CN114456402A - 负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法 - Google Patents
负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法 Download PDFInfo
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Abstract
本发明提供了一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备，制备方法为：将聚乙二醇与对醛基苯甲酸反应修饰为醛基化聚乙二醇；将羟基磷灰石、氧化石墨烯、醛基化聚乙二醇和羧甲基壳聚糖混合后即可通过醛基化聚乙二醇上的醛基于羧甲基壳聚糖分子中的氨基形成动态可逆席夫碱键的交联网络结构；羟基磷灰石可以抑制肿瘤细胞的增殖并促进其凋亡，氧化石墨烯对于近红外光有较好的红外光谱吸收能力，可作为光热治疗载体应用于肿瘤治疗。该凝胶同时还具有良好的生物相容性、自愈合性和注射性，使得本发明在肿瘤治疗领域具有很好的应用前景。
Description
技术领域
本发明属于生物医学工程领域，智能仿生材料中的高分子材料，具体涉及一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备。
背景技术
现如今癌症仍然是一个严重的全球健康问题，随着人们对癌症生理学知识的不断认识，在诊断与治疗方面达到十足的发展。当前癌症治疗仍然以手术治疗为主，化学治疗手段为主要辅助。但是广泛用于治疗癌症的化疗药物对肿瘤组织生物特异性差、疏水性差、细胞抗药性等缺点，在临床应用受到很大程度上限制。随着医学发展，精准医疗逐渐成为当今研究热点，以肿瘤细胞生理微环境与正常细胞生理微环境的理化差异作为内源性刺激信号，再结合外源性刺激信号(温度、光照、磁场、超声波)共同治疗肿瘤细胞。因此多种手段产生协同治疗，对于推动癌症治疗技术的发展具有重要意义。
自愈合高分子水凝胶(self-healing polymer hydrogel)一种在基体损伤后，触发其自动恢复过程来再生结构及初始功能的一类智能水凝胶。自主要通过离子键、金属配位、疏水相互作用或者通过动态化学键来达到的自愈合能力，可以分为化学交联与物理交联两种。前者更便于通过分离动态共价键来实现同时刺激响应 (例如热、光、pH)。在体内，外部机械力或生理侵蚀容易破坏水凝胶结构的完整性，使其丧失功能。而自愈合水凝胶可以在外界刺激情况下修复自身损伤并恢复其原有结构和性能，从而提高水凝胶的可靠性与安全性。自愈合水凝胶是由共价键和非共价键交联而形成三维网络结构具有较高含水量的材料，由于其与细胞外基质组成较为相似，具有较好的生物相容性等原因，成为替代天然生物软组织材料的优先选项，因此广泛应用于药物递送、细胞培养、组织工程等生物医用领域。
发明内容
针对现有技术中的不足，本发明的首要目的是提供一种掺杂羟基磷灰石、氧化石墨烯的近红外响应性自愈合水凝胶的制备方法。
为达到上述目的，本发明的解决方案是：
一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法，其包括步骤：
将纳米针状羟基磷灰石(HAP)和纳米氧化石墨烯(GO)加入羧甲基壳聚糖 (CMC)的磷酸盐缓冲液内超声分散均匀得到混合物，将醛基化聚乙二醇 (DF-PEG)的磷酸盐缓冲液加入到混合物中并搅拌，5min内实现溶胶至凝胶的转变，得到包载两种纳米粒子的自愈合水凝胶。
其中，纳米针状羟基磷灰石和纳米氧化石墨烯属于物理掺杂，不参与该自愈合水凝胶骨架的构建。
优选地，醛基化聚乙二醇的磷酸盐缓冲液和羧甲基壳聚糖的磷酸盐缓冲液的体积比为3:2。
优选地，所述醛基化聚乙二醇的磷酸盐缓冲液中醛基化聚乙二醇的含量为 5.0±0.5wt％，所述羧甲基壳聚糖的磷酸盐缓冲液中羧甲基壳聚糖的含量为 4.0±0.5wt％；加入的纳米针状羟基磷灰石含量为0.4±0.1wt％，纳米氧化石墨烯含量为0.6±0.1wt％。
优选地，醛基化聚乙二醇的制备过程包括：
将聚乙二醇(Polyethylene glycol,PEG)溶解在溶剂A内得到第一混合物，将对醛基苯甲酸、N,N’二环己基碳二亚胺(Dicyclohexylcarbodiimide,DCC)和 4-二甲氨基吡啶(4-Dimethylaminopyridine,DMAP)溶解在所述第一混合物内，经过抽真空-充氮气后，反应得到第二混合物，过滤第二混合物得到滤液，将滤液在溶剂B中沉淀后，抽滤并在25℃下真空干燥得到醛基化聚乙二醇(DF-PEG)。
优选地，溶剂A选自无水四氢呋喃、二氯甲烷或三氯甲烷中的一种以上；
优选地，所述溶剂B选自无水乙醚、石油醚、正己烷中的一种以上。
优选地，对醛基苯甲酸、N,N’二环己基碳二亚胺和4-二甲氨基吡啶的摩尔比为1:10:1.2-1.5:0.05:0.1；
优选地，反应的时间为20-24h。
一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统由上述的制备方法制备得到。
由于采用上述方案，本发明的优点：
本发明的原料均可工业化生产，价格低廉；另外，本发明的制备方法简单易行，具有较好的推广应用价值。本发明制备的自愈合水凝胶具有近红外响应性，并且具有良好的生物相容性、自愈合性，从而实现了作为一种用于肿瘤治疗的水凝胶所需的可注射性和降解率。
附图说明
图1为本发明的一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统合成图
图2为实施例负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶冻干后扫描电镜图
图3为实施例负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶自愈合效果图
图4为实施例负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶可注射行效果图
图5为实施例负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统体外治疗效果
具体实施方式
本发明提供了一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法。
负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统是由聚乙二醇和壳聚糖的两种无毒害高分子合成得到，聚乙二醇(Polyethylene glycol) 具有良好的水溶性，广泛用于化妆品工业和制药工业中的应用很广泛。羧甲基壳聚糖(Carboxymethylchitosan)是一种水溶性壳聚糖衍生物，在化妆品、保鲜、医药等方面有多种应用。本发明的制备方法利用DCC反应将醛基化的聚乙二醇与水溶性的羧甲基壳聚糖混合，添加纳米针状羟基磷灰石以及纳米氧化石墨烯制备得到近红外响应性的自愈合水凝胶，可进一步用于肿瘤治疗。
实施例
<负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法>
如图1所示，本发明的负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法包括如下步骤：
将纳米针状羟基磷灰石(HAP)和纳米氧化石墨烯(GO)加入羧甲基壳聚糖 (CMC)的磷酸盐缓冲液内超声分散均匀得到混合物，将醛基化聚乙二醇 (DF-PEG)的磷酸盐缓冲液加入到混合物中并搅拌，5min内实现溶胶至凝胶的转变，得到包载两种纳米粒子的自愈合水凝胶。
其中，醛基化聚乙二醇的磷酸盐缓冲液和羧甲基壳聚糖的磷酸盐缓冲液的体积为比3:2；醛基化聚乙二醇的磷酸盐缓冲液中醛基化聚乙二醇的含量为5.0±0.5 wt％，羧甲基壳聚糖的磷酸盐缓冲液中羧甲基壳聚糖的含量为4.0±0.5wt％；加入的纳米针状羟基磷灰石含量为0.4±0.1wt％，纳米氧化石墨烯含量为0.6±0.1 wt％。
通过醛基修饰的聚乙二醇中的醛基与羧甲基壳聚糖中的氨基形成可逆共价键希弗碱形成网络状结构，受到外力作用时，可逆动态共价键吸收应力，破坏变为醛基和氨基；在无外界干扰的条件下醛基与氨基再一次自动结合变为希弗碱，将基体重新连接，从而实现该水凝胶自愈合。
其中，<醛基化聚乙二醇的制备过程>
醛基化聚乙二醇(醛基改性聚乙二醇)的制备过程包括如下步骤：
聚乙二醇(PEG)溶解在溶剂A内得到第一混合物，将对醛基苯甲酸、N,N’二环己基碳二亚胺(DCC)和4-二甲氨基吡啶(DMAP)溶解在所述第一混合物内，经过抽真空-充氮气后，反应得到第二混合物，过滤第二混合物得到滤液，将滤液在溶剂B中沉淀后，抽滤并在25℃下真空干燥得到醛基化聚乙二醇 (DF-PEG)。
其中，溶剂A为无水四氢呋喃；
溶剂B为无水乙醚。
对醛基苯甲酸、二环己基碳二亚胺和4-二甲氨基吡啶的摩尔比为1:10:1.2；
反应的时间可为20h；
图2为本实施例负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶冻干后扫描电镜图，其自愈合效果如图3所示，其可注射行效果如图4所示，其自愈合复合水凝胶抗癌系统体外治疗效果如图5所示。
Claims (6)
1.一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统的制备方法，其特征在于：其包括步骤：
将纳米针状羟基磷灰石和纳米氧化石墨烯加入羧甲基壳聚糖的磷酸盐缓冲液内超声分散均匀得到混合物；
将醛基化聚乙二醇的磷酸盐缓冲液加入到混合物中并搅拌，5min内实现溶胶至凝胶的转变，得到包载两种纳米粒子的自愈合水凝胶。
2.根据权利要求1所述的制备方法，其特征在于：羧甲基壳聚糖的磷酸盐缓冲液和醛基化聚乙二醇的磷酸盐缓冲液体积比为3:2；
所述醛基化聚乙二醇的磷酸盐缓冲液中醛基化聚乙二醇的含量为5.0±0.5wt％，所述羧甲基壳聚糖的磷酸盐缓冲液中羧甲基壳聚糖的含量为4.0±0.5wt％；加入的纳米针状羟基磷灰石含量为0.4±0.1wt％，纳米氧化石墨烯含量为0.6±0.1wt％。
3.根据权利要求1所述的制备方法，其特征在于：所述醛基化聚乙二醇的制备过程包括：
将聚乙二醇溶解在溶剂A内得到第一混合物，将对醛基苯甲酸、N,N’二环己基碳二亚胺和4-二甲氨基吡啶溶解在所述第一混合物内，经过抽真空-充氮气后，反应得到第二混合物，过滤第二混合物得到滤液，将滤液在溶剂B中沉淀后，抽滤并在25℃下真空干燥得到醛基化聚乙二醇。
4.根据权利要求3所述的制备方法，其特征在于：所述溶剂A是无水四氢呋喃、二氯甲烷或三氯甲烷中的一种以上；
所述溶剂B选自无水乙醚、石油醚、正己烷中的一种以上。
5.根据权利要求3所述的制备方法，其特征在于：所述的聚乙二醇分子量为2000；
所述的对醛基苯甲酸、所述N,N’二环己基碳二亚胺和所述4-二甲氨基吡啶的摩尔比为1:10:1.2-1.5:0.05:0.1；
所述反应的时间为20-24h。
6.一种负载石墨烯与纳米羟基磷灰石的可注射自愈合复合水凝胶抗癌系统，其特征在于：其由权利要求1-5任一项所述的制备方法制备得到。
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