聚环氧乙烷（PEO）类聚合物的合成、表征及应用
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摘要
聚环氧乙烷(PEO)是目前最常用的生物相容性聚合物之一。它有很多优异的性能：毒性低、水中溶解性很好、免疫性和抗原性极低等。药物可以用PEO修饰、也可以装载于具有PEO外层的纳米胶囊中，其结果都可以提高循环系统中药物的半衰期，得到极好的药代动力学性能和体内分布。具有支化结构的第二代PEO主要应用于蛋白质药物的修饰，其对小分子药物的修饰还研究甚少。另外，PEO修饰的液核纳米微胶囊较难功能化，而聚合物胶束的载药量又不太高。我们试图找到一个新的方法，得到载药量较高的液核纳米微胶囊，同时具有胶束易于功能化，易于修饰的优点。
主要结果如下：
1．首先合成了单甲氧基PEO(mPEOs，Mn=2000，3000，4700)，然后将其端羟基转化为羧基，得到了端基转化效率很高的产物。然后用羧端基的mPEO-COOH和赖氨酸的两个氨基偶合，得到不同分子量的支化PEO(mPEO_2)(Mn=4000，6000，9400)，将支化PEO通过官能化反应结合顺铂[cis-diammine(dichloro)platinum(Ⅱ)，CDDP]。为了比较，我们还合成了相同分子量的线型PEO修饰的顺铂。细胞毒性实验显示支化PEO修饰的顺铂比相同分子量线型PEO药物对C6人乳腺癌细胞有更好的抑制作用。急毒实验显示，所有的聚合物药物毒性都远小于未修饰的顺铂。
2．通过阴离子聚合，合成了环氧乙烷和乙氧基乙基缩水甘油共聚物，水解后得到聚环氧乙烷为主链、侧链挂有羟基的亲水聚合物。将部分侧链羟基和共轭亚油酸酯化，然后和油一起分散于水中。聚合物吸附于油滴表面，通过交联得到液核纳米微胶囊。胶囊的粒径小于350nm，分布一般较窄(＜0.2)。通过改变乳化条件可以很容易地调节粒径。胶囊在水中非常稳定，至少可以保持5个月，用乙醇溶去核后其壳仍保持完整。我们还测试了胶囊对芘的装载，通过紫外检测，装载效率最高可达94％。因此我们提供了一个在界面上交联聚合物得到液核纳米微胶囊的新方法。
3．用聚环氧乙烷大分子引发剂，通过ATRP聚合，合成了环氧乙烷／二甲氨基乙基甲基丙烯酸酯(DMA)嵌段共聚物。然后部分DMA单元通过季铵化接枝十八烷基溴，得到两亲性聚合物。所得的两亲性聚合物和油一起制备细乳液，聚合物吸附于油的表面。通过加入1，4-二溴丁烷使聚合物交联，得到稳定的pH响应的液核纳米微胶囊，并通过核磁共振测定实际交联的程度。我们还研究了胶囊对pH的响应，当pH降到3时，微胶囊的粒径会突然增大。不同壳核质量比的胶囊对pH的响应程度略有区别，壳层质量越大，粒径增幅越大，直径最大的增幅为80nm。壳层交联程度也对胶囊pH响应幅度有影响。
Poly(ethylene oxide) (PEO) is one of the most popular biocompatible polymers. It possesses an ideal array of properties: very low toxicity, excellent solubility in aqueous solutions, extremely low immunogenicity and antigenicity. Drugs can be chemically modified with PEO or lodded in the nanoparticles with PEO corona and reach long-circulating half-lives and excellent pharmacokinetic and biodistribution behavior. Yet the second generation Pegylation is focused on protein and peptide. As one method of the second generation Pegylation, branched PEO has been used to modify low molecular weight drugs rarely. However, the PEO modified liquid-core nanocapsules are difficult to be functionalized and the loading content by polymer micelles is not high. We try to find a novel method to prepare liquid-core nanocapsules with high loading content and varied functionalities. The main results have been obtained as follows:
1. Monomethoxy-polyethylene oxides (mPEOs, Mn= 2000, 3000, 4700) were synthesized and the terminal hydroxyl group was converted to carboxyl group with high efficiency, and then mPEO-COOH was obtained. Two-arm branched PEO (mPEO_2) with different molecular weight (M_n=4000, 6000, 9400) were synthesized by coupling the carboxyl groups of mPEO-COOH with the amino groups of one lysine molecule. Then the obtained branched polymer was used as carrier for immobilization of cisplatin (cis-diammine (dichloro) platinum (II), CDDP). As a contrast, CDDP modified with linear mPEOs were also synthesized. All these polymeric drugs modified with branched PEO are water soluble and show higher cytotoxic activity against C6 human breast cancer cells than cisplatin modified with linear mPEO with the same molecular weight. All the polymeric CDDP showed the much lower toxicity than the CDDP.
2. The hydrophilic copolymers poly[(ethylene oxide)-co-glycidol] [poly(EO-co-Gly)] was prepared by anionic polymerization of ethylene oxide (EO) and ethoxyethyl glycidyl ether (EEGE) first, then the hydroxyl groups on the backbone were recovered after hydrolysis and partly modified by hydrophobic conjugated linoleic acid (CLA). The copolymer with multiple linoleate pendants was absorbed at the oil/water interface and then crosslinked to form stable nanocapsules. The mean diameter of the nanocapsule was below 350nm and the size distribution was relatively narrow (<0.2) at low concentration of oil in acetone (<10 mg/mL). The particle size could be tuned easily by variation of the emulsification conditions. The nanocapsule was stable in water for at least 5 months, and the shell still kept integrity after removal of the oily core by solvent. Pyrene was encapsulated in these nanocapsules and high loading efficiency as 94% was measured by UV spectroscopy. Thus a convenient approach to prepare the liquid-core nanocapsules by cross-linking amphiphilic copolymer at oil-water interface was provided.
3. Poly(ethylene oxide)-block-poly[2-(dimethylamino)ethyl methacrylate] (PEO-b-PDMA) was synthesized by ATRP polymerization of DMA using PEO-based macroinitiator. Then the DMA units of the block copolymer were partly modified with bromooctadecane. The obtained amphiphilic copolymer was absorbed at the oil/water interface and to form stable nanocapsules, the cross-linking procedure was performed by adding 1,4-dibromobutane and the efficiency was estimated by ~1H NMR. The pH-responsive properties of the capsules were investigated. When the pH of the dispersion decreased to 3, the diameters of the nanocapsules increased sharply. Capsules with different core/shell mass ratio showed the different PH-responsive properties, the larger the core/shell mass ratio, the higher the diameter increase, and the maximum change of the diameter was 80nm. The cross-linking degree also affects the increasing degree.
主要结果如下：
1．首先合成了单甲氧基PEO(mPEOs，Mn=2000，3000，4700)，然后将其端羟基转化为羧基，得到了端基转化效率很高的产物。然后用羧端基的mPEO-COOH和赖氨酸的两个氨基偶合，得到不同分子量的支化PEO(mPEO_2)(Mn=4000，6000，9400)，将支化PEO通过官能化反应结合顺铂[cis-diammine(dichloro)platinum(Ⅱ)，CDDP]。为了比较，我们还合成了相同分子量的线型PEO修饰的顺铂。细胞毒性实验显示支化PEO修饰的顺铂比相同分子量线型PEO药物对C6人乳腺癌细胞有更好的抑制作用。急毒实验显示，所有的聚合物药物毒性都远小于未修饰的顺铂。
2．通过阴离子聚合，合成了环氧乙烷和乙氧基乙基缩水甘油共聚物，水解后得到聚环氧乙烷为主链、侧链挂有羟基的亲水聚合物。将部分侧链羟基和共轭亚油酸酯化，然后和油一起分散于水中。聚合物吸附于油滴表面，通过交联得到液核纳米微胶囊。胶囊的粒径小于350nm，分布一般较窄(＜0.2)。通过改变乳化条件可以很容易地调节粒径。胶囊在水中非常稳定，至少可以保持5个月，用乙醇溶去核后其壳仍保持完整。我们还测试了胶囊对芘的装载，通过紫外检测，装载效率最高可达94％。因此我们提供了一个在界面上交联聚合物得到液核纳米微胶囊的新方法。
3．用聚环氧乙烷大分子引发剂，通过ATRP聚合，合成了环氧乙烷／二甲氨基乙基甲基丙烯酸酯(DMA)嵌段共聚物。然后部分DMA单元通过季铵化接枝十八烷基溴，得到两亲性聚合物。所得的两亲性聚合物和油一起制备细乳液，聚合物吸附于油的表面。通过加入1，4-二溴丁烷使聚合物交联，得到稳定的pH响应的液核纳米微胶囊，并通过核磁共振测定实际交联的程度。我们还研究了胶囊对pH的响应，当pH降到3时，微胶囊的粒径会突然增大。不同壳核质量比的胶囊对pH的响应程度略有区别，壳层质量越大，粒径增幅越大，直径最大的增幅为80nm。壳层交联程度也对胶囊pH响应幅度有影响。
Poly(ethylene oxide) (PEO) is one of the most popular biocompatible polymers. It possesses an ideal array of properties: very low toxicity, excellent solubility in aqueous solutions, extremely low immunogenicity and antigenicity. Drugs can be chemically modified with PEO or lodded in the nanoparticles with PEO corona and reach long-circulating half-lives and excellent pharmacokinetic and biodistribution behavior. Yet the second generation Pegylation is focused on protein and peptide. As one method of the second generation Pegylation, branched PEO has been used to modify low molecular weight drugs rarely. However, the PEO modified liquid-core nanocapsules are difficult to be functionalized and the loading content by polymer micelles is not high. We try to find a novel method to prepare liquid-core nanocapsules with high loading content and varied functionalities. The main results have been obtained as follows:
1. Monomethoxy-polyethylene oxides (mPEOs, Mn= 2000, 3000, 4700) were synthesized and the terminal hydroxyl group was converted to carboxyl group with high efficiency, and then mPEO-COOH was obtained. Two-arm branched PEO (mPEO_2) with different molecular weight (M_n=4000, 6000, 9400) were synthesized by coupling the carboxyl groups of mPEO-COOH with the amino groups of one lysine molecule. Then the obtained branched polymer was used as carrier for immobilization of cisplatin (cis-diammine (dichloro) platinum (II), CDDP). As a contrast, CDDP modified with linear mPEOs were also synthesized. All these polymeric drugs modified with branched PEO are water soluble and show higher cytotoxic activity against C6 human breast cancer cells than cisplatin modified with linear mPEO with the same molecular weight. All the polymeric CDDP showed the much lower toxicity than the CDDP.
2. The hydrophilic copolymers poly[(ethylene oxide)-co-glycidol] [poly(EO-co-Gly)] was prepared by anionic polymerization of ethylene oxide (EO) and ethoxyethyl glycidyl ether (EEGE) first, then the hydroxyl groups on the backbone were recovered after hydrolysis and partly modified by hydrophobic conjugated linoleic acid (CLA). The copolymer with multiple linoleate pendants was absorbed at the oil/water interface and then crosslinked to form stable nanocapsules. The mean diameter of the nanocapsule was below 350nm and the size distribution was relatively narrow (<0.2) at low concentration of oil in acetone (<10 mg/mL). The particle size could be tuned easily by variation of the emulsification conditions. The nanocapsule was stable in water for at least 5 months, and the shell still kept integrity after removal of the oily core by solvent. Pyrene was encapsulated in these nanocapsules and high loading efficiency as 94% was measured by UV spectroscopy. Thus a convenient approach to prepare the liquid-core nanocapsules by cross-linking amphiphilic copolymer at oil-water interface was provided.
3. Poly(ethylene oxide)-block-poly[2-(dimethylamino)ethyl methacrylate] (PEO-b-PDMA) was synthesized by ATRP polymerization of DMA using PEO-based macroinitiator. Then the DMA units of the block copolymer were partly modified with bromooctadecane. The obtained amphiphilic copolymer was absorbed at the oil/water interface and to form stable nanocapsules, the cross-linking procedure was performed by adding 1,4-dibromobutane and the efficiency was estimated by ~1H NMR. The pH-responsive properties of the capsules were investigated. When the pH of the dispersion decreased to 3, the diameters of the nanocapsules increased sharply. Capsules with different core/shell mass ratio showed the different PH-responsive properties, the larger the core/shell mass ratio, the higher the diameter increase, and the maximum change of the diameter was 80nm. The cross-linking degree also affects the increasing degree.
引文
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