CN106668878A - 一种集t1、t2双模式为一体的多功能介孔碳小球及其制备方法 - Google Patents
一种集t1、t2双模式为一体的多功能介孔碳小球及其制备方法 Download PDFInfo
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- CN106668878A CN106668878A CN201710011979.6A CN201710011979A CN106668878A CN 106668878 A CN106668878 A CN 106668878A CN 201710011979 A CN201710011979 A CN 201710011979A CN 106668878 A CN106668878 A CN 106668878A
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Abstract
本发明涉及功能纳米材料技术领域,具体为一种集T1、T2双模式核磁成像及载药性能为一体的多功能介孔碳小球及其制备方法。本发明所述的多功能介孔碳小球含有T1造影剂顺磁磷酸钆,T2造影剂超顺磁氧化铁,造影剂其颗粒高度均匀分散在介孔碳小球的碳骨架中,磷酸钆和氧化铁的质量含量是0.5%~25%,磷酸钆、磁氧化铁的颗粒尺寸1~10nm;该多功能介孔碳小球在制备过程中,将铁—钆金属簇核物一步引入到介孔碳小球的前驱体中,然后经一步原位碳化制备而成。本发明实现了T1、T2双模式造影功能与载药功能的集成,同时具有低细胞毒性特点,实现了诊疗一体的功能,在临床和基础医学研究中具有广泛的应用前景。
Description
技术领域
本发明涉及功能纳米材料技术领域,具体涉及一种集T1、T2双模式核磁成像及载药性能为一体的多功能介孔碳小球及其制备方法。
背景技术
复合功能纳米材料,尤其是集临床诊断与治疗性能为一体的多功能材料在现代医疗及基础医学研究领域越来越受到人们的关注。诊疗结合手段可以在疾病早期提高治疗效果。可以用诊断技术检测疾病,同时将药物传送到病变部分,并即时检测药物的传送与分布情况,因此可以更好的调控用药剂量及治疗手段,降低副反应的发生。
核磁共振成像是目前少有的对人体没有任何伤害的安全、快速、准确的临床诊断方法。为提高核磁成像的敏感性,检测时需加入造影剂。造影剂分为两种:顺磁性的T1加权造影剂,如钆的螯合物,GdPO4、Gd2O3、MnO2等;超顺磁性T2加权造影剂,如Fe3O4、γ-Fe2O3等。目前,各种各样的多孔材料作为载体用于负载核磁成像造影剂和药物分子,从而将核磁成像与载药特性结合,实现诊疗一体目的。文献报道较多的是单一模式(T1加权造影剂或者T2加权造影剂)成像与载药特性结合的复合材料,如葡萄聚糖包裹的纳米氧化铁颗粒(Acc. Chem. Res. 2011, 44, 842–852)氧化锰/介孔氧化硅纳米颗粒(Biomaterials 2012, 33,2388–2398)、偶联叶酸靶向的四氧化三铁/介孔二氧化硅/硫化铜纳米复合粒子(中国,105920601A,2016-09-07)。但是单一模式成像诊断技术存在一些缺点,如T2加权核磁成像图片为暗信号,容易与血液骨骼信号混淆,另外会出现磁敏感伪影。而将T1、T2加权造影剂结合的双模式核磁成像造影剂可以避免单一模式的缺点,从而提供更加准确,可信赖性强的诊断信息。因此,一种集T1、T2 双模式成像与载药性能为一体的复合功能型材料具有更加广泛的应用前景及价值。
介孔碳小球是一类具有开放的孔道结构,高比表面积,大小可调控的孔道多孔材料,由于自身是碳元素具有极好的生物兼容性,可以作为载体应用到生物医药等领域。小尺寸的碳小球可以通过细胞内吞作用进入细胞,实现对于药物、基因、蛋白及成像制剂的传送,在生物医学和制药领域具有潜在的应用价值。
发明内容
本发明的目的是提供一种集T1、T2双模式核磁成像及载药性能为一体的多功能介孔碳小球及其制备方法,制备的多功能介孔碳小球体外实验显示出良好的弛豫值和优良负载抗癌药盐酸阿霉素性能,具有潜在的基础临床应用和基础医学研究的前景。
为了实现上述目的,本发明采用的技术方案具体如下:
一种集T1、T2双模式核磁成像及载药性能为一体的多功能介孔碳小球,介孔碳小球直径尺寸大小在50至300nm,介孔孔径2~4nm,集成的T1造影剂是顺磁磷酸钆,集成的T2造影剂是超顺磁氧化铁,所述的造影剂其颗粒高度均匀分散在介孔碳小球的碳骨架中,磷酸钆和氧化铁的质量含量是0.5%~25%,磷酸钆、磁氧化铁的颗粒尺寸在1~10nm范围内。
上述多功能介孔碳小球的制备方法,具体步骤为:
步骤一:用水热合成方法,制备酚醛树脂/介孔造孔剂高分子小球,作为碳小球前驱体;
步骤二:通过溶液浸渍吸附的方法,负载铁—钆簇核物于复合高分子小球中;
步骤三:将复合高分子小球经惰性气氛高温焙烧,并进行羧酸化处理,获得具有顺磁性T1加权造影剂、超顺磁性T2加权造影剂和介孔孔径的多功能介孔碳小球。
上述技术方案步骤一中,制备的酚醛树脂/介孔造孔剂高分子小球时,所用原料为苯酚、甲醛、造孔剂、水,其用量摩尔比为1:(3~5):(0.006~0.03):(2000~5000),水热反应温度为100~150℃,水热反应时间为24~36小时。
上述技术方案中步骤一中,所述介孔造孔剂是聚氧乙烯聚氧丙烯醚嵌段共聚物,或其它两亲性嵌段共聚物。
上述技术方案步骤二中,所选的铁—钆簇核物分子通式为:
[FeIII 6GdIII 6(μ 3-O)2(CO3)(O2C t Bu)18(O3PR)6],分子量为3000~5000,有特征性结构。
上述技术方案步骤二中,将铁—钆簇核物和酚醛树脂/造孔剂高分子小球加入到溶剂中进行超声,所述的酚醛树脂/造孔剂高分子小球和铁—钆簇核物的用量比为20mg:(3~18)mg,所述的溶剂选用乙醇、乙酸乙酯、四氢呋喃,乙醚中的至少一种,超声时间为0.5~12小时,超声结束后将混合液在一定温度下搅拌蒸干,蒸干温度为25~50℃。
上述技术方案步骤三中,惰性气氛为氮气或者第VIII族气体中至少一种,碳化温度为600 ~900℃,碳化时间为1~6小时;表面羧酸化方式为空气氛下200~400℃下处理0.5~2小时。
本发明提供一种根据所述功能化碳小球的制备方法制备的功能化碳小球的体外T1、T2双模式核磁成像和载药的研究。
所述功能化碳小球可用作T1、T2双模式核磁成像造影剂,并且具有负载抗癌药物盐酸阿霉素的功能。
本发明方法是在介孔碳小球前驱体中引入一种特殊的铁—钆金属簇合物,然后经一步原位碳化得磷酸钆和氧化铁负载的功能化介孔碳小球。该复合材料实现了T1、T2双模式造影功能与载药功能的集成,在临床和基础医学研究中具有广泛应用前景。
附图说明
图1为实施例1制备的功能化介孔碳小球的透射电镜图。介孔碳小球190nm左右,金属化合物均一分散在碳小球上,粒径大约4nm。
图2为实施例2制备的功能化介孔碳小球的透射电镜图。介孔碳小球120nm左右,金属化合物均一分散在碳小球上,粒径大约3nm。
图3为实施例3制备的功能化介孔碳小球的透射电镜图。介孔碳小球190nm左右,金属化合物均一分散在碳小球上,粒径大约5nm。
图4为实施例4功能化介孔碳小球在盐酸阿霉素溶液(1 mg ml–1)中浸渍次数与其对盐酸阿霉素吸附量的关系曲线。功能化介孔碳小球载药量为132 mg g–1,载药含量满足临床治疗和研究的要求。
图5为实施例5功能化介孔碳小球的体外核磁成像图(a)及弛豫率r1、r2值(b)。弛豫率r1、r2分别为8.2 and 94.3 mM-1 s-1,能够满足医学核磁成像诊断和研究的要求。
具体实施方式
下面通过实施例对本发明作进一步的阐述。
实施例1
(1)介孔碳小球前驱体(酚醛树脂/F127)的制备:0.6 g苯酚先于45℃水浴中融化,再加入15 mL浓度为0.1 M的氢氧化钠溶液,搅拌10 min。接着加入2.1 mL浓度为37 wt%的甲醛溶液,上述混合物升温至70℃,搅拌0.5小时,得低分子量的酚醛树脂。另称量0.96 g F127溶于15 mL水中,完全溶解后缓慢倒入上溶液。混合溶液在66℃下搅拌2小时,之后再加入50ml水稀释该混合溶液,混合溶液以约340 rpm的速率搅拌16–18小时。反应过程中溶液颜色会从无色到粉红最后到深红色,并且瓶底会有沉积物出现。静置,待沉积物溶解取17.7 mL反应溶液加水稀释(56 mL)的去离子水,密封于100 mL水热釜中,置于烘箱中130℃水热处理24小时。冷却至室温,重复离心洗涤收集所得沉积物,室温下干燥,得淡黄色干燥固体粉末,为酚醛树脂/F127前驱体。
(2)T1、T2核磁成像与载药功能化介孔碳小球的制备:
9 mg {Fe6Gd6P6}([Fe6Gd6(μ 3-O)2(CO3)(O3PPh)6(O2C t Bu)18])超声溶解到2 ml乙醇溶液中,向该溶液中加入20 mg酚醛树脂/F127前驱体,超声使其在乙醇溶液中分散均一。该混合溶液在室温下将溶剂搅拌蒸干,得{Fe6Gd6P6}/酚醛树脂/F127复合材料,将该材料置于管式炉中,氮气氛下600℃焙烧3小时,即得氧化铁—磷酸钆/介孔碳小球。再将该功能化碳小球在空气氛下300℃焙烧1个小时,得羧酸化氧化铁—磷酸钆/介孔碳小球,即图1所示。
实施例2
(1)介孔碳小球前驱体(酚醛树脂/F127)的制备:0.5 g苯酚先于45℃水浴中融化,再加入12.5 mL浓度为0.1 M的氢氧化钠溶液,搅拌10 min。接着加入1.9 mL浓度为37 wt%的甲醛溶液,上述混合物升温至70℃,搅拌0.5小时,得低分子量的酚醛树脂。另称量0.82 gF127溶于15 mL水中,完全溶解后缓慢倒入上溶液。混合溶液在66℃下搅拌2小时,之后再加入50 ml水稀释该混合溶液,混合溶液以约340 rpm的速率搅拌16–18小时。反应过程中溶液颜色会从无色到粉红最后到深红色,并且瓶底会有沉积物出现。静置,待沉积物溶解取17.7mL反应溶液加水稀释(56 mL)的去离子水,密封于100 mL水热釜中,置于烘箱中130℃水热处理24小时。冷却至室温,重复离心洗涤收集所得沉积物,室温下干燥,得淡黄色干燥固体粉末,为酚醛树脂/F127前驱体。
(2)T1、T2核磁成像与载药功能化介孔碳小球的制备:
9 mg {Fe6Gd6P6}([Fe6Gd6(μ 3-O)2(CO3)(O3PPh)6(O2C t Bu)18])超声溶解到2 ml乙醇溶液中,向该溶液中加入20 mg酚醛树脂/F127前驱体,超声使其在乙醇溶液中分散均一。该混合溶液在室温下将溶剂搅拌蒸干,得{Fe6Gd6P6}/酚醛树脂/F127复合材料,将该材料置于管式炉中,氮气氛下600℃焙烧3小时,即得氧化铁—磷酸钆/介孔碳小球。再将该功能化碳小球在空气氛下300℃焙烧1个小时,得羧酸化氧化铁—磷酸钆/介孔碳小球,即图2所示。
实施例3
按照实施例1合成介孔碳小球前驱体酚醛树脂/F127。
9 mg {Fe6Gd6P6}([Fe6Gd6(μ 3-O)2(CO3)(O3PPh)6(O2C t Bu)18])超声溶解到2 ml四氢呋喃中,向该溶液中加入20 mg酚醛树脂/F127前驱体,超声使其在四氢呋喃溶液中分散均一。该混合溶液在室温下将溶剂搅拌蒸干,得{Fe6Gd6P6}/酚醛树脂/F127复合材料,将该材料置于管式炉中,氮气氛下600℃焙烧3小时,即得氧化铁—磷酸钆/介孔碳小球。再将该功能化碳小球在空气氛下300℃焙烧1个小时,得羧酸化氧化铁—磷酸钆/介孔碳小球,即图3所示。
实施例4
将10 mg 实施例1得到的功能化介孔碳小球分散到2 ml (1 mg ml–1)的盐酸阿霉素溶液中,然后将混合液在室温下避光搅拌12小时。最后该材料离心分离,洗涤,收集所有上层溶液做UV-Vis分析,测得481 nm处的吸光度值,根据盐酸阿霉素标准曲线,结合载药前盐酸阿霉素溶液浓度得到功能化介孔碳小球的载药量。将载有盐酸阿霉素的功能化碳小球重复上述步骤,直至复合材料对盐酸阿霉素吸附饱和。如图4,计算得功能化介孔碳小球的载药量。
实施例5
核磁成像弛豫时间及T1、T2加权成像图片是在0.5 T MRI (MicroMRI.上海纽迈电子科技有限公司)上获得,测试温度为32℃。将实施例1得到的功能化介孔碳小球,配成不同Gd3+(Fe3+)浓度的水溶液置于核磁共振分析与成像系统中,最终得到T1、T2加权成像图及r1、r2弛豫率,结果分别见图5(a)和图5(b)。
Claims (8)
1.一种集T1、T2双模式核磁成像及载药性能为一体的多功能介孔碳小球,其特征在于,介孔碳小球直径尺寸大小为50至300nm,介孔孔径为2~4nm,集成的T1造影剂是顺磁磷酸钆,集成的T2造影剂是超顺磁氧化铁,所述的造影剂均匀分散在介孔碳小球的碳骨架中,磷酸钆和氧化铁的质量含量是0.5%~25%,磷酸钆、磁氧化铁的颗粒尺寸在1~10nm范围内。
2.如权利要求1所述的多功能介孔碳小球的制备方法,其特征在于,具体步骤为:
步骤一:用水热合成方法,制备酚醛树脂/介孔造孔剂高分子小球,作为碳小球前驱体;
步骤二:通过溶液浸渍吸附的方法,负载铁—钆簇核物于复合高分子小球中;
步骤三:将复合高分子小球经惰性气氛高温焙烧,并进行羧酸化处理,获得具有顺磁性T1加权造影剂、超顺磁性T2加权造影剂和介孔孔径的多功能介孔碳小球。
3.根据权利要求2所述的多功能介孔碳小球的制备方法,其特征在于,步骤一中,制备酚醛树脂/介孔造孔剂高分子小球时,所用原料为苯酚、甲醛、造孔剂、水,其用量摩尔比为1:(3~5):(0.006~0.03):(2000~5000),水热反应温度为100~150℃,水热反应时间为24~36小时。
4.根据权利要求2或3所述的多功能介孔碳小球的制备方法,其特征在于,步骤一中,所述介孔造孔剂是聚氧乙烯聚氧丙烯醚嵌段共聚物,或其它两亲性嵌段共聚物。
5.根据权利要求4所述的多功能介孔碳小球的制备方法,其特征在于,步骤二中,所选的铁—钆簇核物分子通式为:
[FeIII 6GdIII 6(μ 3-O)2(CO3)(O2C t Bu)18(O3PR)6],分子量为3000~5000。
6.根据权利要求2、3或5所述的多功能介孔碳小球的制备方法,其特征在于,步骤二中所述溶液浸渍吸附的方法的流程为:将铁—钆簇核物和酚醛树脂/造孔剂高分子小球加入到溶剂中进行超声,所述的酚醛树脂/造孔剂高分子小球和铁—钆簇核物的用量比为20mg:(3~18)mg,所述的溶剂选用乙醇、乙酸乙酯、四氢呋喃,乙醚中的至少一种,超声时间为0.5~12小时,超声结束后将混合液在25~50℃温度下搅拌蒸干。
7.根据权利要求6所述的多功能介孔碳小球的制备方法,其特征在于,步骤三中,惰性气氛为氮气或者第VIII族气体中至少一种,碳化温度为600~900℃,碳化时间为1~6小时;表面羧酸化方式为空气氛下200~400℃下处理0.5~2小时。
8.如权利要求1所述的多功能介孔碳小球在制备T1、T2双模成像剂和载药系统中的应用。
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Cited By (6)
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CN107412790A (zh) * | 2017-09-08 | 2017-12-01 | 丽水市中心医院 | 一种核磁共振纳米材料的制备方法 |
CN107412790B (zh) * | 2017-09-08 | 2019-02-22 | 丽水市中心医院 | 一种核磁共振纳米材料的制备方法 |
CN108147390A (zh) * | 2017-12-07 | 2018-06-12 | 西安交通大学 | 一种金属-天然多酚配合物纳米球及其纳米多孔金属/碳基复合材料及制备方法 |
CN112023063A (zh) * | 2020-08-24 | 2020-12-04 | 复旦大学 | 集核磁成像造影和递药功能一体的双铁基介孔碳纳米材料及其制备方法和应用 |
CN112023063B (zh) * | 2020-08-24 | 2021-09-28 | 复旦大学 | 集核磁成像造影和递药功能一体的双铁基介孔碳纳米材料及其制备方法和应用 |
CN112168983A (zh) * | 2020-09-28 | 2021-01-05 | 复旦大学 | 一种诊疗一体的中空碳纳米复合材料及其制备方法和应用 |
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