth and reduce side effects. The second part of the research examines the therapeutic efficacy of a nanocage loaded with a chemotherapy drug and photosensitizer. Apoferritin nanocages were loaded with doxorubicin (AF-DOX NCs), and the ADS-780 molecules were assembled on the surface of AF-DOX NCs to form a homogenously self-assembled structure, called “apoferritin loaded with doxorubicin (DOX) and ADS-780 near-infrared (NIR) fluorescent dye-decorated NPs (ADNIR NPs).” The ADNIR NPs were disrupted into AF-DOX NCs and increased the release of doxorubicin, which enhanced the cytotoxicity. Then, the photothermal theranostics was evaluated by injecting the ADNIR NPs into tumor-bearing mice and then exposing them to an NIR laser light after the nanoparticles substantially accumulated in the tumor site in 24 h. The results showed that the tumor growth was efficiently inhibited under the NIR light irradiation region, and the normal tissue had no obvious damage. In summary, we hope to establish a platform based on an apoferritin nanocage. It has a unique structure, wherein the inner cavity could be loaded with small molecules, and the outer surface could be modified with antibody- or peptide-targeting ligands for chemotherapy. Furthermore, the photosensitizer could also be loaded with nanocages for cancer diagnosis and photothermal therapy. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20109 |
DOI: | 10.6342/NTU201800780 |
全文授權: | 未授權 |
顯示於系所單位: | 醫學工程學研究所 |
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