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標題: | 適用於多種亞型的肺癌標的胜肽於複合式藥物傳輸與分子磁振照影之應用 Lung Cancer-Targeting Peptides with Multi-subtype Indication for Combinatorial Drug Delivery and Molecular Magnetic Resonance Imaging |
作者: | Yi-Hsuan Chi 紀怡亘 |
指導教授: | 吳漢忠 |
關鍵字: | 小細胞肺癌,非小細胞肺癌,標的胜?,微脂體藥物,分子磁振照影, Small cell lung cancer (SCLC),non-small cell lung cancer (NSCLC),targeting peptides,liposomal drugs,molecular magnetic resonance imaging, |
出版年 : | 2016 |
學位: | 博士 |
摘要: | 背景:
肺癌位居全世界癌症死亡率之首。目前已有的肺癌標靶藥物主要是針對肺腺癌的表皮細胞生長因子 (EGFR) 或間變性淋巴瘤激酶 (ALK) 所設計的的酪胺酸激酶抑制劑 (TKIs) 。到目前為止,還沒有針對大細胞癌和小細胞肺癌有效的標靶藥物。因此,我們的研究目標希望尋找能廣泛辨識小細胞肺癌和非小細胞肺癌各種亞型的標的胜肽,可應用於肺癌的偵檢和治療。 結果: 由於近期的研究將大細胞癌歸類為各種肺癌亞型中“未分化”的腫瘤型態。因此我們運用噬菌體顯現法,針對H460大細胞癌細胞株,期望篩選出廣效型的肺癌標的胜肽。三條標的胜肽 (HSP1、HSP2和HSP4) 及其所對應的的噬菌體 (HPC1、HPC2和HPC4) 可以結合小細胞肺癌和非小細胞肺癌的細胞株和臨床病人檢體,且不會與正常細胞結合。在活體的噬菌體光學照影及胜肽接合超順磁氧化鐵奈米粒子的磁振照影實驗顯示,HSP1最適合發展為多重模式的分子影像探針。HSP1可以導引氧化鐵在H460腫瘤中累積並造成T2磁振訊號下降42%。在T2的磁振造影模式中,HSP2的水分子自旋子吸引效應及其卓越的腫瘤標的能力造成奈米粒子周圍局部磁場不均勻的現象,使HSP2-HDex-Fe3O4奈米粒子成為有前景的顯影劑,可以將細微的腫瘤結構顯像並可運用於未來臨床中於低信號的肺實質中偵測肺癌病灶。HSP1可與肺癌細胞表面緊密結合,相反的,HSP4則傾向於導引內噬作用與細胞內的藥物傳輸,因此顯著的增進活體的治療指數。在非小細胞肺癌 (H460和H1993) 的動物模式中,HSP1、HSP2和HSP4接合的小紅莓微脂體顯著地增進非標的微脂體藥物的療效。在更惡性的A549原位癌移植動物模式中,HSP4接合的穩定型長春瑞濱微脂體及HSP4接合的小紅莓微脂體的複合式療法能更近一步地增進非標的微脂體藥物的中位存活率,由84天延長至131天( P值0.0248)。 結論: 總結而言,在未來的應用上,這三條標的胜肽可以導引針對各樣的肺癌亞型特製之“治療診斷試劑”,對於發展標靶治療、非侵入式照影、小細胞肺癌和非小細胞肺癌的偵檢極具臨床潛力。 Background: Lung cancer is the leading cause of cancer-related death worldwide. Most targeting drugs approved for lung cancer treatment are tyrosine kinase inhibitors (TKIs) of EGFR or ALK, mainly for adenocarcinoma. At present, there is no effective or tailored targeting agent for large cell carcinoma (LCC) or small cell lung cancer (SCLC); we therefore aimed to identify targeting peptides with broad subtype specificity for SCLC and non-small cell lung cancer (NSCLC) for diagnostic and therapeutic purposes. Results: We performed phage display biopanning of H460 LCC cells to select “broad-spectrum” lung cancer-binding peptides, since LCC has recently been categorized as an undifferentiated tumor type within other histological subcategories of lung cancer. Three targeting phage (HPC1, HPC2, and HPC4) and their respective displayed peptides (HSP1, HSP2, and HSP4) were able to bind to both SCLC and NSCLC cell lines and clinical specimens, but not to normal pneumonic tissues. In vivo optical imaging of phage homing and magnetic resonance imaging (MRI) of peptide-SPIONs revealed that HSP1 was the most favorable probe for multimodal molecular imaging, which resulted in a decrease of T2-weighted MR signal of up to 42% in H460 xenografts. The water spin collection effect and prominent tumor homing capability of HSP2 contribute to an inhomogeneous local magnetic field around the nanoparticles, making HSP2-HDex-Fe3O4 a promising contrast agent for visualizing subtle tumor structures and for detecting foci of lung cancer in hypointense lung parenchyma clinically by using common T2 MRI. Contrary to the tight binding of HSP1 to cancer cell surfaces, HSP4 favors endocytosis and intracellular drug delivery, thereby significantly improving the therapeutic index in vivo. Liposomal doxorubicin (LD) conjugated to HSP1, HSP2, or HSP4 had significantly greater therapeutic efficacy than non-targeting liposomal drugs in NSCLC (H460 and H1993) animal models. Combined therapy with an HSP4-conjugated stable formulation of liposomal vinorelbine (sLV) further improved median overall survival (131 vs. 84 days; P = 0.0248), even in aggressive A549 orthotopic models. Conclusions: Overall, these peptides have the potential to guide a wide variety of tailored “theranostic agents” for targeting therapy, non-invasive imaging, and clinical detection of SCLC and NSCLC. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/18889 |
DOI: | 10.6342/NTU201602814 |
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顯示於系所單位: | 病理學科所 |
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