CN111676011A - 一种吲哚菁绿-磷脂复合物及其制备方法和应用 - Google Patents
一种吲哚菁绿-磷脂复合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种吲哚菁绿‑磷脂复合物及其制备方法和应用。本发明中制备的两亲性ICG‑磷脂复合物在体外和体内同时展现出良好的鳌合铁离子的能力。通过该螯合作用，铁磁学性质和ICG自身光谱性质会受到影响，并且可通过检测核磁共振信号变化值、荧光信号以及光声信号变化值定量体内外活性铁量，从而用于诊断铁过载疾病程度。本发明还涉及所述ICG/磷脂复合物可显著降低活体动物铁负荷，展示出优于临床用去铁敏(DFO)的去铁疗效。本发明中使用的ICG和磷脂为临床应用药物，构建的复合物具有很强的临床应用可行性，从而使得该两亲性ICG‑磷脂复合物为铁过载疾病的临床诊疗提供了新的方案。
Description
技术领域
本发明涉及吲哚菁绿-磷脂复合物及其制备方法和应用。
背景技术
铁过载是指铁代谢异常，体内铁含量超过正常水平所导致的一种病理状态。当体内铁含量超过转铁蛋白的结合能力时，铁便会在体内某些部位沉积，通过Fenton反应产生大量氧化自由基，引起脂质、蛋白质、核酸损伤，从而导致肝脏、心脏、胰腺、垂体、关节等重要部位的结构损害和功能障碍，与肝癌、贫血、骨质疏松、子宫内膜异位等多种疾病有关，其中肝脏是最主要的肝代谢和储存器官，故体内铁沉积情况对肝脏健康状态有非常大的影响，并且与肝细胞癌(HCC)关系尤为密切。遗传因素和输血过量都可能引起铁过载的发生，当患者接受了20个单位以上的红细胞输注或血清铁蛋白大于1000ug/L，就可诊断为铁过载。鉴于铁过载患者症状多样、病情发展缓慢、早期不易被发现，但肝脏中的过量铁沉积会加重某些肝病原有的损伤、促使其发生纤维化甚至肝硬化的事实，准确定量检测、尽早发现并降低铁过载对防止铁代谢紊乱发展成肝癌至关重要。
目前，测量铁过载的方法主要有肝组织活检、血清铁蛋白(serum ferritin，SF)检测、SQUID检测、CT检查、磁共振成像(magnetic resonance imaging，MRI)等，其中MRI因其高准确性、良好的可重复性以及无创的特点而备受青睐。MRI是检测铁过载程度的一种新兴的方法。它利用肝脏中铁沉积会引起肝内水质子扩散的磁性不均匀的现象对肝脏中的信号改变进行监测，从而来间接测量肝铁浓度，敏感性较为出色。目前国内外用于检测铁过载的MRI方法主要有：信号强度测量法(包括信号强度比(signal intensity ratio，SIR)和同反相位信号强度差异)、T2/R2测量法(如多回波mapping技术和Ferri Scan技术)、T2/R2测量法、Dixon及其衍生技术、超短回波时间(ultroshort echo time，UTE)成像技术及磁敏感加权成像技术(包括常规磁敏感加权成像和定量磁敏感图(quantitative susceptibilitymapping，QSM))。但是在使用MRI进行铁过载测量时，损伤肝脏中的脂肪量和由大量铁过载引起的异常信号会提供不准确的铁浓度评估，因此,改进当前MRI检测方法或引入其他成像方法来精确、无创地检测体内过量的铁具有临床必然性。
发明内容
针对现有铁过载疾病诊疗技术的不足，本发明的主要目的在于提供一种基于ICG(吲哚菁绿)-磷脂复合物的制备方法及其应用。
本发明利用一种基于ICG的自组装复合体系作为造影剂和光敏剂，将MRI与PAI(光声成像)结合起来，构建一种多模态铁过载检测方法，能够实现对肝脏中铁浓度的精确、无创、动态测量。
本发明提供的ICG及ICG-磷脂复合物具有良好的生物相容性和荧光性质、优异的铁螯合性能。该ICG-磷脂与铁形成络合物造成的荧光性质和铁磁性质变化提供了荧光和核磁检测信号。本发明所述ICG-磷脂与铁形成络合物提供890nm波长处光学性质的变化，便于实现进一步光声成像性能，为铁过载诊疗附加更多的功能。且ICG-磷脂体现出增加体内铁排泄和降低活体血清铁蛋白水平的功能。
与现有技术相比，本发明取得的突出技术效果包括：
(1)利用Fe3+与ICG-磷脂复合物结合过程中，Fe3+浓度与T1值负相关的特性，实现使用多种核磁共振成像方法对铁沉积浓度的精确定量检测与动态监测。
(2)利用Fe3+与ICG-磷脂复合物结合过程中，Fe3+浓度与荧光信号值相关的特性，实现使用荧光成像仪对铁沉积浓度的精确定量检测与动态监测。
(3)利用Fe3+与ICG-磷脂复合物结合过程中，Fe3+浓度与890nm激发光下光声信号值相关的特性，实现使用光声成像仪对铁沉积浓度的精确定量检测与动态监测。
(4)提供一种新的针对铁过载的多模态成像检测方法，将由磁共振成像(MRI)提供的高空间分辨率和由在890nm处吸光增强的光声成像(PAI)信号提供的丰富的光学对比度结合起来,从而更好地提供治疗计划和评估治疗结果。
(3)利用ICG-磷脂可以显著促进体内铁排泄和降低活体内血清铁蛋白水平的特性，实现对铁过载的诊疗一体化。
附图说明
图1单纯铁离子、磷脂+铁离子、吲哚菁绿+磷脂+铁离子、吲哚菁绿+铁离子在1.5T核磁共振仪中的1/T1信号值。
图2吲哚菁绿-磷脂中加入不同浓度铁离子对应的光声信号值。附图为光声信号图。
图3 100μM铁离子中加入吲哚菁绿和吲哚菁绿+磷脂，离心取上清铁浓度测定。
具体实施方式
以下通过具体的制备例和实施例可使本发明得到更清楚的说明，但本发明的整体构思并不局限于该实施例，本领域的专业技术人员往往可以通过同样的思路对实验中的某一步进行替换，但本发明的整体思路仍受保护：
本发明所述的一种ICG-磷脂复合物，包括ICG、磷脂以及作为溶剂的水，其中，所述的ICG：磷脂摩尔比例为1:10-10:1，磷脂和ICG在水中的浓度分别为0.05-5mg/mL。
在本发明中，所述的磷脂是含有磷酸的脂类中的任意一种。作为优选，所述的磷脂为大豆卵磷脂。
本发明一种ICG-磷脂复合物的制备方法，包括以下步骤：
磷脂和ICG分别分散为水溶液，并且浓度分别为0.1-10mg/mL；将两种溶液进行混合。
本发明靶标中活性铁离子浓度的检测方法，包括如下步骤：
(1)制备前述的ICG-磷脂复合物；
(2)对成像目标注射所述ICG-磷脂复合溶液，利用核磁共振成像仪中的包括T1,T1*,T2,T2*,GRE,QSM在内的序列扫描所述成像目标的待扫描区域，成像出具有铁范围的结构图像并获得信号值，及计算出信号变化值对应总铁浓度；或
对成像和治疗目标注射所述ICG-磷脂复合溶液，利用光声成像仪中890nm处波长的光源激发扫描所述成像目标的待扫描区域并且成像出具有铁范围的结构图像并获得信号变化值，及计算出信号值对应总铁浓度；或
对成像和治疗目标注射所述ICG-磷脂复合溶液，利用荧光成像仪光源激发扫描所述成像目标的待扫描区域并且成像出具有铁范围的结构图像。
在本发明的优选实施例中，所述成像目标为含铁活性铁离子的物质，包括液体、病理切片、生物组织中的至少一种。
在本发明的优选实施例中，所述荧光信号值为激发波长在230-1000nm。
两亲性ICG(吲哚菁绿)是一种已经被FDA批准用于临床的药物，已被用来作为动态评估肝功能和病人心输出量的标准。
实施例1
(a)吲哚菁绿溶液：首先，称取1mg吲哚菁绿小分子，加入1mL去离子水溶液并利用超声波清洗器超声2min使其完全溶解；
(b)吲哚菁绿-磷脂复合物：分别称取1mg吲哚菁绿小分子和大豆卵磷脂，分别加入1mL去离子水溶液并利用超声波清洗器超声2min使其完全溶解；而后1:1混合均匀备用；
实施例2
结合附图，在一些实施方式中，下述的成像目标为含铁水溶液。
(1)在100μL不同浓度(0-500μM)的高铁水溶液中加入100μL所述ICG(500μM)-磷脂(1mM)复合溶液，混合均匀，利用核磁共振成像仪扫描所述成像目标的待扫描区域和计算出信号值。如图1所示，可以看出本发明中制备的ICG-磷脂复合溶液890nm处光声值随铁离子浓度升高而升高，补充增强了MRI成像灵敏度不足的问题。
(2)在100μL不同浓度(0-500μM)的高铁水溶液中加入100μL ICG(500μM)、磷脂(1mM)、ICG(500μM)-磷脂(1mM)复合溶液，混合均匀，利用核磁共振成像仪扫描所述成像目标的待扫描区域并及计算出信号值。如图2所示，可以看出本发明中制备的ICG(500μM)、ICG-磷脂复合溶液可完全屏蔽铁离子浓度的T1信号值，这为用MRI定量活性铁离子浓度提供新的思路。在实际操作中，T2信号值也具备相应的信号变化趋势。
(3)在1mL 500μM的高铁水溶液中加入1mL所述ICG(500μM)、ICG(500μM)-磷脂(1mM)复合溶液,后5000转/分钟离心5分钟取上清。如图3所示，ICG、ICG-磷脂与活性铁离子结合后皆可增大结构密度，从而达到离心去除铁的作用，这将有利于促进体内过载铁的排泄。结合上述成像方式，利于实现对铁过载程度的动态监测和诊疗一体化。
Claims (9)
1.一种ICG-磷脂复合物，所述的复合物包括ICG、磷脂以及作为溶剂的水，其中，所述的ICG：磷脂摩尔比例为1:10-10:1，磷脂和ICG在水中的浓度分别为0.05-5mg/mL。
2.如权利要求1所述一种ICG-磷脂复合物，其特征在于，所述的磷脂是含有磷酸的脂类中的任意一种。
3.如权利要求1所述一种ICG-磷脂复合物，其特征在于，所述的磷脂为大豆卵磷脂。
4.如权利要求1至3任一项所述的一种ICG-磷脂复合物的制备方法，包括以下步骤：
磷脂和ICG分别分散为水溶液，并且浓度分别为0.1-10mg/mL；将两种溶液进行混合。
5.如权利要求1至3任一项所述的ICG-磷脂复合物在制备铁过载诊断试剂中的应用。
6.如权利要求1至3任一项所述的ICG-磷脂复合物在制备铁过载的铁排泄药物中的应用。
7.靶标中活性铁离子浓度的检测方法，包括如下步骤：
(1)制备权利要求1至3任一项所述的ICG-磷脂复合物；
(2)对成像目标注射所述ICG-磷脂复合溶液，利用核磁共振成像仪中的包括T1,T1*,T2,T2*,GRE,QSM在内的序列扫描所述成像目标的待扫描区域，成像出具有铁范围的结构图像并获得信号值，及计算出信号变化值对应总铁浓度；或
对成像和治疗目标注射所述ICG-磷脂复合溶液，利用光声成像仪中890nm处波长的光源激发扫描所述成像目标的待扫描区域并且成像出具有铁范围的结构图像并获得信号变化值，及计算出信号值对应总铁浓度；或
对成像和治疗目标注射所述ICG-磷脂复合溶液，利用荧光成像仪光源激发扫描所述成像目标的待扫描区域并且成像出具有铁范围的结构图像。
8.如权利要求7所述的方法，其特征在于，所述成像目标为含铁活性铁离子的物质，包括液体、病理切片、生物组织中的至少一种。
9.如权利要求如权利要求7所述的方法，其特征在于，所述荧光信号值为激发波长在230-1000 nm。
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| CN103690486A (zh) * | 2013-12-27 | 2014-04-02 | 深圳先进技术研究院 | 一种吲哚菁绿纳米靶向脂质体及其制备方法和应用 |
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| CN108578696A (zh) * | 2018-05-15 | 2018-09-28 | 厦门大学 | 一种脂质体微泡载金属-icg自组装复合体系 |
| CN110960694A (zh) * | 2019-12-12 | 2020-04-07 | 深圳先进技术研究院 | 一种用于近红外二区荧光检测的吲哚菁绿脂质体及其制备方法和用途 |
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