CN107522773B - 一种五肽改性罗丹明b化合物及其制备方法和应用 - Google Patents
一种五肽改性罗丹明b化合物及其制备方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药技术领域,具体涉及一种五肽改性罗丹明B化合物及其制备方法和应用。
背景技术
当前癌症治愈的关键在于临床上早期发现、早期诊断、早期治疗,即是否能较早地发现微小病灶,并进行及时有效地治疗。近年来,随着光学成像和荧光标记技术的迅速发展,活体荧光成像作为一种生物光学成像方法应运而生,被广泛地应用于细胞示踪、肿瘤诊断与药物开发等方面,在临床应用上显现出广阔的应用前景。活体荧光成像技术的基本原理是利用荧光探针对生物特定组织进行标记,采用高灵敏度的光学检测设备,实现对活体内的荧光信号进行实时和原位检测。与磁共振成像等传统成像技术相比,活体荧光成像具有许多独特的优点,包括较高的空间和时间分辨率,无电离辐射,能够进行长期高频的监测,性质稳定,能够获得定量的结果与较高的组织对比度,可以适用于多参数复合测量,成像结果直观,且仪器设备价格适中。
一般情况下,生物分子其自身荧光较弱或者基本无荧光,探测灵敏度非常低,使得人们用强荧光的标记试剂物即荧光探针对待测的目标分子进行标记或衍生,形成荧光强度较高的非共价或者共价结合的物质,从而可大大地降低检出限。荧光探针主要分为三大类:通过化学反应合成的荧光小分子;细胞自身通过基因编码产生的可发出荧光的蛋白质;以分子直径大和高量子产量为特点的纳米颗粒。
由于荧光发光是通过激发荧光物质的核外电子到达高能级状态,然后产生发射光,在进行活体动物荧光反射成像时,生物体的毛发、皮肤、食物等都会在激发光的激发下产生荧光,对信号荧光的采集和提取造成干扰。基于有机荧光染料探针的荧光成像技术因具有背景干扰低、对细胞损伤小、样品穿透性强、检测灵敏度高等优点,显示了较好的应用前景。一般来说,亮度高、分子量小、亲水性好和不带电荷的小分子荧光基团更适合体内成像。有机荧光染料探针如荧光素、氟硼荧染料、罗丹明类和青色素衍生物、5-氨基乙酰丙酸、六氨基乙酰丙酸酯、金丝桃素等已得到开发与应用。
然而罗丹明类、5-氨基乙酰丙酸、六氨基乙酰丙酸酯等目前所使用的荧光探针都是小分子化合物,在体内根据各部位代谢的不同需要而在人体内进行分布,不具有组织、器官选择性或靶向性,尤其对肿瘤没有特异性的作用,对肿瘤的成像效果较差,在体内代谢速度快,存留时间短,利用率低,国内外还没有肿瘤靶向性荧光探针进入临床应用,对肿瘤靶向的荧光探针以及用于癌症成像检测的研究较少,因此研制具有我国自主知识产权的肿瘤靶向性荧光探针,提高我国肿瘤临床早期诊断与良恶性肿瘤的鉴别诊断水平,具有十分重要的意义与深远的影响。
发明内容
本发明所要解决的技术问题是针对现有技术中存在的上述不足,提供一种灵敏度高、具有肿瘤靶向性并且毒性低的五肽改性罗丹明B化合物及其制备方法和应用。
为解决上述技术问题,本发明提供的技术方案是:
提供一种五肽改性罗丹明B化合物,所述五肽改性罗丹明B化合物具有式Ⅰ的化学结构式:
其中Q具有如下的化学结构式:
其中R1选自亚烷基、亚芳基或者是带有一个或多个羟基、氧、仲氨基、烷氧基、芳基或芳氧基的亚烷基;R2、R3分别独立地选自N(CH2CH3)2、N+H(CH2CH3)2、=O、OH、NH2、=N+H2中的一种。
按上述方案,所述式Ⅰ中Q结构式为:
本发明还提供上述五肽改性罗丹明B化合物的制备方法,其步骤如下:
1)采用固相多肽合成法制备酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸;
2)将酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸化合物与罗丹明B分子混合,通过酰胺键偶联反应得到五肽改性罗丹明B化合物。
按上述方案,所述酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸化合物与罗丹明B分子摩尔比为1:1。
本发明还包括上述五肽改性罗丹明B化合物在荧光成像方面的应用。
五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR)对肿瘤具有较好的靶向性,可作为肿瘤靶向性基团。本发明采用五肽化合物与罗丹明B反应,所得五肽改性罗丹明B化合物可用于人体或其他哺乳动物体内肿瘤的荧光分析与医学荧光成像诊断的荧光探针。小鼠体内药物分布实验表明,五肽改性罗丹明B化合物可被肿瘤选择性摄取与富集,在肿瘤中的浓度较高,从而实现肿瘤靶向成像,提高成像对比度和清晰度。
本发明的有益效果在于:1、本发明提供的五肽改性罗丹明B化合物具有肿瘤靶向性或选择性,作为荧光成像的示踪剂可实现肿瘤靶向成像,提高成像对比度和清晰度,另外,本发明提供的五肽改性罗丹明B化合物使用剂量比罗丹明B可以减少一半,而且水溶性好,便于配成溶液进行灌注或注射使用。2、本发明所述制备方法工艺简单,产率较高。
附图说明
图1为本发明实施例1所制备的五肽改性罗丹明B化合物、罗丹明B与生理盐水(对照组)对小鼠体内乳腺癌4T-1肿瘤的荧光成像对比照片。
具体实施方式
为使本领域技术人员更好地理解本发明的技术方案,下面结合附图对本发明作进一步详细描述。
实施例1
制备五肽改性罗丹明B化合物,步骤如下:
1)采用固相多肽合成法制备五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR);
2)将0.5g五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR,0.84mmol)加入容器中,加入9-(2-羧基苯基)-3,6-双(二乙氨基)占吨翁氯化物(罗丹明B,0.4g,0.84mmol)和二异丙基乙胺(0.11g,0.84mmol)的DMF溶液(10mL),搅拌反应1.5小时,过滤,收集滤液及洗涤液,旋蒸浓缩后滴加到冷***中得到红色沉淀,抽滤洗涤制得0.51g五肽改性罗丹明B化合物红色固体粉末,产率60%。
测试本实施例制备的五肽改性罗丹明B化合物作为荧光成像的示踪剂的效果,并以相同剂量的罗丹明B作为对照,测试方法如下:
在三组BAL B/C小鼠(每组6只)后大腿皮下种植乳腺癌4T-1肿瘤,将相同剂量的罗丹明B小分子荧光化合物(RhB)、本实施例制备的五肽改性罗丹明B荧光化合物(YIGSR-RhB)的生理盐水溶液,以及生理盐水(对照组)分别通过皮下注射入种植乳腺癌小鼠体内,将小鼠用倒置荧光显微成像仪对小鼠乳腺癌肿瘤进行荧光成像(480nm)。如图1所示为分别注射本实施例所制备的五肽改性罗丹明B化合物、罗丹明B及对照组(生理盐水)的小鼠体内乳腺癌4T-1肿瘤的荧光成像对比照片,可以看出注射罗丹明B(RhB)及生理盐水的小鼠体内乳腺癌4T-1肿瘤的荧光成像较差,而注射五肽改性罗丹明B荧光化合物(YIGSR-RhB)的小鼠体内乳腺癌4T-1肿瘤可得到较好的荧光成像,表明本实施例制备的YIGSR-RhB对乳腺癌4T-1肿瘤具有较好的肿瘤靶向作用。另外,五肽改性罗丹明B化合物成像效果突出、水溶性好,因此使用剂量上可比罗丹明B减少一半。
实施例2
制备五肽改性罗丹明B化合物,步骤如下:
1)采用固相多肽合成法制备五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR);
2)将1g五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR,1.68mmol)加入容器中,加入9-(2-羧基苯基)-3,6-双(氨基)占吨翁氯化物(0.62g,1.68mmol)和二异丙基乙胺(0.22g,1.68mmol)的DMF溶液(20mL),搅拌反应2小时,过滤,收集滤液及洗涤液,旋蒸浓缩后滴加到冷***中得到红色沉淀,抽滤洗涤制得1.11g五肽改性罗丹明B化合物红色固体粉末,产率70%。
实施例3
制备五肽改性罗丹明B化合物,步骤如下:
1)采用固相多肽合成法制备五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR);
2)将5g五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR,8.4mmol)、9-(2-羧基苯基)-3,6-双(羟基)占吨翁化合物(0.4g,8.4mmol)、二环己基碳二亚胺(DCC,1.73g,8.4mmol)和三乙胺(0.85g,8.4mmol)溶于二甲基亚砜溶液(100mL)中,冰水浴下搅拌反应4小时,用乙醇/***混合溶剂(体积比1/5)沉淀,过滤收集固体。然后将固体用DMF溶解,再用乙醇/***混合溶剂(体积比1/5)进行重沉淀,过滤收集固体,真空干燥24小时,制得6.16g五肽改性罗丹明B化合物红色固体粉末,产率80%。
实施例4
制备五肽改性罗丹明B化合物,步骤如下:
1)采用固相多肽合成法制备五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR);
2)将10g五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR,16.8mmol)、9-(2-异氰酸酯-丁基-氨基甲酸(乙二胺)酯-甲酰胺基-苯基)-3,6-双(二乙氨基)占吨翁氯化物(11.458g,16.8mmol)和三乙胺(1.7g,16.8mmol)溶于300mL DMF中,冰水浴下搅拌反应2小时,室温搅拌反应4小时,用乙醇/***混合溶剂(体积比1/5)沉淀,过滤收集固体,然后将固体用DMF溶解,再用乙醇/***混合溶剂(体积比1/5)进行重沉淀,过滤收集固体,真空干燥24小时,制得19.14g五肽改性罗丹明B化合物红色固体粉末,产率90%。
Claims (4)
2.一种权利要求1所述的五肽改性罗丹明B化合物的制备方法,其特征在于步骤如下:
1)采用固相多肽合成法制备酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸;
2)将酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸化合物与罗丹明B分子混合,通过酰胺键偶联反应得到五肽改性罗丹明B化合物。
3.根据权利要求2所述的制备方法,其特征在于所述酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸化合物与罗丹明B分子摩尔比为1:1。
4.根据权利要求1所述的五肽改性罗丹明B化合物在荧光成像方面的应用,该应用是非治疗或非诊断目的的。
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