熱感應性智慧型凝膠之製備與性質研究

Studies on Preparation and Properties of Thermosensitive Intelligent Hydrogels

蔡翰學(Han-Hsueh Tsai)

指導教授 ： 李文福

大同大學/工程學院/化學工程學系所/碩士(2010年)

摘要

Part 1
本研究是以N-isopropyl acrylamide (NIPAAm)為主體，並加入不同含量的Nano silica AE200，和改質過表面帶有胺基的二氧化矽微粒Nano silica mAE200，透過溶液聚合法與溶膠凝膠反應製備一系列溫度敏感性有機無機混成水膠，探討不同Nano silica添加量和改質過的Silica對在混成膠體膨潤度的影響。結果顯示，膨潤度隨著Silica AE200、Silica mAE200添加量增加而降低，而改質過的Silica 因表面接Aminopropyltriethoxysilan (APTEOS)有親水性的胺基，因此膨潤度比未改質過的Silica稍為較高。在藥物釋放的研究，膠體吸收的藥物包含不帶電的藥物：咖啡因(小分子量), 維他命B12(大分子量)和帶電的藥物：紫晶 (帶正電),酚紅(帶負電)。含有二氧化矽和改質的二氧化矽的膠體在藥物釋放的實驗中證明，在藥物為咖啡因(小分子)和維他命B12(大分子)，其釋放量會被藥物分子大小所影響。然而在帶有離子性的膠體，在藥物為紫晶 (帶正電)，酚紅(帶負電) 其釋放量會被藥物帶的電荷造成很大的影響。
Part 2
本研究先利用4-fluorobenzonitrile與aniline進行親核取代反應合成4, 4-dicyano triphenylamine，隨即再以鹼性條件下水解二腈中間產物而得到4, 4-dicarboxy triphenylamine。再進一步利用酯化反應將4,4-dicarboxy triphenylamine接上2-Hydroxyethylmethacrylate成為具有雙鍵的Dimethacryloyloxy ethylene oxycarbonyl triphenylamine(DMETPA)。而4-cyano triphenylamine也同樣利用4-fluorobenzonitrile與diphenylamine進行親核取代反應合成4-cyano triphenylamine，隨即再以鹼性條件下水解腈基中間產物而得到 4-carboxy triphenylamine。之後再利用酯化反應將4-carboxy triphenylamine接上PLGA-PEG-PLGA成為具光致發光及生物可分解的材料的TPA-capped PLGA-PEG-PLGA，探討其發光性質與生物細胞毒性測試。
將Dimethacryloyloxy ethylene oxycarbonyl triphenylamine當交聯劑與NIPAAm聚合而成膠體，利用NIPAAm具有親水基與疏水基之熱感應性特性，加上三苯胺光致發光特性，使之結合製備成具有光致發光凝膠，並使用加入不具三苯胺結構的EGDMA交聯劑作成的膠體作對照。另外再將主體改換成不具熱感應性的HEMA添加DMETPA與EGDMA作成一系列的膠體，探討對膨潤度、機械強度和發光特性的影響。
結果顯示，在膨潤度方面，以NIPAAm為主體的膠體添加DMETPA與EGDMA含量越多則膨潤度越低。而添加相同含量的DMETPA膠體與EGDMA膠體互比，其含三個苯環結構的DMETPA膠體疏水性較大，故膨潤度較含EGDMA的膠體相對較小。另外將主體換成HEMA其一系列膠體膨潤度都會比以NIPAAm為主體的小。其原因為HEMA為疏水性的單體而NIPAAm為親水性的單體，故以HEMA為主體其膨潤度會較小。在機械強度方面，DMETPA與EGDMA含量越多其機械強度越大，且加DMETPA的膠體會比添加EGMDA的膠體還大。而以HEMA為主體的相同成分膠體機械性質會相對比以NIPAAm為主的還要大，其原因HEMA為疏水性的單體因此在水中不易膨潤故內部結構還是很緊密，而NIPAAm為親水性單體故在水中膨潤其水分會相對大於HEMA，因此相同成分不同主體的情況下機械強度HEMA會大於NIPAAm。
光致發光行為上，結果顯示膠體含有三苯胺結構的DMETPA交聯劑，在UV燈下會有螢光的產生而膠體含有EGDMA交聯劑則無螢光的產生，且膠體的發光強度隨DMETPA 含量增加而發光強度略為增強。另外將TPA-capped PLGA-PEG-PLGA 溶於不同極性的溶劑觀察其發光強度與最大吸收波長。結果發現吸收波長會隨溶劑極性越高越往紅位移方向移動。生物細胞毒性測試結果顯示，含苯環結構的三苯胺衍生物TPA-capped PLGA-PEG-PLGA會對生物細胞產生毒性，以目前樣本的處理方式評估為有毒性不適合應用在人體。

關鍵字

凝膠 ； 溫度感應性 ； 有機無機混成水膠 ； 三苯胺 ； 光致發光 ； 光致發光凝膠

並列摘要

Part 1
A series of thermosensitive organic-inorganic hybrid hydrogels based on N-isopropyl acrylamide (NIPAAm) and nanosilica (AE200) or surface modification of AE200 (mAE200) were prepared by solution polymerization and sol-gel reaction. The hydrogels were modulated by adding different amount of AE200 or mAE200. The effects of AE200 and mAE200 content on the swelling ratios were investigated. Results showed that swelling ratios of hybrid hydrogels would decrease with increasing AE200 and mAE200 amount. The particle surface of mAE200 due to aminopropyl triethoxysilane (APTEOS) grafted onto AE200 has hydrophilic amino group, so the hybrid gels containing mAE200 would have higher swelling ratios than those containing original silica, AE200. In drug release studies, model drugs including nonionic drugs, caffeine (lower molecular size) and vitamin B12 (higher molecular size), and ionic drugs crystal violet (cationic) and phenol red (anionic) were loaded into the hybrid hydrogels. The results showed that drug release experiment of hybrid hydrogels which content AE200 and mAE200, the hydrogels loaded in caffeine and vitamin B12 would be affect by the molecular size of drug on the release behavior. However, the hydrogels loaded in crystal violet and phenol red would be affect by the charge of drug on the release behavior.

Part 2
In this study, 4, 4-dicyano triphenylamine was firstly synthesized by nucleophilic substitution of 4-fluorobenzonitrile and aniline, followed by alkaline hydrolysis of the dinitrile intermediate to obtain 4, 4-dicarboxy triphenylamine. Furthermore, the esterification process of 4, 4-dicarboxy triphenylamine and 2-hydroxyethyl methacrylate to produce dimethacryloyloxy ethylene oxycarbonyl triphenylamine (DMETPA). In addition, 4-cyano triphenylamine was also synthesized by nucleophilic substitution of 4-fluorobenzonitrile and diphenylamine, followed by alkaline hydrolysis of the dinitrile intermediate to obtain 4-carboxy triphenylamine. Then, 4-carboxy triphenylamine was reacted with PLGA-PEG-PLGA to produce TPA-capped PLGA-PEG-PLGA, which had photoluminescence and biodegradable properties materials.
A series of hydrogels having photoluminescence and thermosensitive properties were prepared from DMETPA as crosslink agent and NIPAAm by photo-polymerization in DMSO. The effect of DMETPA content on the properties of the hydrogels was investigated. In comparison, a series of hydrogels were prepared with ethylene glycol dimethacrylate (EGDMA) replacing DMETPA as crosslink agent in the hydrogel. The results show that the swelling ratios for the hydrogels crosslinked with DMETPA and EGDMA decrease with an increase of crosslinker content. The results also show that the swelling ratios for DMETPA crosslinked hydrogels are lower than those for EGDMA crosslinked hydrogels. This is because DMETPA containing three aromatic ring structures has a higher hydrophobic tendency.
Another series of hydrogels without thermosensitive were also prepared by HEMA with DMETPA or EGDMA to contrast their swelling ratios, mechanical strength, and photoluminescence. The results show that the swelling ratios of the HEMA series hydrogels are also lower than those of NIPAAm series hydrogels. The reason is because the hydrophobicity of HEMA is lower than NIPAAm, so the swelling ratios for the hydrogels based on HEMA decreased.
In mechanical strength experiment, the gel strength of the present hydrogels increase with increasing of DMETPA and EGDMA content. Also, the gel strength for the hydrogel crosslinked with DMETPA tends to be larger than the gels crosslinked with EGDMA. The gel for HEMA as main structure had higher mechanical strength than the gel for NIPAAm as main structure due to HEMA having hydrophobic property. So under the same content, HEMA has a greater mechanical strength than NIPAAm.
In the photoluminescence behavior, results show that the gels crosslinked with DMETPA exhibit fluorescence under UV irradiation, but for the gels crosslinked with EGDMA exhibits no fluorescence. Also, the intensity of fluorescence depends on the content of DMETPA.
In addition, the fluorescent intensity and the maximum absorption wavelength of the DMETPA and the TPA-capped PLGA-PEG-PLGA monomer dissolved in different polarity solvents are observed. The results showed that the DMETPA and TPA-capped PLGA-PEG-PLGA monomer in different polarity solvent exhibits red shift as the polarity increases.
In cell culture cytotoxicity, the TPA-capped PLGA-PEG-PLGA biodegradable material shows cytotoxic and not suitable in humans according to decolorized zones index and cell lysis index.

並列關鍵字

hydrogel ； thermosensitive ； organic-inorganic hybrid ； triphenylamine ； photoluminescence ； photoluminescence of hydrogel

參考文獻

1. Lee, W. F.; Yeh, Y. C. “Studies on preparation and properties of NIPAAm/hydrophobic monomer copolymeric hydrogels”. European Polym 2005, 41, 2488.

2. Ricka, J.; Tanaka, T. “Swelling of Ionic Gels: Quantitative Performance of the Donnan Theory”. Macromolecules 1984, 17, 2916.

3. Hirokawa, Y.; Tanaka, T. “Volume phase transition in a nonionic gel”. J Chem Phys 1984, 81, 6379.

4. Grignon, J.; Scallan, A. M. “Effect of pH and neutral salts upon the swelling of cellulose gels”. J Appl Polym Sci 1980, 25, 2829.

5. Hoffman, A. S. “Applications of thermally reversible polymers and hydrogels in therapeutics and diagnostics”. J Control Release 1987, 6, 297.