多功能生物奈米材料之合成與分析及其生醫應用

Preparation and Characterization of Multifunctional Bionanomaterials and Their Biomedical Applications

黃景弘(Jing-Hong Huang)

指導教授 ： 劉如熹

國立臺灣大學/理學院/化學研究所/博士(2011年)

https://doi.org/10.6342/NTU.2011.00506

摘要

摘要

於過去二十年以來，奈米材料之發展促使人類對奈米材料於生物醫學之應用產生新的見識以及新穎之知識。為設計出對於應用所需的奈米材料，數種合成與形狀控制之奈米材料方法逐漸被科學家提出，從一開始之開發，奈米材料為高度均勻之單一功能化，但對於應用之需求而考慮對於運用之廣泛性，逐漸轉變為多功能化之奈米材料。對於奈米合成來說，單一奈米材料必須經過修飾之處理而將其轉成複雜的組成而形成多功能化之材料，因此應用之需求逐漸變成奈米材料發展之趨勢。為運用於生醫領域，奈米材料之生物相容性與生物可分解性成為非常重要之議題，根據表面修飾的發展，奈米材料之生物修飾不只提高奈米材料於生物應用上之安全性，也賦予奈米材料對於生物體內之目標細胞具有生物辨能性。
於本研究，主要分為兩大主題，包含合成細胞標靶性材料與熱療試劑。於合成之過程，生物材料如甲殼素與運鐵蛋白，由於其之生物相容性與可分解性，因此被採用來修飾與合成奈米材料。而於合成標靶性奈米材料分為兩主題，第一部分為關於藉由形成共價鍵之方法而達到定量將分子修飾於奈米材料，再將其導入於體外之細胞實驗，於分析過程中發現其奈米材料之標靶能力與速度可被成功的藉由修飾生物分子之含量而達到控制。第二部分之研究，乃用為第一個使用六偏磷酸鈉(sohium hexametaphosphate)合成具有高度生物相容性之金奈米顆粒，並接續藉用靜電修飾法將生物分子修飾於奈米材料上而形成標靶性材料，並應用於體外細胞實驗具有顯著之效果。另外一方面為熱療試劑之製備，兩種奈米材料之熱療試劑被成功之研發出與其相關之應用。金奈米顆粒之表面電漿共振具有吸光放熱之效果，而可應用於熱療試劑。但對於金奈米顆粒之形態控制，其表面需要經由軟式模板之修飾而成長為具形狀化，通常使用之試劑為十八烷基三甲基溴化銨(CTAB; cetyltrimethylammonium bromide) ，於生物應用缺點為其具有毒性。因此本實驗利用甲殼素之取代法將其取代而使其形成具高度生物相容性之熱療試劑。藉由取代之效果發現其對於熱穩定性相對高出許多，因此首先提出長期熱療型之熱療試劑之合成法。. 第二種熱療試劑為新穎性之金結合上轉換螢光粉之多功能奈米組成。於熱療法乃採用具有穿透較深之紅外線為激發源，其中上轉換材料可藉吸收紅外光而將其能量轉為較高之綠光，再藉由能量之轉移而被金吸收，最後轉換為熱，值得注意的，此奈米材料乃使用可快速合、可量產、熱穩定與方便合成之金奈米顆粒。於此部分，生物修飾法之觀念亦加入此熱療實驗之分析，細胞死亡率與速度均有因為生物分子之修飾而相當顯著之提升。

關鍵字

甲殼素 ； 多功能奈米材料 ； 奈米金 ； 標靶 ； 熱療

並列摘要

Abstract

Nanotechnology is developed intensively for over past decade to peruse the new view and knowledge for new applications such as biomedicine. To match our demands, the nanostructure of nanomaterials gradually turns form single function into multifunction for treating various applications. In biomedicine fields, the biocompatibility and biodegradability of nanomaterials are significantly issue for the bio-safety. Hence, the biomodification of nanomaterials not only increases the degree of biosafety but also gives the nanomaterials the ability of biorecognition toward living cells.
In our studies, there are two main topics including the preparation of cell targeting and hyperthermia reagent. In the synthesis process, the biomaterials, such as chitosan, transferrin (Tf), are accepted for surface modification of nanomaterials owing their biocompatibility and biodegradability. The part of cell targeting nanomaterials is divided into two parts. First part is associated with the control of biomolecule modification, whose novel findings indicate that the modulation of targeting efficiency and rate are successfully achieved by quantitatively controlling Tf modification of nanoparticles via covalent modification. Second part is the first time to introduce hexametaphosphate to modify Au nanoparticle as stabilizer, the targeting nanomaterials is fabricated rapidly via electrostatic interaction and successfully applied in vitro. In aspect of hyperthermia, the two kind of hyperthermia reagents are prepared and successfully applied in hyperthermia treatment. The CTAB (cetyltrimethylammonium bromide) modified shaped Au nanomaterials with SPR (surface Plasmon resonance) in NIR (near infrared) region provides a useful light to heat converter as hyperthermia reagent. The replacement of CTAB by chitosan improves the biosafety of shaped Au nanomaterials. First proposal is that improvement of the thermal stability of Au nanomaterials become potential used as long-term hyperthermia reagent via chitosan modification. The second hyperthermia reagent, novel Au-NaYF4:Yb3+,Er3+ nanoparticles, is successfully fabricated. It is capable of providing the dual applications of call label and hyperthermia treatment based on the energy transfer and upconversion mechanism. In this section, the concept of cell targeting is introduced into the synthesis of Au-NaYF4:Yb3+,Er3+ nanoparticles. It is found to raise the hyperthermia efficiency a lot and consistent with the finding in part of cell targeting nanomaterials. Hence, the biomolecular modification strengthens the applicability and their related properties.

並列關鍵字

Chitosan ； multifunctional nanomaterials ； nanogold ； targeting ； hyperthermia

參考文獻

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