CN106279667B - 一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用 - Google Patents

一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用 Download PDF

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CN106279667B
CN106279667B CN201610604268.5A CN201610604268A CN106279667B CN 106279667 B CN106279667 B CN 106279667B CN 201610604268 A CN201610604268 A CN 201610604268A CN 106279667 B CN106279667 B CN 106279667B
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任艳蓉
贺浩哲
王延鹏
刘保英
丁涛
房晓敏
徐元清
徐浩
张文凯
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Abstract

本发明公开了一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用。所述聚乙二醇空心球由将两亲性梳形聚醚胺溶于水中,经紫外光照射1‑2h,水解,经沉析、分离及干燥得到交联的聚乙二醇空心球,所述的两亲性梳形聚醚胺亲水链段由聚乙二醇构成,疏水链段由脂肪族羧酸构成,主链由香豆素构成,其结构单元结构式如下:式中,R为H或CH3或CH2CH3,R’为碳原子数6~30的脂肪链,n=10~230,且n为整数。所述聚乙二醇空心球具有良好的生物相容性、pH敏感性,可作为脂溶性物质的载体使用。

Description

一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用
技术领域
本发明涉及高分子材料和生物医用材料领域,具体涉及一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用。
背景技术
聚合物纳米空心球作为一种新型给药系统,在药学领域有着和一般纳米载药系统相同的优点:具有被动靶向性、较好的控/缓释效果、可降低药物的毒副作用及提高药物的稳定性。此外,它还有一些独特的特点,如具有较大的内部空腔,可以包裹更多的药物,提高载药量,有效得提高药物的生物利用度。(GD Fu, GL Li, KG Neoh, ET Kang. Hollowpolymeric nanostructures-Synthesis, morphology and function. Prog. Polym.Sci., 2011, 36, 127-167.)。
聚合物纳米空心球主要有3种常用的制备方法:自组装法、模板法和微乳聚合法。其中,自组装法是制备聚合物纳米空心球的重要方法,主要利用嵌段或接枝聚合物在水溶液中的自组装体制备聚合物纳米空心球。但目前所报道的大多数聚合物空心球存在以下缺点:生物相容性较差,在制备过程中需要使用大量的表面活性剂,在除去聚合物胶束内核时需用大量有机溶剂,且聚合物纳米颗粒壳层的交联不可逆,这些都影响给药系统的安全性。
聚乙二醇(PEG)是一类广泛应用于生物材料和蛋白药物修饰的大分子,很多研究表明:PEG分子对材料表面的修饰可以明显提高材料的生物相容性,用PEG分子修饰的蛋白分子,可以降低蛋白药物免疫原性和延长药物在体内的半衰期 (WJ Li, FC Szoka.Lipid-based nanoparticles for nucleic acid delivery. Pharm. Res., 2007, 24,438–449)。
基于PEG组分的聚醚胺制备方法简单,无需催化剂或引发剂;聚醚胺分子链中含有叔氨基基团,能对环境的pH条件产生响应;通过单体的设计选择,能够简单方便的赋予聚醚胺各种优异性能(YR Ren, XS Jiang, GL Yin, J Yin. Multi-stimuli responsiveamphiphlic graft poly (ether amine) (agPEA): synthesis, characterization andself-assembly in aqueous solution. J. Polym. Sci. Part A: Polym. Chem., 2009,48:327-335; YR Ren, XS Jiang, R Liu, J Yin. Multi-stimuli responsive graftedpoly (ether tert-amine) (gPEA): synthesis, characterization and controlledmorphology in aqueous solution. J. Polym. Sci. Part A: Polym. Chem., 2009,47:6353-6361; YR Ren, XS Jiang, J Yin. Poly(ether tert-amine): A novel familyof multiresponsive polymer. J. Polym. Sci. Part A: Polym. Chem., 2009, 47:1292-1297; R Wang, XS Jiang, GL Yin, J Yin. Well-defined multi-stimuliresponsive fluorinated graft poly(ether amine)s (fgPEAs). Polymer, 2011, 52:368-375.)。因此,可以利用聚醚胺设计开发一种制备方法简单,制备条件温和、具有多重功能性的PEG聚合物纳米空心球。
发明内容
本发明的目的是克服现有技术中的不足,提供一种pH敏感光交联的聚乙二醇空心球、其制备方法及应用。
基于上述目的,本发明采取如下技术方案:
一种pH敏感光交联的聚乙二醇空心球的制备方法,将两亲性梳形聚醚胺溶于水中,经紫外光照射1-2h,水解,经沉析、分离及干燥得到交联的聚乙二醇空心球,
所述的两亲性梳形聚醚胺亲水链段由聚乙二醇构成,疏水链段由脂肪族羧酸构成,主链由香豆素构成,其结构单元结构式如下:
式中,R为H或CH3或CH2CH3,R’为碳原子数6~30的脂肪链,n=10~230,且n为整数。
所述两亲性梳形聚醚胺的具体制备步骤如下:
将单氨基聚乙二醇甲氧醚(mPEG-NH2)与含双环氧基香豆素类单体(DGC)溶解于溶剂中,在60~90℃下反应8~30小时,经沉析、分离及干燥,得到以香豆素为主链、聚乙二醇为侧链的聚醚胺,然后将这种聚醚胺与脂肪族羧酸在DCC和DMAP存在下进行酯化得到两亲性梳形聚醚胺粗产物,两亲性梳形聚醚胺粗产物经离心、沉析、分离及干燥得到两亲性梳形聚醚胺纯品。
所述的单氨基聚乙二醇甲氧醚与含双环氧基香豆素类单体摩尔比例为(0.9~1.1)︰(0.9~1.1)。
所述的溶剂为乙醇、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
上述制备方法制得的pH敏感光交联的聚乙二醇空心球。
上述的pH敏感光交联的聚乙二醇空心球作为脂溶性物质载体的应用。
所述的脂溶性物质为姜黄素、紫杉醇、多西紫杉醇、喜树碱、喜树碱衍生物、阿霉素、阿霉素类似物、脂溶性铂类抗癌药、脂溶性诊断试剂或荧光试剂。
本发明将两亲性梳形聚醚胺溶于水中,自组装形成胶束,经紫外光照射使聚醚胺主链交联,再水解除去疏水内核,得到交联的聚乙二醇空心球。
本发明设计、制备的pH敏感光交联的聚乙二醇空心球,反应条件温和,操作过程简单,制备得到的聚乙二醇空心球具有良好的生物相容性、稳定性、pH敏感性、高载药量,同时所述的聚乙二醇空心球在紫外光照射下可以光降解。
附图说明
图1是本发明实施例1中中间产物gPEAC、中间产物acPEAC、最终产物hPEAC的核磁谱图;
图2是本发明实施例1中聚乙二醇空心球hPEAC的TEM照片;
图3是本发明试验例1中阿霉素在不同pH缓冲液中的释放曲线;
图4是本发明试验例2中聚乙二醇空心球的细胞毒性测试结果。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例进一步说明。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其它实施例,都属于本发明保护的范围。
实施例1
pH敏感的光交联聚乙二醇空心球的制备过程如下所示:
具体制备步骤:
a)含香豆素基团的聚醚胺(gPEAC)的制备
2 g mPEG-NH2(数均分子量Mn=2000 g/mol)和0.304 g 4-甲基-5,7-二(2,3-环氧丙氧基)香豆素(即DGC),溶于10 mL无水乙醇中,在氮气保护下充分搅拌,于80 ℃下反应15小时后,取出冷却至室温;将反应混合物沉析至正己烷中,分离所得固体并干燥得到gPEAC。所得gPEAC的核磁谱图见图1(化学位移为3.3-3.8、5.8/6.4的峰分别属于聚乙二醇上亚甲基和香豆素基团的氢原子)。
b)两亲性梳状聚醚胺(acPEAC)的制备
将1.4g gPEAC、0.274 g十四酸、0.248 g DCC(N,N'-二环己基碳二亚胺)和8 mgDMAP(4-二甲氨基吡啶)溶于10 mL二氯甲烷,氮气保护,室温下反应24小时,旋转蒸发除去二氯甲烷,加入乙酸乙酯溶解粗产物,离心后取清液,沉析于正己烷中,分离所得固体并干燥得到acPEAC。所得acPEAC的核磁谱图见图1(经酯化后,acPEAC的核磁谱图上在化学位移1.2处出现烷基链的质子峰)。
c)聚乙二醇空心球hPEAC的制备
将acPEAC配成浓度为2 g/L的水溶液,在搅拌状态下于波长为365 nm的紫外灯下光照2小时。取200 mL光照后的溶液,用冰水浴冷冻至0 ℃,在快速搅拌下逐滴加入0.3 mL三氟乙酸,反应在 0 ℃进行30分钟后,在室温下继续反应4小时。旋转蒸发掉溶剂后溶于四氢呋喃中,用正己烷沉析,收集沉淀并干燥,得到hPEAC。所得hPEAC的核磁谱图见图1(经光交联后,香豆素基团上氢原子的峰强度大幅减弱;水解后,烷基链的峰强度大幅减弱),TEM照片见图2,清晰看见外径约为100nm的聚乙二醇空心球。
实施例2
pH敏感的光交联聚乙二醇空心球的制备过程:
a)含香豆素基团的聚醚胺(gPEAC)的制备
1 g mPEG-NH2(数均分子量Mn = 1000 g/mol)和0.304 g4-甲基-5,7-二(2,3-环氧丙氧基)香豆素(即DGC),溶于10 mL乙醇中,在氮气保护下充分搅拌,于70 ℃下反应20小时后,取出冷却至室温;将反应混合物沉析至正己烷中,然后干燥沉淀物,得到gPEAC。
b)两亲性梳状聚醚胺(acPEAC)的制备
将0.8 g gPEAC、0.27 g十四酸、0.25 g DCC和8 mg DMAP溶于10 mL二氯甲烷,氮气保护,室温下反应16小时。旋转蒸发除去二氯甲烷,加入乙酸乙酯溶解粗产物,离心后取清液,沉析于正己烷中,分离所得固体并干燥得到acPEAC。
c)聚乙二醇空心球hPEAC的制备
将acPEAC配成浓度为1 g/L的水溶液,在搅拌状态下于波长为365 nm的紫外灯下光照1小时。取200 mL光照后的溶液,用冰水浴冷冻至0 ℃,搅拌下逐滴加入0.2 mL三氟乙酸,反应在 0 ℃进行30 分钟后,在室温下继续反应4小时。旋转蒸发掉溶剂后溶于四氢呋喃中,用正己烷沉析,收集沉淀并干燥得到hPEAC。
实施例3
pH敏感的光交联聚乙二醇空心球的制备过程:
a)含香豆素基团的聚醚胺(gPEAC)的制备
5 g mPEG-NH2(数均分子量Mn = 5000 g/mol)和0.3 g 5,7-二(2,3-环氧丙氧基)香豆素(即DGC),溶于10 mL乙醇中,在氮气保护下充分搅拌,于80 ℃下反应24小时后,取出冷却至室温;将反应混合物沉析至正己烷中,分离所得固体并干燥得到gPEAC。
b)两亲性梳状聚醚胺(acPEAC)的制备
将2.4 g gPEAC、0.35 g十八酸、0.25 g DCC和8 mg DMAP溶于15 mL二氯甲烷,氮气保护,室温下反应16小时。旋转蒸发除去二氯甲烷,加入乙酸乙酯溶解粗产物,离心后取清液,沉析于正己烷中,分离所得固体并干燥得到acPEAC。
c)聚乙二醇空心球hPEAC的制备
将acPEAC配成浓度为2 g/L的水溶液,在搅拌状态下于波长为365 nm的紫外灯下光照2小时。取200 mL光照后的溶液,用冰水浴冷冻至0 ℃,搅拌下逐滴加入0.3 mL三氟乙酸,反应在 0 ℃进行30 分钟后,在室温下继续反应2小时。旋转蒸发掉溶剂后溶于四氢呋喃中,用正己烷沉析,分离所得固体并干燥得到hPEAC。
试验例1
(1)聚乙二醇空心球hPEAC冻干粉的制备
将实施案例1中的hPEAC分散在水中得到浓度为5mg/mL的分散液,将分散液置于节流分子量3500 g/mol的透析袋中, 水中透析3天,每隔6小时换水,得到的产物冻干后得到聚乙二醇空心球hPEAC冻干粉。
(2)聚乙二醇空心球hPEAC包裹脂溶性药物阿霉素冻干粉的制备
取20 mg 阿霉素盐酸盐和20 μL三乙胺溶于5 mL水中,搅拌30分钟后加入200 mg步骤(1)制备的聚乙二醇空心球冻干粉,搅拌2小时,逐滴加入15 mL去离子水,搅拌24小时,然后透析48小时,每6小时换1次水,得到的产物冻干后得到聚乙二醇空心球hPEAC包裹阿霉素冻干粉。
(3)包裹阿霉素聚乙二醇空心球体外释放行为的测定
取两份步骤(2)制备的聚乙二醇空心球hPEAC包裹阿霉素冻干粉20 mg,分别置于20 ml两种不同pH值(pH 5.0、pH 7.4)的磷酸盐缓冲盐释放介质中,在37 ℃的恒温振荡器(100次/分钟)中进行体外释放实验。在规定时间点取出6 mL释放介质,同时补充同体积的新鲜释放介质。取出的样品用荧光光谱测定阿霉素的含量,计算阿霉素的累积释放率。结果如图3所示,结果表明:在pH 7.4条件下,阿霉素60小时后只释放了9.2%,而在pH 5.0条件下阿霉素释放了23%,显示出良好的缓释能力和pH响应性。
试验例2
聚乙二醇空心球的细胞毒性
用MTT法检测材料的细胞毒性,细胞选用子宫颈癌细胞HeLa。具体实验过程如下:HeLa细胞培养于DMEM培养基中(37 ℃条件下含10%胎牛血清、饱和湿度、5% CO2)。细胞接种前,使用0.25 vol%胰蛋白酶的磷酸盐溶液对细胞进行消化。HeLa细胞接种于96孔细胞培养板中,细胞密度1.0×104/孔。将接种后的HeLa细胞置于组织培养箱中培养24小时,加入试验例1中聚乙二醇空心球冻干粉,以不加样品的细胞作为对照,每个样品做三个重复。培养24小时后加入20 μL浓度为5 mg/mL的MTT的PBS溶液。继续培养4小时,吸除培养基后,用150μL的DMSO溶解生成的蓝色晶体。5分钟后,利用酶标仪检测每孔中的吸收,工作波长490 nm。各个重复吸光度的平均值作为样品吸光度值,细胞存活率=样品吸光度/细胞对照吸光度。
如图4所示,在浓度高至1.0 mg/mL时,所有HeLa细胞的存活率均为80%以上,表明聚乙二醇空心球胶束对HeLa细胞几乎不具有毒副作用,因而具有良好的生物相容性。

Claims (7)

1.一种pH敏感光交联的聚乙二醇空心球的制备方法,其特征在于,将两亲性梳形聚醚胺溶于水中,经紫外光照射1-2h,水解,经沉析、分离及干燥得到交联的聚乙二醇空心球,
所述的两亲性梳形聚醚胺亲水链段由聚乙二醇构成,疏水链段由脂肪族羧酸构成,主链由香豆素构成,其结构单元结构式如下:
式中,R为H或CH3或CH2CH3,R’为碳原子数6~30的脂肪链,n=10~230,且n为整数。
2.根据权利要求1所述的pH敏感光交联的聚乙二醇空心球的制备方法,其特征在于,所述两亲性梳形聚醚胺的具体制备步骤如下:
将单氨基聚乙二醇甲氧醚与含双环氧基香豆素类单体溶解于溶剂中,在60~90℃下反应8~30小时,经沉析、分离及干燥,得到以香豆素为主链、聚乙二醇为侧链的聚醚胺,然后将这种聚醚胺与脂肪族羧酸在DCC和DMAP存在下进行酯化得到两亲性梳形聚醚胺粗产物,两亲性梳形聚醚胺粗产物经离心、沉析、分离及干燥得到两亲性梳形聚醚胺纯品。
3.根据权利要求2所述的pH敏感光交联的聚乙二醇空心球的制备方法,其特征在于,所述的单氨基聚乙二醇甲氧醚与含双环氧基香豆素类单体摩尔比例为(0.9~1.1)︰(0.9~1.1)。
4.根据权利要求2所述的pH敏感光交联的聚乙二醇空心球的制备方法,其特征在于,所述的溶剂为乙醇、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺。
5.权利要求1至4任一所述的制备方法制得的pH敏感光交联的聚乙二醇空心球。
6.权利要求5所述的pH敏感光交联的聚乙二醇空心球作为脂溶性物质载体的应用。
7.根据权利要求6所述的pH敏感光交联的聚乙二醇空心球作为脂溶性物质载体的应用,其特征在于,所述的脂溶性物质为姜黄素、紫杉醇、多西紫杉醇、喜树碱、喜树碱衍生物、阿霉素、阿霉素类似物、脂溶性铂类抗癌药、脂溶性诊断试剂或荧光试剂。
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