CN114409679A - 一种靶膜小分子及其制备方法和应用 - Google Patents
一种靶膜小分子及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种多功能靶膜小分子BBT及其制备方法和在制备抗癌药物中的应用。该方法包括对起始原料1‑溴‑3,4,5‑三甲氧基苯经甲氧基脱除反应,卤素置换反应等进行修饰得到最终产物BBT,操作简单,产率高,损耗少。所制备的BBT具有高效的细胞嵌膜效果,可实现近红外二区的荧光标记,同时材料自身能够有效诱导细胞凋亡,抑制肿瘤生长,具有良好的化疗和光热治疗的效果。
Description
技术领域
本发明涉及抗癌药物技术领域,具体涉及一种用于癌症治疗的多功能靶膜小分子BBT及其制备方法和应用。
背景技术
化疗是当前癌症治疗中广泛运用的形式之一,主要通过化疗药物达到控制及杀死癌细胞的目的。化疗药物可以在体内绝大多数组织和器官中实现流通,可适用于转移性肿瘤等的治疗。但是它会导致一系列副作用,包括疲劳、恶心、呕吐、脱发和血细胞减少等。光热治疗是当前新兴的癌症治疗方式,是指将光热材料注射到生物体内,通过靶向识别技术聚集到肿瘤部位,在外部光源照射下,将光能转换为热能,达到杀灭癌细胞的效果,避免了手术后通常会遇到的严重感染相关综合征,也避免了化疗药物的副作用,具有微创及较低生物毒性等优点。
相对化疗和光疗,癌症的靶向治疗技术仍显得较为稚嫩,许多问题尚未得到解答。但近年来,靶向治疗的发展已提出了数种效果显著的治疗方案。在靶向治疗中,主要是靶向关键致癌信号蛋白的小分子激酶抑制剂。通过对这些激酶的竞争性和非竞争性抑制,以及它们激活的途径,癌症可以被减轻甚至彻底根除[3]。使用抗体或纳米材料的靶向治疗虽然提高了癌症治疗的准确性和安全性,然而,肿瘤内已确定的分子靶点的缺乏和异质性导致靶向药物的分布不均匀,影响了治疗效果]。因此靶向肿瘤细胞膜的药物开发显得至关重要。
细胞膜上具有丰富的磷脂和蛋白,磷脂双分子层的骨架上有各种各样的载体蛋白、通道蛋白等,具有选择透过性,在维持细胞内稳态、以及多项生命活动中都扮演者十分重要的角色,细胞出现的异常情况在细胞膜上也会有所体现,因此检测细胞膜的状况对于癌症治疗有着重要的意义。
细胞膜靶向探针可用于活体和体外活细胞成像、疾病诊断和肿瘤靶向治疗。然而,目前大多数可用的细胞膜探针是蓝色或绿色发射荧光团,均在可见光发射光区域,在组织中的穿透深度很低。近红外荧光(NIRF)探针的发射波长在650~1450nm之间,生物组织在这一光学区域的光吸收较低。因此,现有技术中的NIRF探针已可实现一定程度上的有效地避免背景干扰,具备一定的深层组织的生物成像能力。与传统荧光探针相比,NIRF探针具有更深的组织穿透性,有利于体内和体外成像,但是目前现有技术中的近红外荧光探针产率不高且不能实现近红外二区的可靠的荧光标记。
发明内容
为了进一步提高细胞膜的靶向和标记效率,且进一步降低靶向探针受生物样品背景干扰,实现对深层组织的生物成像;本发明提供了一种用于癌症治疗的多功能靶膜小分子BBT的制备方法及应用,能够实现对肿瘤相关的膜类物质在近红外二区进行可靠的荧光标记,且材料本身具有一定的化疗和光热治疗的效果。
第一方面,本发明提供一种靶膜小分子,是一种可用于癌症治疗的多功能靶膜小分子,其化学结构式如下所示,以下简称:BBT。
需要说明的是,上述化学式中的Me代表甲基。
制备过程如下:
(1)制备中间体1的合成方法,其结构为:合成步骤包括:起始原料以二氯甲烷作溶剂,在干冰/丙酮中冷却至-78℃下稳定并加入三溴化硼脱除甲氧基,后在40℃下缓慢反应,反应后加入饱和氯化铵水溶液淬灭反应,混合物用乙酸乙酯进行萃取并用硫酸镁干燥,后进行过柱纯化得到中间体1。
(3)中间体3的结构为:合成步骤包括:中间体2与醋酸钾、联硼酸频那醇酯、1,4-二氧六环以四氢呋喃作溶剂,抽真空鼓氮气,加入催化剂1×1`双(三苯基膦)二茂铁于95℃反应,用二氯甲烷萃取后过柱纯化得到中间体3。
第三方面,本发明还提供了上述靶膜小分子在制备抗癌药物中的应用,通过上述步骤合成了目标分子BBT,通过实验数据分析可得,BBT水溶液在近红外二区有较强的荧光信号,因此,与传统的荧光探针相比,它可以更好地避免背景干扰,实现对深层组织的生物成像。同时,由于BBT分子独特的阳离子聚合物结构,使得材料本身带正电荷,在与细胞共孵育15min后,大量的BBT镶嵌在带负电荷的细胞膜上,实现了在近红外二区靶向和标记细胞膜的功能,为后续细胞膜状况的检测及药物治疗提供帮助。此外,本课题组还发现,0.05mg/mL的BBT就可对癌细胞造约70%的杀伤,材料表现出优异的化疗效果。对材料施加808nm激光照射,表现出良好的光热转换能力,能在低功率密度的照射下,有效抑制人乳腺癌细胞的生长,提高乳腺癌的治疗效率,可用于生物体的光热治疗。本发明的近红外二区多功能靶膜小分子合成方法简单,材料成分是有机分子,不引入有毒成分,不存在有毒试剂残留问题,生物安全性高。
附图说明
图1是目标产物多功能靶膜小分子BBT的核磁共振氢谱图;
图2是多功能靶膜小分子BBT的紫外吸收光谱,荧光发射光谱;
图3是多功能靶膜小分子BBT和细胞膜荧光探针DiD共定位实验的细胞靶膜效果图;
图4是多功能靶膜小分子BBT的细胞毒性实验结果图;
图5是不同浓度的BBT水溶液在808nm激光器,1w/cm2功率密度的照射下,温度随时间的变化情况实验结果图;
图6是BBT水溶液在不同功率密度的808nm激光器的照射下,温度随时间的变化情况实验结果图;
图7是BBT水溶液在808nm激光器,1w/cm2的功率密度下,四次升降温循环曲线图;
图8是多功能靶膜小分子BBT在808nm激光照射下的细胞毒性实验结果图。
具体实施方式
下面结合说明书附图和具体的实施例,对本发明作详细描述。
实施例1:中间体1的制备
将1-溴-3,4,5-三甲氧基苯(5.0g,1.0eq)溶于100mL二氯甲烷中,抽真空鼓氮气,在干冰/丙酮浴中冷却至-78℃约30min后,逐滴加入三溴化硼(20.0g,,4.0eq),在-78℃下保温30min,随后将溶液缓慢升温至40℃。反应24h后,加入饱和氯化铵水溶液淬灭反应,将混合物过滤并用乙酸乙酯洗涤,后将滤液用乙酸乙酯萃取,用硫酸镁干燥有机相并使用硅胶柱层析分离纯化(乙酸乙酯:正己烷=3:10),得到中间体1。
实施例2:中间体2的制备
将碳酸钾(4.0g,6.0eq)和中间体1溶于100mL丙酮中,抽真空鼓氮气,加入5-溴-1,2,3-苯三酚(1.0g,1.0eq),在90℃下加热回流并搅拌24h。反应结束后用二氯甲烷萃取并使用硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1),得到中间体2。
实施例3:中间体3的制备
将中间体2(1.0g,1.0eq)和醋酸钾(0.4g,2.5eq)、联硼酸频那醇酯(0.6g,1.3eq)、催化剂1×1'双(三苯基膦)二茂铁二氯化钯(24.0mg)加入反应瓶中,加入20.0mL 1,4-二氧六环,抽真空鼓氮气,于100℃下反应2h。反应结束后用二氯甲烷萃取,旋干并使用硅胶柱层析分离纯化(石油醚:二氯甲烷=10:2),得到中间体3。
实施例4:中间体4的制备
将中间体3(100.0mg,2.2eq)与(80.0mg,1.0eq)、碳酸钾(60.0mg,3.0eq)加入反应瓶中,添加10mL甲苯中、3mL乙醇及3mL水,抽真空鼓氮气,加入四丁基溴化铵及四(三苯基膦)钯(13.0mg),鼓氮气5min,并于115℃下反应20h,回流。反应结束后用二氯甲烷萃取并使用硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1),得到中间体4。
实施例5:中间体5的制备
将中间体4(100.0mg,1.0eq)和碘化钠(0.8g,100.0eq)溶于20mL丙酮中,在85℃下反应6天。反应结束后用二氯甲烷萃取并使用硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1),得到中间体5。
实施例6:终产物6的制备
将中间体5(100.0mg)溶解于20mL四氢呋喃中,在干冰/丙烯酸乙酯浴中冷却至-80℃,加入0.7mL三甲胺(4.2M)并于室温下反应24h,反应结束后用1000KD透析袋透析24h,进行冷冻干燥得到终产物BBT,如图1所示为产物6的核磁共振氢谱图。
1H NMR(400MHz,CDCl3)δ=8.93(s,2H),6.81(s,4H),4.06-3.94(d,12H),3.34(s,12H),3.07-3.03(m,54H),2.78(s,4H),1.81-1.70(m,26H),1.55-1.51(m,14H),1.38-1.36(m,10H)1.16–1.00(m,66H),0.80-0.77(m,12H)ppm.
实施例7:用于癌症治疗的多功能靶膜小分子BBT的紫外吸收光谱及荧光发射光谱。
取实施例6制备得到的BBT配置成0.05mg/mL的水溶液,测量其紫外吸收和荧光发射,结果如图2所示。结果表明,如图2中左图所示BBT材料在800nm左右有紫外吸收,如图2中右图所示在1100nm左右有较强的荧光信号。此结果说明成功合成了在近红外二区具有独特吸收峰的小分子材料BBT。
实施例8:用于癌症治疗的多功能靶膜小分子BBT的靶膜性能
将人体***细胞(Hela cell)接种在共聚焦皿中,每孔接种105个细胞,待细胞密度长至60%即可使用。将BBT水溶液用培养基稀释到50μM,在含有95%空气和5%CO2气体的培养箱中于37℃下作用15min,用PBS缓冲溶液冲洗3遍,在共聚焦显微镜设备上观察材料的嵌膜效果。同时,用购自凯基生物的商业细胞膜荧光探针DiD作为参照,验证BBT的靶膜性能。
图3是分别实施细胞膜荧光探针DiD和BBT进入Hela细胞后,在共聚焦显微镜设备上的荧光成像图、两者的荧光成像叠加图及荧光线性图,其中,a图和b图分别是单独使用BBT和DiD处理后的细胞膜荧光成像图,c图是a图和b图中的荧光成像图进行叠加后的荧光成像叠加图;在c图所示的细胞膜上取3个点分别对应c图中的1、2、3三个点,再分别作出三个点对应的荧光线性图,分别如d图、e图和f图所示。实验结果表明BBT与细胞共孵育15min后,成功实现细胞嵌膜,产生的荧光与细胞膜荧光探针DiD的荧光重合,证实了BBT能够对肿瘤相关的膜类物质在近红外二区进行可靠的荧光标记。
实施例8:用于癌症治疗的多功能靶膜小分子BBT的细胞毒性测试
将BBT水溶液配制成不同浓度(0.05、0.10、0.30、0.60、1.00mg/mL)进行MTT测试。先将Hela细胞(人***细胞)接种在96孔板上,孵育24h,细胞密度约80%,将孔内的培养液移出,加入不同浓度的材料,继续孵育24h,后吸出培养液,用PBS缓冲液冲洗三遍。加入MTT试剂之后再孵育4h,最后加入DMSO,在恒温摇床上进行摇匀,利用酶标仪测定吸收峰为490nm的吸收值。同样的操作进行BBT对4T1细胞(小鼠乳腺癌细胞)以及正常细胞Smoothmuscle cell(平滑肌细胞)和Fibroblast cell(成纤维细胞)的毒性测试。
图4是分别实施不同浓度的BBT水溶液对于Hela细胞、4T1细胞以及Smooth muscle细胞和Fibroblast细胞的细胞毒性图,其中图4左侧图为不同浓度的BBT水溶液对于Hela细胞、4T1细胞的细胞毒性图,图4右侧图为不同浓度的BBT水溶液对于Smooth muscle细胞和Fibroblast细胞的细胞毒性图;实验结果表明0.05mg/mL的BBT就对癌细胞造成了约70%的杀伤,材料表现出优异的化疗效果。
实施例9:用于癌症治疗的多功能靶膜小分子BBT的光热转换性能测试
为了评价本发明制备的BBT材料在近红外激光照射下的升温效果,取终产品用超纯水分别配置成10μg/mL、50μg/mL、100μg/mL的溶液,在808nm激光射下(10min),功率密度控制为1w/cm2,进行光热转换性能测试。以超纯水作为空白对照,结果如图5所示,可知在实验浓度范围内,BBT溶液表现出优异的光热转换能力,随着照射时间的延长,溶液的温度明显升高,而且升温效果随着浓度的增加而提高。
随后,分别将功率密度设定为1w/cm2、1.5w/cm2、1.75w/cm2,测试100μg/mL的BBT溶液在808nm激光射下(10min),的光热转换能力。结果如图6所示,可知在实验功率密度范围内,BBT溶液表现出优异的光热转换能力,随着照射时间的延长,溶液的温度明显升高,而且升温效果随着功率密度的增大而提高。
最后,通过在808nm激光射下,功率密度控制为1w/cm2,测试100μg/mL的BBT溶液循环升温降温曲线,结果如图7所示,可知BBT溶液具有稳定的光热转换能力。
实施例10:用于癌症治疗的多功能靶膜小分子BBT在激光照射下的细胞毒性测试
将BBT水溶液配制成不同浓度(20、40、60、80μg/mL)进行MTT测试。先将Hela细胞接种在两块96孔板上,细胞密度长至约80%后,将孔内的培养液移出,加入不同浓度的材料,其中一块板予以808nm激光照射10min,功率密度控制为1w/cm2,继续孵育24h,吸出培养液,用PBS缓冲液冲洗3遍。加入MTT试剂之后再孵育4h,最后加入DMSO,在恒温摇床上进行摇匀,利用酶标仪测定吸收峰为490nm的吸收值。
图8是分别实施不同浓度的BBT对于Hela细胞在施加激光照射后的细胞毒性对比图。实验结果表明施加激光照射即对应图中的BBT+laser,BBT溶液在较低的使用浓度下,就可以对癌细胞造成明显的杀伤,表现出一定的光热治疗效果。
Claims (10)
9.如权利要求1所述多功能靶膜小分子在制备抗癌药物中的应用,其特征在于,所述靶膜小分子具有细胞膜靶向功能和近红外二区光热性能。
10.如权利要求1所述多功能靶膜小分子在制备抗癌药物中的应用,其特征在于,所述靶膜小分子的浓度为0.05mg/mL。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110655640A (zh) * | 2019-08-02 | 2020-01-07 | 中国科学院大学 | 一种室温柔性日盲型短波红外聚合物光电探测器及其制备方法 |
CN111569068A (zh) * | 2020-05-14 | 2020-08-25 | 南京邮电大学 | 一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法 |
CN113861391A (zh) * | 2021-10-08 | 2021-12-31 | 桂林理工大学 | 一种用于近红外二区成像的双给体共轭聚合物及应用 |
CN114163618A (zh) * | 2022-01-27 | 2022-03-11 | 香港中文大学(深圳) | 基于苯并双噻二唑或噻二唑喹喔啉的窄带隙聚合物及其制备方法和应用 |
CN115710283A (zh) * | 2022-10-18 | 2023-02-24 | 郑州中科生物医学工程技术研究院 | 化合物及其制备方法和应用、近红外-IIa荧光成像造影剂的制备方法 |
-
2022
- 2022-01-26 CN CN202210093910.3A patent/CN114409679B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110655640A (zh) * | 2019-08-02 | 2020-01-07 | 中国科学院大学 | 一种室温柔性日盲型短波红外聚合物光电探测器及其制备方法 |
CN111569068A (zh) * | 2020-05-14 | 2020-08-25 | 南京邮电大学 | 一种有机无机杂化光敏剂及杂化纳米诊疗试剂的制备方法 |
CN113861391A (zh) * | 2021-10-08 | 2021-12-31 | 桂林理工大学 | 一种用于近红外二区成像的双给体共轭聚合物及应用 |
CN114163618A (zh) * | 2022-01-27 | 2022-03-11 | 香港中文大学(深圳) | 基于苯并双噻二唑或噻二唑喹喔啉的窄带隙聚合物及其制备方法和应用 |
CN115710283A (zh) * | 2022-10-18 | 2023-02-24 | 郑州中科生物医学工程技术研究院 | 化合物及其制备方法和应用、近红外-IIa荧光成像造影剂的制备方法 |
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