CN111569073A - 一种负载光敏剂的介孔普鲁士蓝-锰纳米粒及其制备方法 - Google Patents

一种负载光敏剂的介孔普鲁士蓝-锰纳米粒及其制备方法 Download PDF

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CN111569073A
CN111569073A CN202010555918.8A CN202010555918A CN111569073A CN 111569073 A CN111569073 A CN 111569073A CN 202010555918 A CN202010555918 A CN 202010555918A CN 111569073 A CN111569073 A CN 111569073A
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prussian blue
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张良珂
张蓥
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Chongqing Medical University
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Abstract

本发明公开了一种负载光敏剂的普鲁士蓝‑锰纳米粒及其制备方法。该纳米粒具有优良的光热转换率，在激光照射条件下可以产生光热治疗效果，同时激活光敏剂产生活性氧，起到光动力治疗作用，还可以释放一氧化氮，产生气体疗法效果。并且，纳米结构中引入了锰，有望改善肿瘤部位乏氧环境，增强光动力治疗效果。本次构建的负载光敏剂的普鲁士蓝‑锰纳米粒有望通过光热治疗、光动力治疗和一氧化氮治疗的联合应用，提高对肿瘤的治疗效果。

Description

一种负载光敏剂的介孔普鲁士蓝-锰纳米粒及其制备方法
技术领域
本发明属于医药技术领域，具体涉及一种负载光敏剂的介孔普鲁士蓝-锰纳米粒及其制备方法。
背景技术
目前，大部分抗癌药物体内注射后出现非靶向释放，且在肿瘤部位浓度较低，导致常规化疗产生严重的副作用，治疗效果不佳。在过去几十年中，光动力疗法(PhotodynamicTherapy，PDT)和光热治疗(Photothermal Therapy，PTT)已经逐渐成为临床研究和实践中有效的肿瘤治疗方法。PDT通过特定波长的光激活光敏剂(Photosensitizer，PS)，激发后的PS将能量传递给周围的氧气分子，产生可杀伤肿瘤细胞的活性氧物质(Reactive OxygenSpecies，ROS)，其中包括单线态氧(1O2)、羟基自由基(·OH)和超氧阴离子(O2 -)，从而起到对肿瘤的杀灭作用。PTT主要是借助于各种靶向技术将纳米光热材料聚集在肿瘤组织处，然后利用具有较强组织穿透力的外部光源(目前研究较多的是近红外光)辐射肿瘤组织，将外部光源的光通过纳米光热材料转换为热能，从而使肿瘤组织局部温度升高，进而杀灭肿瘤细胞达到***的目的。吲哚菁绿(ICG)作为一种近红外(NIR)吸收染料，已获得美国食品及药物管理局(FDA)批准使用。其衍生物包括IR780，IR820对近红外光有强烈吸收，可用作光敏剂用于光动力疗法。
一氧化氮(NO)是一种重要的内源性气体介质，参与多种与心血管稳态相关的生理和生物途径，免疫反应，神经传递，细胞凋亡等过程。肿瘤细胞内高浓度(微摩尔浓度)的NO可抑制肿瘤细胞DNA修复，消耗肿瘤细胞内还原型谷胱甘肽，诱导组蛋白的谷胱甘肽化，抑制缺氧诱导因子(Hypoxia-induced Factors，HIF)，激活p53基因表达，诱导肿瘤细胞发生凋亡，从而起到抑制肿瘤生长、诱导肿瘤细胞凋亡甚至杀伤肿瘤细胞的作用。同时研究表明，NO可以与O2 -反应生成细胞毒性更强的活性氮物质(Reactive Nitrogen Species，RNS)，其中包括过氧亚硝酸盐(ONOO-)，二氧化氮和亚硝基硫醇。
硝普钠(Sodium Nitroprussude，SNP)是一种在临床上用于扩张血管的降压药，化学结构中含有[Fe(CN)5NO]2-，在机体中分解释放一氧化氮，可作为NO供体。普鲁士蓝(Prussian Blue，PB)是一种六氰合铁酸的混合价铁，被用于放射性中毒的治疗。基于PB的材料具有独特的性质，如在近红外区域具有强吸收，磁性，沸石特性，半导体行为，良好的生物相容性等。由于肿瘤组织具有缺氧，低pH、高H2O2浓度的特点，在纳米粒结构中引入MnO2，可与肿瘤组织的H2O2反应产生Mn2+和O2，改善肿瘤部位乏氧环境，增强PDT效果。
我们成功制备出一种负载光敏剂的介孔普鲁士蓝-锰纳米粒，一方面在NIR激光照射下，纳米粒可以通过优异的光热转换诱导肿瘤细胞的热消融以及裂解结构中的Fe-NO配位键从而产生游离NO分子，同时被激发的光敏剂产生ROS，进而O2 -与NO分子反应生成对肿瘤细胞杀伤作用更强的ONOO-；另一方面结构中掺杂的MnO2不仅可以控制纳米粒的粒径，还能和肿瘤细胞内的H2O2反应产生氧气，提高PDT效果。相比于传统单一的PTT或PDT，本次构建的纳米粒有望通过PTT，PDT和NO疗法，提高对肿瘤的治疗效果。
发明内容
本发明的目的在于弥补传统化疗的毒副作用大、易产生耐药性等不足，实现光热治疗、光动治疗和NO疗法的联合应用。该纳米体系以普鲁士蓝-锰为载体，负载光敏剂，其纳米载体结构中通过配位键结合了NO和MnO2结构。在NIR激光照射后，该纳米粒对肿瘤细胞可产生光热治疗，光动治疗和一氧化氮治疗的效果，同时MnO2与H2O2生成的氧气可以提高肿瘤部位的氧气浓度，增强治疗作用。
本发明的目的可以通过以下技术方案实现：
步骤1：取适量的铁***、硝普钠、聚乙烯吡咯烷酮和盐酸溶液于烧瓶中，另取适量的高锰酸钾用一定量的盐酸溶液溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
步骤2：将步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入一定量的光敏剂，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
作为本发明的进一步改进，步骤(1)具体为：取7.5～120mg铁***、61.1～977.5mg硝普钠、0.375～6g聚乙烯吡咯烷酮和4～72mL盐酸溶液(0.1mol/L)于烧瓶中，另取3.1～50mg高锰酸钾用1～8mL盐酸溶液溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应2h～24h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒。
作为本发明的进一步改进，步骤(2)具体为：取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mg光敏剂，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
本发明通过“一锅法”制备出介孔普鲁士蓝-锰纳米粒，进一步成功制备了负载光敏剂的介孔普鲁士蓝-锰纳米粒，该纳米粒具有制备工艺简单、重复性好、生物相容性好以及改善肿瘤微环境的特点。
本发明的优点：本发明所制备出的介孔普鲁士蓝-锰纳米粒具有粒径小、分散性好、稳定性高以及优良的光热转换效率的优点。在激光照射后，纳米粒能通过光热转换效果和一氧化氮杀伤肿瘤细胞，同时负载的光敏剂在激光激发后产生光动治疗效果。通过普鲁士蓝-锰纳米粒结构中的MnO2与肿瘤微环境相互作用，改善肿瘤乏氧环境，进一步增强光动疗法疗效。
附图说明
图1为负载光敏剂的介孔普鲁士蓝-锰纳米粒的外观图
图2为负载光敏剂的介孔普鲁士蓝-锰纳米粒的透射电镜图
图3为负载光敏剂的介孔普鲁士蓝-锰纳米粒的粒径分布图
图4为负载光敏剂的介孔普鲁士蓝-锰纳米粒的体外光热效果图
图5为负载光敏剂的介孔普鲁士蓝-锰纳米粒的体外产生活性氧图
图6为负载光敏剂的介孔普鲁士蓝-锰纳米粒的体外释放NO图
图7为不同浓度负载光敏剂的介孔普鲁士蓝-锰纳米粒对肿瘤细胞的抑制作用图
具体实施方式
以下通过实施例对本发明进一步详细说明：
实施例1
本实施例为负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，包括以下步骤：
(1)取7.5mg铁***、61.1mg硝普钠、0.375g聚乙烯吡咯烷酮和4mL盐酸溶液(0.1mol/L)于烧瓶中，另取3.1mg高锰酸钾用1mL盐酸溶液(0.1mol/L)溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应2h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
(2)取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mgIR820，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
实施例2
本实施例为负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，包括以下步骤：
(1)取60mg铁***、488.7mg硝普钠、3g聚乙烯吡咯烷酮和36mL盐酸溶液(0.1mol/L)于烧瓶中，另取25mg高锰酸钾用4mL盐酸溶液(0.1mol/L)溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应2h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
(2)取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mgIR820，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
实施例3
本实施例为负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，包括以下步骤：
(1)取60mg铁***、488.7mg硝普钠、3g聚乙烯吡咯烷酮和36mL盐酸溶液(0.1mol/L)于烧瓶中，另取25mg高锰酸钾用4mL盐酸溶液(0.1mol/L)溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应24h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
(2)取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mgIR820，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
实施例4
本实施例为负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，包括以下步骤：
(1)取120mg铁***、977.4mg硝普钠、6g聚乙烯吡咯烷酮和72mL盐酸溶液(0.1mol/L)于烧瓶中，另取50mg高锰酸钾用8mL盐酸溶液(0.1mol/L)溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应2h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
(2)取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mgIR820，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
实施例5
本实施例为负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，包括以下步骤：
(1)取120mg铁***、977.4mg硝普钠、6g聚乙烯吡咯烷酮和72mL盐酸溶液(0.1mol/L)于烧瓶中，另取50mg高锰酸钾用8mL盐酸溶液(0.1mol/L)溶解后，再加入烧瓶中混合。避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应24h，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
(2)取12.5mg步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入1.5mgIR820，室温下避光搅拌14h，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
实施例6
所制备出负载光敏剂的介孔普鲁士蓝-锰纳米粒的外观如图1所示；透射电镜照片如图2所示；粒径检测结果如图3所示。由图可知，负载光敏剂的介孔普鲁士蓝-锰纳米粒形状呈圆型，粒径较小且分布均匀，平均粒径为100nm左右。
实施例7
用功率密度为1.5W/cm2的808nm激光照射负载光敏剂的介孔普鲁士蓝-锰纳米粒混悬液(0.2mg/mL)，记录照射10分钟内的温度变化。结果如图4所示，负载光敏剂的介孔普鲁士蓝-锰纳米粒混悬液随着激光照射时间的增加，温度逐渐上升，表明该纳米粒具有良好的光热转换性能。
实施例8
将负载光敏剂的介孔普鲁士蓝-锰纳米粒混悬液与1,3-二苯基异苯并呋喃(DPBF)混合，用不同的激光照射时间处理混合液，然后用紫外可见分光光度计检测DPBF在455nm处的吸光度值。结果如图5所示，通过激光照射后，混合液中的DPBF在455nm处的吸光度值明显下降，表明负载光敏剂的介孔普鲁士蓝-锰纳米粒在激光照射条件下可以产生活性氧，并且随着照射时间的延长，下降越明显，说明产生活性氧的量也在逐渐增加。
实施例9
用功率密度为2.0W/cm2的808nm激光照射负载光敏剂的介孔普鲁士蓝-锰纳米粒混悬液(1mg/mL)，照射时间20分钟，再离心后取上清液，通过Griess法测量NO的释放量。结果如图6所示，负载光敏剂的介孔普鲁士蓝-锰纳米粒可以在激光照射条件下释放NO，且随着照射时间的延长，NO的释放量也逐渐增加。
实施例10
采用MTT法考察负载光敏剂的介孔普鲁士蓝-锰纳米粒在激光照射下对4T1细胞的抑制作用。将处于对数生长期的4T1细胞以每孔5×103个的数量接种于96孔板中，在37℃、5％CO2培养箱中培养18h后至细胞贴壁。空白组为不含药物的培养液，实验组为含有不同浓度负载光敏剂的介孔普鲁士蓝-锰纳米粒的细胞培养液，每组浓度设置6个复孔，培养24h后。实验组每孔给予1.0W/cm2的激光照射5分钟。每孔再重新加入MTT(1mg/mL)，于细胞培养箱中孵育4h，弃去培养液，每孔加入150μL DMSO，振摇20min后，用酶标仪测定波长490nm处的吸光值。结果如图7所示，在激光照射后负载光敏剂的介孔普鲁士蓝-锰纳米粒对4T1肿瘤细胞有显著的抑制作用。

Claims (5)

1.一种负载光敏剂的介孔普鲁士蓝-锰纳米粒，其特征在于制剂中各组分重量百分比为：铁***20～40份，硝普钠300～500份，聚乙烯吡咯烷酮1000～3000份，高锰酸钾10～30份，光敏剂1～3份；
该负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法包括，
步骤(1)，取适量的铁***、硝普钠、聚乙烯吡咯烷酮和盐酸溶液于烧瓶中，另取适量的高锰酸钾用盐酸溶液溶解后，再加入烧瓶中混合，避光室温搅拌15min后，将其置于80℃水浴锅中，避光搅拌反应，离心后将沉淀用水洗涤三次，得到介孔普鲁士蓝-锰纳米粒；
步骤(2)，将步骤(1)所得介孔普鲁士蓝-锰纳米粒用去离子水分散，加入光敏剂，室温下避光搅拌14小时，离心后将沉淀用水洗涤三次，得到负载光敏剂的介孔普鲁士蓝-锰纳米粒。
2.如权利要求1所述的负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，其特征在于，所述步骤(1)中，所述避光搅拌反应的时间为2h～24h。
3.如权利要求1所述的负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，其特征在于，所述步骤(1)中，所述盐酸溶液的浓度为0.01mol/L～0.2mol/L。
4.如权利要求1所述的负载光敏剂的介孔普鲁士蓝-锰纳米粒的制备方法，其特征在于，所述步骤(2)中，所述光敏剂为IR820，IR780，二氢卟吩e6(Ce6)的一种或两种以上的混合物。
5.如权利要求1所述的负载光敏剂的介孔普鲁士蓝-锰纳米粒，其特征在于，所述纳米粒平均粒径为50nm-300nm。
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