CN108815135A - 两亲双面神结构纳米粒子的制备方法及其应用 - Google Patents

两亲双面神结构纳米粒子的制备方法及其应用 Download PDF

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CN108815135A
CN108815135A CN201810686256.0A CN201810686256A CN108815135A CN 108815135 A CN108815135 A CN 108815135A CN 201810686256 A CN201810686256 A CN 201810686256A CN 108815135 A CN108815135 A CN 108815135A
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张凌宇
李鹿
王春刚
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Northeast Normal University
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Abstract

本发明提供一种单分散两亲双面神结构聚己内酯‑金纳米笼/氢氧化铁‑聚丙烯酸(PCL‑AuNC/Fe(OH)3‑PAA)纳米粒子的制备方法及其应用。本发明利用界面张力在不同环境下的改变，结合选择性生长及修饰方法，开发一种简单的方法制备单分散两亲双面神结构PCL‑AuNC/Fe(OH)3‑PAA纳米粒子，所得产品分散性好，粒径均匀，生物相容性好，在亲疏水药物共输送和生物成像等领域具有非常广阔的应用前景。

Description

两亲双面神结构纳米粒子的制备方法及其应用
技术领域
本发明属于纳米复合材料及其应用技术领域，具体涉及一种两亲双面神结构聚己内酯-金纳米笼/氢氧化铁-聚丙烯酸(PCL-AuNC/Fe(OH)3-PAA)纳米粒子的制备方法及其应用。
背景技术
随着纳米技术和材料的开发与完善，具有多功能的纳米材料为肿瘤的精确定位、早期诊断和联合治疗带来了新的希望，并取得了显著的研究进展。1991年，Pierre-Gillesde Gennes教授在诺贝尔颁奖大会上首次提出双面神粒子，这种能将两种材料本身性质、表面性质或其他性质结合到一个粒子上的特性为各个领域的科学研究开辟了新的篇章。特别是，双面神纳米粒子克服了传统杂化纳米粒子，如核-壳、蛋黄-蛋壳结构纳米粒子表面单一、多重修饰时分子间相互干扰的弊端，使其在生物医学方向更是得到广泛的应用。[参考文献：A.Walther,A.H.E.Müller,Chem.Rev.2013,113,5194.]由于双面神纳米材料独特的结构特性，双面神纳米粒子的两端可分别负载疏水和亲水的抗癌药物，达到同一纳米粒子对双药物的运输；或在其中一个表面修饰靶向分子，另一表面负载抗癌症药物；抑或不同pH调控两种材料两阶段药物释放；也可以结合两种不同成像模式，如核磁共振(MR)成像和荧光成像等不同成像模式。但是，目前对于双面神纳米粒子的研究还比较浅显，在合成上，对于得到具有新颖形貌和特殊性质的双面神纳米粒子的研究已成为国内外的研究热点；[参考文献：X.Li,L.Zhou,Y.Wei,A.M.El-Toni,F.Zhang,D.Zhao,J.Am.Chem.Soc.2014,136,15086；J.He,Y.Liu,T.C.Hood,P.Zhang,J.Gong,Z.Nie,Nanoscale 2013,5,5151；Y.Li,Z.Di,J.Gao,P.Cheng,C.Di,G.Zhang,B.Liu,X.Shi,L.-D.Sun,L.Li,C.-H.Yan,J.Am.Chem.Soc.2017,139,13804.]在生物医学应用上，目前主要是简单的结合两种材料或利用表面的双修饰，对药物的负载效率也比较低，得到的生物探针功能单一，不能有效的实现多模式诊疗一体化，在生物医学的研究也主要在细胞水平，动物体内的研究有待进一步开展。
金纳米笼(AuNC)吸收峰可以移动至近红外区，在近红外(NIR)激光照射下，实现皮下深层组织的光热治疗，同时它还具有计算机断层(CT)成像性质，使其在生物医学上的研究取得了长足的进步。特别是，其具有中空的笼子结构，可以将药物负载在此区域内，达到保护药物，实现成功运输药物到指定位置的功能。[参考文献：Y.Xia,W.Li,C.M.Cobley,J.Chen,X.Xia,Q.Zhang,M.Yang,E.C.Cho,P.K.Brown,Acc.Chem.Res.2011,44,914；S.E.Skrabalak,J.Chen,Y.Sun,X.Lu,L.Au,C.M.Cobley,Y.Xia,Acc.Chem.Res.2008,41,1587.]但是，单纯的AuNC空间十分有限，无法负载更多药物，对于癌症治疗的功能过于单一化。Dongyuan Zhao课题组研发二氧化硅包覆金纳米笼核-壳结构纳米粒子，复合的二氧化硅增加纳米材料的药物负载量并承载光热响应聚合物，用于近红外控制光热促进药物释放。[J.Yang,D.Shen,L.Zhou,W.Li,X.Li,C.Yao,R.Wang,A.M.El-Toni,F.Zhang,D.Zhao,Chem.Mater.2013,25,3030.]Xiaogang Qu课题组开发磷酸钙包覆四氧化三铁覆盖的金纳米笼复合物，其结合了磁靶向，光热治疗和化疗为癌症治疗提供了一种新方案。[P.Shi,K.Qu,J.Wang,M.Li,J.Ren,X.Qu,Chem.Commun.2012,48,7640.]从以上叙述中可以看出，由于金纳米笼的特殊性能，使其在纳米医药领域表现出很高的应用价值，但是，对基于金纳米笼的多功能复杂纳米结构构筑的研究较少，特别是对于以金纳米笼为主体材料的单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子的构筑还未有报道。此外，现有合成双面神结构纳米粒子方法普遍存在分散性差、纳米尺寸难调控、整体形貌较差等缺陷。因此，开发具一种简单易行，制备单分散、纳米尺寸的多功能两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子是一个具有挑战性的新课题。
发明内容
本发明提供一种单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子的制备方法及其应用。使用该方法制备的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子具有分散性好、粒径均匀在纳米尺度、生物相容性好等特点，可用于具有不同性质的(亲水和疏水)双药物输送及多模式生物成像等领域。
本发明单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子的制备方法包括如下步骤：
(1)在150℃条件下，在圆底烧瓶内加入6mL乙二醇，然后取70～100μL硫化钠(3mM)加入搅拌9min，然后依次加入1.5mL聚乙烯吡咯烷酮(K-30，0.02mg mL-1)，再加入0.5mL 0.12g硝酸银(0.048mg mL-1)，反应直到溶液变成黄绿色，加入丙酮，9000rpm离心10min，重新分散在去离子水中。
(2)在25℃条件下，取60～80μL聚丙烯酸(Mw＝1800，0.2mg mL-1)加入到10mL含有合成好的1.5～2mg的银立方体的去离子水中，超声10min后，加入80～120μL氨水(25-28％)，滴加40mL异丙醇搅拌12～24h使其混合均匀。
(3)取4～6mg的氯化亚铁加入步骤(2)得到的溶液中搅拌12～24h，反应完成后9000rpm离心10min，水洗1次后重新分散在4mL去离子水中待用。
(4)100℃条件下，在250mL三颈圆底烧瓶中依次加入100mL去离子水，1～1.5g聚乙烯吡咯烷酮(Mw＝55,000)，搅拌10～20min。然后加入步骤(3)的溶液，继续搅拌10～20min。加6～9mL氯金酸(1mM)，搅拌直至溶液变为淡蓝色，冷却至室温，8000～9000rpm离心8～10min得到产物分散在4mL乙醇中。
(5)在室温条件下，将5～10mg巯基-聚己内酯分散于1mL四氢呋喃溶液中与步骤(4)的溶液磁力搅拌反应12～24h，再加入1mL含有1～1.5mg巯基-聚乙二醇(Mw＝5000)去离子水溶液，搅拌6～12h。
(6)将步骤(5)得到的混合溶液进行离心分离(8000～9000rpm，8～10min)，所得固体再用乙醇洗涤1～3次，即得PCL-AuNC/Fe(OH)3-PAA纳米粒子。
本发明具有如下优点：
1.本发明合成方法简单，合成高分散、粒径为纳米尺度均一的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子。在此反应过程中，利用界面张力在不同环境下的改变，结合再次选择生长和刻蚀的方法得到形貌独特的金纳米笼和氢氧化铁结合的多功能双面神结构纳米粒子。
2.本发明得到的单分散两亲结构双面神PCL-AuNC/Fe(OH)3-PAA纳米粒子粒径均匀、为纳米尺度，可在双面神的两侧分别负载两种不同性质药物(亲水和疏水)用于双药物输送及多模式生物成像。
3.由于双面神的特殊结构，相比单纯金纳米笼，两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子，可以在其两个不同部分分别负载两种不同性质药物，且通过光热调节释放及光热治疗。还具有CT和MR同时成像的能力。
附图说明
图1、为本发明制备得到的单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子透射电镜图片，插图为单个两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子透射电镜图片；
图2、为本发明制备得到的单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子的紫外吸收曲线；
图3单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子对Balb/c鼠的体内光热成像图片；
图4、单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子在溶液中CT成像；
图5、单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子对Balb/c鼠的体内CT成像图片；
图6、单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子在溶液中MR成像；
图7、单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子对Balb/c鼠的体内MR成像图片；
图8、负载阿霉素和紫杉醇双药物单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子对Balb/c鼠的肿瘤抑制效果。
具体实施方式
下面结合具体实施例进一步阐述本发明，实施例仅用于说明本发明而不用于限制本发明的保护范围。
具体实施例
实施例1：
在25℃条件下，取80μL聚丙烯酸(Mw＝1800)加入到10mL含有合成好的2mg的银立方体的去离子水中，超声10min后，加入120μL氨水(25-28％)，滴加40mL异丙醇搅拌24h使其混合均匀后加入6mg的氯化亚铁，再搅拌24h，反应完成后9000rpm离心10min，水洗1次后重新分散在4mL去离子水中待用。然后，在100℃条件下，将1g聚乙烯吡咯烷酮(Mw＝55,000)加入100mL去离子水中，搅拌10min。然后加入上述得到离心后的4mL溶液，继续搅拌10min。滴加9mL氯金酸(1mM)，搅拌直至溶液变为淡蓝色，冷却至室温，9000rpm离心10min得到产物分散在4mL乙醇中。再加入1mL含有10mg巯基-聚己内酯四氢呋喃溶液，在室温条件下磁力搅拌反应24h，再加入1mL含有1mg巯基-聚乙二醇(Mw＝5000)去离子水溶液，搅拌12h。离心分离(9000rpm，10min)，所得固体再用乙醇洗涤3次，即得PCL-AuNC/Fe(OH)3-PAA纳米粒子。
实施例2：
在25℃条件下，将2mg的银立方，60μL聚丙烯酸(Mw＝1800)加入到10mL去离子水中，超声10min后，加入90μL氨水(25-28％)，40mL异丙醇，搅拌12h后加入4mg的氯化亚铁，再搅拌12h，反应完成后9000rpm离心10min，水洗1次。得到产物分散在100mL含有1.2g聚乙烯吡咯烷酮(Mw＝55,000)的溶液中，搅拌条件下，升温到100℃。加入7mL氯金酸(1mM)，搅拌直至溶液变为淡蓝色，冷却至室温，9000rpm离心10min得到产物分散在4mL乙醇中。再加入1mL含有8mg巯基-聚己内酯四氢呋喃溶液，在室温条件下磁力搅拌反应12h，再加入1.5mg巯基-聚乙二醇(Mw＝5000)去离子水溶液，搅拌6h。离心分离(9000rpm，10min)，所得固体再用乙醇洗涤1次，即得PCL-AuNC/Fe(OH)3-PAA纳米粒子。
实施例3：
在25℃，磁力搅拌条件下，将10mL去离子水，1.5mg的银立方，80μL聚丙烯酸(Mw＝1800)，80μL氨水(25-28％)，40mL异丙醇依次加入圆底烧瓶中，每样加入间隔10min，再搅拌12h后加入4mg的氯化亚铁，再搅拌6h，反应完成后9000rpm离心10min，水洗1次。得到产物加入100℃的100mL水中，搅拌条件下，再加入1.5g聚乙烯吡咯烷酮(Mw＝55,000)。反应10min，加入6mL氯金酸(1mM)，搅拌直至溶液变为淡蓝色，冷却至室温，8000rpm离心8min得到产物分散在4mL乙醇中与1mL含有10mg巯基-聚己内酯四氢呋喃溶液在室温条件下磁力搅拌反应24h，再加入1mg巯基-聚乙二醇(Mw＝5000)去离子水溶液，搅拌12h。离心分离(8000rpm，8min)，所得固体再用乙醇洗涤2次，即得PCL-AuNC/Fe(OH)3-PAA纳米粒子。
上述制备出的单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子可用于负载具有不同性质(亲水和疏水)的双药物及多模式生物成像(CT成像和MR成像)。
体内光热成像步骤为：将用PBS配制的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子溶液通过尾静脉注射入小鼠体内。24h后，按照每千克给麻药10mL(戊巴比妥钠0.7％)的量麻醉小鼠。然后，用808nm近红外激光照射肿瘤部位，然后用Sweden-T460SC光热成像仪获得光热图像。
体外CT/MR成像步骤为：用PBS配制不同浓度两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子溶液，然后用西门子六十四排容积CT机获得CT图像，(参数如下：电压120kV,电流280mA,狭层厚度0.9mm)用GE Discovery MR750的MR仪器获得MR图像。(参数如下：头部线圈，厚度2.0mm)
体内CT/MR成像步骤为：将用PBS配制的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子溶液通过尾静脉注射入小鼠体内。24h后，按照每千克给麻药10mL(戊巴比妥钠0.7％)的量麻醉小鼠。最后，进行CT/MR成像。
体内肿瘤抑制步骤为：对小鼠分别通过尾静脉注射PBS，两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子，负载阿霉素和紫杉醇的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子(每组10只)。24h后，从以上每组选出来5只老鼠设为其对应激光组，在其肿瘤部位照近红外激光(808nm，1.0W，5min)。每2天注射药物一次，激光组是隔日照射激光。第11天处死老鼠，取出肿瘤观察其对肿瘤抑制效果。

Claims (3)

1.本发明单分散两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子的制备方法包括如下步骤：
(1)在25℃条件下，取60～80μL聚丙烯酸(Mw＝1800，0.2mg mL-1)加入到10mL含有合成好的1.5～2mg的银立方体的去离子水中，超声10min后，加入80～120μL氨水(25-28％)，滴加40mL异丙醇搅拌12～24h使其混合均匀。
(2)取4～6mg的氯化亚铁加入步骤(1)得到的溶液中搅拌12～24h，反应完成后9000rpm离心10min，水洗1次后重新分散在4mL去离子水中待用。
(3)100℃条件下，在250mL三颈圆底烧瓶中依次加入100mL去离子水，1～1.5g聚乙烯吡咯烷酮(Mw＝55,000)，搅拌10～20min。然后加入步骤(2)的溶液，继续搅拌10～20min。加6～9mL氯金酸(1mM)，搅拌直至溶液变为淡蓝色，冷却至室温，8000～9000rpm离心8～10min得到产物分散在4mL乙醇中。
(4)在室温条件下，将5～10mg巯基-聚己内酯分散于1mL四氢呋喃溶液中与步骤(3)的溶液磁力搅拌反应12～24h，再加入1mL含有1～1.5mg巯基-聚乙二醇(Mw＝5000)去离子水溶液，搅拌6～12h。
(5)将步骤(4)得到的混合溶液进行离心分离(8000～9000rpm，8～10min)，所得固体再用乙醇洗涤1～3次，即得PCL-AuNC/Fe(OH)3-PAA纳米粒子。
2.按照权利要求1所述的方法制备的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子。
3.按照权利要求2所述的两亲双面神结构PCL-AuNC/Fe(OH)3-PAA纳米粒子在癌症诊疗中的应用。
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* Cited by examiner, † Cited by third party
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CN112338199B (zh) * 2020-10-20 2022-05-31 华中科技大学同济医学院附属协和医院 金纳米笼的制备方法及其应用

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