具酸鹼應答特性之磷脂質包覆金奈米粒子於癌症標靶藥物治療之應用

近年來，生醫科技與奈米科技的快速發展，提升了在生醫治療上創新及多功能性平台的快速開發。設計磷脂質包覆的環境應答型奈米載體應用於癌症治療，在靶向傳輸及藥物控制釋放上具新穎性及研究潛力。本研究中，將具有二硫鍵 (disulfide bond) 的 3- (2-Pyridyldithio) propionyl hydrazide (PDPH) 透過腙鍵 (hydrazone bond) 與 Dox 鍵結而成的 pDox 前驅藥物分子，共價鍵結於檸檬酸鈉 (citrate) 還原而成的 13 nm 金奈米粒子上 (pDox-Au NPs)，此一藥物設計具有酸鹼應答的概念，可以在細胞內酸性胞器環境進行藥物釋放。接著，將對於人類急性白血病 T 細胞 (CCRF-CEM cells, CCL-119 T-cell, human acute lymphoblastic leukemia) 上的 protein tyrosine kinase 7 (PTK7) 具有辨識性的適體 (aptamer) T30-sgc8c，修飾於金奈米粒子上 (sgc8c/pDox-Au NPs)，再將載體以仿生材料脂質進行包覆，脂質組成為 1：1 的二肉豆蔻醯磷脂醯膽鹼 (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC) 與 1-十四醯-2-羥基卵磷脂 (1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine, MHPC)。磷脂質包覆的金奈米藥物載體 (AL:sgc8c/pDox-Au NPs) 透過動態光散射分析儀 (Dynamic light scattering, DLS)、穿透式電子顯微鏡 (Transmission electron microscope, TEM) 及 DiI 螢光探針進行鑑定。奈米藥物載體與 CCRF-CEM 的專一性作用則透過流式細胞儀 (Flow cytometric analyses)、石墨爐原子吸收光譜儀 (Graphite furnace absorption spectrometry)、螢光顯微鏡 (Fluorescence microscopy)、暗視野顯微鏡 (Dark field microscopy)、共軛焦螢光顯微鏡 (Confocal fluorescence microscope) 及細胞存活率進行分析。整體而言，以非共價性脂質包覆的金奈米藥物載體成功被開發，而酸鹼應答及適體的結合也使藥物能針對目標細胞進行更精準的控制釋放，應用於癌症治療中更具優勢。

關鍵字

金奈米粒子；酸鹼應答；適體應用於標靶藥物治療；脂質奈米粒子

並列摘要

In recent years, progress on biotechnology and nanotechnology has facilitated a rapid development of innovative multifunctional platforms in applications of biomedical therapy. The design of environmental-responsive nanocarriers on the basis of lipid-encapsulated nanoparticles is particularly promising for targeted delivery and controlled drug release in cancer research. In this report, we describe the synthesis of doxorubicin (Dox) conjugated 13-nm gold nanoparticles (pDox-Au NPs), which exhibited a pH-responsive drug release profile, followed by the modification of multiple aptamers, T30-sgc8c, with the capability to recognize protein tyrosine kinase 7 (PTK7) on leukemia human T cell lymphoblast-like (CCRF-CEM) cell line. Furthermore, lipid-encapsulation was achieved by trapping the nanoparticles, sgc8c/pDox-Au NPs within the biocompatible assembled lipid, which constituted 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1-myristoyl-2-hydroxy -sn-glycero-3-phosphocholine (MHPC). The lipid layer of AL:sgc8c/pDox-Au NPs, was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM) and DiI probe. Flow cytometric, atomic absorption spectroscopic, fluorescence microscopic, dark field microscopic, confocal microscopic and MTT assay also describe the specific interactions between AL:sgc8c/pDox-Au NPs and CCRF-CEM cells. Overall, a gold-based drug nanocarrier with nonthiol containing phospholipid was successfully established to improve the therapeutic efficacy in tumor cells. The pH-responsiveness was furthermore, highly promising for precise drug releasing in targeted drug delivery.

並列關鍵字

gold nanoparticle ； pH responsive ； aptamer-based targeted drug delivery ； lipid nanoparticle

參考文獻

[1]. Love, J. C.; Estroff, L. A.; Kriebel, J. K.; Nuzzo, R. G.; Whitesides, G. M., Self-Assembled Monolayers of Thiolates on Metals as a Form of Nanotechnology. Chem. Rev. 2005, 105, 1103-1170.

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[4]. Nam, J.; Won, N.; Bang, J.; Jin, H.; Park, J.; Jung, S.; Park, Y.; Kim, S., Surface engineering of inorganic nanoparticles for imaging and therapy. Adv. Drug Deliver. Rev. 2012.

[6]. Jain, P. K.; El-Sayed, I. H.; El-Sayed, M. A., Au nanoparticles target cancer. Nano Today 2007, 2, 18-29.

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具酸鹼應答特性之磷脂質包覆金奈米粒子於癌症標靶藥物治療之應用

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