癌症早期診斷與治療可大幅提升腫瘤治癒的機會。然而傳統癌症檢測所造成的侵入性以及臨床上的分子成像技術對過小的腫瘤組織靈敏性不足的限制，為目前癌症在早期診斷上的困境。腫瘤細胞特定的高度表達基因對於提供早期且靈敏的分子診斷應用深具潛力，其可作為監測早期階段的腫瘤增生並評估患者在接受治療性處理後的療效。本研究提出一種磁性球型核酸－分子信標系統，可應用於癌症活細胞之基因表達即時分析與基因應答性藥物傳遞。
分子信標(Molecular Beacon, MB) 為寡核苷酸的一種，其中一股具有螢光淬滅劑，另一股則帶有螢光基團，可以透過序列雜合的方式達到癌症基因專一性檢測。此磁性球型核酸－分子信標系統主要利用超順磁性氧化鐵奈米粒子(Superparamagnetic Iron Oxide Nanoparticle, SPION) 作為核心，在外層透過共價鍵結的方式修飾上分子信標，形成高生物相容性之載體，並使其同時具有磁導引與基因診斷的能力。
本研究的第一個部分為探討此系統作為癌細胞基因檢測的可行性。製備出的磁性球型核酸粒子，其水合直徑為146.4 nm，表面電荷為-23.6 mV，於TEM下觀察SPION-MB之團簇，粒徑大小與DLS量測結果相仿，亦可於強力磁場下表現出良好的順磁性。除此之外，SPION-MB不僅於血清環境中具有優異的膠體穩定性，更呈現抵抗核酸降解酶的特性，使得SPION-MB在細胞外測試中顯示對survivin gene極高的專一性。在癌細胞顯影的實驗中，則藉由顯微鏡及流式細胞儀進行觀察，證實了SPION-MB在搭配磁導引之下，能夠達到短時間內促進細胞攝取並增強細胞顯影之效果，確立了SPION-MB具有作為基因探針的潛力。
第二部分則延續此一系統，藉由MB的雙股螺旋片段攜載抗癌藥物阿黴素(doxorubicin, DOX)，透過靜電作用力於載體表面修飾細胞穿膜胜肽TAT以提升其逃脫內吞體的能力。首先利用測定DOX與MB結合後產生之消光效應確立SPION-MB對DOX的攜載能力，並探討其對互補對基因的反應性與專一性，證實基因應答造成藥物釋放之效果。而在細胞攝取的實驗中，可明顯觀察到DOX的專一性累積。另一方面，由流式細胞儀的定量結果得知，當SPION-MB結合TAT peptide後，可增進細胞攝取效率並提高基因表達分析之螢光訊號強度。因此我們認為，透過SPION-MB攜載DOX與TAT peptide，並搭配磁導引的作用之下，能夠成為癌症mRNA及時診斷與基因應答性藥物釋放的平台，藉此達到癌症有效的診斷並減低化療藥物在臨床使用上所造成的副作用。

Early theragnosis greatly increases the chances of successful cancer treatment. However, current state of traditional cancer diagnosis is invasive and poor sensitivity on detecting early stage of tumor development which are the major challenge on early cancer theragnosis. The overexpressed tumoral mRNA could be a useful target for early molecular diagnostic applications, monitoring the tumor progression and afterward assess the responses of cancer cells after receiving therapeutic treatment. In this study, we propose a magnetic spherical nucleic acid systems combined with molecular beacon for real-time gene expression analysis in living cancer cells and gene-responsive drug delivery.
Molecular beacon (MB), oligonucleotide hybridized probes modified with a fluorescence quencher and fluorophore on end of DNA strand, are capable of detecting cancer-specific genes via sequence hybridization principle. The magnetic spherical nucleic acid system is composed of superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with molecular beacon shells via covalent bonding, exhibits high biocompatibility and the ability for both magnetic guidance and genetic diagnosis agent at the same time.
In the first part of this thesis is to explore the feasibility of using this system for cancerous gene detection. The hydrodynamic diameter and surface potential of fabricated SPION-MB system were determined to 146.4 nm and -23.6 mV, respectively. TEM images of SPION-MB showed cluster-like morphology and similar particle size. Besides, SPION-MB showed good ferrofluid behavior under an externally applied magnetic field. SPION-MB not only demonstrated good colloidal stability in serum containing environment but also protected nucleic acid from enzymatic degradation. SPION-MB also showed high specificity to survivin gene under intracellular mimicking condition. In vitro cell imaging was performed by human breast cancer line (MCF-7) uptaking SPION-MB under external magnetic field. The results, observed by both fluorescence microscope and flow cytometry, showed SPION-MB could effectively uptake into cells and detecting the survivin gene expression analysis in a short time. These findings suggested that SPION-MB is a potential MB delivery platform for gene probing.
In the second part of the thesis, both doxorubicin (DOX), an anti-cancer drug, and TAT, a type of cell-penetrating peptide, were introducing to SPION-MB system. DOX could intercalate into MB duplex spontaneously; while TAT peptide, which is capable of enhancing cellular uptake and escaping endosomal escape, was coated via electrostatic attraction. To quantitate the DOX loading efficiency, the fluorescence quenching effect of DOX after binding to SPION-MB was studied and confirmed the intercalation between DOX and SPION-MB. Next, the specific gene-responsive DOX release from SPION-MB/DOX was investigated. In the cell uptake experiment, DOX could accumulate in nuclei specifically; moreover, the SPION-MB was uptake more efficiently by TAT coating, and the result of flow cytometry showed that could improve the intensity of fluorescence signal for gene expression analysis. Therefore, we believe that SPION-MB combined with DOX and TAT peptide are potential for real-time cancer mRNA diagnosis and served as gene-responsive drug release platform, which can achieve effective diagnosis of cancer and reduce the side effects of chemotherapy drugs in the clinical use.

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