製備光可調控溫度敏感型複合載體以作為藥物控制釋放系統

淡江大學機構典藏 > 工學院 > 化學工程與材料工程學系暨研究所 > 學位論文 > Item 987654321/87893

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题名:	製備光可調控溫度敏感型複合載體以作為藥物控制釋放系統
其它题名:	Preparation of optical-controlled thermal-responsive composite carrier for drug delivery system
作者:	林昱伸;Lin, Yu-Shen
贡献者:	淡江大學化學工程與材料工程學系碩士班董崇民
关键词:	溫度敏感型;可逆加成-斷裂鏈轉移聚合;奈米金桿;藥物釋放系統;thermal-responsive;Reversible addition-fragmentation chain transfer polymerization;Gold Nanorod;drug delivery system
日期:	2012
上传时间:	2013-04-13 11:50:39 (UTC+8)
摘要:	本研究主要在製備具有光可調控的溫度敏感性複合載體以作為藥物控制釋放載體，希望利用可穿透皮膚組織的近紅外光照射藥物載體，進而產生光熱效應而引起溫度上升，使載體收縮而釋放出藥物。此研究選擇聚氮-異丙基丙烯醯胺(Poly(N-isopropyl acrylamide)，PNIPAAm)作為溫感性高分子的主體，而為了調控低臨界溫度值(Lower critical solution temperature，LCST)，也嘗試在合成反應系統中加入單端碳雙鍵的乙二醇甲醚丙烯酸酯寡聚物(Semi-telechelic oligo(ethylene glycol) methyl ether acrylate，OEGA)，不僅可提高LCST值，也可增進生物相容性。合成反應是將NIPAAm及OEGA溶解在DMF溶劑中，以2-(十二烷基三硫代碳酸酯基)-2-甲基丙酸(2-(Dodecylthiocarbonothioylthio)-2-methylpropionic acid，DMP)作為鏈移轉劑(Chain transfer agent，CTA)及 4,4''-偶氮雙(4-氰基戊酸) ((4,4′-azobis(4-cyanovaleric acid)，ACVA)起始劑以可逆加成-斷裂鏈轉移聚合(Reversible addition- fragmentation chain transfer polymerization，RAFT)活性自由基聚合方法合成末端帶有酸基和十二烷基三硫代碳酸酯的窄分子量分佈HOOC-P(N-OEG)-CTA高分子。當添加的親水性單端碳雙鍵OEGA含量為6%時，可以得到LCST略高於人體溫度的38.5°C。接著利用硼氫化鈉(NaBH4)將末端的三硫代碳酸酯基還原成巰基(-SH)，結果卻發現也會將共聚物中的親水OEG侧基還原成酸基及醇基，造成共聚物的LCST值下降。光熱效應(Opto-thermal effect)則是利用奈米金桿的表面電漿共振效應(Surface plasmon resonance，SPR)，利用種晶生成法合成出長35.9(±4.6) nm和寬10.2(±1.26) nm，長寬比值(Aspect ratio，AR)為3.52(±0.61)，且形狀均一之奈米金桿(GNR)，其表面電漿共振頻率(SPL,max)約在793 nm的近紅外光。最後加入不同比例的HOOC-PNIPAAm-CTA(MW= 8503 kDa，PDI= 1.12，LCST= 31.6°C)及HOOC-P(N-OEG6)-CTA(MW= 11512 kDa，PDI= 1.01，LCST= 38.5°C)溫感性高分子(Thermo-responsive polymer，TRP)於奈米金桿溶液中進行接枝反應以形成TRP/GNR複合材料。實驗發現50 mg之TRP與2.11×10-10 M的GNR在pH7下接枝反應24 h後，複合材料會有較佳之穩定性，並藉由STEM證實硫元素僅吸附於奈米金桿表面，而在TEM影像顯示奈米金桿受到高分子鏈之保護。接枝後，PNIPAAm/GNR及P(N-OEG6)/GNR複合材料的的LCST值分別為31.4°C及38.6°C，表示TRP在接枝上GNR後，對LCST值並無影響。最後將TRP/GNR複合材料溶液進行紅外光雷射引導(808 nm)及細胞培養等測試。TRP/GNR溶液經過近紅外光(1000 mW)照射5分鐘後，由於奈米金桿的表面電漿共振效應，溫度可從25°C上昇至43°C，此溫度上昇進而引發TRP的相變化；同時此溫度敏感性行為在經過近紅外光開關5次循環後，仍具有可逆變化。TRP/GNR複合材料不但具有光熱轉換之效應，且具可逆性，並且明顯改善原奈米金桿之生物毒性，在經過HOOC-PNIPAAm-CTA及HOOC-P(N-OEG6)-CTA接枝保護後，細胞存活率從原先的44%分別提升至86%及93%。 In this study, optical-controlled thermal-responsive composites based on thermo-responsive polymers (TRP) and gold nanorod (GNR) were prepared as a potential carrier for drug delivery system. When the composites were irradiated by near IR laser which could penetrate deep into tissues, the GNR could transform the absorbed light into heat due to the surface plasmon effect (SPR) and thus raised the temperature, which leaded to the volume shrinkage of the TRP and thereby releasing the encapsulated drug. Copolymers based on N-isopropyl acrylamide (PNIPAAm) and telechelic oligo(ethylene glycol) methyl ether acrylate (OEGA) were synthesized as the TRP. The OEGA was added into the reaction system to modulate the lower critical solution temperature (LCST) and increase the biocompatibility of the resulting copolymers. First, NIPAAm monomer and semi-telechelic OEGA with different molar ratios were dissolved in DMF. Subsequently, 2-(dodecyl thiocarbonothioylthio)-2-methylpropionic acid (DMP) as the chain transfer agent (CTA) and 4,4′-azobis(4-cyanovaleric acid) (ACVA) as the initiator were added into the solution to undergo the reversible addition-fragmentation chain transfer (RAFT) polymerization. The produced HOOC-P(N-OEG)-CTA copolymers with α-carboxylic acid and ω-dodecyltrithiocarbonate end groups were proved to have a very low dispersity in molecular weight. When the feeding molar ratio of the OEGA was 0.06, the resulting HOOC-P(N-OEG)-CTA copolymer had a LCST value of 38.5°C, slightly higher than the physiological temperature. Subsequently, the terminal trithiocarbonate group of the copolymers was reduced by NaBH4 to obtain thiol-terminated thermo-responsive copolymers. However, it was found that the acrylate side group of the OEGA was reduced as well to carboxylic and even hydroxyl groups, resulting in a decrease in the LCST value. Opto-thermal effect was induced by surface plasmon effect of gold nanorod (GNR). Using the seed-mediated growth method, the synthesized GNR was very uniform in both size and shape with a dimension of 35.9(±4.6) nm in length and 10.2(±1.26) nm in width, thus having an aspect ratio (AR) of 3.52(±0.61) and a corresponding SPL,max of 793 nm. Both the HOOC-PNIPAAm-CTA (MW=8503 kDa, PDI=1.12, LCST=31.6°C) and HOOC-P(N-OEG6)-CTA (MW=11512 kDa, PDI=1.01, LCST=38.5°C) with different amounts were tried to graft onto the GNR to produce opto-thermal responsive TRP/GNR composites. It was found the TRP/GNR composites prepared by grafting 50 mg TRP onto 3 mL GNR (2.11×10-10 M) at pH7 for 24 h had the best stability. STEM results confirmed that the trithiocarbonate group could be adsorbed onto the surface of GNR, and the TEM image showed that the GNR was protected by a surrounding polymer layer. After grafting, the HOOC-PNIPAAm-CTA/GNR and HOOC-P(N-OEG6)-CTA)/GNR had LSCT values at 31.4°C and 38.6°C, respectively, indicating that the grafting process did not affect the LCST values. The TRP/GNR solution was tested for the near-IR irradiation-induced thermo-responsibility and cell compatibility. Because of the surface plasmon effect of GNR, the irradiation of near-IR (808 nm, 1000 mW) for 5 min could induce the temperature to rise from 25°C to 43°C. The thermo-responsibility was also reversible during five test cycles. Moreover, the protection polymer layer could decrease the cytotoxicity of the GNR. Cell viability was increased from 44% for the GNR to 86% and 93% for the HOOC-PNIPAAm-CTA/GNR and HOOC-P(N-OEG6)-CTA/GNR, respectively.
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