CN111450269A - 一种多功能超声造影剂及其制备方法 - Google Patents
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Abstract
本发明公开了一种多功能超声造影剂，为核壳结构，其中，聚(乳酸‑羟基乙酸)共聚物为壳，全氟己烷为核，聚(乳酸‑羟基乙酸)共聚物中负载有超顺磁性氧化铁和IR780碘化物。本发明还公开了该造影剂的制备方法：(1)将聚(乳酸‑羟基乙酸)共聚物、超顺磁性氧化铁、IR780碘化物和全氟己烷溶于有机溶剂中，得到混合液；(2)在步骤(1)后得到的混合液中加入聚乙烯醇溶液，进行超声乳化，得到乳化液；(3)将步骤(2)后得到的乳化液进行搅拌，经离心后，用水洗涤沉淀，沉淀即为多功能超声造影剂。本发明的造影剂集近红外荧光/磁共振/超声的多模态显像以及光热治疗于一体的多功能造影剂，实现了在多种影像模式引导下的光热治疗。
Description
技术领域
本发明属于生物医药技术领域，尤其涉及一种多功能超声造影剂及其制备方法。
背景技术
传统超声对人体许多器官成像的作用受到常规彩色和光谱多普勒成像功能的限制。多普勒成像从灌注水平检测血流信息的能力有限，特别是低速血流。然而，超声造影模式下，超声造影剂利用微气泡产生强烈的非线性谐波回波，增强血液中的多普勒信号，可显示组织的微循环和组织灌注。目前临床上广泛运用的造影剂，是一种直径为1-8um的血池造影剂。随着纳米医学不断发展，纳米技术可应用于生物医学成像、监测、诊断治疗，为癌症的诊断和治疗提供潜在的新技术和新方法。其中，治疗诊断学就是近几年发展起来的癌症诊治新方法，它将多模式成像诊断技术和成像引导下的治疗有机结合在一起，使得对癌症的高效和个性化诊治成为可能。因此，多功能纳米造影剂还能装载药物、基因、光热材料、免疫抑制剂等物质，在超声或激光的触发下释放，从而成为集显像及治疗于一体的多功能造影剂。值得注意的是，肿瘤通常表现为血管渗漏和/或缺损，并且在380-780nm范围内具有较小的切孔尺寸，但微泡(传统造影剂)无法从肿瘤脉管系统迁移至细胞靶位，无法发挥精准的诊断与治疗效果。
超顺磁性氧化铁(Superparamagnetic iron oxides,SPIO)具有良好的生物相容性、优异的磁学特性、灵敏的磁共振负性增强显像效应等特点，已被越来越多的研究者重视，将其用于诊疗一体化的研究中。我们前期的研究也证实了这一点，将装载了SPIO的纳米粒静脉注射到乳腺癌荷瘤鼠体内，在肿瘤表面施加磁场吸引来实现被动靶向策略，能明显提高肿瘤组织纳米粒的到达量，实现肿瘤部位的近红外荧光/磁共振/超声的多模态显像以及光热治疗，为实现肿瘤部位的精准显像与治疗提供了更多的依据。
癌症的光热治疗(PTT)是近年来迅速发展的一种新的局部疗法。它基于将高度富集的外源性热疗法治疗剂引向肿瘤部位的原理，其中，肿瘤部位是在近红外光的激发下产生高热的(650-900nm)诱导急性坏死性细胞凋亡和免疫反应，以抑制肿瘤的生长。光诱导的PTT是一种非侵入性的局部肿瘤治疗方法，与传统的化疗、放疗和手术相比具有强大的优越性。IR780碘化物(简称IR780，CAS:207399-07-3)作为近红外荧光成像染料之一，具有出色的体内近红外荧光成像性能、优异的PTT效果，一旦被激光辐照，IR780还可以高效地产生高温，能迅速地杀死细胞。IR780还被证实优先聚集在线粒体中，可以作为线粒体靶向剂进行修饰。线粒体是关键的细胞器，在能量产生、ROS生成、氧化还原(redox)状态调节和凋亡介导的细胞死亡调节中起着至关重要的作用。针对线粒体的纳米技术以其优异的治疗效果、低毒性、几乎无副作用和降低多药耐药性而受到了关注。此外，先前的报道表明，经修饰以靶向线粒体的纳米粒子PS一旦受到辐照可以更有效地引发肿瘤细胞的凋亡。然而，IR780的水溶性差，不能在获得突出的治疗效果的同时实现肿瘤蓄积的剂量，在癌症PTT的直接应用受到严重限制。
多功能超声造影剂中，可利用全氟化碳作为纳米颗粒的内核。其中，液态全氟化碳家族，是一种惰性、液态的、具有较高气体溶解度的化合物，PFP(perfluoropentane)的沸点是29℃，当作为纳米粒的内核，经过激光照射下，吸收光能转化为热能，使内部温度升高至其沸点以上，可以产生气核，发生液－气相转变，体积由纳米级迅速增长为微米级，从而起到类似传统超声微泡造影剂的增强效果。但是由于PFP的沸点较低，人体的生理温度远高于此，作为内核部分的PFP可能会提前气化成微米级，限制了其进一步的临床应用。ZhifeiDai团队利用液态PFOB(perfluorooctylbromide)作为纳米超声造影剂，但是液态PFOB在超声造影模式下，对比增强效果不明显。
发明内容
本发明所要解决的技术问题是，治疗诊断学的发展需要多种功能集合的试剂/药物，且需要使这些不同的功能都可以得到有效发挥，目前相关的多功能的试剂/药物远不能满足需求。
为解决上述技术问题，本发明提供一种多功能超声造影剂，所述多功能超声造影剂为颗粒状，所述多功能超声造影剂为核壳结构，其中，聚(乳酸-羟基乙酸)共聚物为壳，全氟己烷为核，聚(乳酸-羟基乙酸)共聚物中负载有超顺磁性氧化铁和IR780碘化物。
优选地，所述多功能超声造影剂的粒径为100-500nm。纳米级超声造影剂可以利用其粒径优势，通过肿瘤的EPR(permeation and retention)效应，更多的靶向聚集于肿瘤中。为了体现更好的肿瘤选择性，使让更多在脉管系统中的造影剂移植细胞靶位，本发明还引入磁靶向，双靶向可提供肿瘤更高的灰度对比度，也使得治疗药物更多聚集在肿瘤区域。
本发明的纳米结构造影剂的结构，具有封装和释放IR780到肿瘤微环境的能力，从而使得IR780可被应用于癌症PTT。
作为同一个发明构思，本发明还提供一种多功能超声造影剂的制备方法，包括以下步骤：
(1)将聚(乳酸-羟基乙酸)共聚物、超顺磁性氧化铁、IR780碘化物和全氟己烷溶于有机溶剂中，得到混合液；
(2)在步骤(1)后得到的混合液中加入聚乙烯醇溶液，进行超声乳化得到乳化液；
(3)将步骤(2)后得到的乳化液进行搅拌，经离心后，用水洗涤沉淀，沉淀即为多功能超声造影剂。
优选地，步骤(1)中，所述有机溶剂为二氯甲烷，聚(乳酸-羟基乙酸)共聚物的质量与二氯甲烷的体积之比以mg/mL计为100︰2-4；IR780碘化物的质量与二氯甲烷的体积之比以mg/mL计为0.7-1.3︰1，全氟己烷与二氯甲烷的体积之比为1︰10-20。
优选地，步骤(1)中，步骤(1)中，超顺磁性氧化铁的粒径为10nm，超顺磁性氧化铁以浓度为25mg/mL的超顺磁性纳米氧化铁分散液进行添加，所述超顺磁性纳米氧化铁分散液与二氯甲烷的体积之比为1︰15。
优选地，所述步骤(2)中，超声乳化的功率为100-120W，超声乳化的时间为100-150s；聚乙烯醇溶液的质量浓度为3-5％，聚乙烯醇溶液与所述有机溶剂的体积之比为3-7︰1。
优选地，所述步骤(3)中，搅拌的时间为2-3h；离心速度为10000-15000rpm，时间为6-8min。
优选地，由上述制备方法制备的超声造影剂中超顺磁性氧化铁的含量为9.228±3.20ug/g；多功能超声造影剂中IR780碘化物包封率为48.26±2.11％，载药率为1.77±0.23％，其中，
包封率(％)＝WE/WT×100％，
载药率(％)＝WE/WNP×100％，
WE是多功能超声造影剂中封装的IR780量，WT是总添加IR780量，WNP是制备的多功能超声造影剂的重量。
我们通过研究发现全氟己烷(Perfluorohexane，PFH)的沸点在50℃左右，并且通过合适的制备方法可将其包封入内核，经过局部激光照射后，可发生液－气相转变，在肿瘤区域体积由纳米级迅速增长为微米级，达到诊疗一体化的最佳效果。
因此，本发明的纳米造影剂可在近红外荧光、磁共振、超声的多模态显像引导下实行光热治疗，为癌症的治疗和诊断提供新的方向。
本发明在聚(乳酸-羟基乙酸)共聚物(PLGA)内填充全氟己烷(PFH)形成聚(乳酸-羟基乙酸)共聚物纳米粒，在聚乳酸－羟基乙酸上负载有IR780和SPIO。SPIO具有良好的生物相容性、优异的磁学特性、灵敏的磁共振负性增强显像效应等特点，将其用于诊疗一体化的研究中，在肿瘤表面施加磁场吸引来实现被动靶向策略，能明显提高肿瘤组织纳米粒的到达量。IR780作为近红外荧光成像染料，具有出色的体内近红外荧光成像性能、优异的PTT效果，一旦被激光辐照，IR780还可以高效地产生高温，能迅速地杀死细胞，IR780还被证实优先聚集在线粒体中，可以作为线粒体靶向剂进行修饰。全氟己烷(Perfluorohexane，PFH)纳米粒在激光激发下，将吸收光能转化为热能，使内部温度升高至其沸点以上，可以产生气核，发生液－气相转变，体积由纳米级迅速增长为微米级，从而起到类似传统超声微泡造影剂的增强效果，从而实现肿瘤部位的近红外荧光、磁共振、超声的多模态显像以及光热治疗。
与现有技术相比，本发明的优点在于：
本发明利用简单的单乳化法，在PLGA纳米粒中封装PFH，并将IR780碘化物、SPIO装载在PLGA纳米粒壁上，形成的结构是一个核壳结构，制备成集近红外荧光/磁共振/超声的多模态显像以及光热治疗于一体的多功能造影剂，实现了在多种影像模式引导下的光热治疗。该多功能超声造影剂，将具有多种成像和治疗效果的物质基于一体，弥补了单一模式影像的限制，例如X线、CT等，可以获得更加全面、丰富、精准的影像信息，不仅提高疾病的检出率，而且还能够达到精确治疗效果。
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为实施例1中多功能超声造影剂的结构示意图；
图2为实施例1中多功能超声造影剂的透射电镜图；
图3为实施例1中多功能超声造影剂的粒径分布图；
图4为实施例1中多功能超声造影剂的电位分布图；
图5为实施例1中多功能超声造影剂的体外磁铁吸引图；
图6为实施例1中多功能超声造影剂的紫外吸收光谱图；
图7为实施例1中多功能超声造影剂的光热稳定性图；
图8为实施例1中多功能超声造影剂的荧光稳定性图；
图9为实施例1中多功能超声造影剂的体外升温图；
图10为实施例1中多功能超声造影剂的体内荧光显像图；
图11为实施例1中多功能超声造影剂的体内超声显像图；
图12为实施例1中多功能超声造影剂的体内磁共振显像图；
图13为实施例1中多功能超声造影剂的抗肿瘤效果图；
图14为实施例2中多功能超声造影剂的粒径分布图；
图15实施例1中多功能超声造影剂的冷却温度的线性回归曲线。
具体实施方式
为了便于理解本发明，下文将结合说明书附图和较佳的实施例对本文发明做更全面、细致地描述，但本发明的保护范围并不限于以下具体实施例。
除非另有定义，下文中所使用的所有专业术语与本领域技术人员通常理解含义相同。本文中所使用的专业术语只是为了描述具体实施例的目的，并不是旨在限制本发明的保护范围。
除非另有特别说明，本发明中用到的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。
下述实施例中采用的超顺磁氧化铁(SPIO)分散液购自美国海洋纳米技术有限公司，粒径为10nm、浓度为25mg/ml。
实施例1：
一种本发明的多功能超声造影剂的制备方法，步骤如下：
(1)溶解有机相：将100mg聚(乳酸-羟基乙酸)共聚物溶于3ml二氯甲烷中，依次加入200ul SPIO分散液、3mg IR780搅拌至完全溶解，再加入200ul PFH，得到混合液。
(2)乳化：在步骤(1)后得到的混合液中加入15ml浓度为4％聚乙烯醇溶液，进行超声乳化得到乳化液，其中，超声乳化的功率为110W，超声乳化的时间为120s。
(3)挥发有机相：将步骤(2)后得到的乳化液进行磁力搅拌2-3h，使微球表面固化，二氯甲烷尽量自然挥发，再以12000rpm高速离心7min，取沉淀漂洗3次后并用双蒸水洗涤留沉淀，即得到多功能超声造影剂；其中，漂洗3次是指：离心-去上清液-重悬沉淀-再次离心，如此循环3次。
将多功能超声造影剂重悬于PBS中，配制成不同浓度的多功能超声造影剂分散液。
经过检测分析：测试浓度为10mg/ml的多功能造影剂分散液中超顺磁性氧化铁含量是92.28μg ml-1；测试IR780碘化物包封率和载药率是48.26％和1.77％。
本实施例得到的多功能超声造影剂的透射电镜图如图2所示。由透射电镜图分析可知，本实施例的多功能超声造影剂，在PLGA纳米粒中封装PFH，并将IR780、SPIO装载在PLGA超声纳米粒壁上，是集近红外荧光/磁共振/超声的多模态显像以及光热治疗于一体的多功能造影剂，其结构示意如图1所示。
本实施例得到的多功能超声造影剂的粒径分布如图3所示，可知该造影剂的粒径为334nm。
本实施例得到的多功能超声造影剂的电位分布如图4所示，由图可知该造影剂的电位是-1.55mV，说明其稳定性能优异。
本实施例得到的多功能超声造影剂的体外磁铁吸引如图5所示，由图可知该造影剂优越的磁响应性。
本实施例得到的多功能超声造影剂的紫外吸收光谱如图6所示，由图可知该造影剂的在近红外区具有很强的吸收和发射能力。
本实施例得到的多功能超声造影剂的光热、荧光稳定性如图7、8所示，由图可知造影剂具有良好的光热学和显像性能。
实验一：本实施例的多功能超声造影剂可作光热治疗剂，具体步骤如下：
将1毫升2mg/mL造影剂(溶剂为PBS)倒入Eppendorf管中，并用808nm激光照射5分钟，强度为1.0W/cm2，使用红外热像仪(FLIR C2，美国)记录温度。辐照后的温度变化如图9所示，与FDA认证的吲哚青绿(ICG)相比，多功能造影剂的最高温度达到55℃。而ICG远低于它。
通过给浓度2mg/mL的造影剂施加808nm激光辐照(1.0W/cm2)评估了它的光热转换效率(η)。记录造影剂随激光照射3分钟并冷却10分钟而产生的温度变化，得到温度冷却时间(t)对-ln(θ)的线性回归曲线(图15)，计算出造影剂的光热转换效能高达37.5％，说明它是一种高效率的光热剂。
将荷瘤小鼠随机分为3组(n＝5)：(1)多功能超声造影剂组；(2)多功能超声造影剂+激光组；(3)多功能超声造影剂+激光辐照+磁靶向组。按以上分组，经小鼠尾静脉向小鼠身体内注入0.2mL多功能超声造影剂的盐水，并且在(3)组紧邻肿瘤位置放置一块磁铁(最大磁场强度＝32.5Gs)2h。在注射造影剂24h后，用808nm激光照射(2)、(3)组中的小鼠的肿瘤，激光强度为1.0W/cm2，照射时间为5min。14天后的小鼠肿瘤图像如图13所示，(1)组的肿瘤体积增加了8.5倍；(2)组的肿瘤体积增加了5.1倍，结果表明在近红外激光辐射下的纳米粒具有明显的体内抗肿瘤作用；而(3)组肿瘤体积明显小于其他两组，这表明磁靶向可以在局部肿瘤中聚集更多的纳米粒，增加局部纳米粒的浓度，有助于光热疗法。
实验二：本实施例的多功能超声造影剂可作为荧光显像剂，具体步骤如下：
将200μL造影剂(10mg/mL)从两组(n＝5)的荷瘤小鼠尾静脉中注射：实验组一具有磁靶向、实验组二无磁靶向。将最大磁场强度为40.6Gs的磁铁施加到肿瘤旁4h，磁铁磁场随距离逐渐衰减。当距磁体5mm时，最大磁场强度为34.2Gs。在每组中，肿瘤的深度约为5mm。随后，使用Lumina IVIS光谱成像系统(PerkinElmer，美国)对小鼠进行活体成像。成像图如图10所示，施加了磁靶向组的肿瘤比没有磁靶向组的荧光强度更强，磁靶向组的荧光强度最高有2.0×109，而无磁靶向组的荧光强度甚至低于2.0×109，说明磁靶向有利于造影剂的聚集。
实验三：本实施例的多功能超声造影剂可作为超声显像剂，具体步骤如下：
将10只荷瘤小鼠在Siemens S3000US扫描仪上成像，并随机分为2组(n＝5)：A组：激光辐照和磁靶向组，B组：激光辐照组。将0.2mL造影剂(20mg/mL)经静脉注射到小鼠中。A组在肿瘤附近放置一块磁铁(最大磁场强度＝32.5Gs)2小时。造影剂注射后24小时，用808nm激光(1.0W/cm2，10分钟)照射组A组和B组。然后，对小鼠肿瘤进行B型和CEUS型超声成像，成像图如图11所示，激光照射后，两种超声成像模式均显示出随时间变化的明显回声，并且施加了磁靶向的组回声更强。这表明，增加的回声强度与微泡的产生同步，且磁靶向吸引了更多的造影剂到靶部位。
实验四：本实施例的多功能超声造影剂可作为磁共振显像剂，具体步骤如下：
对于体内MRI，将10只荷瘤小鼠在3.0T MRI扫描仪上成像，并随机分为2组(n＝5)：第一组磁性靶向组、第二组无磁性靶向组。通过尾静脉将0.2mL的20mg/mL造影剂注射入小鼠。在磁性靶向组中，将最大磁场强度为32.5Gs的磁体放置在肿瘤附近2小时。未经磁性靶向处理的小鼠用作对照。24小时后，在3.0T Siemens Skyra MRI上成像扫描仪(德国)进行肿瘤成像。获得T2加权涡轮旋转自旋回波MR图像图如图12所示(重复时间＝72ms，回波时间＝9ms，翻转角＝90，切片厚度＝3mm，视场＝180mm)，磁性靶向降低了T2加权SI，这与非磁性靶向显着不同。说明造影剂可以通过缩短周围质子的横向弛豫来显着负面增强T2加权信号。而磁场的使用可以促进更多的造影剂在肿瘤中聚集，这与本发明中荧光和超声成像的结果一致。在图12中显示为磁铁靶向组的病灶区域T2低信号，更暗。无磁铁靶向组病灶区域T2高信号，更亮。
实施例2：
一种本发明的多功能超声造影剂，其制备步骤如下：
(1)溶解有机相：将100mg聚(乳酸-羟基乙酸)共聚物溶于3ml二氯甲烷中，依次加入200ul SPIO、3mg IR780搅拌至完全溶解，再加入200ul PFH，得到混合液。
(2)乳化：在步骤(1)后得到的混合液中加入15ml浓度为5％聚乙烯醇溶液，进行超声乳化得到乳化液；超声乳化的功率为110W，超声乳化的时间为120s。
(3)挥发有机相：在步骤(2)后得到的乳化液进行磁力搅拌2-3h，使微球表面固化，二氯甲烷尽量自然挥发，再以13000rpm高速离心，时间为7min，取沉淀漂洗3次后并用双蒸水洗涤留沉淀。
本实施例得到的多功能超声造影剂的粒径分布如图14所示，可知该造影剂的粒径为295nm。
Claims (8)
1.一种多功能超声造影剂，所述多功能超声造影剂为颗粒状，其特征在于，所述多功能超声造影剂为核壳结构，其中，聚(乳酸-羟基乙酸)共聚物为壳，全氟己烷为核，聚(乳酸-羟基乙酸)共聚物中负载有超顺磁性氧化铁和IR780碘化物。
2.根据权利要求1所述的多功能超声造影剂，其特征在于，所述多功能超声造影剂的粒径为100-500nm。
3.根据权利要求1所述的多功能超声造影剂，其特征在于，所述超顺磁性氧化铁的含量为6.028-12.428ug/g；所述多功能超声造影剂中IR780碘化物包封率为46.15-50.37％，载药率为1.54-2.00％。
4.一种如权利要求1-3任一项所述的多功能超声造影剂的制备方法，其特征在于，包括以下步骤：
(1)将聚(乳酸-羟基乙酸)共聚物、超顺磁性氧化铁、IR780碘化物和全氟己烷溶于有机溶剂中，得到混合液；
(2)在步骤(1)后得到的混合液中加入聚乙烯醇溶液，进行超声乳化，得到乳化液；
(3)将步骤(2)后得到的乳化液进行搅拌，经离心后，用水洗涤沉淀，沉淀即为多功能超声造影剂。
5.根据权利要求4所述的制备方法，其特征在于，步骤(1)中，所述有机溶剂为二氯甲烷，聚(乳酸-羟基乙酸)共聚物的质量与二氯甲烷的体积之比以mg/mL计为100︰2-4；IR780碘化物的质量与二氯甲烷的体积之比以mg/mL计为0.7-1.3︰1，全氟己烷与二氯甲烷的体积之比为1︰10-20。
6.根据权利要求4所述的制备方法，其特征在于，步骤(1)中，超顺磁性氧化铁的粒径为10nm，超顺磁性氧化铁以浓度为25mg/mL的超顺磁性纳米氧化铁分散液进行添加，所述超顺磁性纳米氧化铁分散液与二氯甲烷的体积之比为1︰15。
7.根据权利要求4所述的制备方法，其特征在于，步骤(2)中，超声乳化的功率为100-120W，超声乳化的时间为100-150s；聚乙烯醇溶液的质量浓度为3-5％，聚乙烯醇溶液与有机溶剂的体积之比为3-7︰1。
8.根据权利要求4所述的制备方法，其特征在于，步骤(3)中，搅拌的时间为2-3h；离心速度为10000-15000rpm，时间为6-8min。
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| CN113598820A (zh) * | 2021-08-18 | 2021-11-05 | 南京超维景生物科技有限公司 | 超声成像方法及装置 |
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| CN115282295A (zh) * | 2022-06-24 | 2022-11-04 | 四川大学 | 一种新型多功能集成的磁共振造影剂及其制备方法与应用 |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113598820A (zh) * | 2021-08-18 | 2021-11-05 | 南京超维景生物科技有限公司 | 超声成像方法及装置 |
| CN114522253A (zh) * | 2021-12-24 | 2022-05-24 | 重庆医科大学附属第二医院 | 多功能纳米粒及其制备方法、应用 |
| CN114522253B (zh) * | 2021-12-24 | 2023-05-26 | 重庆医科大学附属第二医院 | 多功能纳米粒及其制备方法、应用 |
| CN115282295A (zh) * | 2022-06-24 | 2022-11-04 | 四川大学 | 一种新型多功能集成的磁共振造影剂及其制备方法与应用 |
| CN115282295B (zh) * | 2022-06-24 | 2023-08-08 | 四川大学 | 一种多功能集成的磁共振造影剂及其制备方法与应用 |
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