CN105838013B - 一种基于甲基乙烯基醚马来酸共聚物及壳聚糖pH敏感复合纳米凝胶及其制备方法 - Google Patents
一种基于甲基乙烯基醚马来酸共聚物及壳聚糖pH敏感复合纳米凝胶及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种基于甲基乙烯基醚马来酸共聚物及壳聚糖pH敏感复合纳米凝胶及其制备方法,其为互穿网络结构,是由壳聚糖中的氨基与甲基乙烯基醚马来酸共聚物的羧基发生静电作用形成聚电解质复合物,先形成P(MVE‑alt‑MA)‑CS半互穿网络结构,之后通过交联剂N,N’‑亚甲基双丙烯酰胺并加热使N,N’‑亚甲基双丙烯酰胺双键与壳聚糖中的氨基发生聚合,进一步形成互穿网络结构得到纳米级凝胶。本发明的优点在于该纳米凝胶的合成过程简单绿色,反应条件温和,适用于大规模生产。该纳米凝胶在药物载体、催化体系、污染处理等方面具有潜在的应用价值。
Description
技术领域
本发明属于聚合物纳米凝胶技术领域,特别涉及一种基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶的制备方法。
背景技术
纳米凝胶(microgel)为交联聚合物粒子,直径在1-1000nm之间。与块状凝胶相比,纳米凝胶具有较大的比表面积和较高的负载量,且可以更加迅速、准确地对环境的刺激作出响应,因此,纳米凝胶在药物载体、催化体系、污染处理等方面具有巨大的潜在应用价值。纳米凝胶的主要制备方法有分散聚合、沉淀聚合、反相悬浮聚合、反相乳液聚合以及反相微乳液聚合等。
甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))作为一种亲水性、生物相容性和粘附性,聚羧酸聚合物,已在生物技术领域有许多重要的应用,尤其药理和保健应用,如增稠剂、悬浮剂、牙齿粘附剂和漱口水,病毒的捕获,核酸的分离,细胞的封装及培养;另一方面,P(MVE-alt-MA)具羧酸官能团,可以在聚合物主链为聚阴离子特性以及易于化学改性。
壳聚糖(CS)是自然界唯一大量存在的碱性多糖,具有良好的生物相容性、生物可降解性、抗肿瘤及抗菌性能。壳聚糖吡喃糖环上的氨基化学性质活拨,易于发生各种化学反应,可用于对壳聚糖进行修饰。壳聚糖仅能溶于酸性溶液,这一特性限制了它的应用,在壳聚糖的各种水溶性改性中,降解改性受到了广泛的关注壳聚糖降解后得到的低聚物,特别是分子量在1万以下的低聚糖,在提髙巨唾细胞吞噬能力、促进肝脏抗体增长和抑制肿瘤细胞转移等方面表现出明显优势。
癌症严重威胁人类健康。化学疗法是临床上治疗肿瘤的主要手段之一,由于抗癌药物存在缺乏选择性、稳定性差、体内半衰期短等缺点,会对正常组织和细胞产生毒副作用。为了克服癌症治疗药物的诸多缺点,制备具有良好的生物相容性、能够智能控制药物释放的抗癌药物载体已成为当前的研究热点。本发明以壳聚糖中的氨基与P(MVE-alt-MA)的羧基发生静电作用形成聚电解质复合物,通过N,N’-亚甲基双丙烯酰胺(MBAAm)交联壳聚糖形成纳米级凝胶。该纳米凝胶具有pH敏感性。
发明内容
本发明的目的是提供一种基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶及其制备方法,以解决现有技术中纳米凝胶合成步骤复杂,稳定性差,生物相容性差等缺陷。
为实现上述目的,本发明采用的技术方案为:
一种基于甲基乙烯基醚马来酸共聚物及壳聚糖pH敏感复合纳米凝胶,其为互穿网络结构,是由壳聚糖(CS)中的氨基与甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))的羧基发生静电作用形成聚电解质复合物,先形成P(MVE-alt-MA)-CS半互穿网络结构,之后通过交联剂N,N’-亚甲基双丙烯酰胺(MBAAm)并加热使N,N’-亚甲基双丙烯酰胺(MBAAm)双键与壳聚糖(CS)中的氨基发生聚合,进一步形成互穿网络结构得到纳米级凝胶。
一种制备上述的基于甲基乙烯基醚马来酸共聚物及壳聚糖pH敏感复合纳米凝胶的方法,包括如下步骤:
步骤一、制备水溶性壳聚糖(WSC);于室温下配制浓度为0.25mg/mL~1.0mg/mL的水溶性壳聚糖溶液;
步骤二、将甲基乙烯基醚马来酸酐共聚物(P(MVE-alt-MAH))于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA)),室温下配制浓度为0.25mg/mL~1.0mg/mL的甲基乙烯基醚马来酸共聚物的水溶液;
步骤三、取步骤二配制的甲基乙烯基醚马来酸共聚物溶液于容器中,加入步骤一配置的壳聚糖溶液,容器接有冷凝管,并在容器中通入N2,磁力搅拌12h;加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm),在N2纯化下缓慢加热至60℃,继续反应1h;然后将反应液冷却至室温,用过滤孔径为10μm的滤纸过滤除去聚集体,透析,得到所述复合纳米凝胶。
进一步的,步骤一中,采用双氧水氧化降解的方法制备水溶性壳聚糖:将壳聚糖分散到浓度为3wt.%的双氧水溶液中,于70℃搅拌3h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即为水溶性壳聚糖;其中壳聚糖与双氧水溶液的质量体积比为10:72g/ml。
进一步的,所述壳聚糖的脱乙酰度为80%~95%。
进一步的,所述聚甲基乙烯基醚共聚马来酸的数均分子量为80000~311000。
进一步的,步骤三中,甲基乙烯基醚马来酸共聚物与壳聚糖的体积比为:100:100~100:10。
进一步的,步骤三中,磁力搅拌的转速为600rpm-2000rpm。
进一步的,步骤三中,透析时使用的透析袋截留分子量为8000~14000,透析时间不少于3天。
进一步的,步骤三中,交联剂的用量为壳聚糖质量的2%~20%。
进一步的,步骤三中反应溶液的pH保持在pH=4.8±0.2。
有益效果:本发明具有以下优点:
1、本发明原料廉价,合成路线简单,周期短,无污染,适用于大规模生产。
2、由于P(MVE-alt-MA)分子中含有大量的羧基及WCS氨基,因此所制备的纳米凝胶具有pH敏感性,其粒径,表面电荷及稳定性等性能可通过pH值调节,使其适应更广泛的生物医学应用。
3、由于P(MVE-alt-MA)分子中含有大量的羧基,因此本发明所制备的纳米凝胶表面在一定的pH条件下带有负电荷,可防止蛋白吸附,延长粒子在体内的循环。
4、本发明所制备的纳米凝胶可通过所含有羧基有利于与含氨基药物(如盐酸阿霉素等)通过静电作用进行药物负载。
附图说明
图1是实施例2获得的基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶透射电镜图。
图2是实施例2制备的基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶在不同pH值条件下粒径分布图。
具体实施方式
下面结合具体实施方式对本发明作更进一步的说明。
甲基乙烯基醚马来酸共聚物P(MVE-alt-MA)是对人体和动物无毒无害的高分子材料,具有良好亲水性、化学稳定性、生物相容性、生物黏附性的多元羧酸聚合物而被广泛应用于生物技术、药理学及保健应用。如作为稳定剂,增塑剂,粘合剂和缓释剂等。P(MVE-alt-MA)的微阵列结构能够支持人多能干细胞(hPSCs)(HUES1,HUES9和iPSCs)的黏附,增殖和自我更新。在P(MVE-alt-MA)上培养的人多能干细胞hPSCs能维持其特征形貌,表达了高水平多能性标记物和保持正常的染色质组型。基于该聚合物良好的生物相容性,稳定性,本发明采用分散聚合法制备基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶。可应用于药物控释载体等。
本发明基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶,在低浓度条件下,壳聚糖溶液加入到P(MVE-alt-MA)溶液中,壳聚糖中的氨基与P(MVE-alt-MA)的羧基发生静电作用形成聚电解质复合物(-NH3+(CS)/-COO-(P(MVE-alt-MA))),从而形成P(MVE-alt-MA)-CS半互穿网络结构,之后加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm)并加热使MBAAm双键与壳聚糖中的氨基发生聚合,进一步形成互穿网络结构得到具有pH敏感复合纳米凝胶。
上述基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶的制备方法,包括如下步骤:
步骤一、采用双氧水氧化降解的方法制备水溶性壳聚糖(WSC):将壳聚糖分散到浓度为3wt.%的双氧水溶液中,其中,壳聚糖与双氧水溶液的质量体积比为10:72g/ml;于70℃搅拌3h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即为水溶性壳聚糖。室温下配制水溶性壳聚糖溶液,其浓度为0.25mg/mL~1.0mg/mL;
其中,壳聚糖的脱乙酰度为80%~95%。
步骤二、将甲基乙烯基醚马来酸酐共聚物(P(MVE-alt-MAH))于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA)),室温下制备配制P(MVE-alt-MA)的水溶液,其浓度为0.25mg/mL~1.0mg/mL;
其中,聚甲基乙烯基醚共聚马来酸的数均分子量为80000~311000。
步骤三、取步骤二配制的甲基乙烯基醚马来酸共聚物P(MVE-alt-MA)溶液于250mL三口烧瓶,加入步骤一配置的壳聚糖水溶液,三口烧瓶接有冷凝管,并通入N2,转速600rpm-2000rpm下磁力搅拌12h。加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm),N2纯化下缓慢加热至60℃,继续反应1h。反应液冷却至室温,用过滤孔径10μm滤纸过滤除去聚集体,透析不少于三天,透析使用的透析袋截留分子量为8000~14000;反应溶液的pH保持在pH=4.8±0.2;
其中,甲基乙烯基醚马来酸共聚物与壳聚糖的反应体积比为:100:100~100:10;
交联剂的用量为壳聚糖质量的2%~20%。
下面结合一些实施例对本发明做进一步说明。以下实例所采用的原料来源说明:聚甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))购自百灵威科技有限公司;壳聚糖(chitosan,CS,脱乙酰度95%,数均分子量1.06×106),上海晶纯化工有限公司;N,N’-亚甲基双丙烯酰胺(MBAAm)购自上海阿拉丁生化科技股份有限公司;双氧水(H2O2)为分析纯,未经纯化直接使用。所有溶液均由去离子水配制。
实施例1
(1)、水溶性壳聚糖溶液(WCS)的配制
将10g壳聚糖分散到72ml浓度为3wt.%的双氧水溶液中,70℃搅拌3h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即水溶性壳聚糖。室温下配制水溶性壳聚糖溶液浓度为0.25mg/mL;
(2)、P(MVE-alt-MA)溶液的配制
将甲基乙烯基醚马来酸酐共聚物(P(MVE-alt-MAH))于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA)),室温下制备配制P(MVE-alt-MA)溶液浓度为1.0mg/mL;
(3)、纳米凝胶的制备
取100mL P(MVE-alt-MA)溶液于250mL三口烧瓶,按P(MVE-alt-MA)溶液与WCS溶液体积比100:70加入上述配置的壳聚糖溶液,三口烧瓶接有冷凝管,并通入N2,磁力搅拌12h。加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm),N2纯化下缓慢加热至60℃,反应继续1h。反应液冷却至室温,用过滤孔径10μm滤纸过滤除去聚集体,透析三天(用截留分子量为:8000~14000,室温下用稀盐酸调节pH=4.8±0.2)。
实施例2
(1)、水溶性壳聚糖溶液(WCS)的配制
将10g壳聚糖分散到72ml浓度为3wt.%的双氧水溶液中,70℃搅拌3h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即水溶性壳聚糖。室温下配制水溶性壳聚糖溶液浓度为0.5mg/mL;
(2)、P(MVE-alt-MA)溶液的配制
将甲基乙烯基醚马来酸酐共聚物(P(MVE-alt-MAH))于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA)),室温下制备配制P(MVE-alt-MA)溶液浓度为1.0mg/mL;
(3)、纳米凝胶的制备
取100mL P(MVE-alt-MA)溶液于250mL三口烧瓶,按P(MVE-alt-MA)溶液与WCS溶液体积比100:50加入上述配置的壳聚糖溶液,三口烧瓶接有冷凝管,并通入N2,磁力搅拌12h。加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm),N2纯化下缓慢加热至60℃,反应继续1h。反应液冷却至室温,用过滤孔径10μm滤纸过滤除去聚集体,透析三天(用截留分子量为:8000~14000,室温下用稀盐酸调节pH=4.8±0.2)。
图1是本实施例制备的基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶的透射电镜图,该纳米凝胶呈球状结构,此种结构使得该凝胶具有较大的比表面积。图2是本实施例制备的基于甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA))及壳聚糖(CS)pH敏感复合纳米凝胶在不同pH值条件下粒径分布图,该测试结果表明该纳米凝胶的粒径可随pH值变化而不同,可通过pH值调节。
实施例3
(1)、水溶性壳聚糖溶液(WCS)的配制
将10g壳聚糖分散到72ml浓度为3wt.%的双氧水溶液中,70℃搅拌3h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即水溶性壳聚糖。室温下配制水溶性壳聚糖溶液浓度为0.5mg/mL;
(2)、P(MVE-alt-MA)溶液的配制
将甲基乙烯基醚马来酸酐共聚物(P(MVE-alt-MAH))于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物(P(MVE-alt-MA)),室温下制备配制P(MVE-alt-MA)溶液浓度为0.5mg/mL;
(3)、纳米凝胶的制备
取100mL P(MVE-alt-MA)溶液于250mL三口烧瓶,按P(MVE-alt-MA)溶液与WCS溶液体积比100:30加入上述配置的壳聚糖溶液,三口烧瓶接有冷凝管,并通入N2,磁力搅拌12h。加入交联剂N,N’-亚甲基双丙烯酰胺(MBAAm),N2纯化下缓慢加热至60℃,反应继续1h。反应液冷却至室温,用过滤孔径10μm滤纸过滤除去聚集体,透析三天(用截留分子量为:8000~14000,室温下用稀盐酸调节pH=4.8±0.2)。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:包括如下步骤:
步骤一、制备水溶性壳聚糖;于室温下配制浓度为0.25 mg/mL ~ 1.0 mg/mL的水溶性壳聚糖溶液;
步骤二、将甲基乙烯基醚马来酸酐共聚物于90℃加热2h进行水解得到甲基乙烯基醚马来酸共聚物,室温下配制浓度为0.25 mg/mL ~ 1.0 mg/mL的甲基乙烯基醚马来酸共聚物的水溶液;
步骤三、取步骤二配制的甲基乙烯基醚马来酸共聚物溶液于容器中,加入步骤一配置的壳聚糖溶液,容器接有冷凝管,并在容器中通入N2,磁力搅拌12h;加入交联剂N,N’ -亚甲基双丙烯酰胺,在N2纯化下加热至60℃,继续反应1h;然后将反应液冷却至室温,用过滤孔径为10μm的滤纸过滤除去聚集体,透析,得到所述复合纳米凝胶。
2.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤一中,采用双氧水氧化降解的方法制备水溶性壳聚糖:将壳聚糖分散到浓度为3 wt.%的双氧水溶液中,于70℃搅拌3 h,抽滤,取滤液冷冻干燥,得到淡黄色粉末,即为水溶性壳聚糖;其中壳聚糖与双氧水溶液的质量体积比为10:72g/ml。
3.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:所述壳聚糖的脱乙酰度为80%~95%。
4.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:所述甲基乙烯基醚马来酸共聚物的数均分子量为80000 ~311000。
5.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤三中,甲基乙烯基醚马来酸共聚物溶液与壳聚糖溶液的体积比为:100:100 ~100:10。
6.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤三中,磁力搅拌的转速为600rpm-2000rpm。
7.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤三中,透析时使用的透析袋截留分子量为8000 ~14000,透析时间不少于3天。
8.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤三中,交联剂的用量为壳聚糖质量的2% ~20%。
9.根据权利要求1所述的制备基于甲基乙烯基醚马来酸共聚物及壳聚糖 pH敏感复合纳米凝胶的方法,其特征在于:步骤三中,反应溶液的pH保持在pH=4.8±0.2。
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