CN114225055B - 一种用于高场磁共振成像的仿生纳米诊疗剂及其制备方法 - Google Patents
一种用于高场磁共振成像的仿生纳米诊疗剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于超高场磁共振成像的仿生纳米诊疗剂及其制备方法，所述纳米诊疗剂Ho‑MPDA通过聚合前掺杂金属的方法，由水溶性的多巴胺(PDA)掺杂钬离子(Ho3+)制备得到。Ho‑MPDA在超高场强7.0T下具有明显的T2对比增强效果，显著缩短横向电子弛豫时间。而且Ho‑MPDA在超高场强7.0T下横向弛豫速率T2(102.71mM‑1S‑1)是T2造影剂(25.52mM‑1S‑1)的4.02倍，成像效果大幅提升。同时聚多巴胺载体具有较好的生物相容性，具有优良的光热转化能力和良好的光稳定性，在超高场磁共振成像引导下实现光热治疗。
Description
技术领域
本发明涉及生物医学材料技术领域，具体地说，涉及一种用于高场磁共振成像的仿生纳米诊疗剂及其制备方法。
背景技术
癌症是世界各国非自然死亡病例的主要原因，全球癌症发病率、死亡率逐年增加。根据2020年世界卫生组织癌症报告显示，癌症已成为全球第二大死因，其发病率和死亡率增加近2040倍。癌症的高死亡率是由于其大多在晚期被确诊，因此早期诊断和高效药物治疗是提高癌症患者生存率的关键。
在癌症的诊断，治疗和预后中，医学成像技术扮演着不可或缺角色，如磁共振成像(MRI)、计算机断层扫描成像(CT)、荧光成像、正电子发射断层扫描成像(PET)等，它们在检测灵敏度、穿透深度和图像分辨率方面有所不同。在这些成像技术中，作为一种非侵入性和非电离成像方式，磁共振成像(MRI)技术可以将原子核磁化信号重建成二维/三维图像，以实现多参数(T1/T2)的解剖学诊断。其中磁共振成像T1加权(正)造影剂，通过缩短质子的纵向弛豫时间产生更亮的图像，适用于观察脂肪组织，关节等部位；T2加权(负)造影剂，通过缩短质子的横向弛豫时间产生较暗的磁共振图像，更好地显示富水结构和局部炎症。MRI因其具有高成像信噪比(SNR)、高软组织分辨率、高空间分辨率、无辐射、等优点，在肿瘤的早期诊断和精确治疗的实时监控中发挥了重要作用。
目前，MRI成像的一个重要发展趋势是向更高的磁场(>3.0T)发展，以实现更大的空间分辨率、更高的信噪比和更快的采集速度。超高场(UHF，≥7T)MRI通常可以获得比低场MRI(≤3T)更高质量的MR图像。目前临床上常用的造影剂是基于钆基螯合物的T1型造影剂(GBCA)和基于超顺磁性氧化铁纳米粒子(SPIONs)的T2型造影剂。然而GBCA这类造影剂分子量较低，体内循环时间短且被报道存在一些毒副作用，此外，GBCA在超高场下T1成像效果减弱，灵敏度降低，导致其用于超高场成像准确度下降。而基于SPIONs的T2造影剂的高磁矩会引起局部磁场不均匀，产生“晕染效应”，从而使得诊断出来的病灶区域变大，图像模糊，并且这种效应随着磁场强度的增加而变强，在超高场下更为明显，因此SPION也不适用于超高场磁共振成像。总体来说，能够适用于超高场MRI以进一步提高成像灵敏度的造影剂还有待深入研究。
为了解决这个问题，基于钬离子(Ho3+)的新型造影剂(包括螯合物和纳米材料)已被开发用于超高场MRI成像，Ho3+作为具有最高磁矩的顺磁性镧系元素，由于它自身非对称的电子基态，使得其具有短电子弛豫时间(≈10-13s)和较高的有效磁矩(≈10.0μB)，且其本身的大磁矩不会在高磁场下磁化饱和，可以在超高磁场强度下诱导产生局域磁场梯度从而缩短横向弛豫弛豫时间，适用于作为高磁场成像造影剂，与各自的螯合物相比，其纳米结构的造影剂通常表现出更多的优势。现有已知的Ho基纳米结构主要限于氧化物(如Ho2O3 NPs)和氟化物(如NaHoF4 NPs)，只具备低场强成像能力且无法用于治疗。因此，迫切需要开发用于超高场MRI成像的新型纳米结构的纳米诊疗剂。
发明内容
本发明的目的在于克服现有技术中存在的上述缺陷和不足，提供一种钬-介孔聚多巴胺纳米粒的制备方法。
本发明的第二个目的在于提供所述制备方法制备得到的钬-介孔聚多巴胺纳米粒。
本发明的第三个目的在于提供所述钬-介孔聚多巴胺纳米粒的应用。
本发明的上述目的是通过以下技术方案给予实现的：
一种钬-介孔聚多巴胺纳米粒的制备方法，包括如下步骤：
S1.将盐酸多巴胺和Ho3+前体物在溶剂中进行螯合反应，得到钬螯合-多巴胺溶液；
S2.将钬螯合-多巴胺溶液与溶于无水乙醇的表面活性剂F127混合，避光搅拌；
S3.向步骤S2混合溶液中加入1,3,5-三甲苯(TMB)，形成乳白色溶液后加入Tris溶液反应至形成黑色纳米粒子分散液；1,3,5-三甲苯与钬螯合-多巴胺溶液的体积比为(2～3)：3；
S4.收集反应完成的溶液，离心，用无水乙醇与去离子水清洗，重悬于水溶液中得到钬-介孔聚多巴胺纳米粒。
本发明通过聚合前掺杂金属的方法，由水溶性的多巴胺(PDA)掺杂钬离子(Ho3+)，利用聚多巴胺的邻苯二酚基官能团对金属离子的螯合作用实现Ho3+的高效负载，同时采用聚合前掺杂金属进一步提高了Ho3+的掺杂效率，通过调控1,3,5-三甲苯的用量，成功制备得到球形，粒径均一，呈现均匀分布的介孔结构的钬-介孔聚多巴胺纳米粒。
优选地，步骤S1所述盐酸多巴胺与Ho3+前体物的质量比20～90：1。
进一步优选地，步骤S1所述Ho3+前体物为五水硝酸钬、氧化钬或八水合硫酸钬的一种或多种混合。
优选地，其特征在于，所述混合反应体系反应中三价钬离子的浓度为0.001～1.0mmol/L。
优选地，表面活性剂F127与钬螯合-多巴胺溶液的质量体积比为120mg:1mL。
优选地，所述Tris水溶液的浓度为40mg/mL，所述Tris水溶液与与钬螯合-多巴胺溶液的体积比为(10～12)：3。
本发明还提供上述任一项所述制备方法制备得到的钬-介孔聚多巴胺纳米粒。钬-介孔聚多巴胺纳米粒由于其具有的介孔和中空结构成为一种良好的药物载体，而且纳米药物可以通过增强的渗透和保留效应(EPR效应)有效的靶向肿瘤部位，针对癌症提供光热治疗和影像学诊断。可用于超高场MRI成像引导的肿瘤光热治疗。
优选地，所述钬-介孔聚多巴胺纳米粒中三价钬离子含量为0.1％～5.0wt％。
因此，本发明还提供所述钬-介孔聚多巴胺纳米粒在超高场磁共振成像中的应用。
本发明还提供所述钬-介孔聚多巴胺纳米粒在制备超高场磁共振成像的诊疗剂中的应用。
本发明还提供一种纳米诊疗剂，含上述任一所述钬-介孔聚多巴胺纳米粒。
与现有技术相比，本发明具有以下有益效果：
本发明将Ho3+利用聚合前掺杂方法构建一种超高场磁共振成像的介孔聚多巴胺纳米诊疗剂Ho-MPDA，可提高Ho在超高场强中的横向弛豫速率，Ho-MPDA在超高场强7.0T下具有明显的T2对比增强效果，显著缩短电子弛豫时间。而且Ho-MPDA在超高场强7.0T下横向弛豫速率T2(102.71mM-1S-1)是临床常见T2造影剂SPIONs(25.52mM-1S-1)的4.02倍，成像效果大幅提升。同时聚多巴胺载体具有较好的生物相容性，具有优良的光热转化能力和良好的光稳定性，在超高场磁共振成像引导下实现光热治疗，有望大幅度提高癌症的诊断和治疗效果，减轻全身化疗的毒副作用，为癌症早期诊断及高效治疗的新型纳米诊疗剂研发提供思路。
附图说明
图1为Ho-MPDA纳米粒子制备过程中混合溶液的变化图。
图2为Ho-MPDA纳米粒子的透射电镜图。
图3为Ho-MPDA纳米粒子的粒径分布图和粒径电位表。
图4为Ho-MPDA纳米粒子的扫描电镜图。
图5为Ho-MPDA纳米粒子的XPS图谱。
图6为Ho-MPDA纳米粒子的氮气吸附/脱附曲线测定。
图7为近红外激光照射下(A)不同浓度和(B)不同激光功率Ho-MPDA溶液的升温曲线；(C)近红外激光照射下Ho-MPDA溶液温度随时间的变化曲线；(D)Ho-MPDA溶液在近红外激光照射下的光热效果图(插入图为冷却时间与温度的负对数曲线图)。
图8为不同浓度的Ho-MPDA纳米粒子在3.0T(A)和7.0T(B)场强下成像效果以及横向弛豫速率(1/T2)与载体浓度的关系。
图9为在7.0T场强下SPIONs和Ho-MPDA的T2成像效果以及横向弛豫速率(1/T2)与载体浓度的关系。
图10为不同浓度的Ho-MPDA纳米粒子的溶血率。
图11为不同浓度的Ho-MPDA纳米粒子有无激光照射与HUVEC细胞孵育24h后的细胞存活率。
图12为不同浓度的Ho-MPDA纳米粒子有无激光照射与Hepa1-6细胞孵育24h后的细胞存活率。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1纳米诊疗剂Ho-MPDA的制备
1、Ho-MPDA纳米粒子的制备：
(1)将90mg盐酸多巴胺、3mg五水硝酸钬溶解于3mL超纯水中180rpm避光搅拌24h，得到钬螯合-多巴胺溶液；
(2)将36mg表面活性剂F127与0.3mL钬螯合-多巴胺溶液加入到6mL乙醇与6mL超纯水的混合溶液中，180rpm避光搅拌15min，得到呈无色透明溶液，如图1(1)所示；
(3)在25℃水浴超声(4kHz)中边摇晃边加入0.1mL 1,3,5-三甲苯(TMB)溶液，持续超声分散5min至乳白色，如图1(2)所示；
(4)在180rpm磁力搅拌下逐滴加入1mL浓度为40mg/mL的Tris水溶液，如图1(3)，溶液变为粉红色并逐渐加深；
(4)随后180rpm避光搅拌6h，最终形成黑色的纳米粒子分散液，如图1(4)所示。将所得溶液分装于2mL离心管中，13000rpm离心10min，所得沉淀重悬于无水乙醇中，水浴超声5min，随后在相同条件下用超纯水洗涤2次，所得产物即为Ho-MPDA纳米粒。
2、Ho-MPDA透射电子显微镜观察：
将制备得到的Ho-MPDA配制成100μg/mL样品溶液，充分超声分散后，取10μL滴于碳支持膜铜网的正面，置于干燥器中室温条件下自然风干后于120KV电压条件下，使用透射电子显微镜(FEI，Tecnai G2 Spirit)观察Ho-MPDA的微观形态。由透射电镜图2A可以看出，制得的Ho-MPDA为雾状，纳米粒形态不均一，粒径不均一，没有聚合成均匀的球状结构。
实施例2纳米诊疗剂Ho-MPDA的制备
1、同实施例1步骤，区别在于1,3,5-三甲苯(TMB)的量为200μL。
2、Ho-MPDA透射电子显微镜观察：
将实施例2制备得到的Ho-MPDA配制成100μg/mL样品溶液，充分超声分散后，取10μL滴于碳支持膜铜网的正面，置于干燥器中室温条件下自然风干后于120KV电压条件下，使用透射电子显微镜(FEI，Tecnai G2 Spirit)观察Ho-MPDA的微观形态。由透射电镜图2B可以看出，制得的Ho-MPDA为球形，粒径均一，约为130nm，呈现均匀分布的介孔结构。可通过改变1,3,5-三甲苯的量，控制纳米诊疗剂的形态。
实施例3纳米诊疗剂Ho-MPDA的制备
同实施例1步骤，区别在于1,3,5-三甲苯(TMB)的量为300μL，Tris水溶液添加量为1.2mL。制得的Ho-MPDA为球形，粒径均一，约为130nm，呈现均匀分布的介孔结构。
实施例4纳米诊疗剂Ho-MPDA的粒径与电位
将实施例2制备的Ho-MPDA纳米粒子在超纯水中重悬，稀释至50μg/mL后超声均匀，利用动态光散射法(DLS)检测该纳米粒子样品的水合粒径、多分散性系数和Zeta电位。
如表1、图3所示，Ho-MPDA纳米粒子粒径分布范围较窄，表明粒径比较均一。水合粒径约为206.4nm，且处于电负性。透射电镜与动态光散射法测量结果有所差异，原因是后者得到的是纳米粒子为水合状态下的粒径，溶剂效应使得纳米颗粒显示出更大的水合粒径。
表1为Ho-MPDA纳米粒子的分散性、粒径与Zeta电位
实施例5纳米诊疗剂Ho-MPDA的SEM扫描电镜
将实施例2制备得到的Ho-MPDA配制成50μg/mL的Ho-MPDA乙醇溶液，取少量Ho-MPDA纳米粒子的乙醇溶液滴于硅片上，晾干后置于G500高分辨场发射扫描电镜(Gemini500，Zeiss/Brμker)下观察粒子形貌。
如图4所示，可以直观地观察到Ho-MPDA纳米粒子为粒径均匀的圆球形，并与透射电镜图像有一致的表面介孔结构。
实施例6实验Ho-MPDA的X射线光电子能谱分析
将实施例2适量制备的Ho-MPDA样品冻干后均匀铺在贴有双面胶(约2mm×2mm)的铝箔上，压片机压平后用X-射线光电子能谱仪(Nexsa，Thermo Fisher)测定样品中Ho元素的含量与价态。如图5所示，与Ho元素的标准谱图对比发现Ho-MPDA样品中的Ho价态为Ho3+。
实施例7纳米诊疗剂Ho-MPDA的氮气吸附/脱附曲线测定
将实施例2烘干的100mg MPDA样品，仪器测定氮气吸附/脱附曲线，如图6所示，利用BJH法计算出实施例2制备的MPDA纳米粒子的比表面积为48.960m2/g，DFT法计算出孔径大小约为2.7691nm。
实施例8纳米诊疗剂Ho-MPDA的体外光热性质研究
将实施例2制备得到的Ho-MPDA配制成不同浓度(0μg/mL、50μg/mL、100μg/mL、200μg/mL)的Ho-MPDA水溶液，然后置于2mL比色皿中，用808nm近红外激光照射(0.5W/cm2、1.0W/cm2、1.5W/cm2、2.0W/cm2)，对Ho-MPDA纳米粒子的升温曲线、光热稳定性以及光热转换效率进行表征。
如图7A/B所示，Ho-MPDA材料展现出浓度、激光功率依赖的升温变化，该结果表明Ho-MPDA具有良好的光热转换能力，可以有效地将近红外光能转化为热能。如图7C所示，四次升降温循环中Ho-MPDA溶液温度变化(ΔT)差别不大，表明Ho-MPDA具有良好的光热稳定性。随后计算Ho-MPDA的光热转换效率(η)，如图7D所示，通过公式(1)计算得到其具有高的光热转换率，η值为36.03％，公式中的τs经线性拟合为315.08s。
实施例9纳米诊疗剂Ho-MPDA的磁共振成像研究
将制备得到的Ho-MPDA配制成水溶液，然后分别进行梯度稀释，各取150μL加入96孔板中，在3.0T核磁共振成像仪下进行扫描，表征T2加权MRI成像效果。将制备得到的Ho-MPDA配制成水溶液，然后分别进行梯度稀释，各取600μL加入注射器中，在7.0T核磁共振成像仪下进行扫描，表征其T2加权MRI成像效果。
如图8，以Ho3+离子物质的量浓度为横坐标，以纵向弛豫率r2(1/T2)为纵坐标进行线性拟合，Ho-MPDA在7.0T场强下具有更高的横向弛豫速率(102.71mM-1S-1)是3.0T场强下(34.69mM-1S-1)的2.94倍。如图8中的map图像显示，随着Ho浓度的升高，T2加权信号逐渐升高，图像明显呈现出由白变黑的趋势，说明Ho-MPDA可作为超高场T2造影剂用于磁共振成像。
实施例10纳米诊疗剂Ho-MPDA与SPIONs的磁共振成像研究
将购买的SPIONs(油酸修饰的四氧化三铁磁性纳米颗粒，东纳公司，Mag3000)和制备得到的Ho-MPDA水溶液，然后分别进行梯度稀释，各取600μL加入注射器中，在7.0T核磁共振成像仪下进行扫描，表征其T2加权MRI成像效果。
如图9，以Ho/Fe离子物质的量浓度为横坐标，以纵向弛豫率r2(1/T2)为纵坐标进行线性拟合，Ho-MPDA在7.0T场强下具有更高的横向弛豫速率(102.71mM-1S-1)是SPIONs在同等条件下(25.52mM-1S-1)的4.04倍。如图9中的map图像显示，随着Ho/Fe浓度的升高，T2加权信号逐渐升高，图像明显呈现出由白变黑的趋势，且Ho-MPDA具有更明显的颜色深浅变化，说明Ho-MPDA可作为超高场T2造影剂用于磁共振成像。与商用造影剂SPIONs相比，Ho-MPDA诊疗剂可使MRI造影信号显著增强。
实施例11纳米诊疗剂Ho-MPDA的体外生物相容性研究
取2mL健康人抗凝全血，使用pH 7.4PBS溶液离心(1000rpm，10min)洗涤，直至上清无明显红色，经过细胞计数，稀释后得到浓度为3.0×107个/mL的红细胞悬液。将MPDA纳米粒子稀释成不同浓度。以PBS溶液为阴性对照组，Triton X-100(0.1％，w/v)溶液为阳性对照组，各取500μL MPDA浓度范围为50-500μg/mL的不同样品与等体积的红细胞悬液混合，轻轻摇匀，置于37℃恒温箱中，共孵育2h。孵育结束后，从各个样品组中取10μL混合溶液滴于干净的载玻片上，显微镜观察各组红细胞的形态。后将每组混合溶液离心(1000rpm，10min)，利用酶标仪检测各组样品上清液在413nm处吸光值，根据公式(2)计算溶血率：
如图10左图，实验中测定不同浓度MPDA的溶血率，结果显示即使浓度高达500μg/mL，其溶血率仅为1.97％。图10右图是对照组以及最大浓度样品组与红细胞共孵育2h后红细胞的显微镜图，图中可以看出，与缓冲溶液相比，样品组红细胞的形态和数量并无明显变化，依然保持双盘状，而TritonX-100组的红细胞出现严重破损，视野范围内已经没有完整的红细胞。以上结果表明MPDA具有良好的血液相容性。
实施例12纳米诊疗剂Ho-MPDA的体外细胞相容性研究
通过噻唑蓝(MTT)比色法探究不同浓度(12、25、50、100、200、400μg/mL)的Ho-MPDA对HUVEC细胞(人脐静脉内皮细胞)活力的影响。在96孔板中以每孔5000个细胞的密度将HUVEC细胞在培养箱中培养过夜。然后去除原培养基，分别加入不同浓度的Ho-MPDA，对照组加入等量新鲜的培养基，激光组在材料添加4h后使用激光器照射(1W/cm2，5min)。孵育24h后，用PBS清洗，加入含有20μL/孔MTT溶液的培养基(5mg/mL)，再孵育4h，去除剩余培养基，并加入适量二甲基亚砜溶解，利用酶标仪检测490nm处的吸光值A。按照公式(3)计算细胞存活率：
如图11所示，随着样品浓度的升高，HUVEC细胞的存活率基本保持不变，无明显的细胞损伤。当Ho-MPDA浓度高达400μg/mL，共孵育24h后HUVEC细胞是存活率仍超过90％，且添加激光组存活率仍超过80％，表明Ho-MPDA具有较好的生物相容性。
实施例13纳米诊疗剂Ho-MPDA的体外细胞毒性研究
通过噻唑蓝(MTT)比色法探究不同浓度(12、25、50、100、200、400μg/mL)的Ho-MPDA对Hepa1-6细胞(小鼠肝癌细胞)活力的影响。在96孔板中以每孔5000个细胞的密度将Hepa1-6细胞在培养箱中培养过夜。然后去除原培养基，分别加入不同浓度的Ho-MPDA，对照组加入等量新鲜的培养基，激光组在材料添加4h后使用激光器照射(1W/cm2，5min)。孵育24h后，用PBS清洗，加入含有20μL/孔MTT溶液的培养基(5mg/mL)，再孵育4h，去除剩余培养基，并加入适量二甲基亚砜溶解，利用酶标仪检测490nm处的吸光值A。按照公式(3)计算细胞存活率。
如图12所示，随着样品浓度的升高，Hepa1-6细胞的存活率基本保持不变，均接近100％。当Ho-MPDA浓度高达400μg/mL，共孵育24h后HUVEC细胞是存活率仍超过80％，且添加激光组发现存活率明显下降，低于20％，表明Ho-MPDA具有较好的肿瘤光热治疗能力。
综上可见，本发明制备得到的Ho-MPDA粒径分布在较窄的球形范围内，粒径均一，呈现均匀分布的介孔结构，具有良好的稳定性；Ho元素掺杂效率和螯合作用高；具有良好的光热转换能力，光热转换率为36.03％，光热稳定性好；具有较好的生物相容性；Ho-MPDA在7.0T场强下具有更高的横向弛豫速率(102.71mM-1S-1)是3.0T场强下(34.69mM-1S-1)的2.94倍，具有超高场增强成像优势且成像能力是市售造影剂的4倍；可作为一种超高场磁共振成像的介孔聚多巴胺纳米诊疗剂用于磁共振成像和肿瘤治疗。
Claims (5)
1.一种钬-介孔聚多巴胺纳米粒的制备方法，其特征在于，包括如下步骤：
S1.将盐酸多巴胺和Ho3+前体物在溶剂中进行螯合反应，得到钬螯合-多巴胺溶液；
S2.将钬螯合-多巴胺溶液与溶于无水乙醇的表面活性剂F127混合，避光搅拌；
S3.向步骤S2混合溶液中加入1,3,5-三甲苯，形成乳白色溶液后加入Tris溶液反应至形成黑色纳米粒子分散液；1,3,5-三甲苯与钬螯合-多巴胺溶液的体积比为（2～3）：3；
S4.收集反应完成的溶液，离心，用无水乙醇与去离子水清洗，重悬于水溶液中得到钬-介孔聚多巴胺纳米粒；
步骤S1所述盐酸多巴胺与Ho3+前体物的质量比20～90：1；
步骤S1所述Ho3+前体物为五水硝酸钬、氧化钬或八水合硫酸钬的一种或多种混合；
步骤S3所述Tris溶液的浓度为40mg/mL，所述Tris溶液与与钬螯合-多巴胺复合纳米离子溶液的体积比为（10～12）：3。
2.权利要求1所述制备方法制备得到的钬-介孔聚多巴胺纳米粒。
3.根据权利要求2所述的钬-介孔聚多巴胺纳米粒，其特征在于，所述钬-介孔聚多巴胺纳米粒中三价钬离子含量为0.1%～5.0wt%。
4.权利要求2或3所述钬-介孔聚多巴胺纳米粒在制备超高场磁共振成像的诊疗剂中的应用。
5.一种纳米诊疗剂，其特征在于，含有权利要求2或3所述钬-介孔聚多巴胺纳米粒。
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