CN116603078A - 吲哚七甲川菁类染料在制备近红外荧光显像口服制剂中的应用 - Google Patents
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Abstract
本发明属于生物医药领域,具体涉及吲哚七甲川菁类染料在制备近红外荧光显像口服制剂中的应用。本发明针对恶性肿瘤光学显像需求,制备了吲哚七甲川菁类近红外荧光染料的口服制剂,通过荷瘤小鼠动物模型实验,创造性地发现了该类制剂能够通过灌胃的方式,递送并富集在恶性肿瘤组织中,能够通过近红外荧光对肿瘤进行显像,清楚区别肿瘤边界和周围正常组织。
Description
技术领域
本发明属于生物医药领域,具体涉及吲哚七甲川菁类染料在制备近红外荧光显像口服制剂中的应用。
背景技术
癌症严重危害人们的生命健康。确定肿瘤的位置与大小是制定有效治疗方案的重要因素。手术是实体瘤治疗的重要手段之一,但行外科手术切除肿瘤时,对肿瘤切缘进行快速、准确的识别仍然相当困难。近年来,近红外荧光成像技术在解决这一难题方面表现出了很大的临床应用价值和潜力,具有无射线辐射危害、价格低、敏感性高、可实时成像等突出优点,另外近红外荧光探针发射波长处于650-900nm,与紫外或者可见光区荧光分子探针相比,背景荧光干扰低、组织穿透力强。因此发展具有良好肿瘤靶向性的近红外荧光探针成为目前肿瘤光学检测和手术导航方面的开发热点。
已有研究表明吲哚七甲川菁类近红外荧光染料可以用于肿瘤检测。吲哚菁绿染料(ICG)是一种临床血管造影、肝功能检测药物,近年来也在临床上用于肝癌、口腔癌等多种实体瘤的荧光介导手术。ICG与肿瘤组织结合作用的特异性不高,难以精准指定肿瘤边缘。通过与肿瘤靶向单抗偶联,吲哚七甲川菁类染料可以特异性地在肿瘤组织中聚集,从而更好地区别肿瘤与周围正常组织。已有研究还发现,一些吲哚七甲川菁类染料分子通过静脉注射到荷瘤动物模型后,可以在肿瘤组织处显示增强的近红外荧光信号,具有广谱肿瘤荧光显像性质(ClinCancerRes.2010;16(10):2833)。一些脂溶性的吲哚七甲川菁类染料分子制备成纳米颗粒后也可以通过静脉注射给药的方式,用于肿瘤显像(JMater ChemB.2021;9(20):4079)。将带有磺酸基的吲哚七甲川菁类染料IRDye800CW与靶向整合素αvβ3受体的低分子量配体偶联得到的染料在口服后,可以对乳腺癌进行显像(MolPharmaceutics.2018;15:1746)。
发明内容
现有技术中存在的技术问题是现有肿瘤近红外荧光显像剂绝大部分是非肠道制剂。然而,其他给药途径相比,口服给药被认为是最自然、简单、方便和安全的给药方式。现有的肿瘤整合素αvβ3受体靶向近红外荧光染料虽然可以经口服吸收后,对乳腺癌进行显像,但该显像剂是由结构较小的的靶向基团与具有很大位阻的近红外荧光染料分子偶联而成的,缺乏肿瘤靶向广谱性,难以用于αvβ3受体表达量低的其它恶性肿瘤的显像。
由于口服给药相比静脉注射给药,具有更高的药物安全性和更好的病人依从性。本发明的目的是针对恶性肿瘤光学显像诊断、精准判定边缘和介导手术的需求,提供一种具有良好体内递送并在肿瘤组织中富集性质的、可以用于各种恶性肿瘤近红外荧光显像和介导手术的广谱口服显像制剂,为精准判定恶性肿瘤的边缘、实施精准的切除手术提供简便、可靠的技术方案。
为了解决上述存在的技术问题,本申请提供如下技术方案:
本发明提供吲哚七甲川菁类染料在制备近红外荧光显像口服制剂中的应用,所述吲哚七甲川菁类染料为水溶性化合物或脂溶性化合物,结构式如下:
其中,X选自链烃、环烃、羧酸和磺酸中的一种,Y选自链烃、环烃、羧酸和磺酸中的一种;所述链烃、环烃、羧酸和磺酸的碳链长度均为1-8。
优选的,所述吲哚七甲川菁类染料为MHI-148或IR-783,结构式如下:
优选的,所述吲哚七甲川菁类染料为IR-780,结构式如下:
优选的,所述吲哚七甲川菁类染料为水溶性化合物时,所述近红外荧光显像口服制剂的溶剂为水且pH=5.5-7.8。
进一步地,所述近红外荧光显像口服制剂的pH=6-7。
进一步地,近红外荧光显像口服制剂还包含pH缓冲剂。
具体的,所述pH缓冲剂选自醋酸和醋酸钠组合物、磷酸二氢盐和氢氧化钠组合物、苯二甲酸氢钾和氢氧化钠组合物、枸橼酸和磷酸氢二盐组合物、磷酸氢二盐和磷酸二氢盐组合物中的一种。
进一步地,所述近红外荧光显像口服制剂还包含抗氧化剂;所述抗氧化剂为维生素C和维生素E中的一种或两种。
优选的,所述吲哚七甲川菁类染料为脂溶性化合物时,所述近红外荧光显像口服制剂由以下步骤制备得到:
S1:将摩尔比为0.2-5:45-64.8:35-50的吲哚七甲川菁类染料、磷脂和磷脂-聚乙二醇聚合物溶于有机溶剂后旋蒸,得到干燥脂膜;
S2:向所述干燥脂膜加入水相介质进行水化,过滤,得到所述近红外荧光显像口服制剂;所述有机溶剂为氯仿或乙醇,所述水相介质为水或生理盐水。
进一步地,所述步骤S2中,过滤使用纳米滤膜。
进一步地,所述近红外荧光显像口服制剂的总脂类浓度为10-50mM。
具体的,所述近红外荧光显像口服制剂的总脂类浓度为30mM。
优选的,所述近红外荧光显像口服制剂在服用后进行荧光检测;所述荧光检测的激发波长780nm,荧光发射波长≥810nm。
本发明针对恶性肿瘤光学显像需求,制备了吲哚七甲川菁类近红外荧光染料的口服制剂,通过荷瘤小鼠动物模型实验,创造性地发现了该类制剂能够通过灌胃的方式,递送并富集在恶性肿瘤组织中,能够通过近红外荧光对肿瘤进行显像,清楚区别肿瘤边界和周围正常组织。
本发明的技术方案相比现有技术具有以下优点:
本发明的口服显像制剂具有多方面的技术优点。1、口服显像制剂的制备工艺简便。2、使用安全,具有良好的病人依从性。3、肿瘤显像功能良好。具有广谱肿瘤显像能力,可以实时获取影像,能准确区分肿瘤边界,用于介导肿瘤切除手术有助于提高手术的精准度。
附图说明
图1为吲哚七甲川菁类染料的结构式。
图2为PANC-1细胞胰腺癌荷瘤小鼠给予生理盐水灌胃后的光学影像图。
图3为PANC-1细胞胰腺癌荷瘤小鼠给予磷脂胶束溶液灌胃后的光学影像图。
图4为U87细胞脑胶质瘤移植瘤小鼠给予生理盐水灌胃后的近红外荧光影像图。
图5为U87细胞脑胶质瘤移植瘤小鼠给予生理盐水灌胃后的近红外荧光影像图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,以使本领域的技术人员可以更好地理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1
称取11.5mg近红外荧光染料MHI-148固体粉末,加入5ml生理盐水,超声振荡溶解,得到2.3mg/mL的MHI-148溶液。
实验例2
称取11.25mg近红外荧光染料IR-783固体粉末,加入5ml生理盐水,振荡溶解,得到2.25mg/mL的IR-783溶液。
实验例3
称取2.5mg近红外荧光染料IR-780固体粉末,与82.4mg的二硬脂酰基磷脂酰胆碱(DSPC)、63.7mg的二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)(摩尔比为2.5:55:42.5)混合,溶于8ml乙醇中,减压蒸馏得到干燥脂膜后,再加入4mL的生理盐水进行水化,超声振荡5分钟后,将得到的悬浊液经100nm聚碳酸酯滤膜挤出得到0.625mg/ml的透明澄清的蓝绿色磷脂胶束口服液。
实验例4
采用人胰腺癌PANC-1细胞系建造胰腺癌荷瘤小鼠模型。将100万个细胞与基质胶混合,皮下注射于4-6周龄BALB/c nu/nu小鼠大腿根部,待一周后瘤体积增长到80-100立方毫米,准备进行影像实验。
实验例5
采用U87细胞系建造脑胶质瘤荷瘤小鼠模型。将200万个细胞/0.1mL的PBS溶液皮下注射于4-6周龄雌性BALB/c nu/nu小鼠腋窝下,待两周后瘤体积增长到300-500立方毫米,准备进行影像实验。
实验例6
给予胰腺癌荷瘤小鼠灌胃0.072mg,94nmol MHI-148/0.1mL的生理盐水。24小时后,小鼠经异氟烷气体麻醉,用IVIS小动物活体成像系统摄取光学影像。结果如图2所示,肿瘤部位相比正常组织有明显增强的近红外荧光信号。
实验例7
给予胰腺癌荷瘤小鼠灌胃0.063mg,94nmol IR-780/0.1mL的磷脂胶束溶液。分别于第3天和第六天用异氟烷气体麻醉小鼠,用IVIS小动物活体成像系统摄取光学影像。结果如图3所示,近红外荧光影像能够清楚显示肿瘤部位。
实验例8
给予脑胶质瘤荷瘤小鼠灌胃0.23mg,301nmol MHI-148/0.1mL的生理盐水,分别于第3天和第六天用异氟烷气体麻醉小鼠,用IVIS小动物活体成像系统摄取光学影像。结果如图4所示,近红外荧光影像能够清楚显示肿瘤部位。对小鼠实施安乐死,解剖后摄取光学影像,可见肿瘤组织比周围组织的近红外荧光强度显著增强。
实验例9
给予脑胶质瘤荷瘤小鼠灌胃0.225mg,300nmol IR-783/0.1mL的生理盐水,分别于第3天和第六天用异氟烷气体麻醉小鼠,用IVIS小动物活体成像系统摄取光学影像。结果如图5所示,近红外荧光影像能够清楚显示肿瘤部分。对小鼠实施安乐死,解剖后摄取光学影像,可见肿瘤组织比周围组织的近红外荧光强度显著增强。
效果评价
图2为PANC-1细胞胰腺癌荷瘤小鼠给予0.072mg,94nmol MHI-148/0.1ml生理盐水灌胃24小时后的光学影像。其中,a为白光影像;b为近红外荧光影像。两个数字标示分别代表作为对照区的左侧正常组织、右侧肿瘤组织的荧光辐射效率(p/sec/cm2/sr/(μW/cm2))。白色箭头指向肿瘤部位。
图3为PANC-1细胞胰腺癌荷瘤小鼠给予0.063mg,94nmol IR-780/0.1ml磷脂胶束溶液灌胃后的光学影像。其中,a为第24小时,白光影像;b为第24小时,近红外荧光影像;c为第6天,白光影像;d为第6天,近红外荧光影像。白色箭头指向肿瘤部位。
图4为U87细胞脑胶质瘤移植瘤小鼠给予0.23mg,301nmol MHI-148/0.1ml生理盐水灌胃后的近红外荧光影像。其中a为第3天,俯卧位;b为第6天,俯卧位;c为第6天,仰卧位;白色箭头指向肿瘤部位。
图5为U87细胞脑胶质瘤移植瘤小鼠给予0.225mg,300nmol IR-783/0.1ml生理盐水灌胃后的近红外荧光影像;a为第3天,俯卧位;b为第6天,俯卧位;c为第6天,仰卧位;白色箭头指向肿瘤部位。
显然,上述实施例仅仅是为清楚地说明所作的举例,并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.吲哚七甲川菁类染料在制备近红外荧光显像口服制剂中的应用,其特征在于,所述吲哚七甲川菁类染料为水溶性化合物或脂溶性化合物,结构式如下:
其中,X选自链烃、环烃、羧酸和磺酸中的一种,Y选自链烃、环烃、羧酸和磺酸中的一种;所述链烃、环烃、羧酸和磺酸的碳链长度均为1-8。
2.如权利要求1所述的应用,其特征在于,所述吲哚七甲川菁类染料为MHI-148或IR-783,结构式如下:
3.如权利要求1所述的应用,其特征在于,所述吲哚七甲川菁类染料为IR-780,结构式如下:
4.如权利要求1所述的应用,其特征在于,所述吲哚七甲川菁类染料为水溶性化合物时,所述近红外荧光显像口服制剂的溶剂为水且pH=5.5-7.8。
5.如权利要求4所述的应用,其特征在于,近红外荧光显像口服制剂还包含pH缓冲剂。
6.如权利要求5所述的应用,其特征在于,所述pH缓冲剂选自醋酸和醋酸钠组合物、磷酸二氢盐和氢氧化钠组合物、苯二甲酸氢钾和氢氧化钠组合物、枸橼酸和磷酸氢二盐组合物、磷酸氢二盐和磷酸二氢盐组合物中的一种。
7.如权利要求4所述的应用,其特征在于,所述近红外荧光显像口服制剂还包含抗氧化剂;所述抗氧化剂为维生素C和维生素E中的一种或两种。
8.如权利要求1所述的应用,其特征在于,所述吲哚七甲川菁类染料为脂溶性化合物时,所述近红外荧光显像口服制剂由以下步骤制备得到:
S1:将摩尔比为0.2-5:45-64.8:35-50的吲哚七甲川菁类染料、磷脂和磷脂-聚乙二醇聚合物溶于有机溶剂后旋蒸,得到干燥脂膜;
S2:向所述干燥脂膜加入水相介质进行水化,过滤,得到所述近红外荧光显像口服制剂;所述有机溶剂为氯仿、乙醇和异丙醇中的一种或多种,所述水相介质为水或生理盐水。
9.如权利要求8所述的应用,其特征在于,所述近红外荧光显像口服制剂的总脂类浓度为10-50mM。
10.如权利要求1-9中任一项所述的应用,其特征在于,所述近红外荧光显像口服制剂在服用后进行荧光检测;所述荧光检测的激发波长780nm,荧光发射波长≥810nm。
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