2014-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/678240摘要：如何在不影響正常細胞情況下將mRNA干擾分子精準地送入惡性細胞中使之啟動自動 凋亡程式是分子標靶治療概念所揭諸有關人類戰勝癌症之希望樂章，在此計畫裡我們將 整合既有的適體、DNA酵素、奈米粒子及生物晶片之知識與技術對此生物醫學新領域 貢獻一己之力。我們的目標是研發具標靶基因沉默化治療應用之新穎適體-DNA酵素奈 米藥物，這將藉下列三年研究工作達成：(1) 研發具高度專一性MUC1黏蛋白辯識能力 之多效價適體用以精準輸送微脂體奈米載體至癌細胞(MCF-7)表面；(2) 研發攜有低 KM、高kcat之DNA酵素之微脂體/奈米普魯士藍奈米複合物用以有效裂解癌細胞內 mRNA治療標的(如c-jun、egr1)；(3)合成適體-DNA酵素/PBA奈米藥物用以選擇性摧 毀帶有MUC1表面抗原之癌細胞並進行奈米藥物標靶治療之概念性驗證。此外我們亦將 發展新穎的生物晶片、微流道及奈米技術以促進適體、DNA酵素篩選與再設計、奈米 載體設計與評估以及細胞培養與試驗的研發效率，並且我們會探究此系統中應用磁場輸 送奈米藥物以及光誘導DNA酵素釋放之可能性藉以進一步創造標靶治療的空間選擇 性。我們相信此計畫(若順利獲得補助)將是一項可行、饒富希望且深具影響力的研究工 作，無論是從純粹科學興趣或者是人類健康福祉觀之。<br> Abstract: Precise delivery of RNA-interference molecules to let malignant cells initiate programmed death without affecting other normal cells – idea of molecular targeting therapy – is a symphony of hope about how human will defeat cancers. In this project, we integrate our well-established knowledge and know-hows of aptamers, DNAzymes, nanoparticles, and biochips to contribute in such biomedicalfrontiers. We aim for the R&Ds of a novel aptamer-DNAzyme nanodrug for targeting gene-silencing therapy, which involves the following research activities in three separate years – (1) R&Ds of a multivalent aptamer escort with very low Kdfor precise delivery of liposomal nanocargos into MUC1-positive cancer cells (e.g., breast cancer MCF-7 cells) in a complex matrix; (2) R&Ds of liposome/nano-Prussian blue analogue (PBA)-assisted control release of high kcat/KM DNAzymes for efficient cleavage ofmultiple therapeutic mRNA targets (c-jun and egr-1) that cause apoptosis of MUC1(+) cancer cells; (3) Synthesis of the aptamer-DNAzyme/nPBA nanodrug for selective destroying MUC1(+) cancer cells and proof-of-principle targeting therapy on a biochip. In addition, we will study novel biochips, microfluidics and nano-technologies to enhance the efficiency of aptamer & DNAzyme screening and re-engineering, nanocargo design and evaluation, and cancer cell cultures and assays. Besides, we will study the possibility of magnetic drug delivery and photoinduced release of DNAzyme from nPBA in the present model to further create spatial selectivity for targeting therapy. We anticipate that this work, if granted, is doable,promising, and of great impact, no matter from the aspect of pure scientific interest or human health and welfare.適體(藉由人工演化SELEX程序而得的DNA抗體)DNA酵素(可裂解mRNA 的DNA人工酵素)奈米粒子基因沈默化(關閉基因表現的一種治療方法)MUC1(許 多癌細胞表面會大量表現的一種黏蛋白aptamerDNAzymenanoparticlegene-silencingMUC1c-juncancer.