2013-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/658472摘要：分子影像與治療是一個新興的技術領域，可應用在功能性診斷跟奈米藥物開發。為了符合影像及治療上的需求，因此合成出許多新穎的奈米結構，且具備多樣的特性。然而，即使奈米材料具有良好的物理及化學特性，它所具有的細胞毒性仍是關鍵問題，影響到是否能進一步的臨床應用。首先，在奈米材料的表面作修飾，使其具有生物相容性，並能在體內有效控制藥物釋放，減少副作用產生。使用脂質跟聚合物的材質，來製備奈米粒子，使其在藥物應用上更佔有優勢，這些方法可提高奈米粒子的生物相容性。近幾年，我們製備出一個簡單且多功能性的奈米粒子外殼，去包覆奈米鑽石、氧化鐵奈米粒子、量子點、矽奈米粒子。我們進一步發現這些外殼包覆核心的奈米結構，具備了螢光及共振的特性、非線性的光學影像訊號、顯微影像分析、核磁共振影像，以及由磁力協助的目標遞送。發展出許多種以不同脂質成分及比例，所製備出來的奈米載體。在這篇研究中，我們合成出帶有正電荷，以膽固醇所包覆的氧化鐵奈米粒子(GCC-Fe3O4)，且此種奈米載體，在含有血漿的環境中，仍可達到良好的遞送效果。藉著這類新合成出的正電荷脂質，更可設計出多功能性的奈米粒子，且在體內實驗方面亦達到良好遞送效果。本年度為計畫執行之第二年，工作重點列為奈米粒子之導向性、動物體內之分布及對免疫系統之影響分析。在動物腫瘤模式中，反股寡核苷酸  (AS-ODN) 為首要獲得治療成效的試驗。根據這個平台，我們將以發展短鏈干擾型 RNA(siRNA)和 miRNA 為基礎的奈米載體為目標。此外，研發出在表面修飾輸鐵蛋白或抗體的奈米載體，去專一性標靶輸鐵蛋白受體HER-2，也是我們研究中的目標之一。奈米載體與配體之間，可藉由直接連接或靜電交互作用而建構。使用此策略去有效達到基因遞送，並結合分子影像，使得此奈米載體可作為多功能平台，發展寡核苷酸型藥物，繼而進行臨床上的治療應用。<br> Abstract: Molecular imaging and therapy is the emerging field in functional diagnosis and nanomedicine. Many novel nanostructures were synthesized and characterized for imaging or therapeutic needs. Despite of good physical and chemical properties, the cytotoxicity of these nanomaterials is the main issue for further development in clinical uses. Surface modification of nanostructures is the first step to design such biocompatible nanoparticles with controlled ability in vivo. For these reason, lipidic and polymeric nanoparticles have their advantages in medical application. The feasible approach to render nanostructures more biocompatible is the spontaneous deposition of lipid membrane onto the solid surface of such nanomaterials. For the past few years, we have developed a simple yet versatile formulation of nanosized particles encapsulating nanodiamonds, iron oxide nanoparticles, quantum dots, silica nanoparticles. We further discovered these core-shell nanostructures not only have the fluorescent or resonance properties, but also have the strongest signals in the non-linear optical imaging, microscopic analysis, MRI imaging, as well as for potential use in magnet-assisted targeted delovery. Many types of lipid-based nanocarriers were developed, which are based on different ingredients and the ratio of those lipids. In this study, we synthesized the cationic cholesterol-based-Fe3O4 nanocarriers (GCC-Fe3O4) and developed these nanocarriers for efficient gene delivery even in the presence of serum. By using these newly synthesized cationic lipids and their formulations, we aimed to design multifunctional nanoparticles for effective delivery in vivo. Since this is second year of the long-term project, we aim to develop different surface charged- and targeted nanocarriers for in vivo distribution analysis. We will also focus on exploring immunotoxicity of these designed nanovectors to avoid possible adverse effects. Antisense ODNs (AS-ODN) are the first succeeded surrogate as therapeutic ODNs in the mouse tumor model. Based on this platform, we will further develop the siRNA- and miRNA-based lipid nanocarriers as proposed. The targeted forms of nanocarriers using Tf or antibodies against TfR and anti-HER-2 are also focused in our project. The formulation involved direct conjugation or electrostatic association of ligands, antibodies and antibody fragments to the lipid nanocarriers. Using these strategies for effective gene delivery with imaging capabilities, we will have a versatile platform that allows us to develop the oligonucleotide-based gene medicines for human therapeutics.