合成奈米材料及其在生醫上之應用

Synthesis of Nanomaterials for Biomedical Applications

郭聰榮

指導教授 ： 陳家俊

國立臺灣師範大學/理學院/化學系/博士(2011年)

摘要

近年來，奈米材料應用在生物醫學中的影像分析、藥物傳送和治療是持續被發展的課題。在本研究中，我們結合了二氧化鋅奈米粒子的二倍頻訊號和皮膚角質細胞的螢光訊號來觀察二氧化鋅奈米粒子在化學促進劑如:油酸、乙醇和油酸-乙醇的影響下，在皮膚的穿透行為。除了分析本質上的影像結構，二氧化鋅穿透的特性也同樣的被定量分析，而得到載體對皮膚的分佈係數、二倍頻訊號的強度梯度和有效碰撞路徑長度。這些結果顯示油酸、乙醇和油酸-乙醇能夠有效的增加二氧化鋅奈米粒子在皮膚的穿透深度，是因為增加了皮膚皮酯的流動性或是改變了皮膚角質層的皮酯排列緊密性。
更進一步的，不需要額外的染色步驟，當眼角膜上表皮保護層受到損害後，利用雙光子顯微術也可以觀察到螢光奈米粒子穿透眼角膜和滯留在眼角膜細胞間。在細胞毒性實驗中，我們使用牛眼角膜基質細胞和奈米粒子做細胞培養，可以發現細胞的存活率會隨著奈米粒子的濃度增加和培養時間的增長而有明顯的減少。並且，在老鼠動物實驗中，雙光子顯微術影像顯示出奈米粒子可以滯留在眼角膜中達到26天以上。根據在細胞跟動物實驗所得到的實驗結果，我們推測，當眼角膜的上表皮保護層受到損壞後，奈米粒子可以穿透並長時間滯留在眼角膜中，而對細胞造成毒性。
奈米材料應用在藥物傳遞方面，我們也合成金奈米棒的藥物複合體。金奈棒藥物複合體是將金奈米棒、目標藥物和螢光分子，用電解質聚合物包覆起來。合成好的金奈米棒藥物複合體，在飛秒紅外光雷射照射下，我們也詳細的研究了被釋放螢光分子的藥物動力學。螢光分子會因為吸收了由金奈米棒將紅外光雷射轉換而來的熱，而從金奈米棒的藥物複合體中釋放出去。釋放出去的螢光分子則在紅外光雷射連續性照射和周期性照射兩種不同模式下測量。在照射紅外光雷射時間為五分鐘時，螢光分子的釋放速率在雷射連續性照射和周期性照射下，分別呈現零級和一級的動力學機制。更進一步，我們也設計了金奈米棒藥物複合載體，用電解質聚合物包埋了金奈米棒和抗癌藥物太平洋紫杉醇而形成藥物載體。抗癌藥物太平洋紫杉醇可以用雷射誘導而從金奈米棒複合體中釋放出去。而釋出的抗癌藥物太平洋紫杉醇對乳癌細胞的細胞抑制率則和紅外光雷射的照射方式及照射時間有關。

關鍵字

奈米材料 ； 生醫 ； 金奈米棒

並列摘要

The biomedical applications of nanomaterials in imaging, drug delivery, and therapy have led to ever-growing developments in the past decades. In this work, we combined the second harmonic generation of ZnO nanoparticles and the autofluorescence of the stratum corneum to image the penetration of ZnO nanoparticles under the chemical enhancer conditions of oleic acid, ethanol and oleic acid-ethanol. In addition to qualitative imaging, the microtransport properties of ZnO nanoparticles were quantified to give the enhancements of the vehicle-to-skin partition coefficient, the second harmonic generation intensity gradient and the effective diffusion path length. The results showed that oleic acid, ethanol and oleic acid-ethanol were all capable of enhancing the transdermal delivery of ZnO nanoparticles by increasing the intercellular lipid fluidity or extracting lipids from the stratum corneum.
Furthermore, with no additional staining, the two-photon image showed that fluorescent nanoparticles penetrated and resided within interlamellar space of cornea stroma when corneal epithelium barrier was injured. In vitro cytotoxicity test using bovine corneal stromal cells incubated with nanoparticles indicated that the cell viability decreased significantly as the nanoparticles concentration and incubation period increased. Moreover, two-photon imaging showed that nanoparticles can retain within cornea up to 26 days in an in vivo mouse model. On the basis of our in vivo and in vitro data, we conclude that nanoparticles can penetrate and retain within cornea long enough to cause consequential cytotoxicity, under the circumstance that corneal epithelium barrier is injured.
In drug delivery applications of nanomaterials, the conjugates of gold nanorods and the model drug, fluorescein isothiocyanate (FITC), embedded inside polyelectrolytes (GNRs/FITC@PLE) were synthesized to study the release kinetics of FITC under femtosecond near-infrared (NIR) laser irradiation. The release of FITC from the conjugates was induced by the heat generated from gold nanorods under laser irradiation. The concentration of released FITC was measured as the time of continuous and periodic laser irradiation was varied. Within 5 min of the laser exposure, the release rates of FITC exhibited zero-order and first-order kinetics under continuous and periodic irradiation, respectively. Furthermore, a drug release system was designed based on the conjugates of gold nanorods and the anticancer drug, paclitaxel (PTX), embedded inside polyelectrolytes (GNRs/PTX@PLE). The release of PTX from the conjugates was triggered by NIR laser irradiation, and the inhibition rates of breast cancer cells showed strong dependencies on the irradiation modes and time.

並列關鍵字

Nanomaterials ； Biomedical ； Gold Nanorods

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