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標題: 溫度敏感性與磁性奈米顆粒之製備以及藥物傳輸系統之應用
Preparation and Application of Thermosensitive and Magnetic Nanoparticles in Drug Delivery System
作者: 連怡欣
Lien, Yi-Hsin
關鍵字: 溫度敏感性
drug delivery
出版社: 材料科學與工程學系所
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摘要: 本研究中,利用反微乳化聚合法將二氧化矽披覆在單分散6 nm氧化鐵顆粒表面,藉由反應時間與二氧化矽前驅物之濃度調控複合顆粒尺寸,再將以自由基聚合法合成的聚異丙基丙醯胺[poly(N-isopropylacrylamide), (PNIPAM)]共聚高分子接枝在此複合顆粒表面,即可製備出同時具有溫度敏感性以及磁性的奈米顆粒且結構為典型之核/殼結構。 NIPAM的低臨界轉換溫度(lower critical solution temperature,LCST)約為32°C,在與3-(甲基丙烯酰氧)丙基三甲氧基矽烷[3- (trimethoxysily) propyl methacrylate,MPS]形成共聚物接枝在複合顆粒表面後,PNIPAM共聚物所測得低臨界溶液溫度(lower critical solution temperature,LCST) 上升至35-40°C區間。此外,從動態光散射分析儀(dynamic light scattering,DLS)可觀察到粒徑會隨著溫度的升高逐漸減小,並在35-40°C會有明顯的變化。因此,所製備出的PNIPAM接枝SiO2/Fe3O4奈米顆粒具有接近人體體溫之LCST。包覆氧化鐵的目的,是使奈米顆粒帶有磁性,希望藉由外加磁場的控制,將顆粒引導至癌細胞或是特定細胞的鄰近區域,再將藥物有效控制釋放,尺寸為6 nm的氧化鐵顆粒具有超順磁的特性,表面經過二氧化矽層的披覆,經由超導量子干涉磁量儀(Superconducting Quantum Interference Device,SQUID)的測量,可以發現飽和磁化量的下降,但複合顆粒仍呈現原本的超順磁特性;並且表面接枝PNIPAM後,仍保有超順磁的特性,且不受溫度變化的影響。 將所製備出的PNIPAM接枝SiO2/Fe3O4奈米顆粒與牛血清蛋白(Bovine Serum Albumin,BSA)和維生素D3(vitamin D3)作為兩種模擬藥物,進行藥物承載與釋放試驗,使用UV可見光光譜儀(UV/VIS Spectophotometer,UV)計算所得之結果發現,藥物承載與釋放會受到溫度的影響而有所改變。BSA為水溶性之藥物,但屬於大分子,承載與釋放主要受到與PNIPAM接枝SiO2/Fe3O4奈米顆粒之間的疏水作用力影響。因此,BSA在高於PNIPAM之LCST的溫度,由於披覆在奈米顆粒表面的PNIPAM鏈段會產生糾結形成疏水性的表面,此時可利用疏水作用力與BSA鍵結,將其吸附在表面,反之,在低於LCST的溫度,PNIPAM分子鏈段伸展親水,因而無法吸附BSA。Vitamin D3承載機制表現不同,在高溫的承載量少於低溫的承載量,然而在釋放時,低溫承載的釋放量卻優於高溫承載的釋放量,表示其承載與釋放仍會受到表面PNIAPM鏈段溫度敏感性的影響。從此結果可得知,利用低溫承載較多的vitamin D3,進入人體的環境中,可幫助其釋放,以提昇治療的效果。 細胞實驗主要分為兩部份,第一部分主要探討PNIPAM接枝SiO2/ Fe3O4奈米顆粒的生物相容性,並探討其對細胞的安全性。本部份主要使用兩種細胞,哺乳動物中國倉鼠卵巢細胞(Chinese hamster ovary cell,CHO-K1),以及人類肝癌細胞(Human hepatocellular liver carcinoma,HepG2),經由溴化噻唑蓝四氮唑藍分析(3-(4,5-cimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide,MTT)、錐藍排除分析法(trypan blue)和乳酸去氫酶(Lactate dehydrogenase,LDH)的細胞存活率測試,顯示奈米顆粒呈現良好的生物相容性。並使用光學顯微鏡(Optical Microscopy,OM)觀察顆粒的添加並不會對細胞形態產生影響,也進一步使用TEM確認奈米顆粒進入細胞,並存在於細胞質的位置。第二部份主要探討承載具有活性vitamin D3 (1,25-dihydroxyvitamin D3,1,25(OH)2D3)的PNIPAM接枝SiO2/Fe3O4奈米顆粒是否有效將藥物釋放抑制癌細胞的生長。承載藥物的奈米顆粒,在短時間內從MTT並無觀察到變化,直至5天的培養,細胞存活率顯示為明顯的下降,並從LDH的觀察到細胞傷害的表現。進一步由穿透式電子顯微鏡(Transmission Electron Microscopy,TEM)觀察細胞的形態的變化,可以在第一天即發現承載藥物的奈米顆粒進入細胞,並存在於細胞質間,但還未對細胞造成傷害,將時間培養至第五天時,細胞型態明顯改變,呈現細胞傷害死亡的結果。可知,PNIPAM接枝SiO2/Fe3O4奈米顆粒具備當作藥物載體的潛力,適合應用在藥物傳輸系統上。
In this study, the multi-functional nanoparticles containing thermosensitive polymers grafted onto the surfaces of the 6-nm monodispersed Fe3O4 magnetic nanoparticles coated by silica were synthesized using reverse microemulsions. The magnetic properties of SiO2/Fe3O4 nanoparticles show superparamagnetic behavior. Thermosensitive PNIPAM [poly(N-isopropylacrylamide)] was then grafted onto the surfaces of SiO2/Fe3O4 nanoparticles, generating thermosensitive and magnetic properties of nanocomposites. The sizes of fabricated nanoparticles with core-shell structure are controlled at about 20 nm and each nanoparticle contains only one monodispersed Fe3O4 core. For thermosensibility analysis, the phase transition temperatures of multi-functional nanoparticles measured using differential scanning calorimetry (DSC) and dynamic light scanning (DLS) were at around 35~40�C. The magnetic characteristics of these multi-functional nanoparticles were also superparamagnetic. The loading and release of Bovine serum albumin (BSA) and vitamin D3 were also discussed. The main driving force to adsorb BSA is hydrophobic interaction between nanoparticles and BSA. Thus, at 50�C and 37�C, the polymeric shell presented as hydrophobic chains and could adsorb BSA; in contrast, the nanoparticles have no significant absorption at 25�C. Vitamin D3 loading and release behavior were also found to be dependent on the lower critical solution temperature (LCST) of the PNIPAM/SiO2/Fe3O4 nanoparticles. However, it is different to adsorption of BSA. These results show the loading vitamin D3 increases with increasing time and reaches a plateau over the 24 hours study at 25 and 37�C. At 37�C, the lower loading amount of vitamin D3 ~19.3 wt% is observed; while higher loading amount ~37.7 wt% is reached at 25�C, which is below the LCST of nanoparticles. In vitro drug release, drug squeezed out from the nanoparticles was observed when loading drug at 25�C and releasing at 37�C; nevertheless, the drug release system will undergo at physiological temperature so that loading temperature is better under the LCST. Cytotoxicity studies were apart from two parts. The first part was conducted on Chinese hamster ovary (CHO-K1) cells and liver cancer cells (HepG2) using 3-(4,5-cimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assays revealed that cell viability of 1 mg/mL PNIPAM grafted on SiO2/Fe3O4 nanoparticles was slightly decreased after 24h incubation as compared to the lower concentration of nanoparticles. Furthermore, the concentration of 0.5 mg/mL PNIPAM grafted on SiO2/Fe3O4 nanoparticles was totally biocompatible for 48h; however, had low cytotoxicity after 72h incubation. These PNIPAM grafted on SiO2/Fe3O4 nanoparticles did not induce the morphological change in their cellularity after the exposure for 24 and 108h. The second part was observed the effect of 1,25(OH)2D3 loading of PNIPAM grafted on SiO2/Fe3O4 nanoparticles incubated with HepG2 cells. After 5 days incubation of HepG2 liver cancer cells with 1,25(OH)2D3 loading of PNIPAM grafted on SiO2/Fe3O4 nanoparticles, cell viability significant decreased that discernible from MTT and lactate dehydrogenase (LDH) assays, which is further supported by the TEM images. In conclusion, the current study demonstrated a PNIPAM grafted on SiO2/Fe3O4 nanoparticles may be used as a potential drug delivery system for controlled release.
其他識別: U0005-0407201210430800
Appears in Collections:材料科學與工程學系



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