CN111228490B - 一种钙磷复合多孔纳米碳纤维光热试剂的制备方法 - Google Patents

一种钙磷复合多孔纳米碳纤维光热试剂的制备方法 Download PDF

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CN111228490B
CN111228490B CN202010114673.5A CN202010114673A CN111228490B CN 111228490 B CN111228490 B CN 111228490B CN 202010114673 A CN202010114673 A CN 202010114673A CN 111228490 B CN111228490 B CN 111228490B
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CN111228490A (zh
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刘蓉
刘树森
张光宇
臧传峰
张伟
李素英
张瑜
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Nantong University
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Abstract

本发明公开了一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，多孔纳米碳纤维采用静电纺丝技术制得，然后对其进行共价功能修饰，提高其分散性，再进行酰胺化处理，进一步提高多孔纳米碳纤维的生物相容性。最后通过表面层层自组装反应，在其表面包覆羟基磷灰石，制得所述产品。在本发明中，对照已有技术的有益效果是，此光热试剂对于肿瘤治疗的增强属于双功能协同效应，一方面钙磷复合多孔纳米碳纤维的光热转化效率高，可以在红外光作用下，杀死肿瘤细胞；另一方面碳纤维表面Ca2+的释放同样可以导致肿瘤细胞的凋亡，因此双功能协同效应的钙磷复合多孔纳米碳纤维光热试剂具有良好的肿瘤抑制效果。

Description

一种钙磷复合多孔纳米碳纤维光热试剂的制备方法
技术领域
本发明涉及生物医学技术领域，具体为一种钙磷复合多孔纳米碳纤维光热试剂的制备方法。
背景技术
近年来，癌症的发病率和死亡率在世界范围内迅速增长，严重影响人类生命安全，阻碍社会发展。目前，常用的传统治疗手段如外科手术治疗，放射疗法以及化学疗法等，简单有效，但容易切除不完整，有辐射或是产生耐药性等副作用。新型治疗手段多采用微创，很大程度上减轻了患者身体负担，如生物治疗是利用自身免疫抗癌，相对于传统疗法具有较高的针对性和安全性，多适用于实体肿瘤；光动力学治疗是利用植入的光敏剂吸收可见光，产生活性氧造成细胞死亡。这种方法毒性低，疗效快但是最主要的弊端是光的毒副作用，全程需在黑暗中进行，避免健康部位接触可见光。
光热治疗作为第五大肿瘤治疗手段，是利用纳米光热试剂吸收 700nm-1100nm的近红外作为光源，将光能转化为热能，对患者病灶部加热，使肿瘤细胞或组织温度上升至有效治疗温度范围(40～46℃)，诱导细胞凋亡或对细胞产生直接致死效应，在不损伤健康组织细胞的前提下，达到杀灭肿瘤的效果。该方法微创高效，毒副作用小，具有很好的光学安全性和组织渗透性。纳米碳基材料作为光热试剂在肿瘤抑制领域已有广泛的应用，但目前纳米碳基材料多采用石墨烯、碳纳米管等，价格昂贵，制备繁琐。纳米碳纤维则克服了以上缺点，它制备简单，来源广泛，目前以纳米碳纤维为碳源的相关研究还比较少。
申请号为201710412890.0的发明专利公开了一种用于肿瘤治疗的多孔纳米碳纤维基载药光热试剂及其制备方法，将表面酸化的多孔纳米碳纤维依次分散在壳聚糖和海藻酸钠溶液中，通过聚合物的层层自组形成表面修饰后的纳米碳纤维，最后分散于抗癌药物水溶液中，得到最终载药光热试剂，是以化学-光热联合治疗来提高肿瘤抑制率的方法。该发明制得的碳纤维基光热试剂为三层结构，以壳聚糖和海藻酸钠提高其分散性和生物相容性，但两者均没有光热转化能力，多层包覆会造成纳米碳纤维的光热转化效率不佳，且该纳米碳纤维基光热材料需通过载药才能达到较好的抗肿瘤效果。
发明内容
本发明的目的是在不影响或提高纳米碳材料光热转化效率的前提下克服其分散性差，低生物相容性的问题，提供一种钙磷复合多孔纳米碳纤维光热试剂的制备方法。所述试剂由表面酸化再酰胺化的多孔纳米碳纤维为基材，包覆CaP，形成壳核结构，不仅提高了纳米碳材料的分散性、生物相容性和光热转化效率，且Ca2+的释放具有PH和温度双响应效应，在近红外的照射下，发挥光热治疗与Ca2+的协同作用，提高肿瘤抑制效率。
为实现上述目的，本发明提供如下技术方案：一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，包括以下步骤：
A、采用静电纺技术制备多孔纳米碳纤维:
首先，按照质量分数分别为7％-50％的聚丙烯腈，5％-10％的聚甲基丙烯酸甲酯，40％-88％的二甲基甲酰胺为基材配置纺丝溶液，60-80℃下搅拌溶融至溶液混合均匀后，进行纺丝,根据溶液的粘稠度设置不同的工艺参数，如纺丝速度0.010mL/min-0.020mL/min，纺丝喷头到接受面的距离10-20cm；
然后，将纺出的薄膜先在230-260℃环境中进行预氧化，再在700-900℃中碳化，整个过程在氮气环境中进行,将碳化后形成的多孔纳米碳纤维研磨成粉末状备用；
B、对纳米碳纤维进行表面改性时，先用浓硫酸和硝酸混合液酸化，再进行酰胺化处理；进一步提高纳米碳纤维的生物相容性和分散性，具体方法如下:
将步骤A中的多孔纳米碳纤维浸没在浓硫酸和浓硝酸(3:1)的混合液中， 60-80℃下搅拌3-5h；然后以6800-7830rpm转速离心，清洗多次，冻干。将冻干后的多孔纳米碳纤维进行氨基化处理；所述纳米碳纤维表面氨基化有如下制备方法：
1)按纳米碳纤维与PEG以1:10-30的质量比混合均匀，溶于去离子水中，再依次加入DMAP和DCC，60-80℃反应24h，离心清洗，冻干备用；
2)按纳米碳纤维与硫脲1:5-10的质量比混合均匀，放入管式碳化炉中氮气环境下80℃反应30-60min，100℃保温30min，130-178℃反应2-4h，降至室温离心清洗，冻干备用；
3)将CTAB和NaOH溶解在去离子水中，70-90℃搅拌1-2h，加入多孔纳米碳纤维、缓慢滴加TEOS和硅烷偶联剂KH550，80℃下搅拌1-3h，离心清洗，分散在稀盐酸溶液中，搅拌24h，再次离心清洗，冻干备用；
C、表面氨基化的纳米碳纤维与CaP聚合物自组装，制备的最终稳定、光热转化率高的光热试剂，具体方法如下：
将步骤B中表面氨基化的多孔纳米碳纤维通过层层自组装与钙磷复合。在磁力搅拌下，向10mL的去离子水中加入5mg的Ca(OH)2和100μL的PAA溶液(0.1g/mL-0.3g/mL)，然后取表面改性后的多孔纳米碳纤维形成的水溶液 5mL加入上述溶液中，缓慢滴加20mL的IPA，再加入15mg磷酸氢二钠，室温搅拌8-12h，离心后用氨水和去离子水离心清洗多次、冻干，获得最终具有增强肿瘤治疗效果的多孔纳米碳纤维复合钙磷光热试剂。
优选的，所述多孔纳米碳纤维来源包括聚丙烯腈碳纤维、沥青基碳纤维、粘胶基碳纤维、酚醛基碳纤维、气相生长碳纤维中的一种或多种混合物。
优选的，所述多孔纳米碳纤维的粒径为10-800nm，长度为100-500nm。
优选的，所述多孔纳米碳纤维与CaP的复合比例为1-3：1；具体步骤为：向聚丙烯酸溶液中依次加入钙离子，表面改性后的纳米碳纤维，异丙醇和磷元素，室温搅拌8-12h，去离子水离心清洗多次，备用；钙源包括但不限于硝酸钙，氯化钙、氢氧化钙，磷源包括但不限于磷酸氢二钠，磷酸二氢钠，磷酸二氢钾。
优选的，在低PH环境或近红外激光的照射下，都能够促进所述光热试剂包覆的CaP中Ca2+的释放；Ca2+进入肿瘤细胞后破坏线粒体中钙离子的稳态，从而使细胞凋亡。
优选的，当所述光热试剂分散液浓度小于400μg/mL时，细胞存活率高于80％；当所述光热试剂分散液的浓度在50μg/mL-400μg/mL时，在波长为 808nm的近红外激光照射下5min，温度可由室温升高到35℃-70℃；将所述光热试剂分散在细胞培养液中，浓度为50μg/mL-400μg/mL时，肿瘤抑制率达 85％。
优选的，一种钙磷复合多孔纳米碳纤维光热试剂，光热试剂分散液的浓度在50μg/mL-400μg/mL时，在波长为808nm的近红外激光照射下5min，温度可由室温升高到35℃-70℃，在近红外的照射和肿瘤酸性环境下Ca2+的释放浓度达80％-100％，在光热治疗与Ca2+的的协同作用下肿瘤抑制率可达85％。
与现有技术相比，本发明的有益效果是：本发明制备了稳定、光热转化效率高的光热试剂，具有优良的生物相容性和分散性，其吸收波长范围在 700nm-1100nm，浓度为200μg/mL时，在波长为808nm的近红外激光照射下 5min，温度可由室温升高到35℃-70℃，在近红外的照射和肿瘤酸性环境下 Ca2+的释放浓度达80％-100％，在光热治疗与Ca2+的的协同作用下肿瘤抑制率 70％-85％；本发明以环保无污染为原则，使用原料来源广，采用静电纺丝技术制备多孔纳米碳纤维，纳米碳纤维的粒径易于控制，最终产品的生物相容性好，分散性好，光热转化性优良。
附图说明
图1为本发明扫描电镜图。
图2为在功率2W的808nm近红外照射下，不同浓度的光热试剂的升温曲线。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，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做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
请参阅图1-2，本发明提供一种技术方案：一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，包括以下步骤：
A、采用静电纺技术制备多孔纳米碳纤维；
B、对纳米碳纤维进行表面改性时，先用浓硫酸和硝酸混合液酸化，再进行酰胺化处理；进一步提高纳米碳纤维的生物相容性和分散性；
C、表面氨基化的纳米碳纤维与CaP聚合物自组装，制备的最终稳定、光热转化率高的光热试剂。
步骤A具体操作如下：
采用静电纺技术制备多孔纳米碳纤维。首先，按照质量分数分别为7％-50％的聚丙烯腈(PAN)，5％-10％的聚甲基丙烯酸甲酯(PMMA)，40％-88％的二甲基甲酰胺(DMF)为基材配置纺丝溶液，60-80℃下搅拌溶融至溶液混合均匀后，进行纺丝。根据溶液的粘稠度设置不同的工艺参数，如纺丝速度 0.010mL/min-0.020mL/min，纺丝喷头到接受面的距离10-20cm等。
然后，将纺出的薄膜先在230-260℃环境中进行预氧化，再在700-900℃中碳化，整个过程在氮气环境中进行。将碳化后形成的多孔纳米碳纤维研磨成粉末状备用。
其中，多孔纳米碳纤维来源包括聚丙烯腈碳纤维、沥青基碳纤维、粘胶基碳纤维、酚醛基碳纤维、气相生长碳纤维中的一种或多种混合物；多孔纳米碳纤维的粒径为10-800nm，长度为100-500nm。
步骤B具体操作方法如下：
将步骤A中的多孔纳米碳纤维浸没在浓硫酸和浓硝酸(3:1)的混合液中， 60-80℃下搅拌3-5h。然后以6800-7830rpm转速离心，清洗多次，冻干。将冻干后的多孔纳米碳纤维进行氨基化处理。所述纳米碳纤维表面氨基化有如下制备方法：
1)按纳米碳纤维与PEG以1:10-30的质量比混合均匀，溶于去离子水中，再依次加入DMAP和DCC，60-80℃反应24h，离心清洗，冻干备用。
2)按纳米碳纤维与硫脲1:5-10的质量比混合均匀，放入管式碳化炉中氮气环境下80℃反应30-60min，100℃保温30min，130-178℃反应2-4h，降至室温离心清洗，冻干备用。
3)将CTAB和NaOH溶解在去离子水中，70-90℃搅拌1-2h，加入多孔纳米碳纤维、缓慢滴加TEOS和硅烷偶联剂KH550，80℃下搅拌1-3h，离心清洗，分散在稀盐酸溶液中，搅拌24h，再次离心清洗，冻干备用。
步骤C具体操作 方法如下：
将步骤B中表面氨基化的多孔纳米碳纤维通过层层自组装与钙磷复合。在磁力搅拌下，向10mL的去离子水中加入5mg的Ca(OH)2和100μL的PAA溶液(0.1g/mL-0.3g/mL)，然后取表面改性后的多孔纳米碳纤维形成的水溶液 5mL加入上述溶液中，缓慢滴加20mL的IPA，再加入15mg磷酸氢二钠(Na2HPO4)，室温搅拌8-12h，离心后用氨水和去离子水离心清洗多次、冻干，获得最终具有增强肿瘤治疗效果的多孔纳米碳纤维复合钙磷光热试剂。
在低PH环境或近红外激光的照射下，都能够促进所述光热试剂包覆的CaP 中Ca2+的释放；Ca2+进入肿瘤细胞后破坏线粒体中钙离子的稳态，从而使细胞凋亡。
本发明制备了稳定、光热转化效率高的光热试剂，具有优良的生物相容性和分散性，其吸收波长范围在700nm-1100nm，浓度为200μg/mL时，在波长为808nm的近红外激光照射下5min，温度可由室温升高到35℃-70℃，在近红外的照射和肿瘤酸性环境下Ca2+的释放浓度达80％-100％，在光热治疗与 Ca2+的的协同作用下肿瘤抑制率70％-85％；本发明以环保无污染为原则，使用原料来源广，采用静电纺丝技术制备多孔纳米碳纤维，纳米碳纤维的粒径易于控制，最终产品的生物相容性好，分散性好，光热转化性优良。
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。

Claims (6)

1.一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，其特征在于：包括以下步骤：
A、采用静电纺技术制备多孔纳米碳纤维:
首先，按照质量分数分别为7％-50％的聚丙烯腈，5％-10％的聚甲基丙烯酸甲酯，40％-88％的二甲基甲酰胺为基材配置纺丝溶液，60-80℃下搅拌溶融至溶液混合均匀后，进行纺丝,根据溶液的粘稠度设置不同的工艺参数，纺丝速度0.010mL/min-0.020mL/min，纺丝喷头到接受面的距离10-20cm；
然后，将纺出的薄膜先在230-260℃环境中进行预氧化，再在700-900℃中碳化，整个过程在氮气环境中进行,将碳化后形成的多孔纳米碳纤维研磨成粉末状备用；
B、对纳米碳纤维进行表面改性时，先用浓硫酸和硝酸混合液酸化，再进行酰胺化处理；进一步提高纳米碳纤维的生物相容性和分散性，具体方法如下:
将步骤A中的多孔纳米碳纤维浸没在浓硫酸和浓硝酸3:1的混合液中，60-80℃下搅拌3-5h；然后以6800-7830rpm转速离心，清洗多次，冻干；将冻干后的多孔纳米碳纤维进行氨基化处理；所述纳米碳纤维表面氨基化有如下制备方法：
1)按纳米碳纤维与PEG以1:10-30的质量比混合均匀，溶于去离子水中，再依次加入DMAP和DCC，60-80℃反应24h，离心清洗，冻干备用；
2)按纳米碳纤维与硫脲1:5-10的质量比混合均匀，放入管式碳化炉中氮气环境下80℃反应30-60min，100℃保温30min，130-178℃反应2-4h，降至室温离心清洗，冻干备用；
3)将CTAB和NaOH溶解在去离子水中，70-90℃搅拌1-2h，加入多孔纳米碳纤维、缓慢滴加TEOS和硅烷偶联剂KH550，80℃下搅拌1-3h，离心清洗，分散在稀盐酸溶液中，搅拌24h，再次离心清洗，冻干备用；
C、表面氨基化的纳米碳纤维与CaP聚合物自组装，制备得最终稳定、光热转化率高的光热试剂，具体方法如下：
将步骤B中表面氨基化的多孔纳米碳纤维通过层层自组装与钙磷复合，在磁力搅拌下，向10mL的去离子水中加入5mg的Ca(OH)2和100μL的PAA溶液0.1g/mL-0.3g/mL，然后取表面改性后的多孔纳米碳纤维形成的水溶液5mL加入上述溶液中，缓慢滴加20mL的IPA，再加入15mg磷酸氢二钠，室温搅拌8-12h，离心后用氨水和去离子水离心清洗多次、冻干，获得最终具有增强肿瘤治疗效果的多孔纳米碳纤维复合钙磷光热试剂。
2.根据权利要求1所述的一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，其特征在于：所述多孔纳米碳纤维的粒径为10-800nm，长度为100-500nm。
3.根据权利要求1所述的一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，其特征在于：在低PH环境或近红外激光的照射下，都能够促进所述光热试剂包覆的CaP中Ca2+的释放；Ca2+进入肿瘤细胞后破坏线粒体中钙离子的稳态，从而使细胞凋亡。
4.根据权利要求1所述的一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，其特征在于：当所述光热试剂分散液浓度小于400μg/mL时，细胞存活率高于80％；当所述光热试剂分散液的浓度在50μg/mL-400μg/mL时，在波长为808nm的近红外激光照射下5min，温度可由室温升高到35℃-70℃；将所述光热试剂分散在细胞培养液中，浓度为50μg/mL-400μg/mL时，肿瘤抑制率达85％。
5.根据权利要求4所述的一种钙磷复合多孔纳米碳纤维光热试剂的制备方法，其特征在于：所述光热试剂的分散液为去离子水，磷酸缓冲溶液，细胞培养液或血清，所述光热试剂在分散液中都有很好的分散性，放置一周没有明显沉淀现象。
6.采用如权利要求1-5任一项所述的制备方法制得的一种钙磷复合多孔纳米碳纤维光热试剂，其特征在于：光热试剂分散液的浓度在50μg/mL-400μg/mL时，在波长为808nm的近红外激光照射下5min，温度可由室温升高到35℃-70℃，在近红外的照射和肿瘤酸性环境下Ca2+的释放浓度达80％-100％，在光热治疗与Ca2+的协同作用下肿瘤抑制率可达85％。
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