CN112587677A - 一种iRGD磁性靶向微泡造影剂及其应用 - Google Patents
一种iRGD磁性靶向微泡造影剂及其应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域,具体公开了一种iRGD磁性靶向微泡造影剂及其应用,所述iRGD磁性靶向微泡造影剂包括磁性iRGD靶向的PLGA微泡和包载PLGA微泡表面上的四氧化三铁纳米颗粒。本发明将iRGD和四氧化三铁纳米颗粒颗粒共载于PLGA微泡,进一步提高了PLGA微泡靶向新生微血管效果,实现了超声/磁共振双模态成像,有利于观察子宫内膜血管生成变化的过程。
Description
技术领域
本发明涉及生物技术领域,尤其是涉及一种iRGD磁性靶向微泡超声/磁共振的双模态造影剂及其应用。
背景技术
体外受精-胚胎移植(IVF-ET)是帮助妇女怀孕的常用且有效的替代性生殖技术。然而,由于子宫内膜容受性不足,即使移植的胚胎是正常的,仍有一半以上的胚胎无法植入子宫内膜。子宫内膜容受性也称为胚胎植入的“窗口”,是指子宫内膜在结构和功能上准备接受胚胎植入子宫内膜的状态。通常情况下,这是一个时空受限的种植窗。这一时期在黄体生成激素达峰6-8天后开始,在人类中持续约48小时,即分泌中期和(或)黄体中期,并且以某些子宫内膜生长因子、细胞因子、黏附分子的上调为特征。其中,血管生成被认为是妊娠早期胚胎正常植入的关键步骤。受精后,子宫内膜的血管增生,使得子宫内膜肥沃到足以接受胚胎的植入。传统的子宫内膜活检属于有创的检查,不适用于IVF周期。
神经蛋白-1(NRP-1)在结合血管内皮生长因子(VEGF)的子宫内膜血管内皮细胞中表达,并增强VEGF与VEGFR2的结合。这表明NRP-1,除了已知的VEGF受体,可能在VEGF诱导的血管生成中发挥重要作用。研究证实NRP-1在人子宫内膜样本整个月经周期中的mRNA和蛋白表达。NRP-1在增殖期表达增强,提示其可能参与激素调控的子宫内膜血管生成变化,为胚胎着床准备子宫内膜。NRP-1的表达可能作为VEGF的辅助因子,增强血管生成刺激。
血管新生是在原有血管基础上长出新的毛细血管,存在于组织生长发育和修复过程中。而整合素αvβ3是一种细胞表面糖蛋白受体,由于其在血管生成过程中上调了血管内皮细胞的表达,已被证实为血管生成的标志。传统的RGD多肽能特异性结合到血管内皮细胞表面的整合素αvβ3,并在将药物、显像剂、纳米颗粒和病毒载体输送到血管中发挥重要作用。而iRGD多肽具有短氨基酸序列(Arg-Gly-Asp),可控制细胞的通透性,调节细胞内化和外渗,促进组织深部渗透,提高成像敏感性和治疗效果。其作用机制如下:首先,iRGD基序介导与新生血管内皮细胞上过表达的整合素αvβ3结合。其次,蛋白酶的裂解暴露了CendR基序,该基序是NRP-1的结合基序。第三,暴露的CendR介导与NRP-1结合。
近年来,微气泡超声造影剂在超声治疗领域得到更多关注,在靶向基因/药物转染、肿瘤消融和放射疗法等方面得以应用。磁性纳米颗粒已经广泛应用在核磁共振成像中,可以提高空间分辨率和软组织对比度,从而提高临床诊断的准确性。四氧化三铁纳米颗粒(Fe3O4)具有比表面积大、易于修饰、磁响应性强、生物相容性好、低毒性等优点,被广泛地应用于核磁共振成像、药物输送、肿瘤治疗等生物医药领域。
目前,将肿瘤穿透肽iRGD联合四氧化三铁纳米颗粒(Fe3O4)靶向新生微血管还暂无相关报道。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种iRGD磁性靶向微泡造影剂及其应用,本发明造影剂稳定性佳,成像效果好;本发明将iRGD和四氧化三铁纳米颗粒颗粒共载于PLGA微泡,进一步提高了PLGA微泡靶向新生微血管效果,实现了超声/磁共振双模态成像,有利于观察子宫内膜血管生成变化的过程。
本发明的第一目的是提供了一种iRGD磁性靶向微泡造影剂,为实现上述目的,本发明采取的技术方案为:
一种iRGD磁性靶向微泡造影剂,所述iRGD磁性靶向微泡造影剂包括磁性iRGD靶向的PLGA微泡和包载PLGA微泡表面上的四氧化三铁纳米颗粒。
本发明将iRGD和四氧化三铁纳米颗粒颗粒共载于PLGA微泡,进一步提高了新生微血管的靶向性,避免了引入大分子蛋白的安全隐患,实现了超声/磁共振双模态成像。通过无创分子成像更加特异地探测出子宫内膜血管生成在分子水平的变化,能够更加精确地对子宫内膜血管生成变化过程的实现监测。
并且本发明的PLGA微泡是通过调节气泡壳的弹性来设计的,使用脂质融入到PLGA壳中,碳酸氢铵作为产气剂。PLGA微泡含有软化的壳体和多孔气泡表面,使其产生更强的谐波信号,更容易受到超声照射,使得其在体内外超声造影和超声触发MB破坏方面表现优异。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述磁性iRGD靶向的PLGA微泡由聚乳酸-羟基乙酸共聚物、二硬脂酰磷脂酰胆碱和DSPE-PEG-iRGD组成的脂质双分子层膜。更优选地,聚乳酸-羟基乙酸共聚物选自2万~4万分子量PLGA 50:50。
聚乳酸-羟基乙酸共聚物(PLGA)是由乳酸(lactic acid,LA)和羟基乙酸(GA)这两种单体按照不同比例缩聚而成,且经美国FDA批准用于组织工程、医用材料、药物载体的生物降解高分子聚合物。PLGA具有良好的生物相容性、生物可降解性、合成简单、稳定性高、降解速度可调节以及可塑性良好等特点。采用PLGA作为成膜材料制备的PLGA微泡具有稳定性佳、成像效果好等优点,为实现靶向超声成像提供了良好的基础。
PLGA分子量不同,制备微泡粒径存在差异,分子量越大,粒径越大;但差异无统计学意义。由体外成像证实(参考图5):当聚乳酸-羟基乙酸共聚物的分子量为1~2万时,其成像效果不佳,而当分子果与6~8万分子量相近;然而高分子量地的PLGA量为2~4万时成像效A更容易降解,因此,本发明选择2~4万分子量的PLGA。
在本发明的技术方案中,增加DSPE-PEG-iRGD,可以使得PLGA微泡具有靶向性,在添加DSPE-PEG-iRGD的基础上增加磁靶向,可以进一步提高其靶向性能。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述四氧化三铁纳米颗粒小于30nm。
在本明的技术方案中,四氧化三铁纳米颗粒的生物相容性好、可降解,对人体无毒副作用;四氧化三铁纳米颗粒能明显缩短T2弛豫时间,降低磁共振信号,是一种理想的磁共振阴性对比剂;此外,其颗粒小,不容易团聚,使得造影剂的分散系更好。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述DSPE-PEG-iRGD为DSPE-PEG2000-IRGD。
本发明使用DSPE-PEG2000-IRGD使得更好的携带靶点,提高了微泡的子宫内膜局部组织血管生成的靶向性,实现了超声/磁共振双模态成像。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述聚乳酸-羟基乙酸共聚物、二硬脂酰磷脂酰胆碱、DSPE-PEG-iRGD和四氧化三铁纳米颗粒之间的质量比为50:(1-2):(0.5-1.5):0.4。更优选地,聚乳酸-羟基乙酸共聚物、二硬脂酰磷脂酰胆碱、DSPE-PEG-iRGD和四氧化三铁纳米颗粒之间的质量比为50:1.5:1:0.4。
在本发明的技术方案中,DSPE-PEG-iRGD与二硬脂酰磷脂酰胆碱不同质量制备的PLGA微泡实验中发现,本发明的PLGA微泡具有较强的黏附能力,进一步提高了PLGA微泡靶向新生微血管效果。尤其当二硬脂酰磷脂酰胆碱和DSPE-PEG-iRGD的质量比为1.5:1,其形成的PLGA微泡再配合四氧化三铁纳米颗粒双靶向新生微血管效果更佳。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述磁性iRGD靶向的PLGA微泡的制备方法包括以下步骤:
S1.称取四氧化三铁纳米颗粒分散在双蒸水中形成混悬液,破碎乳化,制得四氧化三铁纳米颗粒储存液;
S2.称取聚乳酸-羟基乙酸共聚物溶于有机溶剂中,混合溶解后加入二硬脂酰磷脂酰胆碱、DSPE-PEG-iRGD与上述步骤S1制备的四氧化三铁纳米颗粒储存液混合,加入碳酸氢钠溶液进行乳化,再加入聚乙烯醇溶液,均质搅拌,得混合液;
S3.将上述步骤S2制得的混合液通风搅拌,使得有机溶剂完全挥发,然后将混合液离心,弃去上清液,重悬,冻干,制得PLGA微泡。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述步骤S1中混悬液的浓度为2mg/ml。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述磁性iRGD靶向的PLGA微泡的粒径为5097-5758nm。
本发明PLGA微泡的直径小于红细胞,可以自由通过肺循环,但不透过血管,实现血管池显像。
作为本发明所述iRGD磁性靶向微泡造影剂的优选实施方式,所述磁性iRGD靶向的PLGA微泡浓度为0.625-10mg/ml。
在本发明的技术方案中,磁性iRGD靶向的PLGA微泡浓度为0.625-10mg/ml,其磁性iRGD靶向的PLGA微泡(Mag-iPMB)的超声造影成像强度随PLGA微泡(Mag-iPMB)的浓度的增加而增高。
本发明的第二目的是提供了上述iRGD磁性靶向微泡造影剂在制备靶向新生微血管药物或检测试剂中的用途。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种iRGD磁性靶向微泡造影剂,本发明将iRGD和四氧化三铁纳米颗粒颗粒共载于PLGA微泡,进一步提高了微泡的子宫内膜局部组织血管生成的靶向性,实现了超声造影成像,有利于观察子宫内膜血管生成变化的过程。
附图说明
图1为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的基本表征图;
图1A为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的示意图;图1B为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的扫描电镜图;图1C为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的粒径分布情况图;图1D为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的明场示意图;图1E为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的荧光示意图;图1F为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的合成示意图;图1G为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的体外超声造影成像图;
图2为本发明iRGD靶向的PLGA微泡(Mag-iPMB)磁靶向性的验证实验图;
图2A为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)在磁场作用下移动的光学显微镜图;图2B为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)顺着生理盐水推注方向流动的超声造影模式图;图2C为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)在磁场作用下移动的超声造影模式图;图2D为在静止有磁场状态下磁性iRGD靶向的PLGA微泡(Mag-iPMB)的分布图;图2E为在静止非磁场状态下磁性iRGD靶向的PLGA微泡(Mag-iPMB)的分布图;
图3为本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的靶向粘附能力的验证实验图;
图3A为不同的磁性iRGD靶向的PLGA微泡(Mag-iPMB)在磁场作用下,分别与Bend.3,HUVEC的靶向黏附能力示意图;图3B为不同的PLGA微泡在磁场作用下,与Bend.3的靶向黏附微泡数量图(40倍显微镜);图3C为不同的磁性iRGD靶向的PLGA微泡(Mag-iPMB)在磁场作用下,与HUVEC的靶向黏附微泡数量图(40倍显微镜);
图4为DSPE-PEG2000-IRGD与二硬脂酰磷脂酰胆碱的不同质量比在磁性和非磁性条件下对Bend.3和HUVEC细胞影响示意图;
图5为不同分子量的PLGA微泡(PMB)的体外超声造影成像图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合附图和具体实施例对本发明作进一步说明。
在以下实施例中,若未特别指明,涉及的原料均可从市场上采购得到。
实施例1
所述磁性iRGD靶向的PLGA微泡的制备方法,包括以下步骤:
S1.合成DSPE-PEG2000-IRGD:将游离肿瘤穿透肽IRGD和DSPE-PEG-Maleimide以摩尔比1.5:1比例置于超纯水中,在冰浴的环境下(4℃),使用转子(200r/min)的充分搅拌反应24小时,然后将反应液置于透析袋(MWCO:3500)中透析48h,以滤除杂质,最后将透析过的反应液用移液枪移至西林瓶中并置于-80℃冰箱,冷冻后将西林瓶置于冷冻干燥48h,最终合成DSPE-PEG-iRGD,冻干后置于-20℃冰箱备用。
S2.制备四氧化三铁纳米颗粒储存液:首先将四氧化三铁纳米颗粒分散在双蒸水中,形成浓度为2mg/ml的混悬液,使用超声破碎仪进行乳化20分钟(参数为Time:0:20:00,Pulse:03 03,Ampl:60%),即可制备成四氧化三铁纳米颗粒储存液。使用前需用振荡器震荡1分钟。
S3.制备磁性iRGD靶向的PLGA微泡:称取50mg聚乳酸-羟基乙酸共聚物(PLGA)溶于二氯甲烷中(5%),使用小西林瓶装盛,待其溶解完全后,加入1mg二硬脂酰磷脂酰胆碱和1.5mg DSPE-PEG2000-iRGD,400μl四氧化三铁纳米颗粒储存液;200μl碳酸氢铵水溶液(60mg/ml);使用超声破碎仪将上述溶液乳化(参数为Time:0:02:00,Pulse:03 03,Ampl:30%),后将其加入装有5ml4%PVA水溶液的50ml离心管中,用均质机搅拌约3分钟,再加入10ml双蒸水再次用均质机混匀3分钟;将离心管内溶液倒至烧杯中,在通风橱内搅拌3小时,确保二氯甲醛挥发干净;将上述搅拌完全的溶液转移至50ml离心管内,放入离心机离心(5000转,5分钟);弃去上清液,用1ml双蒸水重悬,重复离心2次;最后用移液枪将悬液转移至中西林瓶内,放于-80摄氏度冰箱内冷冻2小时;冻干24小时即成磁性iRGD靶向的PLGA微泡(命名为Mag-iPMB),置于-20℃冰箱备用。该制备方法可以参照图1A。
实施例2
与实施例1相同,实施例2的区别在于,加入1.5mg二硬脂酰磷脂酰胆碱和1mgDSPE-PEG2000-iRGD,其余参数与制备方法与实施例1相同。
实施例3
与实施例1相同,实施例3的区别在于,加入2mg二硬脂酰磷脂酰胆碱和0.5mgDSPE-PEG2000-iRGD,其余参数与制备方法与实施例1相同。
对比例1
与实施例1相同,对比例1的区别在于,不含有DSPE-PEG2000-iRGD,加入2.5mg二硬脂酰磷脂酰胆碱,其余参数与制备方法与实施例1相同。
试验例一、本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)的基本表征
通过扫描电镜和马尔文粒径分析仪对实施例1制备的磁性iRGD靶向的PLGA微泡(Mag-iPMB)的形貌特征和粒径进行了测定。
参照图1B和图1C,结果显示PLGA微泡(Mag-iPMB)为5455±333.9μm的球形结构。
参考图1D、图1E和图1F,iRGD带有5-FAM荧光标记,结果证实了iRGD成功连接到PLGA微泡,合成了PLGA微泡(Mag-iPMB)。
参考图1G,当PLGA微泡浓度分别为0.625mg/ml、1.25mg/ml、2.5mg/ml、5mg/ml和10mg/ml时,其PLGA微泡(Mag-iPMB)的超声造影成像强度随PLGA微泡(Mag-iPMB)的浓度的增加而增高。
试验例二、本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)磁靶向性的验证实验
方法:1、配置1mg/ml实施例1的Mag-iPMB,将其滴加入培养皿。将其置于光学显微镜下,接着将一块长方形磁铁(40mm×20mm×10mm,3000高斯),并记录磁吸引过程。
2、用3%琼脂糖粉(VetecTM,MO,美国)溶解于去离子水制成仿腔体模,用于检测Mag-iPMB的超声成像能力。在仿腔底部放置长方形磁铁(40mm×20mm×10mm,3000高斯),将配置好的1mg/ml Mag-iPMB注入管腔内,记录磁吸引过程。
3、在装有Mag-iPMB的西林瓶旁放置长方形磁铁(40mm×20mm×10mm,3000高斯),静置10秒钟。
结果显示:参考图2A,在光学显微镜下显示Mag-iPMB在磁场作用下移动,证实其具有良好的磁靶向性。
参考图2B,在超声造影模式下显示,导管内注射Mag-iPMB后继续推注生理盐水,Mag-iPMB顺着推注方向流动。
参考图2C,在超声造影模式下显示,停止注射后,Mag-iPMB在磁场作用下移动,证实其具有较好的靶向性。
参考图2D和图2E,分别在静止状态,磁场(E)和非磁场(D)作用下,Mag-iPMB的分布,结果显示,Mag-iPMB在磁场作用下局部聚集。
通过比较iRGD靶向的PLGA微泡(Mag-iPMB)与非靶向PLGA微泡(PMB)与高表达αvβ3的细胞靶向粘附能力,结果发现iRGD靶向的PLGA微泡(Mag-iPMB)的靶向性能远高于非靶向PLGA微泡(PMB)的靶向性能(参考图2)。
试验例三、本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)靶向粘附能力的验证实验
实验方法:
1、将小鼠脑微血管内皮细胞(Bend.3)置于37摄氏度,5%CO2培养箱中培养。
2、当细胞融合达到80%~90%,用0.25%胰酶消化。
3、将消化下来的细胞按照4×104密度接种在直径35mm培养皿,每孔加入2ml完全培养基。
4、将细胞置于37摄氏度,5%CO2培养箱中培养过夜。
5、分别配置1mg/ml实施例1-3制备的磁性iRGD靶向的PLGA微泡(Mag-iPMB)、iRGD靶向PLGA微泡(iPMB)、磁性PLGA微泡(Mag-PMB)和,PLGA微泡(PMB),PLGA微泡(PMB)即本发明的对比例1。
6、按照分组,将1ml微泡分别加入到Bend.3细胞培养皿,皿底放置磁铁(40mm×20mm×10mm,3000高斯),在摇床上孵育5分钟后,吸弃培养基,PBS洗涤3次,镜检。
实施例1-3制备的磁性iRGD靶向的PLGA微泡(Mag-iPMB)靶向粘附人脐静脉内皮细胞(HUVEC)实验步骤同上。观察各自的靶向黏附能力。
参考图3A,靶向粘附能力大小为:Mag-iPMB>iPMB>Mag-PMB>PMB,证实本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)具有较强的黏附能力;
参考图3B,Mag-iPMB、iPMB、Mag-PMB和PMB在同样的磁场作用下,Mag-iPMB与Bend.3的靶向黏附微泡数量最多(40倍显微镜);参考图3C,Mag-iPMB、iPMB、Mag-PMB和PMB在同样的磁场作用下,Mag-iPMB与HUVEC的靶向黏附微泡数量最多(40倍显微镜),
且参考图4,实施例1制备的Mag-iPMB靶向性最好,与Bend.3或HUVEC靶向黏附微泡数量最多,实施例2-3制备的Mag-iPMB靶向性不及实施例1,而对比例1无靶向效果;说明本发明磁性iRGD靶向的PLGA微泡(Mag-iPMB)具有较强的靶向粘附能力,进一步提高了新生微血管的靶向性,实现了超声/磁共振双模态成像,有利于观察子宫内膜血管生成变化的过程。
最后所应当说明的是,以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (10)
1.一种iRGD磁性靶向微泡造影剂,其特征在于,所述iRGD磁性靶向微泡造影剂包括磁性iRGD靶向的PLGA微泡和包载PLGA微泡表面上的四氧化三铁纳米颗粒。
2.如权利要求1所述的iRGD磁性靶向微泡造影剂,其特征在于,所述磁性iRGD靶向的PLGA微泡由聚乳酸-羟基乙酸共聚物、二硬脂酰磷脂酰胆碱和DSPE-PEG-iRGD组成的脂质双分子层膜。
3.如权利要求1所述的iRGD磁性靶向微泡造影剂,其特征在于,所述四氧化三铁纳米颗粒小于30nm。
4.如权利要求1所述的iRGD磁性靶向微泡造影剂,其特征在于,所述DSPE-PEG-iRGD为DSPE-PEG2000-IRGD。
5.如权利要求2所述的iRGD磁性靶向微泡造影剂,其特征在于,所述聚乳酸-羟基乙酸共聚物、二硬脂酰磷脂酰胆碱、DSPE-PEG-iRGD和四氧化三铁纳米颗粒之间的质量比为50:(1-2):(0.5-1.5):0.4。
6.如权利要求2所述的iRGD磁性靶向微泡造影剂,其特征在于,所述磁性iRGD靶向的PLGA微泡的制备方法包括以下步骤:
S1.称取四氧化三铁纳米颗粒分散在双蒸水中形成混悬液,破碎乳化,制得四氧化三铁纳米颗粒储存液;
S2.称取聚乳酸-羟基乙酸共聚物溶于有机溶剂中,混合溶解后加入二硬脂酰磷脂酰胆碱、DSPE-PEG-iRGD与上述步骤S1制备的四氧化三铁纳米颗粒储存液混合,加入碳酸氢钠溶液进行乳化,再加入聚乙烯醇溶液,均质搅拌,得混合液;
S3.将上述步骤S2制得的混合液通风搅拌,使得有机溶剂完全挥发,然后将混合液离心,弃去上清液,重悬,冻干,制得磁性iRGD靶向的PLGA微泡。
7.如权利要求6所述的iRGD磁性靶向微泡造影剂,其特征在于,所述步骤S1中混悬液的浓度为2mg/ml。
8.如权利要求1所述的iRGD磁性靶向微泡造影剂,其特征在于,所述磁性iRGD靶向的PLGA微泡的粒径为5097-5758nm。
9.如权利要求1所述的iRGD磁性靶向微泡造影剂,其特征在于,所述磁性iRGD靶向的PLGA微泡浓度为0.625-10mg/ml。
10.如权利要求1-9任一项所述的iRGD磁性靶向微泡造影剂在制备靶向新生微血管药物或检测试剂中的用途。
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