CN113476602A - 新型高光热转换效率花菁光敏剂的制备及肿瘤的自靶向光疗 - Google Patents
新型高光热转换效率花菁光敏剂的制备及肿瘤的自靶向光疗 Download PDFInfo
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Abstract
本发明公开了一种具有高光热转换效率的七甲川花菁光敏剂的制备及用于肿瘤靶向光疗。该光敏剂由两分子IR‑780与一分子TPE结构单元组成。溶液实验表明,该探针的光热,光动及光热稳定性均优于IR‑780与ICG,且光热转换效率高达38.5%;动物实验表明,该探针具有良好的肿瘤靶向性,且肿瘤部位荧光信号在测试期(96h)仍表现良好;动物光疗研究表明,该探针在较低的注射浓度下(0.8mg/kg),经两次808nm激光照射(0.8W/cm2),可明显抑制肿瘤生长,且生物安全性良好。该光敏剂制备简单,具有优异的光热转换效率、肿瘤靶向性及荧光持续性,因此,有望应用于临床肿瘤的手术导航及光疗研究中。
Description
技术领域
本发明属于荧光生物诊疗技术领域,具体涉及一种具有高光热转换效率的花菁光敏剂的制备及肿瘤自靶向光疗。
背景技术
光疗,包括光热疗法(Photothermal therapy,PTT)与光动力疗法(photodynamictherapy,PDT),是一种光诱导治疗癌症的模式。PTT是用特定波长的光照射光热剂(Photothermal agents,PTA),受激发的PTA在振动弛豫过程中释放热量引起肿瘤细胞的热损伤;PDT是用特定的光照射光敏剂(photosensitizer,PS),受激发的PS在激发单线态到长寿命三重态的系统间交叉后通过能量和/或电子转移产生大量活性氧物种(reactiveoxygen species,ROS)引起肿瘤细胞的化学损伤。
将两种不同的PDT和PTT分子组合成一个纳米平台是同步PDT和PTT治疗的最常见方法。为了增强肿瘤部位的渗透性和保留效应,纳米系统通常与肿瘤特异性靶标配体结合,以连接癌细胞膜上过表达的生物标志物。然而,由于激发光的穿透性不足和光子捕获能力弱,短波长(<700nm)或低摩尔消光系数的PSs无法在体内治疗中表现出有效的光敏性。同时,由于PTT和PDT试剂的激发行为不同,联合治疗可能需要使用两种不同的激光照射肿瘤,这会使治疗更加繁琐且依从性弱。此外,高肝脏积累和低肿瘤保留也限制了纳米药物的疗效和安全性。
近年来,七甲川花菁染料,因其在NIR区域(>700nm)中具有出色的光吸收、深层组织穿透、易于合成和低生物毒性等特点,作为有前途的近红外(NIR)荧光探针引起了广泛关注。其中,IR-780因具有近红外荧光成像和光疗性能(PTT和PDT,808nm激光),成为最具有代表性研究的光敏剂。最重要的是,其无需与肿瘤靶向配体进行化学偶联即能主动靶向肿瘤组织。然而,IR-780的近红外吸收依靠长的共轭链来实现,光热稳定性较差;共轭链易形成π-π堆积,光热转换效率不高,在光疗研究中同样需要增加剂量与提高激光功率,易造成严重的副作用。因此,提高IR-780的光热转化效率、光热稳定性与ROS产生效率,是 IR-780等花菁光敏剂在光疗研究领域和面临临床转化的首要关键点和难点。
发明内容
本发明的目的在于提供了一种具有PTT/PDT双重光疗效应及高效肿瘤靶向性能的光敏剂分子。该光敏剂具有高光热转换效率、光热稳定性和ROS生成能力;体内研究表现出有效的肿瘤靶向、滞留和低肝脏积累,可用于荧光成像引导光疗,低浓度抑制肿瘤生长。
本发明提供了一种具有高光热转换效率及高效肿瘤靶向性能的花菁光敏剂,其结构式(1)如下所示:
本发明提供的光敏剂合成步骤见附图1
本发明提供了光敏剂的制备方法,包括步骤如下:
氮气保护下,以无水DMF为溶剂,1,2-二苯基-1,2-二(4-羟基苯)乙烯和三乙胺室温搅拌 10分钟后加入含有IR-780碘化物的无水DMF溶液,并在85℃反应4小时。蒸干溶剂,粗产物通过硅胶色谱纯化,用CH2Cl2/CH3OH(v/v=15:1)洗脱,制备得到终产物T780T。
与现有技术相比,本发明的有益效果为:
本发明的高光热转换效率及高效肿瘤靶向性能的花菁光敏剂具有如下特点:(1)该光敏剂为对称性结构,具有正电荷,在水相中易自聚集成纳米粒;(2)该光敏剂具有高效的光热转换效率、光热稳定性与ROS产生效率;(3)该光敏剂在无载体情况下,可主动靶向肿瘤组织,体内研究中表现出有效的肿瘤靶向、保留和低肝脏积累;(4)该光敏剂在肿瘤部位的荧光信号具有时间依赖关系,96h荧光信号表现良好,因此,可用于肿瘤组织切除的手术导航中。(5)该光敏剂具有用量低,一次注射,多次照射的可操作性并有效抑制肿瘤的生长。
附图说明
图1为本发明光敏剂的合成路线。
图2为本发明光敏剂(10μM)分别在DMSO、乙醇、DMEM、水溶液里的紫外吸收图,荧光发射图及对应的TEM图。
图3为本发明光敏剂、IR-780、ICG的热循环与ROS产生对比图。
图4为本发明光敏剂在HeLa细胞中与MitoTracker Green共定位的T780T的共聚焦显微图像。
图5为本发明光敏剂的细胞毒性,光毒性与PTT/PDT占比图。
图6为本发明光敏剂在4T1荷瘤BALB/c小鼠体内静脉注射后的荧光成像,及注射24小时后荧光主要器官的分布和96小时内峰值的变化。Ex=745nm,Em=800nm。
图7为本发明光敏剂在4T1荷瘤BALB/c小鼠体内静脉注射后(24h,48h),808nm 激光(0.8W cm-2)照射不同时间,小鼠肿瘤部位温度变化。
图8为本发明光敏剂对肿瘤的抑制效果图。
图9为本发明光敏剂的安全性评价图。
具体实施方式
下面结合附图和实例,对本发明光敏剂及其制备方法和应用的具体实现作进一步说明。
实施例1:
探针T780T的合成:
合成方法如下:
具体步骤:向10mL两口瓶中加入1,2-二苯基-1,2-二(4-羟基苯)乙烯(7.3mg 0.02mmol),真空-氮气置换3次,用注射器加入2mL无水DMF,0.3mL无水三乙胺,室温搅拌 10分钟,然后用注射器加入1mL含有IR-780碘化物(40mg,0.06mmol)的无水DMF。氮气保护下,加热至85℃反应4h,TLC检测反应,反应完全后,不经其他处理,直接油泵蒸干溶剂,粗产物用硅胶快速柱分离,用CH2Cl2:CH3OH=15:1的洗脱液进行洗脱,得 T780T绿色固体,收率约为40%。1H NMR(400MHz,CDCl3):δ7.4(t,4H),7.26-6.85(m, 34H),6.00(d,4H),4.09(m,8H),2.61(t,4H),2.41(t,4H),1.94-1.81(m,12H),1.30(s,24H),0.98 (t,12H).HRMS(ESI)m/z:[M]+,计算,1371.8349;实际值,1371.8328。
实施例2:
紫外可见吸收光谱及荧光吸收光谱:分别配制10μM T780T的DMSO、乙醇、 DMEM和水溶液,在进行300–900nm的紫外可见光谱扫描并进行荧光测试。透射电子显微镜(TEM):将T780T溶液的稀释悬浮液沉积在碳涂层铜网格上干燥48h,使用透射电子显微镜(TEM)观察样品的形貌,结果如图2。
实施例3:
光稳定性与ROS产生:分别配制5μM T780T、IR-780、ICG的DMSO溶液,用0.3 W cm-2(808nm)激光照射10分钟,然后停止照射冷却至室温,重复此步骤四次,在此过程中每隔特定秒记录一次溶液的温度。用SOSG法测定ROS的产生,用0.3W cm-2( 808nm)激光照射8分钟,每隔特定时间扫描525nm处荧光峰值。结果如图3。
实施例4:
荧光共聚焦激光扫描显微镜成像:将A549细胞接种在35mm玻璃底培养皿中(共聚焦专用),密度为3*105/皿,培养过夜。分别加入5μM的探针T780T,培养1小时后,再加入50nM的Mito-tracker Green,继续培养1小时。吸出培养液,并用PBS洗3次,共聚焦显微镜记录细胞荧光,结果如图4。
实施例5:
细胞毒性及光毒性评价:将HeLa、A549细胞以每孔20000的密度接种于96孔板中,培养24h。将含有T780T的母液分别用培养基稀释成不同的浓度(0、0.6、1.2、2.5、5 、10μM)。将培养板中的培养基吸出,加入不同浓度的探针,24小时后,加入MTT溶液 (每孔20μL,5mgmL-1),孵育4小时。吸出MTT溶液及培养基的混合液,每孔加入 150μL DMSO,摇床震荡10min以充分溶解形成的甲瓒晶体。使用酶标仪记录570nm处的紫外吸收值,并用以下公式计算细胞生长活力:活力(%)=(实验组平均吸光度值/对照组平均吸光度值)*100%,得到细胞毒性数据。将含有T780T的母液分别用培养基稀释成不同的浓度(0、0.6、1.2、2.5、5μM),分为3组,一组加入ROS抑制剂,一组放于4度,一组为对照组,用0.3W cm-2(808nm)激光照射5min,如上测定细胞活性,结果如图5。
实施例6:
体内荧光成像:将悬浮在100μL PBS中的1×107 4T1癌细胞皮下植入每只BALB/c小鼠的右侧,当肿瘤体积达到约100mm3时,将T780T(100μM、100μL)静脉注射到小鼠体内。使用动物光学成像系统(IVIS,Caliper Life Sciences)在注射样品后的不同时间点捕获体内/体外荧光图像。记录注射24小时后荧光主要器官的分布和96小时内峰值的变化,样品在745nm处激发,800nm处发射。结果如图6。
实施例7:
体内光热:当肿瘤体积达到约100mm3时,分为3组,每组5只小鼠。两组小鼠静脉注射T780T(100μM,100μL),一组静脉注射PBS作为对照组。24小时后,用808 nm激光(0.8W cm-2,8分钟)照射一组小鼠。48小时后,再次用808nm激光照射该组小鼠(0.8W cm-2,8分钟),每隔一分钟记录一次温度。结果如图7。
实施例8:
肿瘤抑制与安全性评价:上述三组小鼠使用卡尺确定肿瘤大小并测量12天的持续时间。使用以下公式计算大小:体积=(肿瘤长度)×(肿瘤宽度)2×0.5。14天后,处死所有小鼠,收集所有组织(肿瘤、心脏、肝脏、脾脏、肺和肾脏)并固定在4%甲醛溶液中。取心、肝、脾、肺、肾等主要器官进行苏木精-伊红(H&E)染色进行组织学分析。结果如图8, 9。
Claims (10)
1.高光热转换效率的花菁光敏剂的制备及肿瘤自靶向光疗,其特征在于,光敏剂由两分子IR-780骨架结构与一分子TPE基团(分子运动能力增强基团,扭曲结构)构成。
2.如权利要求1所述的光敏剂,其特征在于,所述分子运动能力增强基团(扭曲结构)包含一个四苯乙烯分子构成的基本骨架。
3.如权利要求1所述的光敏剂,其特征在于,两分子IR-780结构骨架与TPE分子骨架通过氧醚键连接。
5.如权利要求1~4任一所述的光敏剂的制备方法,其特征在于,实验步骤如下:
氮气保护下,以无水DMF为溶剂,1,2-二苯基-1,2-二(4-羟基苯)乙烯和三乙胺室温搅拌10分钟后加入含有IR-780碘化物的无水DMF溶液,并在85℃反应4小时。蒸干溶剂,粗产物通过硅胶色谱纯化,使用CH2Cl2/CH3OH(v/v=15:1)作为洗脱液,制备得到终产物T780T。
6.如权利要求1~4任一所述光敏剂具有线粒体靶向性。
7.如权利要求1~4任一所述光敏剂具有高效的光热转换效率及光热稳定性。
8.如权利要求1~4任一所述光敏剂具有显著的PTT/PDT双重光疗效应。
9.如权利要求1~4任一所述光敏剂具有高效肿瘤靶向性及荧光持续性。
10.如权利要求1~4任一所述光敏剂具有用量低,一次注射,多次照射的可操作性。
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