- 學位論文
乳癌細胞專一性胜肽運用於乳癌之治療及造影
Breast cancer cell-specific peptides for targeted drug delivery and imaging
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摘要
乳癌是女性常見的癌症之一，在所有女性癌症中，乳癌死亡率高居第二名。由於目前的化療藥物大都缺少腫瘤專一性難以將藥物高劑量帶到腫瘤，導致化療效果不彰。因此，發展能夠標的原位或轉移腫瘤的標的配體 (ligand) 是迫切需要的目標，此標的配體可以藉由配體藥引之藥物傳輸系統 (ligand-mediated delivery system) 來提高化療藥物的專一性，除此之外，此配體還可以用於造影系統來診斷癌症的發生或術後的評估。在先前的研究中，我們利用噬菌體顯現法 (phage display) 已尋找出能與乳癌細胞株結合的新穎胜肽，利用流式細胞發現帶有此胜肽的噬菌體可以辨認大部分的乳癌細胞株。更進一步，藉由穿透式的顯微鏡觀察細胞的核內體 (endosome)， 發現相較於對照組有2.4倍的微脂體累積在實驗組中。施打帶有冷光酵素表現的人類乳癌細胞於免疫不全老鼠，藉由冷光造影監測藥物處理後的癌細胞生長情形，可發現攜帶抗癌藥物的標的微脂體可增加癌細胞的死亡，進而抑制腫瘤生長。更甚者，造影的研究顯示，此標的胜肽結合螢光造影物質後可以專一性的辨認腫瘤，在2小時的時候，累積在腫瘤的訊號為對照組的21.8倍。 目前的研究指出，此腫瘤標的胜肽不但可以提高藥物的專一性來增進乳癌的治療效果，未來還能用於造影系統來診斷或追蹤乳癌的發生。
並列摘要
Breast cancer is the most common form of cancer and the second leading cause of cancer-related mortality among women worldwide. The lack of tumor specificity in anticancer drugs leads to dose-limiting toxicity that compromise the effect of chemotherapy. In addition, the development of a novel ligand for targeting of primary and metastatic breast cancers is exigently needed. This targeting ligand would not only improve the specificity of chemotherapy through ligand-mediated delivery system, but can also be used as an imaging system to detect and predict cancer prognosis. In the present study, we discovered a novel peptide, selected from phage-displayed peptide libraries that bound to breast cancer cells. We observed that this targeting phage had higher binding activity to most breast cancer cell lines using flow cytometry. When the targeting peptide was coupled to liposomes carrying doxorubicin, the drug acumination in the endosome of cancer cells was 2.4-fold as compared to control peptide using transmission electron microscopy analysis. Moreover, in severe combined immunodeficiency (SCID) mice bearing luciferase-expressing breast cancer xenografts, the targeting liposomes carrying doxorubicin specifically bound to tumor masses. The ligand-mediated drugs enhance death of cancer cells in xenografts model by monitoring of luminescent imaging from tumor. Furthermore, in the imaging studies, targeting peptides were conjugated with fluorescent agents to monitor cancer localization in tumor-bearing mice. Quantification of the fluorescence showed that 21.8-fold higher fluorescent agents accumulated in tumor from targeting group than of non-targeting group. The current study indicates that tumor-specific peptide may be used to improve the systemic treatment of breast cancer by increasing specificity of anticancer drugs and imaging probes to breast cancer.
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