CN115368508A - 一种酸化响应的透明质酸纳米凝胶及其制法与应用 - Google Patents
一种酸化响应的透明质酸纳米凝胶及其制法与应用 Download PDFInfo
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Abstract
本发明公开了一种酸化响应且拥有半互穿结构透明质酸纳米凝胶的制法与应用,以透明质酸为模板,基于2‑氨基乙基甲基丙烯酸酯盐酸盐、丙烯酸和两个端双键的酰胺化合物水相聚合,可以制备出粒径可控的纳米凝胶,利用单体聚合形成的半互穿网络和聚合物间的非共价作用组装的纳米粒子体现出酸性微环境敏感特征,赋予了其用作活性分子(如:药物)载体的酸响应功能。本发明的透明质酸纳米凝胶分散性高、胶体稳定性好且具有良好的生物相容性,所携带丰富的官能团,给予了凝胶优秀的药物负载能力,未共价损耗羧基的透明质酸拥有细胞特异靶向性。本发明所提供的透明质酸纳米凝胶在药物负载释放领域具有潜在应用价值。
Description
技术领域
本发明属于高分子材料纳米技术领域,具体涉及一种新型酸化响应的透明质酸纳米凝胶及其基于非共价作用与半互穿协同的制备方法和应用。
背景技术
透明质酸(Hyaluronic acid,HA)是一种带负电的非硫酸化糖胺聚糖,由d-葡萄糖醛酸与N-乙酰基-d-葡萄糖胺的重复二糖单元构成。作为广泛分布于结缔组织细胞外基质(ECM)和眼睛玻璃体中的粘多糖,其在细胞内功能方面发挥着重要作用,如:影响细胞增殖与迁移、参与细胞内信号传导的调节。鉴于迷人的理化与生物学特征,透明质酸被开发用作各种功能材料及材料的构造模块。透明质酸也是备受青睐的细胞表面受体配体,CD44、RHAMM和LYVE-1等是过量表达在多种癌细胞(淋巴瘤细胞系、转病毒细胞系、肺巨噬细胞和胶质瘤细胞系等)膜上的HA特异性受体,CD44为跨膜受体,RHAMM为一种膜外受体(Biomaterials Science,2021,9:1363)。以具有CD44受体的细胞为例,低分子量的透明质酸可竞争性的与肿瘤细胞膜上受体结合,影响细胞移动,并能够由受体介导胞吞进入细胞。因此,透明质酸及其衍生物被广泛用于开发大量形貌各异且拥有肿瘤靶向能力的复合材料。
聚合物自组装形成的响应性纳米载体有望成为肿瘤靶向传输并控制释放各类活性小分子(如:小分子抗癌药物、基因试剂和蛋白质)的纳米工具。聚合物组装体的生理环境稳定性是活性分子有效递送的关键(J.Controlled Release,2012,164:108)。然而,赋予组装体稳定性的理化交联却会影响被递送活性分子的病灶点释放,进而减弱诊疗效果。基于该生物学屏障解决的需求,研究者不断进行包含可逆弱键的功能结构探索,以期整合创新性特征设计至纳米级组装体结构内,开发多功能纳米负载系统。通常,微环境响应是这类新型纳米组装体的重要特征。因此,在具有靶向能力的递送系统中,通过各种内源性刺激,诸如温度、pH值、离子强度、酶、乏氧及氧化还原微环境,由“稳定”纳米载体于病灶点触发活性分子富集,进而实现肿瘤等疾病的精确诊疗。
基于交联与非共价相互作用的协同构造形成纳米尺寸天然聚合物水凝胶,因自身生物相容性、可降解性、亲水性及体循环的高通透与滞留效应,备受生物医药领域的专家青睐。尺寸和形貌可调的纳米凝胶用作活性分子载体拥有丰富多样的优点。例如:优秀的分子负载能力、活性分子控制释放能力、灵活的可修饰与设计性、良好的溶胀性能、可延长参与体循环时间、正常生理环境稳定性和控制响应性等。因此,携带丰富功能基团且拥有靶向特定细胞能力的环境响应性天然高分子纳米凝胶,为一些疾病药物制剂的开发提供了有利的平台。
发明内容
针对上述情况,本发明的目的在于提供一种环境酸响应的非共价作用与半互穿协同透明质酸纳米凝胶。
本发明的第二个目的是提供一种上述透明质酸纳米凝胶的制备方法及应用。
为了实现上述目的,本发明采用的技术方案为:一种透明质酸纳米凝胶的制备方法,具体步骤如下:
将2g透明质酸HA和0.5~2.5g丙烯酸AA溶解于1.2L去离子水中,搅拌下加入1~3g2-氨基乙基甲基丙烯酸酯盐酸盐AMH与0.5~2g两个端双键的酰胺化合物并充分溶解,配制成总浓度为3.75~7.08g/L的配方液;在氮气保护条件下,配方液加热至70℃后加入相对于配方液的0.8-3.5mg/mL的过硫酸钾,搅拌反应60~180min,获得白色乳液产品进行过滤,所得滤液用Cut-off分子量为10000的透析袋在去离子水中透析48h以去除体系内的小分子,余下即为酸化响应的透明质酸纳米凝胶。
所述两个端双键的酰胺化合物选自N,N-亚甲基双丙烯酰胺MBAAm、N,N-双(丙烯酰)胱胺酸BACy、N,N’-(丙烷-1,3-二基)二丙烯酰胺PDDA、N,N′-(1,2-二羟乙烯)二丙烯酰胺DHEBA、N,N’-(丁烷-1,4-二基)二丙烯酰胺BDDA中的任何一种。
其中,前驱原料N,N-双(丙烯酰)胱胺酸(BACy)的制备步骤如下:
分别称取24.2g胱氨酸盐酸盐和100mg甲氧基对苯二酚溶解于置有100mL去离子水的反应瓶中,冰水浴且搅拌下条件下,使用滴液漏斗同时滴加26~39mL的丙烯酰氯-二氯甲烷混合溶液(其中丙烯酰氯和二氯甲烷的体积比为:V丙烯酰氯/V二氯甲烷=1.6:1)和80mL1mol/L的NaOH水溶液,限定1~1.5h滴完,滴完后再常温反应4小时;反应结束后,先将反应液倒入分液漏斗中进行分液,分液后取水层并用1mol/L盐酸溶液调节pH至1.5,然后使用减压旋蒸仪旋蒸除去水后加入200mL的四氢呋喃搅拌30min,过滤除去不溶物后旋蒸除去四氢呋喃;再将旋蒸产物中加入200mL丙酮搅拌30min,过滤除去不溶物后旋蒸除去丙酮,得到18.1g微黄色固体,所得微黄色固体为N,N-双(丙烯酰)胱胺酸(BACy)单体。
所述酸化响应的透明质酸纳米凝胶的水合粒径通过动态光散射监测为95.3±2.1nm~1203.8±23.2nm;通过Zeta电位仪检测电位为-45.2±6.1mV~-23.2±3.7mV。
本发明提供的一种酸化响应的透明质酸纳米凝胶,采用上述方法制备得到。
本发明还提供了这种酸化响应的透明质酸纳米凝胶先负载阿霉素后在体外释放和细胞毒性方面的应用,其具体步骤如下:
a.负载阿霉素的酸化响应透明质酸纳米凝胶的制备
取几份分量相同的上述方法制备得的酸响应透明质酸纳米凝胶乳液各5mL用1mol/L的氢氧化钠溶液调节pH至7.4~8,搅拌条件下依次滴加梯度体积的2.5g/L的盐酸阿霉素水溶液;避光条件下分别继续搅拌8~12h,通过高速离心和超声再分散于pH=7.4的磷酸缓冲液PBS中,即得不同负载量阿霉素的透明质酸纳米凝胶;
b.该负载阿霉素的酸化响应透明质酸纳米凝胶在体外释放和细胞毒性方面的应用
取几份分量相同的步骤a制得的负载阿霉素的酸响应透明质酸纳米凝胶溶液各1mL置于Cut-off分子量为10000的透析袋内,将透析袋完全浸入装有不同pH指数的5mL0.01mol/L的PBS液中,在37℃搅拌下进行释放实验;每隔一段时间用等量新鲜的释放介质替换原来介质,用荧光光谱通过标准曲线法测定介质中阿霉素的含量,根据介质中药物含量计算其释放的百分率;
通过MTT法先检测酸化响应的透明质酸纳米凝胶的生物相容性,时间设定为48小时;然后以MTT法测定阿霉素裸药与负载阿霉素的透明质酸纳米凝胶对小鼠肝癌细胞H22细胞的体外杀伤效果,时间为48小时,结果进行比对。
本发明的有益效果:本发明的透明质酸纳米凝胶分散性高、胶体稳定性好且具有良好的生物相容性,所携带丰富的官能团,给予了凝胶优秀的药物负载能力,未共价损耗羧基的透明质酸拥有细胞特异靶向性;本发明所提供的透明质酸纳米凝胶在药物负载释放领域具有潜在应用价值。
附图说明
图1为透明质酸、聚丙烯酸、聚(2-氨基乙基甲基丙烯酸酯盐酸盐)和透明质酸纳米凝胶的红外光谱;
图2为透明质酸纳米凝胶的透射电子显微镜图片;
图3为不同配方物料投料质量比所制备的纳米凝胶水合粒径及表面电位变化;
图4为优选的透明质酸纳米凝胶的水合粒径随介质的pH变化的趋势;
图5为负载阿霉素的透明质酸纳米凝胶在不同pH介质中的药物释放曲线;
图6为不同浓度的酸化响应透明质酸纳米凝胶对小鼠肝癌细胞H22体外细胞毒性试验结果;
图7为各种药物浓度的阿霉素裸药和负载阿霉素透明质酸纳米凝胶对H22细胞抑制效果图。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不局限于这些实施例。实施例中,所有反应原料和溶剂等都为安耐吉试剂产品。
1.前驱原料N,N-双(丙烯酰)胱胺酸(BACy)的制备
分别称取24.2g胱氨酸盐酸盐和100mg甲氧基对苯二酚溶解于置有100mL去离子水的反应瓶中,冰水浴且搅拌下条件下,使用滴液漏斗同时滴加35mL的丙烯酰氯-二氯甲烷混合溶液(其中丙烯酰氯和二氯甲烷的体积比为:V丙烯酰氯/V二氯甲烷=1.6:1)和80mL1mol/L的NaOH水溶液,限定1.5h滴完,滴完后再常温反应4小时;反应结束后,先将反应液倒入分液漏斗中进行分液,分液后取水层并用1mol/L盐酸溶液调节pH至1.5,然后使用减压旋蒸仪旋蒸除去水后加入200mL的四氢呋喃搅拌30min,过滤除去不溶物后旋蒸除去四氢呋喃;再将旋蒸产物中加入200mL丙酮搅拌30min,过滤除去不溶物后旋蒸除去丙酮,得到18.1g微黄色固体,所得微黄色固体为N,N-双(丙烯酰)胱胺酸(BACy)单体。
其产品结构式为:
产品的结构表征如下:1H NMR(D2O,400MHz,δ),6.26-6.38(t,2H),5.87(d,4H),7.92(s,2H),4.82(q,2H),2.8-3.54(t,4H)。
2.酸化响应的透明质酸纳米凝胶制备
将2g透明质酸HA和0.5~2.5g丙烯酸AA溶解于1.2L去离子水中,搅拌下加入1~3g2-氨基乙基甲基丙烯酸酯盐酸盐AMH与0.5~2g两个端双键的酰胺化合物并充分溶解,配制成总浓度为3.75~7.08g/L的配方液;在氮气保护条件下,配方液加热至70℃后加入相对于配方液的0.8-3.5mg/mL的过硫酸钾,搅拌反应60~180min,获得白色乳液产品进行过滤,所得滤液用Cut-off分子量为10000的透析袋在去离子水中透析48h以去除体系内的小分子,余下即为酸化响应的透明质酸纳米凝胶。
上述步骤中两个端双键的酰胺化合物选自N,N-亚甲基双丙烯酰胺MBAAm、N,N-双(丙烯酰)胱胺酸BACy、N,N’-(丙烷-1,3-二基)二丙烯酰胺PDDA、N,N′-(1,2-二羟乙烯)二丙烯酰胺DHEBA、N,N’-(丁烷-1,4-二基)二丙烯酰胺BDDA中的任何一种。
当两个端双键的酰胺化合物为N,N-亚甲基双丙烯酰胺(MBAAm)时
将2g透明质酸(HA)和1~2.5g丙烯酸(AA)溶解于1.2L去离子水中,搅拌下加入1~2.5g 2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)与0.5~1.5g N,N-亚甲基双丙烯酰胺(MBAAm)并充分溶解,配制总浓度为3.75~7.08g/L的配方液;在氮气保护条件下,配方液加热至70℃后加入2.4g的过硫酸钾,搅拌反应60~180min,获得白色乳液产品进行过滤,所得滤液以透析袋(Cut-off分子量为10000)在去离子水中透析48小时以去除体系内的小分子。动态光散射监测所制备纳米凝胶的水合粒径为109.5±1.9nm~1203.8±23.2nm;Zeta电位仪检测纳米凝胶的电位为-41.1±4.5mV~-23.2±3.7mV。此外,透射电子显微镜观测到纳米凝胶良好的球形形貌,见图2。
实施例一
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为1g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为1g,N,N-亚甲基双丙烯酰胺(MBAAm)用量为1g时,制备得到的纳米凝胶的水合粒径为428±12.7nm;Zeta电位仪检测的电位为-36.5±6.5mV。
实施例二
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为1g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为2g,N,N-亚甲基双丙烯酰胺(MBAAm)用量为1.5g时,制备得到的纳米凝胶的水合粒径为580±16.1nm;Zeta电位仪检测的电位为-33.6±7.0mV。
实施例三
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为2.5g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为2g,N,N-亚甲基双丙烯酰胺(MBAAm)用量为1.5g时,制备得到的纳米凝胶的水合粒径为1203.8±23.2nm;Zeta电位仪检测的电位为-38.2±5.2mV。
当两个端双键的酰胺化合物为N,N-双(丙烯酰)胱胺酸(BACy)时
将2g透明质酸(HA)和0.5~2g丙烯酸(AA)溶解于1.2L去离子水中,搅拌下加入1~3g 2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)与1~2g N,N-双(丙烯酰)胱胺酸(BACy)并充分溶解,配制总浓度为3.75~7.5g/L的配方液;在氮气保护条件下,配方液加热至70℃后加入2.4g的过硫酸钾,搅拌反应60~180min,获得白色乳液产品进行过滤,所得滤液以透析袋(Cut-off分子量为10000)在去离子水中透析48小时以去除体系内的小分子。动态光散射监测所制备纳米凝胶的水合粒径为95.3±2.1nm~1017.2±18.4nm;Zeta电位仪检测纳米凝胶的电位为-45.2±6.1mV~-25.6±1.8mV(见图3)。此外,透射电子显微镜观测到纳米凝胶良好的球形形貌。
实施例四
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为1g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为1g,N,N-双(丙烯酰)胱胺酸(BACy)用量为1g时,制备得到的纳米凝胶的水合粒径为415.9±11.5nm;Zeta电位仪检测的电位为-35.0±3.6mV。
实施例五
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为1g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为1g,N,N-双(丙烯酰)胱胺酸(BACy)用量为2g时,制备得到的纳米凝胶的水合粒径为209.2±3.3nm;Zeta电位仪检测的电位为-40.2±5.1mV。
实施例六
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为0.5g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为1g,N,N-双(丙烯酰)胱胺酸(BACy)用量为1.5g时,制备得到的纳米凝胶的水合粒径为95.3±2.1nm;Zeta电位仪检测的电位为-30.7±6.5mV。
实施例七
具体地:当透明质酸(HA)用量为2g,丙烯酸(AA)用量为1g,2-氨基乙基甲基丙烯酸酯盐酸盐(AMH)用量为2g,N,N-双(丙烯酰)胱胺酸(BACy)用量为1.5g时,制备得到的纳米凝胶的水合粒径为752.9±21.5nm;Zeta电位仪检测的电位为-28.1±2.2mV。
实施例八
取7份分量相同的实施例六制备得到的95.3±2.1nm的酸响应透明质酸纳米凝胶乳液各10mL用1mol/L的氢氧化钠溶液调节pH值分别为3、5、6、7、8、9和10,在静置5-8小时后,以动态光散射粒度分析仪检测这些不同pH值溶液的凝胶水合粒径,结果如图4所示,随介质pH值的增加,大量的羧基脱质子化,纳米凝胶水合粒径逐渐由65nm增大至110nm左右,pH大于7后,凝胶的粒径变化趋缓。因此实验时用1mol/L的氢氧化钠溶液调节pH值为7.4~8。
实施例九
a.负载阿霉素的酸化响应透明质酸纳米凝胶的制备
取2份分量相同的实施例六制备得到的95.3±2.1nm的酸响应透明质酸纳米凝胶乳液各5mL用1mol/L的氢氧化钠溶液调节pH至7.4~8,搅拌条件下依次滴加0.5mL和1mL的2.5g/L的盐酸阿霉素水溶液;避光条件下分别继续搅拌8~12h,通过高速离心和超声再分散于pH=7.4的磷酸缓冲液PBS中,即得不同负载量阿霉素的透明质酸纳米凝胶。利用荧光光谱基于阿霉素标准曲线检测并计算得到:滴加0.5mL的2.5g/L的盐酸阿霉素水溶液时得到的负载阿霉素的酸化响应透明质酸纳米凝胶的载药量及载药效率为8.5%和98%,动态光散射测定载药纳米凝胶的平均粒径为104.3±2.8nm;滴加1mL的2.5g/L的盐酸阿霉素水溶液时得到的负载阿霉素的酸化响应透明质酸纳米凝胶的载药量及载药效率为19%和95%,动态光散射测定载药纳米凝胶的平均粒径为121±5.5nm。
b.该负载阿霉素的酸化响应透明质酸纳米凝胶在体外释放和细胞毒性方面的应用
取2份分量相同的步骤a制得的负载量为19%负载阿霉素的酸响应透明质酸纳米凝胶溶液各1mL置于Cut-off分子量为10000的透析袋内,将透析袋完全浸入装有2份不同pH指数的5mL 0.01mol/L的PBS液中(其中一份pH=7.4,另一份pH=5.5),在37℃搅拌下进行释放实验;每隔一段时间用等量新鲜的释放介质替换原来介质,用荧光光谱通过标准曲线法测定介质中阿霉素的含量,根据介质中药物含量计算其释放的百分率,结果见图5,可以看出负载于凝胶的药物显示了持续稳定的释放特性,同时酸性环境将触发药物加速释放。这也说明本发明的酸化响应的透明质酸纳米凝胶作为药物载体效果良好,在人体病灶部位特殊的微环境中有利于药物的释放。
通过MTT法先检测酸化响应的透明质酸纳米凝胶的生物相容性,时间设定为48小时,结果见图6;然后以MTT法测定阿霉素裸药与负载阿霉素的透明质酸纳米凝胶对小鼠肝癌细胞H22细胞的体外杀伤效果,时间为48小时,结果进行比对,结果见图7。结果表明,本发明所制备的酸响应透明质酸纳米凝胶达到高浓度未表现毒性,即纳米凝胶具有良好的生物相容性;负载药物凝胶在较高药物浓度时拥有与阿霉素裸药近相当的杀伤力。
Claims (5)
1.一种酸化响应的透明质酸纳米凝胶的制备方法,其特征在于,所述步骤如下:
将2g透明质酸HA和0.5~2.5g丙烯酸AA溶解于1.2L去离子水中,搅拌下加入1~3g 2-氨基乙基甲基丙烯酸酯盐酸盐AMH与0.5~2g两个端双键的酰胺化合物并充分溶解,配制成总浓度为3.75~7.08g/L的配方液;在氮气保护条件下,配方液加热至70℃后加入0.8-3.5mg/mL的过硫酸钾,搅拌反应60~180min,获得白色乳液产品进行过滤,所得滤液用Cut-off分子量为10000的透析袋在去离子水中透析48h以去除体系内的小分子,余下即为酸化响应的透明质酸纳米凝胶。
2.根据权利要求1所述的一种酸化响应的透明质酸纳米凝胶的制备方法,其特征在于,所述两个端双键的酰胺化合物选自N,N-亚甲基双丙烯酰胺MBAAm、N,N-双(丙烯酰)胱胺酸BACy、N,N’-(丙烷-1,3-二基)二丙烯酰胺PDDA、N,N′-(1,2-二羟乙烯)二丙烯酰胺DHEBA、N,N’-(丁烷-1,4-二基)二丙烯酰胺BDDA中的任何一种。
3.根据权利要求1所述的一种酸化响应的透明质酸纳米凝胶的制备方法,其特征在于,所述酸化响应的透明质酸纳米凝胶的水合粒径为95.3±2.1nm~1203.8±23.2nm;电位为-45.2±6.1mV~-23.2±3.7mV。
4.一种采用权利要求1至3任何一项所述合成方法得到的酸化响应的透明质酸纳米凝胶。
5.权利要求4所述的一种酸化响应的透明质酸纳米凝胶在体外释放和细胞毒性方面的应用,其特征在于,所述步骤如下:
a.负载阿霉素的酸化响应透明质酸纳米凝胶的制备
取几份分量相同的上述方法制备得的酸响应透明质酸纳米凝胶乳液各5mL用1mol/L的氢氧化钠溶液调节pH至7.4~8,搅拌条件下依次滴加梯度体积的2.5g/L的盐酸阿霉素水溶液;避光条件下分别继续搅拌8~12h,通过高速离心和超声再分散于pH=7.4的磷酸缓冲液PBS中,即得不同负载量阿霉素的透明质酸纳米凝胶;
b.该负载阿霉素的酸化响应透明质酸纳米凝胶在体外释放和细胞毒性方面的应用
取几份分量相同的步骤a制得的负载阿霉素的酸响应透明质酸纳米凝胶溶液各1mL置于Cut-off分子量为10000的透析袋内,将透析袋完全浸入装有不同pH指数的5mL 0.01mol/L的PBS液中,在37℃搅拌下进行释放实验;每隔一段时间用等量新鲜的释放介质替换原来介质,用荧光光谱通过标准曲线法测定介质中阿霉素的含量,根据介质中药物含量计算其释放的百分率;
通过MTT法先检测酸化响应的透明质酸纳米凝胶的生物相容性,然后以MTT法测定阿霉素裸药与负载阿霉素的透明质酸纳米凝胶对小鼠肝癌细胞H22细胞的体外杀伤效果,时间为48小时,结果进行比对。
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