CN116103041A - 一种以药物功能保留策略合成的碳点及其制备方法和应用 - Google Patents
一种以药物功能保留策略合成的碳点及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于医药领域，涉及一种以药物功能保留策略合成的碳点及其制备方法和应用。所述以药物功能保留策略合成的碳点以羟基脲和邻苯二胺为前体，以甘露糖进行修饰。其制备方法为：将羟基脲和邻苯二胺加至溶剂中经超声溶解后进行加热反应，反应完毕后过滤，得到p‑CDs溶液，经洗涤、离心得到上清液，然后旋蒸、干燥得到p‑CDs固体；将其与甘露糖加至蒸馏水中超声溶解后，水浴反应得到mp‑CDs溶液，经过滤、干燥后得到mp‑CDs碳点。该碳点在作为肝癌细胞识别和抗肝癌试剂时，在激发光照射下，可借助碳点的荧光性实现裸眼识别肝癌细胞的效果，并且该碳点对肝癌细胞的靶向作用可以诱导肝癌细胞凋亡，有效减少了对正常细胞的损伤。
Description
技术领域
本发明属于医药领域，涉及一种以药物功能保留策略合成的碳点及其制备方法和应用。
背景技术
纳米药物载体上的靶向分子能否高效识别癌细胞并对癌细胞造成杀伤是癌症诊疗的主要挑战之一，常用的靶向癌细胞载体有碳点、介孔二氧化硅、高分子纳米颗粒、金属纳米团簇等。碳点作为一种发光性能优异的碳基纳米材料，具有制备简单、水溶性好、生物毒性低等优点，被广泛应用于环境监测、生物传感、药物传递等领域。发射波长短和荧光量子产率低的碳点容易受到背景干扰且组织穿透能力较弱，故发射波长更长和荧光量子产率高的荧光碳点在生命领域更有应用前景。研究表明，碳点在溶剂热脱水碳化过程中，前驱体分子结构的部分活性官能团会被保留。羟基脲作为一种抗癌药物，主要通过抑制核糖核苷酸还原酶的产生，从而阻碍DNA的合成和修复。甘露糖受体是一种重要的癌症生物标志物，在肝癌细胞中异常上调，而在正常细胞中仅少量存在，这使得通过检测其表达水平来区分肝癌细胞成为可能。甘露糖在细胞微环境中的亲和力和稳定性较高，是甘露糖受体的理想配体，不同于其他纳米颗粒，甘露糖及其纳米结合物容易通过受体介导的内吞作用内化进入细胞。专利CN112158826A公开了一种碳点纳米制剂及其制备方法和应用。该制剂是通过利用甘露糖作为碳点基板，乙二胺作为热源，为葡萄糖反应提供能量，之后经过萃取剂富集目标产物后，利用高分子分离膜与超纯水之间浓度的不同完成透析后，进而得到粒径均一的成品。将该产品注射入肿瘤内后，甘露糖衍生的碳点成品(Man-CDs)可有效捕获多种组蛋白等和肿瘤相关抗原，多种组蛋白等增强了树突状细胞(DCs)的激活，树突状细胞将抗原呈递给T细胞，T细胞完成肿瘤细胞的杀伤。在该专利中，甘露糖直接作为前体使用时，在水热碳化的过程中，甘露糖的部分官能团得到保留，但其自身的结构并不是完整的，导致甘露糖的作用没有得到充分的发挥，并且该碳点不具备对肝癌细胞的靶向识别和荧光成像作用。
发明内容
针对上述技术问题，本发明提出一种以药物功能保留策略合成的碳点及其制备方法和应用。所制备的碳点能够选择性靶向识别肝癌细胞表面过表达的甘露糖受体，结合后可通过内吞作用快速进入细胞。并且碳点中保留的羟基脲分子结构的部分活性官能团与甘露糖联合作用，其药效远大于羟基脲单独作用。同时，在激光照射下，本发明借助碳点的荧光性能实现了裸眼识别肝癌细胞的技术效果。
为了达到上述目的，本发明的技术方案是这样实现的：
一种以药物功能保留策略合成的碳点，以羟基脲和邻苯二胺为前体，以甘露糖进行修饰。
进一步，所述的以药物功能保留策略合成的碳点的制备方法，步骤如下：
(1)p-CDs碳点的制备：将羟基脲和邻苯二胺加至溶剂中超声溶解后，进行加热反应，反应完毕后经过滤、洗涤、离心得到上清液，上清液蒸发浓缩、干燥后得到p-CDs碳点；
(2)mp-CDs碳点的制备：将甘露糖和步骤(1)所得的p-CDs碳点加至蒸馏水中，超声处溶解后，进行水浴反应，过滤、干燥得到mp-CDs碳点，即为以药物功能保留策略合成的碳点。
进一步，所述步骤(1)中羟基脲与邻苯二胺的质量比为1:(0.28～0.33)，溶剂为N,N-二甲基甲酰胺水溶液，N,N-二甲基甲酰胺与水的体积比为1:1。
进一步，所述步骤(1)中加热反应在聚四氟乙烯高压反应釜中进行，加热反应的温度为180～220℃，加热反应的时间为10h。
进一步，所述步骤(1)中洗涤的溶剂为石油醚和乙酸乙酯的混合溶剂，石油醚和乙酸乙酯的体积比为3:1；离心转速为7000～9000r/min，离心时间为10min。
进一步，所述步骤(2)中甘露糖与p-CDs碳点的质量比为(0.09～0.11):1，水浴反应的温度为20～30℃，水浴反应的时间为9～11h。
进一步，所述的以药物功能保留策略合成的碳点在制备靶向识别肝癌细胞的荧光成像试剂中的应用。
进一步，所述的以药物功能保留策略合成的碳点在制备诱导肝癌细胞凋亡的试剂中的应用。
进一步，以药物功能保留策略合成的碳点在制备靶向识别肝癌细胞的荧光成像试剂中的应用，步骤如下：将mp-CDs碳点加至pH＝7.4、浓度为10mM的PBS缓冲溶液中，配制为2mg/mL的mp-CDs碳点溶液，然后将mp-CDs碳点溶液加至待测细胞培养液中，使其浓度为15μg/mL，得到靶向识别肝癌细胞的荧光成像试剂。。
进一步，以药物功能保留策略合成的碳点在制备诱导肝癌细胞凋亡的试剂中的应用，步骤如下：将mp-CDs碳点加至pH＝7.4、浓度为10mM的PBS缓冲溶液中，配制为2mg/mL的mp-CDs碳点溶液，然后将mp-CDs碳点溶液加至待测细胞培养液中，使其浓度为50μg/mL，得到诱导肝癌细胞凋亡的试剂。
本发明具有以下有益效果：
1、本发明以抗癌药羟基脲和邻苯二胺为前体合成粉色碳点，利用甘露糖对碳点进行修饰后得到具有诊疗作用的mp-CDs碳点。避免了现有技术中以甘露糖作为前体水热碳化后甘露糖作用得不到充分发挥的问题，并且通过甘露糖的修饰作用，使甘露糖和p-CDs碳点通过静电作用连接，甘露糖自身的结构得以完整保留，其功效得到充分发挥。
2、本发明保留了羟基脲活性官能团和甘露糖联合，通过先靶向后治疗完成了对肿瘤细胞的杀伤作用。具体的：mp-CDs碳点选择性靶向识别肝癌细胞表面过表达的甘露糖受体，结合后通过内吞作用快速进入细胞；然后通过羟基脲抑制核糖核苷酸还原酶产生，进而阻止核糖核苷酸还原为脱氧核苷酸，干扰嘌呤和嘧啶碱基生物的合成，阻碍DNA的合成，达到诱导肝癌细胞凋亡的目的。在本发明中，mp-CDs碳点保留的羟基脲分子结构的部分活性官能团与甘露糖联合作用后，其药效远大于羟基脲单独作用。并且在激发光为488nm、561nm以及对应的发射波长为560nm和630nm照射下，借助碳点的荧光性能可以实现裸眼识别肝癌细胞。通过该碳点的靶向识别作用可以有效减少对正常细胞的损伤。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例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本发明的一些实施例，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，还可以根据这些附图获得其他的附图。
图1为本发明实施例1制备的p-CDs碳点的透射电子显微镜图(a)和粒径分布图(b)。
图2为本发明实施例1制备的p-CDs碳点(a)和mp-CDs碳点(b)的荧光发射图。
图3为本发明实施例1制备的p-CDs碳点和mp-CDs碳点的水合粒径(a)和zeta电位图(b)。
图4为本发明实施例1制备的mp-CDs碳点在靶向肝癌细胞的细胞成像图，其中a、b、c、d分别为两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2；e为含mp-CDs碳点溶液的四类细胞在红绿通道内的荧光强度。
图5为本发明实施例1制备的p-CDs碳点在靶向肝癌细胞的细胞成像图，其中a、b、c、d分别为两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2；e为含p-CDs碳点溶液的四类细胞在红绿通道内的荧光强度。
图6为利用流式细胞术分析在Annexin V-APC荧光通道(a)和7-AAD荧光通道(b)中，实施例1制备的p-CDs碳点和mp-CDs碳点孵育肝癌细胞的死亡细胞数量图。
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付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。
本发明各实施例所用药品试剂均为市售商品。
实施例1
一种以药物功能保留策略合成的碳点的制备方法，步骤如下：
(1)p-CDs碳点的制备：将0.1g羟基脲和0.03g邻苯二胺置于25mL烧杯中，溶解于10mL体积比为1:1的N,N-二甲基甲酰胺水溶液中，混合溶液超声10min使得前体充分溶解。混合溶液转移到25mL的聚四氟乙烯高压反应釜中200℃加热10h，冷却至室温后，溶液用0.22μm的滤膜过滤，得到纯的p-CDs溶液。将过量的石油醚和乙酸乙酯的混合溶液(体积比为3:1)加至p-CDs溶液中，以洗去残留的有机分子，然后用转速为8000r min-1的离心机离心10min，收集上清液备用。将上清液在60℃旋转蒸发仪上浓缩，然后置于50℃真空干燥箱中过夜获得粉色的p-CDs固体。
图1为本实施例1制备的p-CDs碳点的透射电子显微镜图(a)和粒径分布图(b)。如图所示，p-CDs粒径均一、分布情况良好且没有明显的聚集，平均直径约为11.2nm。
(2)mp-CDs碳点的制备：取0.05g甘露糖和0.5g步骤(1)制备的p-CDs溶于10mL蒸馏水中，超声处理10min使其完全溶解，25℃水浴10h，得到mp-CDs溶液。用0.22μm的滤膜过滤后冷冻干燥，得到mp-CDs粉末，即以药物功能保留策略合成的碳点，其荧光量子产率为46％。
实施例2
一种以药物功能保留策略合成的碳点的制备方法，步骤如下：
(1)p-CDs碳点的制备：将0.1g羟基脲和0.028g邻苯二胺置于25mL烧杯中，溶解于10mL体积比为1:1的N,N-二甲基甲酰胺水溶液中，混合溶液超声10min使得前体充分溶解。混合溶液转移到25mL的聚四氟乙烯高压反应釜中180℃加热10h，冷却至室温后，溶液用0.22μm的滤膜过滤，得到纯的p-CDs溶液。将过量的石油醚和乙酸乙酯的混合溶液(体积比为3:1)加至p-CDs溶液中，以洗去残留的有机分子，然后用转速为9000r min-1的离心机离心10min，收集上清液备用。将上清液在60℃旋转蒸发仪上浓缩，然后置于50℃蒸真空干燥箱中过夜获得粉色的p-CDs固体。
(2)mp-CDs碳点的制备：取0.045g甘露糖和0.5g步骤(1)制备的p-CDs溶于10mL蒸馏水中，超声处理10min使其完全溶解，20℃水浴9h，得到mp-CDs溶液。用0.22μm的滤膜过滤后冷冻干燥，得到mp-CDs粉末，即以药物功能保留策略合成的碳点。
实施例3
一种以药物功能保留策略合成的碳点的制备方法，步骤如下：
(1)p-CDs碳点的制备：将0.1g羟基脲和0.032g邻苯二胺置于25mL烧杯中，溶解于10mL体积比为1:1的N,N-二甲基甲酰胺水溶液中，混合溶液超声10min使得前体充分溶解。混合溶液转移到25mL的聚四氟乙烯高压反应釜中220℃加热10h，冷却至室温后，溶液用0.22μm的滤膜过滤，得到纯的p-CDs溶液。过量的石油醚和乙酸乙酯的混合溶液(体积比为3:1)加至p-CDs溶液中，以洗去残留的有机分子，然后用转速为6000r min-1的离心机离心10min，收集上清液备用。将上清液在60℃旋转蒸发仪上浓缩，然后置于50℃真空干燥箱中过夜获得粉色的p-CDs固体。
(2)mp-CDs碳点的制备：取0.0605g甘露糖和0.5g步骤(1)制备的p-CDs溶于10mL蒸馏水中，超声处理10min使其完全溶解，25℃水浴11h，得到mp-CDs溶液。用0.22μm的滤膜过滤后冷冻干燥，得到mp-CDs粉末，即以药物功能保留策略合成的碳点。
性能测试
(1)将实施例1制备的p-CDs碳点和mp-CDs碳点分别溶解于pH＝7.4的PBS缓冲溶液中，配置成2mg/mL的碳点溶液。分别取2.5mL溶液加到荧光比色皿中在荧光光度仪上检测，激发波长从420nm增加到560nm。
图2为本发明实施例1制备的p-CDs碳点(a)和mp-CDs碳点(b)的荧光发射图。如图2所示，p-CDs碳点和mp-CDs碳点的发射波长几乎不变。表明甘露糖的修饰不影响p-CDs的光学性能。
(2)将实施例1制备的p-CDs和mp-CDs分别溶解于pH＝7.4的PBS缓冲溶液中配置成0.5mg/mL的溶液，然后用0.22μm的滤膜过滤。在激光粒度及zeta电位分析仪中测量p-CDs和mp-CDs的液相粒子直径和zeta电位。
图3为本发明实施例1制备的p-CDs碳点和mp-CDs碳点的水合粒径(a)和zeta电位图(b)。如图3所示，mp-CDs碳点的水合粒径明显高于p-CDs碳点，并且p-CDs碳点和mp-CDs碳点的zeta电位分别为-24.4eV和1.25eV，mp-CDs碳点电负性的增加和水合粒径的增大，说明甘露糖与p-CDs碳点成功结合。
应用例1
以药物功能保留策略合成的碳点(mp-CDs碳点)在靶向识别肝癌细胞的荧光成像试剂中的应用，步骤如下：
配制pH＝7.4、浓度为10mM的PBS缓冲溶液；以实施例1制备的mp-CDs碳点为例，配制2mg/mL的mp-CDs碳点的PBS溶液；将mp-CDs碳点溶液加入细胞培养液中，使其浓度为15μg/mL。与两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2，在37℃、CO2浓度为5％的孵箱中，孵育1h。孵育后，用PBS(pH＝7.4)洗涤三次，然后加入1mL无血清DMEM培养基，并置于共聚焦皿中，在共聚焦显微镜下，分别设置激发波长为488nm、561nm，并分别拍摄对应的发射波长为560nm和630nm的细胞成像图。
图4为本发明实施例1制备的mp-CDs碳点在靶向肝癌细胞的细胞成像图，其中a、b、c、d分别为两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2；e为含mp-CDs碳点溶液的四类细胞在红绿通道内的荧光强度。如图4所示，mp-CDs碳点在HepG2细胞的红色和绿色通道中有明显的荧光出现，但在其他细胞中显示出弱荧光。由此可见mp-CDs碳点具有靶向肝癌细胞成像的能力。
应用例1对比例
以p-CDs碳点在靶向识别肝癌细胞的荧光成像试剂中的应用，步骤如下：
配制pH＝7.4、浓度为10mM的PBS缓冲溶液；以实施例1制备的p-CDs碳点为例，配制2mg/mL的p-CDs碳点的PBS溶液；将p-CDs碳点溶液加入细胞培养液中，使其浓度为15μg/mL。与两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2，在37℃、CO2浓度为5％的孵箱中，孵育1h。孵育后，用PBS(pH＝7.4)洗涤三次，然后加入1mL无血清DMEM培养基，并置于共聚焦皿中，在共聚焦显微镜下，分别设置激发波长为488nm、561nm，并分别拍摄对应的发射波长为560nm和630nm的细胞成像图。
图5为本发明实施例1制备的p-CDs碳点在靶向肝癌细胞的细胞成像图，其中a、b、c、d分别为两类正常细胞小鼠巨噬细胞RAW 264.7和正常肝细胞HL-7702及两类肿瘤细胞宫颈癌Hela细胞和肝癌细胞HepG2；e为含p-CDs碳点溶液的四类细胞在红绿通道内的荧光强度。如图5所示，p-CDs碳点在四类细胞中的通道中均未有明显的荧光出现，表明p-CDs碳点作为对照探针不具有靶向肝癌细胞的能力。
应用例2
所述的以药物功能保留策略合成的碳点在诱导肝癌细胞凋亡的试剂中的应用，步骤如下：
配制pH＝7.4、浓度为10mM的PBS缓冲溶液；以实施例1制备的p-CDs碳点和mp-CDs碳点为例，分别配制2mg/mL的p-CDs碳点和mp-CDs的PBS溶液；将碳点溶液加入细胞培养液中，使其浓度为50μg/mL。p-CDs碳点和mp-CDs碳点与HepG2细胞在37℃、CO2浓度为5％的孵箱中，孵育24h，消化离心后收集细胞。然后在100μL缓冲液中重悬，分别加入5μL AnnexinV-APC和10μL 7-AAD进行染色，室温孵育5min。最后采用流式细胞仪分析不同细胞样本的凋亡情况。
图6为利用流式细胞术分析在Annexin V-APC荧光通道(a)和7-AAD荧光通道(b)中，实施例1制备的p-CDs碳点和mp-CDs碳点孵育肝癌细胞的死亡细胞数量图。如图6所示，在Annexin V-APC和7-AAD荧光通道中，mp-CDs碳点引起的致死细胞数量明显高于p-CDs碳点。诱导细胞凋亡表明mp-CDs碳点对肝癌细胞具有潜在的治疗作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种以药物功能保留策略合成的碳点，其特征在于：所述的以药物功能保留策略合成的碳点以羟基脲和邻苯二胺为前体，以甘露糖进行修饰。
2.权利要求1所述的以药物功能保留策略合成的碳点的制备方法，其特征在于，步骤如下：
(1)p-CDs碳点的制备：将羟基脲和邻苯二胺加至溶剂中超声溶解后，进行加热反应，反应完毕后经过滤、洗涤、离心得到上清液，上清液蒸发浓缩、干燥后得到p-CDs碳点；
(2)mp-CDs碳点的制备：将甘露糖和步骤(1)所得的p-CDs碳点加至蒸馏水中，超声处溶解后，进行水浴反应，过滤、干燥得到mp-CDs碳点，即为以药物功能保留策略合成的碳点。
3.根据权利要求2所述的以药物功能保留策略合成的碳点的制备方法，其特征在于：所述步骤(1)中羟基脲与邻苯二胺的质量比为1:(0.28～0.33)，溶剂为N,N-二甲基甲酰胺水溶液，N,N-二甲基甲酰胺与水的体积比为1:1。
4.根据权利要求2或3所述的以药物功能保留策略合成的碳点的制备方法，其特征在于：所述步骤(1)中加热反应在聚四氟乙烯高压反应釜中进行，加热反应的温度为180～220℃，加热反应的时间为10h。
5.根据权利要求4所述的以药物功能保留策略合成的碳点的制备方法，其特征在于：所述步骤(1)中洗涤的溶剂为石油醚和乙酸乙酯的混合溶剂，石油醚和乙酸乙酯的体积比为3:1；离心转速为7000～9000r/min，离心时间为10min。
6.根据权利要求2、3或5任一项所述的以药物功能保留策略合成的碳点的制备方法，其特征在于：所述步骤(2)中甘露糖与p-CDs碳点的质量比为(0.09～0.11):1，水浴反应的温度为20～30℃，水浴反应的时间为9～11h。
7.权利要求1所述的以药物功能保留策略合成的碳点在制备靶向识别肝癌细胞的荧光成像试剂中的应用。
8.权利要求1所述的以药物功能保留策略合成的碳点在制备诱导肝癌细胞凋亡的试剂中的应用。
9.根据权利要求7所述的应用，其特征在于：将mp-CDs碳点加至pH＝7.4、浓度为10mM的PBS缓冲溶液中，配制为2mg/mL的mp-CDs碳点溶液，然后将mp-CDs碳点溶液加至待测细胞培养液中，使其浓度为15μg/mL，得到靶向识别肝癌细胞的荧光成像试剂。
10.根据权利要求8所述的应用，其特征在于：将mp-CDs碳点加至pH＝7.4、浓度为10mM的PBS缓冲溶液中，配制为2mg/mL的mp-CDs碳点溶液，然后将mp-CDs碳点溶液加至待测细胞培养液中，使其浓度为50μg/mL，得到诱导肝癌细胞凋亡的试剂。
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