CN114588281A - 一种水溶性非晶氧化铁纳米簇的制备方法 - Google Patents
一种水溶性非晶氧化铁纳米簇的制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/12—Macromolecular compounds
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Abstract
本发明公开了一种水溶性非晶氧化铁纳米簇的制备方法，属于纳米材料和生物工程技术领域。该方法通过控制亲水性分子种类和反应条件，精准控制纳米簇尺和表面电荷。用来修饰水溶性非晶氧化铁纳米簇的亲水性分子均带有与氧化铁有较强结合能力的基团：巯基，胺基或羧基，能有效保障纳米簇在水中的分散性、稳定性和生物相容性。本发明所合成的非晶氧化铁纳米簇形貌均一，尺寸分布窄，弛豫率高，能在短时间内从体内完全降解并排出体外，在不影响正常生理活动的情况下实现有效磁共振成像。作为能快速从体内排出的磁共振造影剂，该方法制备出的水溶性非晶氧化铁纳米簇在恶性病变(如肿瘤)的早期诊断等磁共振成像生物医学领域具有十分广泛的应用前景。
Description
技术领域
本发明属于纳米材料和生物工程技术领域，具体涉及一种水溶性非晶氧化铁纳米簇的制备方法。
背景技术
作为医学研究和临床诊断中有效的成像工具，磁共振成像(MRI)由于能对组织坏死、局部缺血和各种恶性病变(如肿瘤)进行有效检测而对病变组织进行早期诊断，还能对器官移植等进行监测。MRI信号来自于永久磁场中形成的低能核自旋的激发，可以通过施加射频脉冲并测量核自旋弛豫过程(即T1恢复或T2衰减)来测试信号强度。不同的化学环境以及水的浓度会产生不同的信号强度，因此MRI信号会在脂肪，组织和骨骼之间形成对比。众所周知，顺磁性化合物可用于通过促进化合物附近水的弛豫来增强MR图像的对比度。目前，临床上使用的T1造影剂都是基于钆(Gd3+)的螯合物(GBCAs)，而GBCA仍具有不良反应风险，包括肾源性全身纤维化和人脑中的Gd沉积。而作为目前临床常用的T2造影剂，超顺磁性氧化铁纳米颗粒(SPINOs)具有良好的生物相容性和低毒性，并且易被生物相容的配体包被且产物具有良好化学和生物稳定性。但是，可购买到的SPINOs造影剂大都由许多分散的无机核组成，水和粒径较大：
较大的水和粒径会阻止现有SPIONs在静脉注射后进行有效的肾脏清除，导致这些SPIONs在体内积聚，并可能在数周或数月内引起持续的负对比，这阻止了重复的成像研究并限制了患者的临床管理。此外，目前的SPINOs造影剂在注射到体内后几乎被定量代谢并吸收到铁库中，可能会因铁超负荷而产生临床副作用。
值得注意的是，小尺寸的SPINOs由于其较小的T2效应，较大的表面积和5个不成对电子增强的T1效应而成为T1造影剂的潜在候选者。研究表明，当这些小尺寸的SPINOs水和粒径小于肾小球的过滤尺寸阈值
时就能部分能从肾脏快速排出，减少其在体内的积累和对身体的危害。由此我们可知，如果能将大尺寸的SPINOs纳米在体内快速降解成能从肾脏排出的小尺寸纳米粒子，就可以在实现MRI成像的同时而最大程度的降低对身体的危害。因此，本发明提供了一种水溶性非晶氧化铁纳米簇的制备方法，通过控制反应条件，可以精准地控制纳米簇尺寸，不仅能制备出能从体内快速排出的小尺寸T1磁共振造影剂，而且能制备出能从体内快速降解排出的大尺寸T2磁共振造影剂，真正实现造影剂的成像功能与生物安全双保障。
发明内容：
本发明拟解决的技术问题是提供一种水溶性非晶氧化铁纳米簇的制备方法，通过控制亲水性分子种类和反应条件，精准控制纳米簇表面电荷和纳米簇尺寸，使制备的纳米簇实现造影剂的成像功能与生物安全双保障。本发明产品表面的亲水性分子均具有良好的生物相容性等优异性能，有效保障水溶性非晶氧化铁纳米簇子在水中的分散性、稳定性和生物相容性。
本发明产品由如下步骤制备：
1.羧基化糖类亲水性分子的制备：将溶解在1mL-50mL水中0.1g-10.0g的糖类亲水性分子缓慢通过10mL-200mL酸化的凝胶柱，并用脂肪胺溶液将糖类亲水性分子的水溶液pH值调节至8.0-11.0。将该碱性溶液冷冻干燥后，得到0.1g-10.0g糖类亲水性分子三丁基铵盐。在氮气下保护下，陆续将0.1g-10.0g糖类亲水性分子三丁基铵盐，5.0g-50.0g丁二酸酐和0.1g-10.0g 4-二甲基氨基嘌呤(DMAP)溶解在10mL-500mL的干燥溶剂N，N二甲基甲酰胺(DMF)中，并在室温下反应24h-72h。待反应完全后，用截留分子量为100-100000(Mw＝100～Mw＝100000)的透析袋将反应液在去离子水透析，并将透析后的水溶液冷冻干燥，得到0.1g-10.0g羧基化糖类亲水性分子；
2.水溶性非晶氧化铁纳米簇的制备：将0.1g-10.0g(1)步骤制备的亲水性分子，1.0mg-100.0mg六水合三氯化铁(FeCl3·6H2O)和1.0mg-100.0mg四水合二氯化铁(FeCl2·4H2O)依次加入1.0mL-100.0mL去离子水中，室温下搅拌30min使试剂完全溶解。在氮气保护下，将氨水(NH3·H2O)缓慢滴加到反应液中调节溶液pH为9.0-11.0后，加热该溶液至10℃-100℃，并在该温度下反应10min-200min。待反应完全后，用截留分子量为100-100000(Mw＝100～Mw＝100000)的透析袋将反应液在pH＝1.0-7.0的去离子水透析1d-4d。最后，将得到的水溶性非晶氧化铁纳米簇保存在去离子水中。
所述步骤2中所用的亲水性分子为胶原蛋白，白明胶，溶菌酶，蛋白氨酸、缬氨酸、异亮氨酸、赖氨酸、苏氨酸、色氨酸、苯丙氨酸，丙氨酸、谷氨酸、天门冬氨酸、甘氨酸、胱氨酸、脯氨酸、酷氨酸、丝氨酸、脯氨酸，聚丙烯酸1000，聚丙烯酸1200，聚丙烯酸1800，聚丙烯酸2000，和聚丙烯酸3000，羧基化的低分子量肝素，壳聚糖，葡聚糖，D-甘露醇，硫酸软骨素，1，6-二磷酸果糖，透明质酸，香菇多糖等糖类药物以及羧基化的聚乙二醇1000，聚乙二醇1500，聚乙二醇2000和聚乙二醇3000中的一种。
所述步骤2中所用的亲水性分子分子量为100～100000。
所述步骤2中透析水溶性非晶氧化铁纳米簇透反应液的水溶液pH值为1.0-7.0。
所述步骤2制备出的水溶性非晶氧化铁纳米簇的磁核尺寸为1.0nm-100.0nm。
所述步骤2制备出的水溶性非晶氧化铁纳米簇的水合动力学粒径为1.0nm-100.0nm，并具有良好的水溶液稳定性。
所述步骤2制备出的水溶性非晶氧化铁纳米簇是以四氧化三铁纳米簇为核心，表面均匀地修饰有亲水性分子。
所述步骤2制备出的水溶性非晶氧化铁纳米簇表面亲水性分子的厚度为0.1nm-10nm。
所述步骤2制备出的水溶性非晶氧化铁纳米簇的是非晶态的，能在生物体内完全降解。
具体实施方式
实施例1：
(1)羧基化糖类亲水性分子的制备：将溶解在10mL水中1.0g的糖类亲水性分子缓慢通过100mL酸化的凝胶柱，并用脂肪胺溶液将糖类亲水性分子的水溶液pH值调节至7.0。将该碱性溶液冷冻干燥后，得到1.5g糖类亲水性分子三丁基铵盐。在氮气下保护下，陆续将1.5g糖类亲水性分子三丁基铵盐，5.0g丁二酸酐和2.0g 4-二甲基氨基嘌呤(DMAP)溶解在100mL的干燥溶剂N，N二甲基甲酰胺(DMF)中，并在室温下反应72h。待反应完全后，用截留分子量为2000的透析袋将反应液在去离子水透析，并将透析后的水溶液冷冻干燥，得到1.5g羧基化糖类亲水性分子
(2)水溶性非晶氧化铁纳米簇的制备：将1.0g(1)步骤制备的亲水性分子，100.0mg六水合三氯化铁(FeCl3·6H2O)和50.0mg四水合二氯化铁(FeCl2·4H2O)依次加入5.0mL去离子水中，室温下搅拌30min使试剂完全溶解。在氮气保护下，将氨水(NH3·H2O)缓慢滴加到反应液中调节溶液pH为9.0后，加热该溶液至50.0℃，并在该温度下反应30min。待反应完全后，用截留分子量为2000的透析袋将反应液在pH＝5.0的去离子水透析2d。最后，将得到的水溶性非晶氧化铁纳米簇保存在去离子水中
实施例2：
(1)同实施例1；
(2)水溶性非晶氧化铁纳米簇的制备：将2.0g(1)步骤制备的亲水性分子，150.0mg六水合三氯化铁(FeCl3·6H2O)和75.0mg四水合二氯化铁(FeCl2·4H2O)依次加入7.0mL去离子水中，室温下搅拌20min使试剂完全溶解。在氮气保护下，将氨水(NH3·H2O)缓慢滴加到反应液中调节溶液pH为9.0后，加热该溶液至70.0℃，并在该温度下反应30min。待反应完全后，用截留分子量为1000的透析袋将反应液在pH＝4.0的去离子水透析3d。最后，将得到的水溶性非晶氧化铁纳米簇保存在去离子水中。
Claims (9)
1.一种水溶性非晶氧化铁纳米簇，其特征在于该纳米簇是以四氧化三铁纳米簇为核心，表面均匀地修饰有亲水性分子。
2.如权利要求1所述的水溶性非晶氧化铁纳米簇，其特征在于所述水溶性非晶氧化铁纳米簇为非晶氧态，能在生物体内完全降解。
3.如权利要求1所述的水溶性非晶氧化铁纳米簇，其特征在于所述非晶氧化铁纳米簇的平均粒径为1nm-100nm。
4.如权利要求1所述的水溶性非晶氧化铁纳米簇，其特征在于所述纳米簇表面的亲水性分子为胶原蛋白，白明胶，溶菌酶，蛋白氨酸、缬氨酸、异亮氨酸、赖氨酸、苏氨酸、色氨酸、苯丙氨酸，丙氨酸、谷氨酸、天门冬氨酸、甘氨酸、胱氨酸、脯氨酸、酷氨酸、丝氨酸、脯氨酸，聚丙烯酸1000，聚丙烯酸1200，聚丙烯酸1800，聚丙烯酸2000，和聚丙烯酸3000，羧基化的低分子量肝素，壳聚糖，葡聚糖，D-甘露醇，硫酸软骨素，1，6-二磷酸果糖，透明质酸，香菇多糖等糖类药物以及羧基化的聚乙二醇1000，聚乙二醇1500，聚乙二醇2000和聚乙二醇3000中的一种。
5.如权利要求1所述的水溶性非晶氧化铁纳米簇，其特征在于所述纳米簇表面的亲水性分子厚度为0.1nm-10nm。
6.一种水溶性非晶氧化铁纳米簇的制备方法，其特征在于该方法包括以下步骤：
(1)羧基化糖类亲水性分子的制备：将溶解在1mL-50mL水中0.1g-10.0g的糖类亲水性分子缓慢通过10mL-200mL酸化的凝胶柱，并用脂肪胺溶液将糖类亲水性分子的水溶液pH值调节至8.0-11.0。将该碱性溶液冷冻干燥后，得到0.1g-10.0g糖类亲水性分子三丁基铵盐。在氮气下保护下，陆续将0.1g-10.0g糖类亲水性分子三丁基铵盐，5.0g-50.0g丁二酸酐和0.1g-10.0g 4-二甲基氨基嘌呤(DMAP)溶解在10mL-500mL的干燥溶剂N，N二甲基甲酰胺(DMF)中，并在室温下反应24h-72h。待反应完全后，用截留分子量为100-100000(Mw＝100～Mw＝100000)的透析袋将反应液在去离子水透析，并将透析后的水溶液冷冻干燥，得到0.1g-10.0g羧基化糖类亲水性分子；
(2)水溶性非晶氧化铁纳米簇的制备：将0.1g-10.0g(1)步骤制备的亲水性分子，1.0mg-100.0mg六水合三氯化铁(FeCl3·6H2O)和1.0mg-100.0mg四水合二氯化铁(FeCl2·4H2O)依次加入1.0mL-100.0mL去离子水中，室温下搅拌30min使试剂完全溶解。在氮气保护下，将氨水(NH3·H2O)缓慢滴加到反应液中调节溶液pH为9.0-11.0后，加热该溶液至10℃-100℃，并在该温度下反应10min-200min。待反应完全后，用截留分子量为100-100000(Mw＝100～Mw＝100000)的透析袋将反应液在pH＝1.0-7.0的去离子水透析1d-4d。最后，将得到的水溶性非晶氧化铁纳米簇保存在去离子水中。
7.如权利要求6所述水溶性非晶氧化铁纳米簇的制备方法，其特征在于所述步骤(2)中透析水溶性非晶氧化铁纳米簇透反应液的水溶液pH值为1.0-7.0。
8.如权利要求6所述水溶性非晶氧化铁纳米簇的制备方法，其特征在于所述步骤(2)制备出的水溶性非晶氧化铁纳米簇的水合动力学粒径为1.0nm-100.0nm，并具有良好的水溶液稳定性。
9.如权利要求6所述水溶性非晶氧化铁纳米簇的制备方法，其特征在于所述步骤(2)制备出的水溶性非晶氧化铁纳米簇的是非晶态的，能在生物体内完全降解。
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| CN105954268A (zh) * | 2016-04-22 | 2016-09-21 | 华南师范大学 | 一种基于四氧化三铁纳米簇催化信号放大的可视化检测传感器及其构建与应用 |
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