CN116370434A - 一种用于靶向治疗血栓性疾病的纳米颗粒及其制备方法和应用 - Google Patents
一种用于靶向治疗血栓性疾病的纳米颗粒及其制备方法和应用 Download PDFInfo
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- CN116370434A CN116370434A CN202310165897.2A CN202310165897A CN116370434A CN 116370434 A CN116370434 A CN 116370434A CN 202310165897 A CN202310165897 A CN 202310165897A CN 116370434 A CN116370434 A CN 116370434A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提出了一种用于靶向血栓的纳米颗粒及其制备方法和应用，属于医药技术领域。表没食子儿茶素没食子酸酯(EGCG)与吲哚菁绿(ICG)在碱性条件下，由MnCl2催化，形成纳米粒，之后引入合成的化合物巯基‑聚乙二醇‑环肽(HS‑PEG‑cRGD)，离心收集，冷冻干燥，得到用于靶向血栓的纳米粒。本发明制备的靶向递药系统利用环状多肽cRGD与活化血小板表面的受体GPIIb/IIIa(糖蛋白受体IIb/IIIa)特异性结合，使药物选择性聚集于血栓部位，提高了药物的靶向性，增强了纳米药物的光热溶栓作用，在血栓性疾病中方面具有广泛的应用前景。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种用于靶向治疗血栓性疾病的纳米颗粒及其制备方法和应用。
背景技术
心血管疾病是全球主要的健康威胁，与高发病率和高死亡率有关，每年约有1790万人死亡(占全球所有死亡人数的31％)。三大心血管疾病：心肌梗塞、缺血性脑卒中、静脉血栓栓塞症是血栓形成的严重并发症。
在血栓部位，急性血管阻塞可导致严重的组织损伤甚至威胁生命。紧急情况下需要快速地清除血栓和恢复血流，而手术干预和溶栓治疗通常是最有效的治疗方法。重组组织型纤溶酶原激活剂(rt-PA)仍然是治疗血栓相关疾病的重要选择。由于溶栓药物半衰期短，大剂量使用溶栓药物及抗凝药物会导致大出血的风险。另一方面神经保护也是缺血性脑卒中的重要组成部分。这些干预措施包括药物诱导的神经递质受体阻断、抗氧化剂、抗炎药、抑制细胞死亡。
近年来，非药物溶栓策略被提出，包括①光热疗法、②光动力疗法、③机械性溶栓。近红外(NIR)介导的纳米药物通过朗道阻尼效应将光能转化为热能，为血栓治疗提供了一种新的治疗策略。2016年，Dash等首次证明了近红外照射的金纳米棒具有溶解纤维蛋白凝块的抗血栓性能。之后，van Hest等人报道了一种基于Janus型红细胞膜包裹微马达的光热溶栓系统。这些研究证明，光热疗法可以作为一种有效的溶栓疗法；目前在光敏剂的辅助下，活性氧介导的光动力疗法已被用于治疗纤维蛋白生物聚合物的多肽损伤，如多肽键、非共价相互作用和N-连接的双触角糖链局域。因此光动力疗法可以破坏血凝块的纤维蛋白骨架，防止光热后碎片的继发栓塞。然而，大多数光敏剂缺乏特异性积累，对光漂白的抵抗力差，在体内半衰期短；机械性溶栓利用超声波或激发相变材料产生微泡，气泡的破裂导致血块的机械溶解。
活化的血小板和纤维蛋白在血栓中的分布普遍。血小板和内皮细胞粘附的主要调节因子是跨膜受体整合素类。在血小板上整合素是数量最多的受体，通过与胶原、纤维蛋白原(Fg)、纤维连接蛋白(Fn)在内的配体相互作用，在介导血小板粘附、激活、聚集和血栓形成中发挥关键作用。RGD是在Fg、层粘连蛋白和Fn等蛋白质中发现的一个关键肽序列，它介导了这些配体与整合素受体(αvβ3、α5β1、αⅡbβ3)的结合，研究显示cRGD或RGD对血小板的均有靶向性。
许多大分子药物载体已被报道，显著改善了药物的药代动力学，但载体仍然只是药物递送的赋形剂。在设计药物载体时，药物与载体的比率是一个重要的考虑因素，因为大量使用载体会导致毒性。然而，如果药物和载体都有治疗效果，这些问题就不再重要。EGCG是茶中最丰富的儿茶素，是表没食子儿茶素和没食子酸的酯，已被证明具有抗癌、抗艾滋病毒、神经保护作用、DNA保护作用、抗血栓作用。EGCG显示了强的抗氧化活性及强的ROS和自由基清除能力。EGCG作为载体是药物递送和生物成像的热点，其中许多的茶多酚已获得美国FDA的批准。
前期课题组研究显示EGCG自聚纳米粒具有很好的抗氧化性能，且EGCG自聚纳米粒具有一定的光热效应，我们将ICG加入到EGCG载体中，使得最终的纳米粒具有一定的光热效应和抗氧化性能，应用到血栓性疾病中来。
发明内容
本发明的目的在于提出一种用于靶向治疗血栓性疾病的纳米颗粒及其制备方法和应用，利用纳米载体表面的环状多肽cRGD与活化血小板的受体特异性结合，提高纳米载体靶向血栓的效率，降低药物的毒副作用。
本发明的技术方案是这样实现的：
本发明提供一种用于靶向血栓性疾病的纳米颗粒的制备方法，表没食子儿茶素没食子酸酯(EGCG)与吲哚菁绿(ICG)在碱性条件下，由MnCl2催化，形成纳米粒，之后引入合成的化合物巯基-聚乙二醇-环肽(HS-PEG-cRGD)，透析，冷冻干燥，得到用于靶向血栓的纳米粒。
作为本发明的进一步改进，包括以下步骤：
(1)将表没食子儿茶素没食子酸酯、吲哚菁绿、MnCl2加入4-羟乙基哌嗪乙磺酸缓冲液中搅拌5-15min，使其形成多自聚化合物；
(2)将1-(3-二甲氨基丙基)-3-乙基碳二亚胺、N-羟基琥珀酰亚胺、巯基-聚乙二醇-羧酸混合溶解，活化3-5h，加入环状多肽cRGD，反应10-14h后，透析提纯，得到巯基-聚乙二醇-环状多肽cRGD(HS-PEG-cRGD)；环状多肽cRGD通过聚乙二醇链连接与EGCG，环状多肽cRGD与PEG的连接方法主要为环状多肽cRGD的巯基，与聚乙二醇链一端的马来酰亚胺基团反应连接制得。
(3)向步骤(1)中体系中加入步骤(2)制得的HS-PEG-cRGD，反应2-9h；
(4)将反应后的溶液离心，冷冻干燥得到表没食子儿茶素没食子酸酯-聚乙二醇-环状多肽cRGD纳米颗粒，即为ICG/EGCG-PEG-cRGD纳米颗粒；
作为本发明的进一步改进，步骤(1)中所述表没食子儿茶素没食子酸酯和MnCl2的摩尔比为1-1.5:1；所述4-羟乙基哌嗪乙磺酸缓冲液的pH值为7.8-8.2。
作为本发明的进一步改进，步骤(2)中所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺、N-羟基琥珀酰亚胺、巯基-聚乙二醇-羧酸、环状多肽cRGD的质量比为0.5-1.5:0.5-1.5:0.5-1.5：600-650。
作为本发明的进一步改进，步骤(3)中所述表没食子儿茶素没食子酸酯与HS-PEG-cRGD的质量比为10-12:1。
作为本发明的进一步改进，步骤(4)中所述离心条件为：15000-17000rpm离心10-20min。
本发明进一步保护一种上述的制备方法制得的用于靶向治疗血栓性疾病的纳米颗粒。
本发明具有如下有益效果：
本发明采用表没食子儿茶素没食子酸酯、吲哚菁绿为基础药物载体，以环状多肽cRGD作为血栓靶向肽，通过聚乙二醇，将表没食子儿茶素没食子酸酯和环状多肽cRGD连接，既有利于延长药物的半衰期，也有利于避免蛋白晕对纳米载体的屏蔽作用，构建血栓靶向纳米递药系统。
本发明设计合理，工艺简单，节能环保。利用表没食子儿茶素没食子酸酯自聚作为药物载体，并利用亲水性强的聚乙二醇，连接环状多肽cRGD与表没食子儿茶素没食子酸酯，装载了吲哚菁绿。
本发明所制备的血栓性疾病靶向递药系统，在体内不会形成栓塞，可用于静脉注射，可使药物选择性在血栓病灶部位富集，达到更优越的药效。
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。
图1为对比例1中非靶向修饰物HS-mPEG的核磁共振氢谱图；
图2为实施例1中制得的靶向修饰物HS-PEG-cRGD的核磁共振氢谱图；
图3为测试例1中制得的纳米载体EGCG-PEG-cRGD(左)、ICG/EGCG-PEG-cRGD(右)的透射电镜图；
图4为测试例2EGCG、EGCG-PEG、EGCG-PEG-cRGD、ICG/EGCG-PEG-cRGD的粒径分布图；
图5测试例2EGCG、EGCG-PEG、EGCG-PEG-cRGD、ICG/EGCG-PEG-cRGD的zeta电位分布图；
图6为测试例3中制得的纳米载体ICG/EGCG-PEG-cRGD的光热效应图；
图7为测试例4纳米载体ICG/EGCG-PEG-cRGD的体外对贫血小板血栓；
图8为测试例4纳米载体ICG/EGCG-PEG-cRGD的体外对富血小板血栓的光热溶栓图；
图9为测试例4纳米载体ICG/EGCG-PEG-cRGD的体外对混合血栓的光热溶栓图；
图10为测试例5中PBS缓冲液、游离ICG、ICG/EGCG-PEG、ICG/EGCG-PEG-cRGD体外靶向血栓的验证对比图及相应的定量图；
图11为测试例5中制得的不同浓度ICG、EGCG-PEG-cRGD体外清除羟基自由基、过氧自由基、一氧化氮自由基；
图12为测试例6中不同浓度ICG/EGCG-PEG-cRGD的溶血率；
图13为测试例7中不同浓度ICG/EGCG-PEG-cRGD对MOVAS的毒性实验
图14为测试例7中不同浓度ICG/EGCG-PEG-cRGD对RAW的毒性实验
图15为测试例7中不同浓度ICG/EGCG-PEG-cRGD对HUVEC的毒性实验
图16为测试例8中假手术组(G1)、模型组(G2)、游离ICG+近红外照射(G3)、ICG/EGCG-PEG+近红外照射(G4)、ICG/EGCG-PEG-cRGD+近红外照射下(G5)处理前、血栓造模、不同干预后的多普勒成像、颈动脉HE染色以及灌注量的定量图；
图17为本发明用于靶向血栓性疾病的纳米颗粒的制备流程图。
具体实施方式
下面将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。
实施例1
如图17，(1)在pH 8.0 10mM HEPES缓冲液中，加入EGCG使其终浓度2.5mM，滴加MnCl2溶液使其终浓度为2mM，加入吲哚菁绿20μL 10mg/mL，25℃恒温水浴剧烈搅拌10min；
(2)20mg EDC溶解于150μL DMSO溶液，置于5mL EP管中，补加100mL DMSO，先后加入50μL DMSO溶解的20mg N-羟基琥珀酰亚胺(NHS)，200μLDMSO溶解的20mg HS-PEG-COOH，混合均匀后活化4h，最后加入500μL水，其中含12.28g cRGD。反应12h后透析提纯，得到HS-PEG-cRGD，并进行核磁共振氢谱表征，如图1所示，另外，纳米载体HS-PEG-COOH的核磁共振氢谱表征，如图2所示。由图可知，成功制得了得到HS-PEG-cRGD，结果如图2。
(3)向步骤(1)中体系中加入步骤(2)制得的HS-PEG-cRGD 40μL100μg·mL-1，25℃恒温水浴剧烈搅拌7h。
(4)取反应液以16000rpm离心20min收集纳米颗粒，用HEPES缓冲液(10mM，pH 7.4)清洗两次，得到ICG/EGCG-PEG-cRGD纳米颗粒。
对比例1
在pH 8.0 10mM 4-羟乙基哌嗪乙磺酸(HEPES)的环境中，加入表没食子儿茶素没食子酸酯(EGCG)使其终浓度2.5mM，滴加MnCl2溶液使其终浓度为2mM，25℃恒温水浴剧烈搅拌10min，加入200μL DMSO溶解的20mg HS-mPEG(图1)，反应7h后离心收集纳米粒EGCG-PEG。
测试例1
取部分得到EGCG-PEG-cRGD、ICG/EGCG-PEG-cRGD纳米颗粒溶解在超纯水中，取中段液体，滴入铜片上，利用透射电镜观察纳米颗粒的外观形貌，可以看出EGCG-PEG-cRGD(左)、ICG/EGCG-PEG-cRGD(右)纳米颗粒，具有较规整的球形以及分散性良好，结果如图3所示。
测试例2
将实施例1制得的ICG/EGCG-PEG-cRGD和对比例1制得的EGCG-PEG复溶于超纯水中，置于马尔文粒径仪中检测粒径分布和电位，样品测试重复三次，取平均值，测得ICG/EGCG-PEG-cRGD的粒径为160nm，zeta电位为-18mV，结果如图4和图5所示。
测试例3
ICG/EGCG-PEG-cRGD光热效应的测定：配制不同浓度的ICG/EGCG-PEG-cRGD纳米颗粒，在808nm，2w/cm2的激光照射下，记录不同时间点的温度，结果如图6所示。
测试例4
ICG/EGCG-PEG-cRGD体外光热溶栓效果的测定：采集SD大鼠血，获得全血，200g15min离心得到富血小板血浆，取上清液继续800g 15min离心，上清液为贫血小板血浆，下层为血小板。将贫血小板血浆、富血小板血浆、混合全血在1u/mL凝血酶，2.5mM CaCl2，于37℃孵育1h，之后加入纳米粒，于808nm,1w/cm2，照射10min，酶标仪记录450nm(血红蛋白)、540nm(纤维蛋白)处吸光度值，结果如图7、图8、图9所示。
测试例5
EGCG-PEG、EGCG-PEG-cRGD体外靶向血栓的验证：将实施例1制得的EGCG-PEG-cRGD和对比例1制得的EGCG-PEG复溶，将染料吲哚菁绿(ICG)溶解在无水乙醇中，加入溶液，混匀，将反应液透析10h，每2h用蒸馏水补充减少的溶液以除去无水乙醇，室温下搅拌1h后，冷冻干燥，得到用于检验靶向血栓性的纳米颗粒。
采集健康小鼠静脉血，加入凝血酶25u/mL，25mM氯化钙，在37℃孵育1h，之后加入不同浓度的上述两种用于检验靶向血栓性的纳米颗粒，孵育10min，之后弃去上清液，并用生理盐水冲洗3次，利用活体成像仪进行荧光拍照并定量，结果如图10。
测试例6
纳米粒溶血性实验：采集SD大鼠血，200g 15min离心，收集下层液体，PBS稀释10倍，加入不同浓度纳米粒37℃孵育4h，之后在3000rpm下，离心10min，酶标仪540nm下测定吸光度值，计算溶血率。结果如图12
测试例7
不同浓度ICG/EGCG-PEG-cRGD纳米粒对MOVAS(图13)、RAW(图14)、HUVEC(图15)细胞的毒性。
测试例8纳米粒的体内溶栓试验：依据文献(ZHAO Z,ZHANG X,ZHANG H,etal.Elaborately Engineering a Self-Indicating Dual-Drug Nanoassembly for Site-Specific Photothermal-Potentiated Thrombus Penetration and Thrombolysis[J].Adv Sci,2021,e2104264.)对大鼠进行颈动脉血栓造模，用多普勒仪器检测颈动脉血流，并对灌注量进行定量。结果如图16。
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 (7)
1.一种用于靶向治疗血栓性疾病的纳米颗粒的制备方法，其特征在于，将表没食子儿茶素没食子酸酯与吲哚菁绿在碱性条件下，由MnCl2催化，形成纳米粒，之后引入合成的化合物巯基-聚乙二醇-环状多肽，透析，冷冻干燥，得到用于靶向血栓的纳米粒。
2.根据权利要求1所述的制备方法，其特征在于，包括以下步骤：
(1)将表没食子儿茶素没食子酸酯、吲哚菁绿、MnCl2加入4-羟乙基哌嗪乙磺酸缓冲液中搅拌5-15min，使其形成多自聚化合物；
(2)将1-(3-二甲氨基丙基)-3-乙基碳二亚胺、N-羟基琥珀酰亚胺、巯基-聚乙二醇-羧酸混合溶解，活化3-5h，加入环状多肽，反应10-14h后，透析提纯，得到巯基-聚乙二醇-环状多肽；
(3)将巯基-聚乙二醇-环状多肽加入反应体系中，反应2-9h；
(4)将反应后的溶液离心或透析，冷冻干燥得到表没食子儿茶素没食子酸酯-聚乙二醇-环状多肽纳米颗粒。
3.根据权利要求2所述的制备方法，其特征在于，步骤(1)中所述表没食子儿茶素没食子酸酯和MnCl2的摩尔比为1-1.5:1；所述4-羟乙基哌嗪乙磺酸缓冲液的pH值为7.8-8.2。
4.根据权利要求2所述的制备方法，其特征在于，步骤(2)中所述1-(3-二甲氨基丙基)-3-乙基碳二亚胺、N-羟基琥珀酰亚胺、巯基-聚乙二醇-羧酸、环状多肽cRGD的质量比为0.5-1.5:0.5-1.5:0.5-1.5：600-650。
5.根据权利要求2所述的制备方法，其特征在于，步骤(3)中所述表没食子儿茶素没食子酸酯与巯基-聚乙二醇-环状多肽的质量比为10-12:1。
6.根据权利要求2所述的制备方法，其特征在于，步骤(4)中所述离心条件为：15000-17000rpm离心10-20min。
7.根据权利要求2所述的制备方法，其特征在于，步骤(5)中所用的透析袋的截留分子量3000-4000。
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