利用氧化還原起始劑合成PMMA奈米顆粒及製備光可調控溫度敏感型共聚物以做為藥物控制釋放載體

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Title:	利用氧化還原起始劑合成PMMA奈米顆粒及製備光可調控溫度敏感型共聚物以做為藥物控制釋放載體
Other Titles:	Synthesis of PMMA nanoparticles by a redox initiator system and the preparation of optical-controlled thermo-responsive carrier for drug delivery system
Authors:	邱作沛;Chiu, Tso-pei
Contributors:	淡江大學化學工程與材料工程學系博士班董崇民;Don, Trong-ming
Keywords:	乳化聚合;Cu2+/HSO3-;氧化還原起始系統;PMMA;裂解活化能;幾丁聚醣;溫度敏感性;氮-異丙基丙烯醯胺;聚甲基丙烯酸聚乙二醇酯;LCST;奈米金桿;emulsion polymerization;Cu2+/HSO3-;redox initiator;Poly(Methyl Methacrylate);apparent activity energy;Chitosan;thermal-responsive;microgel;LCST;PNIPAAm;PEGMA;Gold Nanorod
Date:	2009
Issue Date:	2010-01-11 05:38:30 (UTC+8)
Abstract:	本研究第一部分是以新型硫酸銅和亞硫酸氫鈉(Cu2+/HSO3-)氧化還原起始系統在不同反應溫度下(40oC~60oC)進行PMMA乳膠顆粒的合成，反應2小時後，轉化率可達85 %以上，而乳膠顆粒表面因有亞硫酸根而帶負電。利用SEM觀察乳膠顆粒的形態，結果顯示乳膠顆粒大小均一分佈，而且反應溫度越高其粒徑越小，粒徑平均大小從40oC的223 nm減少至60oC的165 nm之間，趨勢與光散射儀的結果一致。本研究闡明了Cu2+/HSO3-氧化還原起始系統的反應機制，首先銅離子與兩個亞硫酸氫根先形成配位複合物後，銅離子誘使亞硫酸氫根上的氫氧鍵斷鍵產生亞硫酸根自由基和氫原子自由基，氫原子自由基進一步地和銅離子進行氧化還原反應變成氫離子和亞銅離子，而亞硫酸根自由基則起始自由基聚合反應。另外，不同溫度下合成出的PMMA鏈段的立體異構性幾乎是相同的，大約是62~64 % rr、33~35 % mr和3 % mm，而且有幾乎相同的玻璃轉移溫度(125~127oC)，其重量平均分子量在254,000和315,000之間。固定反應溫度在60oC，改變起始劑中銅離子濃度以合成PMMA，實驗結果顯示不同銅離子濃度合成的PMMA，單體轉化率皆可達90 %以上，且Zeta電位皆低於-30 mV，代表乳液有不錯的穩定性。當銅離子濃度從2.0 mM增加至6.0 mM時(MMA維持1 M)，SEM觀察結果顯示乳膠顆粒大小均一分佈，粒徑平均大小從182 nm增加到224 nm。所合成出來的PMMA乳膠顆粒的TGA曲線圖呈現兩階段裂解行為，其中第一階段屬不飽和末端基團PMMA-CR=CH2的熱裂解，第二階段屬飽和末端基團PMMA-H的熱裂解，而隨著銅離子濃度增加，會造成較多的不飽和末端基團的PMMA-CR=CH2生成，因此銅離子不僅僅可用來起始反應，同時又是鏈轉移劑用以終止成長中的高分子自由基鏈段。利用Ozawa法和Boswell法計算裂解活化能的結果顯示，PMMA-CR=CH2的裂解活化能在123.6~134.8 kJ/mol之間，而PMMA-H的裂解活化能在156.4~213.4 kJ/mol之間。本研究第二部分利用具生物相容性的幾丁聚醣(CS)、溫度敏感性的氮-異丙基丙烯醯胺(NIPAAm)單體和可調整溫度敏感值(LCST)的聚甲基丙烯酸聚乙二醇酯(PEGMA)單體，以合成LCST值略高於生理溫度的幾丁聚醣-聚氮-異丙基丙烯醯胺-聚甲基丙烯酸聚乙二醇酯(CS-PN-PEG)共聚物。從批次反應系統所合成的CS-PN-PEG共聚物，因單體反應性的不同，會產生CS-PN-PEG和CS-PN共聚物，因而產生兩個相變化行為。以連續進料系統所合成的CS-PN-PEG共聚物，具有一階段的相變化行為。在pH4的環境下，當溫度到達LCST以上時，CS-PN-PEG共聚物能夠立即收縮，呈現應答快速的一階段相變化行為，隨PEGMA的含量增加，LCST值從33.0oC增加到39.7oC。在pH7的環境下，因CS的鏈展開幅度不大，呈現應答較為緩慢的一階段相變化行為，隨PEGMA的含量增加，LCST值從35.7oC增加到45oC。粒徑分析儀量測CS-PN-PEG共聚物所得的平均粒徑約在290 nm和450 nm之間。其次，利用化學還原法製備奈米金桿，藉由增加銀離子的含量，可使奈米金桿的縱向表面電漿共振吸收(SPL)有紅移的現象。當Ag+/Au3+G比值到達時，有最大的產率，SPL, max最大吸收波長在779 nm附近。利用控制奈米金桿成長的時間，可以得到SPL, max最大吸收波長在806 nm且吸收度為2.35的奈米金桿溶液。利用W/O乳化法製備CS/AuR/CS-PN-PEG10複合載體，可以成功的將奈米金桿包覆，經過載入藥物Diclofenac Sodium (DS)，其承載率為0.669 %，包覆率為78.0 %。CS/AuR/CS-PN-PEG10複合藥物載體經雷射光照射後，導致藥物載體收縮而加速DS的釋放，經過24小時的藥物釋放後，藥物累積釋放百分比為58.9 %。 In the fisrt part of this study, emulsifier-free emulsion polymerization of MMA was initiated directly by the Cu2+/HSO3- redox system. Latex particles with negative charge due to the bonded anionic sulfite ion were successfully synthesized after 2 h of reaction at 40 to 60oC. SEM pictures showed an uniform particle size distribution, and the average size decreased from 223 nm to 165 nm by increasing reaction temperature from 40oC to 60oC. The initiation step in polymerization mechanism was proved to be a redox reaction, in which Cu2+ oxidized the bisulfite ion to produce anionic sulfite radical and proton. The produced anionic sulfite radical then initiated polymerization of MMA. Moreover, Cu2+ not only served as one component in the redox initiator system but also a chain transfer agent that terminated growing polymer chains to produce chains with unsaturated end group (PMMA-CR=CH2). For the present system, about 17 % of PMMA-CR=CH2 was produced. The tacticities of PMMA latex prepared at 40~60oC were almost the same, ca. 62~64 % rr, 33~35 % mr, and 3 % mm. These PMMA latexes had almost the same Tg, 125~127oC, regardless of the reaction temperatures and their weight-average molecular weight was in the range between 254,000 and 315,000. PMMA latex was synthesized in an emulsifier-free emulsion polymerization at 60oC using a Cu2+/HSO3- redox initiator system with different concentrations of Cu2+. The experimental results showed that the monomer conversion reached above 90 % for all systems. Zeta potential was all negative due to the bonded bisulfite ion and the magnitude was greater than 30 mV, providing the stability of PMMA emulsion. The morphology of the latex observed by SEM revealed an uniform particle size and the average particle size increased from 181.9 nm to 234.2 nm as the Cu2+ ion concentration increased from 2.0 mM to 6.0 mM in 1 M of MMA solution. Thermal degradation behavior of synthesized PMMA was studied by TGA, in which a two-stage degradation behavior was observed. These two stages were found to be caused by the degradation of unsaturated end group (PMMA-CR=CH2) and saturated end group (PMMA-H), respectively. In addition, the higher the concentration of Cu2+ ion, the more the proportion of PMMA-CR=CH2 in final product, and in turn giving more weight loss in the first-stage degradation. The copper ion not only acted as a role in the redox initiation, but also as a chain transfer agent to terminate growing polymer chains thus producing PMMA-CR=CH2. The apparent activation energies of the first stage (Ea1) and second stage (Ea2) were calculated by Ozawa’s method as well as Boswell’s method. The results showed that the apparent activation energies of PMMA-CR=CH2 were in the range between 123.6 kJ/mol and 134.8 kJ/mole, and those of PMMA-H were in the range between 156.4 kJ/mol and 213.4 kJ/mole. In the second part this study, Chitosan-PNIPAAm-PEGMA (CS-PN-PEG) microgel copolymers were synthesized with biocompatible Chitosan (CS), thermal-responsive N-isopropylacrylamide (NIPAAm), and non-immunogenic Poly(ethylene glycol) metharcylate (PEGMA) by using ammonium persulfate (APS) as the initiator. In the batch reaction system, two-stage transition behaviors of CS-PN-PEG microgel copolymer were observed because the reaction product was composed of CS-PN-PEG and CS-PN copolymers due to the different monomer reactivity. In the continuous-feeding reaction system, one stage transition behavior of CS-PN-PEG microgel copolymer was observed. At pH4, the LCST values were shifted to higher temperatures from 33.0oC to 39.7oC with increasing the addition of hydrophilic PEGMA monomer. CS-PN-PEG microgel copolymer was immediately shrunk as the temperature reached to LCST due to the well-hydrophilic chitosan chains with excellent mobility tended to disentanglement at acidic condition. At pH7, the LCST values were shifted to higher temperatures from 35.7oC to 45oC with increasing hydrophilic PEGMA monomer. One stage transition behavior of CS-PN-PEG microgel copolymer exhibited slightly delay at neutrality due to the worse chain mobility on chitosan. The average particle size was in the range between 290 nm and 450 nm by using light scattering method. In addition, gold nanorods (AuR) were prepared by a seed-mediated growth approach. The longitudinal surface of plasmon resoncance (SPL) of AuR exhibited red-shifts with increasing the addition of silver ion. As Ag+/Au3+G ratio reached to 0.35, AuR had the maximum yield in which the SPL, max increased to 779 nm. AuR (SPL, max=806 nm and Abs. =2) was obtained by controlling the aging time. Moreover, CS/AuR/CS-PN-PEG10 complex carrier was obtained by using water in oil (W/O) method. After encapsulation of diclofenac sodium (DS), the loading was 0.669 % and encapsulation efficiency was 78 %. When CS/AuR/CS-PN-PEG10 complex carrier was irradiated by near IR light, they transformed the light into heat and thus raised temperature of the carrier. Subsequently, the thermal-responsive component undergoes phase transition causing volume shrinkage to squeeze out DS drug. After 24 hours, drug release amount reached 58.9%.
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