CN115501350B - 一种荧光超分子纳米载体及其制备方法与应用 - Google Patents

一种荧光超分子纳米载体及其制备方法与应用 Download PDF

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CN115501350B
CN115501350B CN202211274074.5A CN202211274074A CN115501350B CN 115501350 B CN115501350 B CN 115501350B CN 202211274074 A CN202211274074 A CN 202211274074A CN 115501350 B CN115501350 B CN 115501350B
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polyethylene glycol
fluorescent
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adamantane
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徐建斌
叶招明
陈霄雨
李睿
陈恒
杨晓波
俞小华
金晓强
郑力铭
蒋利锋
章玮
汪迪
王力维
刘欣
张妍
杨军
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Zhejiang University ZJU
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Abstract

本发明实施例公开了一种荧光超分子纳米载体及其制备方法与应用。一种荧光超分子纳米载体包括：碳量子点；β‑环糊精接枝的聚乙烯亚胺；金刚烷修饰的聚乙二醇；RGD功能化的金刚烷修饰的聚乙二醇。本发明以碳量子点作为超分子纳米载体骨架，并利用其荧光特性，赋予超分子纳米载体荧光性能。本发明提供的超分子纳米载体集自组装、安全低毒、基因输送和示踪成像于一体，发挥调控细胞行为功能，具有治疗转化的前景。

Description

一种荧光超分子纳米载体及其制备方法与应用
技术领域
本发明实施例涉及纳米材料技术和生物医用材料技术领域，具体涉及一种荧光超分子纳米载体及其制备方法与应用。
背景技术
与能够形成/断裂共价键的常规化学合成不同，超分子化学结合了两个基本概念：自组装和分子识别。超分子化学为从分子结构单元制备纳米结构材料提供了一种强大而方便的方法，类似堆积木的方式制备纳米粒子。
碳量子点(C-dots)是近年发现的一种新颖的安全低毒、光稳定性好、易于功能化、来源丰富的纳米材料，已经被广泛应用于生物医学工程领域。但目前尚未见碳量子点应用于超分子纳米载体的相关报道。
发明内容
为此，本发明实施例提供一种荧光超分子纳米载体及其制备方法与应用。
为了实现上述目的，本发明实施例提供如下技术方案：
根据本发明实施例的第一方面，提供一种荧光超分子纳米载体(RGD-C-SNPs)，包括：
碳量子点；
β-环糊精接枝的聚乙烯亚胺(PEI-CD)；
金刚烷修饰的聚乙二醇(PEG-Ada)；
RGD功能化的金刚烷修饰的聚乙二醇(RGD-PEG-Ada)。
进一步地，所述荧光超分子纳米载体的平均粒径为120nm-180nm。
进一步地，所述β-环糊精接枝的聚乙烯亚胺(PEI-CD)的制备方法如下：
将100mg枝化聚乙烯亚胺和1.29g6-对甲苯磺酰基-β-环糊精加入到100ml二甲基亚砜中，于65-75℃下反应2.5-3.5天，之后进行透析、冷冻干燥。
进一步地，所述金刚烷修饰的聚乙二醇(PEG-Ada)的制备方法如下：
将200mg氨基聚乙二醇单甲醚(mPEG-NH2)、25mg 1-金刚烷酰氯和17μl三乙胺加入到10ml氯仿中，于45-55℃下反应18-30h，之后进行浓缩除去溶剂、加水透析、冷冻干燥。
进一步地，所述RGD功能化的金刚烷修饰的聚乙二醇(RGD-PEG-Ada)的制备方法如下：
将200mg马来酰亚胺和氨基修饰的聚乙二醇(MAL-PEG-NH2)和25mg 1-金刚烷酰氯加入到10ml氯仿中，于45-55℃下反应18-30h，之后经透析，冷冻干燥，得马来酰亚胺和金刚烷修饰的聚乙二醇(MAL-PEG-Ada)；
将马来酰亚胺和金刚烷修饰的聚乙二醇(MAL-PEG-Ada)与巯基RGD在PBS缓冲溶液中反应1-3h，之后经透析，冷冻干燥。
根据本发明实施例的第二方面，提供如上所述的荧光超分子纳米载体的制备方法，包括：
在超声波震荡下，向5ml、浓度为1.5mg/ml的β-环糊精接枝的聚乙烯亚胺的PBS缓冲溶液中，依次加入0.42ml、浓度为3mg/l的碳量子点的PBS缓冲溶液；逐滴加入5ml、浓度为9mg/ml的金刚烷修饰的聚乙二醇的PBS缓冲溶液；2.25ml、浓度为1mg/ml的RGD功能化的金刚烷修饰的聚乙二醇的PBS缓冲溶液，之后超声波反复震荡3次，每次5分钟，每次震荡结束后停止10-15秒进行下一次震荡，获得荧光超分子纳米载体。
进一步地，所述超声波震荡的频率为20-40Hz。
本发明对荧光超分子纳米载体的制备方法，包括溶剂的选择、加料顺序、物料浓度、搅拌方式等进行大量研究，发现在上述特定条件下，所制备的荧光超分子纳米载体粒径分布均一，在液体中具有优异的分散性，所形成的悬浮体系稳定性优异。
根据本发明实施例的第三方面，提供如上所述的荧光超分子纳米载体在制备核酸类药物递送系统中的应用。
本发明提供的荧光超分子纳米载体(RGD-C-SNPs)各模块部分的设计合成、各模块部分的自组装，如下：
1.碳量子点(C-dots)作为示踪成像模块：将C-dots引入纳米载体，其不仅作为安全低毒的骨架材料用于维持纳米载体的结构，同时利用其荧光特性对细胞进行示踪成像。
2.PEI-CD作为小分子药物和基因负载模块：β-环糊精(β-cyclodextrin,β-CD)具有疏水性空腔，将其引入纳米载体，可提供结合部位，用于装载小分子药物，从而实现治疗功能；聚乙烯亚胺(PEI)具有核酸吸附特性，将其引入纳米载体，可输送核酸药物如siRNA，从而调控细胞行为功能。
3.RGD-PEG-Ada作为促干细胞摄取模块：RGD多肽是一类含有精氨酸-甘氨酸-天冬氨(Arg-Gly-Asp)序列的促粘附短肽，能与细胞表面的整合素配体特异性结合。将RGD多肽引入纳米载体，通过其表面修饰作用，提高纳米载体的细胞摄取率。
4.各功能模块的自组装：将β-CD引入纳米载体，各功能模块在设计和制备中分别接枝修饰β-CD和金刚烷(Amantadine,Ada)，利用β-CD和Ada之间存在的主客体分子识别作用，在分子间非共价键的控制下，相互作用自发组装(自组装)获得荧光纳米载体RGD-C-SNPs。
本发明实施例具有如下优点：
本发明以安全低毒的碳量子点为骨架，赋予超分子纳米载体荧光性能，实现对细胞的示踪成像。本发明提供的超分子纳米载体集自组装、安全低毒、基因输送和示踪成像于一体，发挥调控细胞行为功能，具有治疗转化的前景。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地，下面描述中的附图仅仅是示例性的，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图引伸获得其它的实施附图。
图1为本发明实施例提供的PEI-CD的1HNMR；
图2为本发明实施例提供的PEG-Ada的1HNMR；
图3为本发明实施例提供的MAL-PEG-Ada的1HNMR；
图4为本发明实施例提供的RGD-PEG-Ada的1HNMR；
图5为本发明实施例提供的RGD-C-SNPs的TEM图像；
图6为本发明实施例提供的RGD-C-SNPs的粒径分布图；
图7为本发明实施例提供的RGD-C-SNPs的紫外-可见光吸收光谱图；
图8为本发明实施例提供的干细胞摄取效果对比图。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效，显然，所描述的实施例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。
实施例1
1.合成β-环糊精接枝的聚乙烯亚胺(PEI-CD)
将枝化聚乙烯亚胺(Mw 25000,100mg,10.0μmol)和6-对甲苯磺酰基-β-环糊精(1.29g,1.0mmol)溶解于100ml二甲基亚砜中，所得溶液在70℃油浴下反应3天，反应结束后，将溶液转移至分子量为1万的透析袋中用去离子水透析6天以除去未反应的6-对甲苯磺酰基-β-环糊精，透析后的溶液经冷冻干燥即可得到β-环糊精接枝的聚乙烯亚胺(PEI-CD)(120mg,6.6μmol,产率66％)。1H NMR(400MHz,D2O)δ4.92(br,C1H of CD),3.27-3.66(m,C2- 6H of CD),2.3-3.0(br,OCH2 of PEI)。β-环糊精的接枝比率可以通过计算环糊精上1号碳原子上氢原子的积分与聚乙烯亚胺上的氢原子比例来确定。(1/(12.17/4))。
2.合成金刚烷修饰的聚乙二醇(PEG-Ada)
金刚烷修饰的聚乙二醇是通过氨基与酰氯的反应制备的。具体方法包括：将200mg末端为氨基的聚乙二醇单甲醚(mPEG-NH2,Mw＝5KD)和25mg1-金刚烷酰氯溶解在10ml的氯仿中，加入17μl(0.12mmol)三乙胺，所得混合溶液在50℃反应24h。反应结束后，通过旋转蒸发仪蒸去溶剂，并用10ml去离子水重新溶解，所得溶液使用3千分子量透析膜透析6天后过滤，冷冻干燥。最终得到金刚烷修饰的聚乙二醇(180mg，产率90％)。
3.合成RGD功能化的金刚烷修饰的聚乙二醇(RGD-PEG-Ada)
金刚烷修饰的聚乙二醇是通过氨基与酰氯的反应制备的。RGD通过马来酰亚胺与巯基的点击反应修饰。具体方法包括：将200mg一端为马来酰亚胺另一端为氨基的聚乙二醇(MAL-PEG-NH2,Mw＝5KD)与25mg1-金刚烷酰氯加入到10ml氯仿中在50℃反应1天。反应结束后，过滤除去不溶的反应物，用分子量为3千的透析膜透析6天后冷冻干燥，便可得到一端为马来酰亚胺另一端为金刚烷修饰的聚乙二醇MAL-PEG-Ada(165mg，产率83％)。取10mg MAL-PEG-Ada溶解在1mLPBS中，并向其中加入2.25mg巯基RGD，在室温下反应2h后，用3千分子量透析膜透析，冷冻干燥，便可得到一端为RGD修饰另一端为金刚烷修饰的聚乙二醇RGD-PEG-Ada(10.5mg，产率78％)。
4.制备荧光超分子荧光纳米粒子(RGD-C-SNPs)
使用PBS缓冲溶液将β-环糊精接枝的聚乙烯亚胺(PEI-CD)、碳量子点、金刚烷修饰的聚乙二醇(PEG-Ada)，以及RGD功能化的金刚烷修饰的聚乙二醇(RGD-PEG-Ada)分别配制成浓度为1.5mg/ml、3mg/l、9mg/ml、1mg/ml的溶液。在频率为30Hz的超声波震荡条件下，向5ml的β-环糊精接枝的聚乙烯亚胺溶液中，依次加入0.42ml的碳量子点溶液；逐滴加入5ml金刚烷修饰的聚乙二醇溶液；2.25mlRGD功能化的金刚烷修饰的聚乙二醇溶液，加料完成后，在上述超声波频率条件下，反复震荡3次，每次5分钟，每次震荡结束后停止10-15秒进行下一次震荡，获得荧光超分子纳米载体。
实施例2
实施例1的荧光超分子纳米载体(RGD-C-SNPs)的表征
TEM图像结果表明(见图5)，C-dots分布于RGD-C-SNPs中。DLS测量结果显示(见图6)，RGD-C-SNPs的粒径分布为～149nm。结果表明，本发明提供的RGD-C-SNPs纳米载体具有较好分散性，粒径分布均一。
实施例3
实施例1的RGD-C-SNPs光学特征与干细胞摄取
紫外-可见光吸收光谱结果表明(见图7)，纳米载体RGD-C-SNPs的荧光发射光谱～477nm，且发射光谱窄而对称，以上内容说明本发明提供的纳米载体可应用于细胞标记、实时成像。插图中为纳米载体在365nm紫外灯照射下的荧光图片。
将贴壁培养24h的骨髓间充质干细胞更换新的培养，然后将商品化的量子点、RGD-C-SNPs分别加入培养体系中孵育4h后，PBS洗涤3次后用多聚甲醛处理15min，核染色后用PBS洗涤3次，置于荧光显微镜下观察。结果见图8，商品化的碳量子点和纳米载体RGD-C-SNPs都可以在4h后被骨髓间充质干细胞摄取，RGD-C-SNPs的摄取效果优于商品化的碳量子点。
虽然，上文中已经用一般性说明及具体实施例对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (6)

1.一种荧光超分子纳米载体的制备方法，其特征在于，所述荧光超分子纳米载体包括：
碳量子点；
β-环糊精接枝的聚乙烯亚胺；
金刚烷修饰的聚乙二醇；
RGD功能化的金刚烷修饰的聚乙二醇；
在超声波震荡下，向5ml、浓度为1.5mg/ml的β-环糊精接枝的聚乙烯亚胺的PBS 缓冲溶液中，依次加入0.42 ml、浓度为3mg/l的碳量子点的PBS缓冲溶液；逐滴加入5ml、浓度为9mg/ml的金刚烷修饰的聚乙二醇的PBS缓冲溶液；2.25 ml、浓度为1mg/ml的RGD功能化的金刚烷修饰的聚乙二醇的PBS缓冲溶液，之后超声波反复震荡3次，每次5分钟，每次震荡结束后停止10-15秒进行下一次震荡，获得荧光超分子纳米载体；
所述β-环糊精接枝的聚乙烯亚胺的制备方法如下：
将100 mg枝化聚乙烯亚胺和1.29 g 6-对甲苯磺酰基-β-环糊精加入到100 ml二甲基亚砜中，于65-75℃下反应2.5-3.5天，之后进行透析、冷冻干燥。
2.根据权利要求1所述的荧光超分子纳米载体的制备方法，其特征在于，所述荧光超分子纳米载体的平均粒径为120 nm-180nm。
3.根据权利要求1所述的荧光超分子纳米载体的制备方法，其特征在于，所述金刚烷修饰的聚乙二醇的制备方法如下：
将200 mg氨基聚乙二醇单甲醚、25 mg 1-金刚烷酰氯和17 µl三乙胺加入到10 ml氯仿中，于45-55℃下反应18-30h，之后进行浓缩除去溶剂、加水透析、冷冻干燥。
4.根据权利要求1所述的荧光超分子纳米载体的制备方法，其特征在于，所述RGD功能化的金刚烷修饰的聚乙二醇的制备方法如下：
将200 mg马来酰亚胺和氨基修饰的聚乙二醇与25 mg 1-金刚烷酰氯加入到10ml 氯仿中，于45-55℃下反应18-30h，之后经透析，冷冻干燥，得马来酰亚胺和金刚烷修饰的聚乙二醇；
将马来酰亚胺和金刚烷修饰的聚乙二醇与巯基RGD在PBS缓冲溶液中反应1-3h，之后经透析，冷冻干燥。
5. 根据权利要求1所述的荧光超分子纳米载体的制备方法，其特征在于，所述超声波震荡的频率为20-40 Hz。
6.权利要求1所述的荧光超分子纳米载体在制备核酸类药物递送系统中的应用。
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