CN116768874A - 一种基于苯并吲哚的i型aie光敏剂及其制备方法和应用 - Google Patents
一种基于苯并吲哚的i型aie光敏剂及其制备方法和应用 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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Abstract
本发明公开了一种基于苯并吲哚的I型AIE光敏剂及其制备方法和应用,属于生物医学材料领域,该I型AIE光敏剂为受体‑供体型,供体部分为连接有联二噻吩的芳香环衍生物给电子基团,受体部分含有苯并吲哚内盐结构;具有Type I活性氧产生能力,对氧气浓度依赖低,能够在肿瘤乏氧环境下实现高效的肿瘤杀伤且生物安全性好;另外,该I型AIE光敏剂具有AIE特性,具有聚集诱导荧光增强和活性氧产生能力增强的效果;且该I型AIE光敏剂具有近红外二区荧光发射,能够实现更深层次的肿瘤成像,还具有诱导细胞焦亡和细胞免疫原性死亡的作用,可作为细胞焦亡和细胞免疫原性死亡的诱导剂被广泛应用。
Description
技术领域
本发明属于生物医学材料领域,具体涉及一种基于苯并吲哚的I型AIE光敏剂及其制备方法和应用。
背景技术
细胞焦亡(pyroptosis)是一种近几年发现的炎性细胞死亡方式,是由炎性小体引发的细胞程序性死亡,表现为细胞不断胀大直至细胞膜破裂,导致细胞内容物释放进而引起强烈的炎症反应。细胞焦亡的发生依赖于炎性半胱天冬酶(caspase)和膜穿孔蛋白Gasdermin D(GSDMD)蛋白家族,被激活的caspase切割GSDMs蛋白,释放出其N端结构域,该结构域结合膜脂并在细胞膜上打孔,导致细胞渗透压的变化,进而发生胀大直至细胞膜破裂。细胞焦亡与神经性疾病、动脉粥样硬化、感染性疾病、阿尔兹海默症病、自身免疫性疾病等的发生和发展相关。但现有技术中能够诱导细胞焦亡的试剂种类比较少,主要是化疗药物分子,而这一类分子往往存在耐药性和一定的毒副作用。因此,开发新型的诱导细胞焦亡的试剂势在必行。
公开号为CN112341379A的中国专利文献公开了一种多芳基硫吡啶正离子盐光控细胞焦亡材料,是以多芳基硫单元为母核,通过去甲基化得到的水溶性材料,该多芳基硫吡啶正离子盐本身没有发光现象,且无AIE特性,但与生物大分子如DNA、BSA、HS等结合后,存在较强磷光现象;当其进入细胞后,在405nm的紫外激光下,细胞会迅速发生细胞焦亡现象,表现为光控细胞焦亡的特性。虽然该发明所公开的材料具有引起细胞焦亡的特性,但是无法实现活体肿瘤方面的应用,也没有提供引起细胞焦亡的通路或者机理,另外,该发明所施加的紫外激光本身对细胞会产生一定的不良影响。
公开号为CN114292276A的中国专利文献公开了一种基于卟啉四氮杂环的光控细胞焦亡材料,是以卟啉单元为母核,外围连有四个氮杂环,通过去甲基化得到的水溶性材料,具有快速的多波段光控细胞焦亡性质,作用波长最大可调至640nm可见光范围,极大地降低了光源本身对于细胞或生物体的伤害,同时也增强了光的穿透性,为光控细胞焦亡技术在肿瘤治疗领域提供了可行性。虽然该发明在一定程度上克服了公开号CN112341379A的发明的不足,但是,卟啉四氮杂环只能在单分子状态下使用,聚集会导致荧光猝灭或者活性氧产生能力降低。另外,该材料所产生的活性氧种类没有加以说明,也没有提供引起细胞焦亡的通路或者机理。
理想的抗肿瘤治疗不仅要破坏原发肿瘤,还要提高肿瘤微环境的免疫原性,光动力治疗可增强免疫刺激反应。光动力治疗的关键因素之一是光敏剂,AIE光敏剂能够有效克服传统光敏剂聚集导致的荧光和活性氧(ROS)产生能力降低的问题。另外,肿瘤微环境是乏氧环境,不利于依赖氧气的II型AIE光敏剂产生充足的单线态氧来杀死肿瘤细胞,而I型AIE光敏剂能克服肿瘤的乏氧环境,产生毒性更强的Type I自由基(H2O2,O2 2-,·OH等),高效杀伤肿瘤。因此,发展近红外发射的I型AIE光敏剂对光动力治疗在临床上的应用具有重要意义。
发明内容
本发明提供了一种基于苯并吲哚的I型AIE光敏剂,分子结构为受体-供体型,该I型AIE光敏剂具有Type I活性氧产生能力,对氧气浓度依赖低,能够在肿瘤乏氧环境下实现高效的肿瘤细胞杀伤,且能够诱导细胞焦亡和细胞免疫原性死亡,在肿瘤诊断和/或肿瘤治疗中应用广泛。
具体采用的技术方案如下:
一种基于苯并吲哚的I型AIE光敏剂,具有供体-受体结构,结构式如式(I)或(II)所示:
式(I)或(II)中,R1为芳香环衍生物给电子基团,包括芳胺取代的苯基、烷胺取代的苯基、烷氧基取代的四苯基乙烯基或四苯基乙烯基;R2为-CH2CH2OH、-CH2CH2COOH、-CH2CH2CH3或-CH2CH2CH2CH2CH3;X为Cl、Br或I。
优选的,所述的芳胺取代的苯基包括式(Ⅲ)所示结构式的任一种:
式(Ⅲ)中,*表示取代位置。
优选的,所述的烷胺取代的苯基包括式(Ⅳ)所示结构式的任一种:
式(Ⅳ)中,n为1~10的自然数,*表示取代位置。
优选的,所述的烷氧基取代的四苯基乙烯基包括式(V)所示结构式的任一种:
式(V)中,m为1~10的自然数,*表示取代位置。
本发明的I型AIE光敏剂具有供体-受体结构,供体部分为AIE荧光团且能够提供电子,中间的联二噻吩结构可以增加供体的供电性,减少分子HOMO与LUMO的能级差,受体部分含有苯并吲哚内盐结构;在苯并吲哚部分的氮原子上引入修饰基团的目的是在氮原子上引入正电荷,因而作为电子受体部分,负电荷的存在只是让整个分子对外表现为电中性,形成内盐,进而使得所得AIE光敏剂具有Type I活性氧产生能力以及聚集诱导荧光增强和活性氧产生能力增强的效果。
本发明还提供了所述的基于苯并吲哚的I型AIE光敏剂的制备方法,具体包括以下步骤:
(1)在钯催化剂、碱性条件下,芳基硼酸和5-溴-2,2'-二噻吩-5'-甲醛为原料以摩尔比1:0.8~1.2发生Suziki偶联反应得到中间体1;
(2)将中间体1和苯并吲哚类化合物为原料以摩尔比1:1~2发生亲核加成反应得到所述的基于苯并吲哚的I型AIE光敏剂;
所述的芳基硼酸的结构式为
所述的苯并吲哚类化合物的结构式为
其中,R1、R2、X的定义同上。
优选的,步骤(1)的反应过程中,采用四三苯基膦钯催化剂,碳酸钾提供碱性条件,在保护性氛围下反应,反应温度为80~130℃,反应时间为12~24h。
优选的,步骤(2)的反应过程中,采用哌啶作为催化剂,在保护性氛围下反应,反应温度为80~130℃,反应时间为6~24h。
本发明还提供了一种纳米颗粒,成分包括所述的基于苯并吲哚的I型AIE光敏剂。
所述的纳米颗粒的制备方法包括以下步骤:将所述的基于苯并吲哚的I型AIE光敏剂与表面活性剂混合,共沉淀制备得到所述的纳米颗粒。
所述的表面活性剂为DSPE-PEG2000,所述的基于苯并吲哚的I型AIE光敏剂与表面活性剂的质量比为1:1~3。
本发明还提供了所述的基于苯并吲哚的I型AIE光敏剂在制备肿瘤诊断和/或肿瘤治疗产品中的应用。
与现有技术相比,本发明的有益效果在于:
(1)本发明提供的基于苯并吲哚的I型AIE光敏剂具有Type I活性氧产生能力,对氧气浓度依赖低,能够在肿瘤乏氧环境下实现高效的肿瘤杀伤,抑制肿瘤的生长,且生物安全性好,不影响生物体的健康;另外,该I型AIE光敏剂具有AIE特性,具有聚集诱导荧光增强和活性氧产生能力增强的效果;其次,该I型AIE光敏剂具有近红外二区荧光发射,能够实现更深层次的肿瘤成像,在小鼠体内具有较亮的荧光信号。
(2)相较于现有技术中报道的I型AIE光敏剂,本发明中基于苯并吲哚的I型AIE光敏剂具有诱导细胞焦亡和细胞免疫原性死亡的作用,可作为细胞焦亡和细胞免疫原性死亡的诱导剂被广泛应用。
附图说明
图1为实施例1中TPA-BTIPS的紫外吸收光谱、荧光发射光谱和AIE曲线,其中,A为紫外吸收光谱,B为荧光发射光谱,C为AIE曲线。
图2为实施例4中TPA-BTIPS NPs的粒径分布图和TEM图,其中,A为动态光散射粒径分析图,B为TEM图。
图3为实施例4中TPA-BTIPS NPs的活性氧、羟基自由基、单线态氧产生能力数据图,其中,A为活性氧,B为羟基自由基,C为单线态氧。
图4为实施例4中TPA-BTIPS NPs在激光和无激光条件下对小鼠乳腺癌(4T1)细胞的毒性测试结果。
图5为TPA-BTIPS NPs在不同实验条件下诱导细胞焦亡的效果图,其中,A为空白对照组,B为空白加激光对照组,C为TPA-BTIPS NPs对照组,D为TPA-BTIPS NPs加激光实验组。
图6为4T1细胞在不同实验条件下的乳酸脱氢酶(LDH)释放统计图。
图7为蛋白质印迹法检测GSDMD和Caspase 1的裂解情况图。
图8为4T1细胞在不同实验条件下的碱性磷酸酶(ATP)释放统计图,其中,***代表P<0.001。
图9为4T1细胞在不同实验条件下引起细胞钙网蛋白外翻的实验结果图,A为空白对照组,C为空白加激光对照组,B为TPA-BTIPS NPs对照组,D为TPA-BTIPS NPs加激光实验组。
图10为4T1细胞在不同实验条件下引起细胞高迁移率组蛋白(HGMB)的实验结果图,A为空白对照组,C为空白加激光对照组,B为TPA-BTIPS NPs对照组,D为TPA-BTIPS NPs加激光实验组。
图11为TPA-BTIPS NPs辅以激光对实验小鼠的皮下瘤近红外二区荧光成像效果随时间的变化图。
图12为不同处理条件对实验小鼠肿瘤体积的影响图。
图13为不同处理条件对实验小鼠体重的影响图。
具体实施方式
下面结合实施例与附图,进一步阐明本发明。应理解,这些实施例仅用于说明本发明,而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施例1TPA-BTIPS的合成
(1)将4-硼酸三苯胺(化合物1,346.8mg,1.2mmol)、5-溴-2,2'-二噻吩-5'-甲醛(化合物2,273.0mg,1mmol),Pd(PPh3)4(69.3mg,0.06mmol)和K2CO3(828mg,6mmol)装入250mL的两口瓶,抽气10~15分钟,充入氮气2~5分钟,重复抽换气三次。然后将四氢呋喃和水的混合溶剂(v/v=2:1)共60毫升,用注射器注入反应瓶中,80℃反应回流24小时之后,将溶剂旋干,重新溶于二氯甲烷,用水洗涤三次,收集有机相,用无水硫酸镁干燥,过滤旋干。用硅胶柱色谱法分离,洗脱剂用石油醚/乙酸乙酯(PE/EA=10:1),得到橙红色粉末化合物3(340.8mg),产率约为78%。
(2)将化合物3(219mg,0.5mmol)和化合物4(253.7mg,0.8mmol)(按照文献Samaniego Lopez C,Lago Huvelle MA,Uhrig ML,Coluccio Leskow F,SpagnuoloCC.Recognition of saccharides in the NIR region with anovel fluorogenicboronolectin:in vitro and live cell labeling.Chem Commun(Camb).2015Mar 21;51(23):4895-8.doi:10.1039/c4cc10425k.合成)装入100mL的两颈瓶中,抽换氮气三次。之后加入30~50mL的乙醇(里面加入3~5滴的哌啶作为催化剂),80℃反应12h。最后将溶剂蒸干,用硅胶柱纯化,洗脱剂用二氯甲烷/甲醇(DCM/MeOH=10:1),得到蓝黑色粉末状的TPA-BTIPS(化合物5,即所述的基于苯并吲哚的I型AIE光敏剂,259mg),产率约为69%。
化合物3的鉴定数据如下:
1H NMR(500MHz,CDCl3)δ9.85(s,1H),7.67(d,1H),7.46(d,2H),7.31(d,1H),7.30(s,1H),7.28(d,2H),7.27(s,1H),7.24(d,1H),7.17(d,1H),7.14(s,2H),7.12(s,2H),7.06(m,4H).
13C NMR(126MHz,CDCl3)δ182.37,171.10,148.04,147.49,147.25,146.28,141.26,137.46,134.00,129.40,127.24,127.08,126.61,124.81,123.66,123.47,123.13,76.76.
TPA-BTIPS的鉴定数据如下:
1H NMR(500MHz,DMSO)δ8.76(d,1H),8.41(d,1H),8.33(d,1H),8.27(d,1H),8.19(t,2H),7.79(t,1H),7.67(m,5H),7.58-7.50(m,2H),7.36(t,4H),7.20-7.04(m,6H),6.99(d,2H),4.97-4.84(m,2H),2.70(s,2H),2.22(s,2H),2.01(s,6H).
13C NMR(126MHz,DMSO)δ181.25,148.05,147.28,147.15,146.07,144.95,139.11,138.36,134.14,133.49,131.53,130.54,130.21,129.01,128.77,127.40,127.33,127.20,126.79,125.16,125.03,124.34,123.58,122.96,113.64,109.98,53.91,47.86,45.88,30.35,26.01,25.22.
实施例2TPE-BTIPS的合成
(1)将4-(1,2,2-三苯基乙烯基)苯基硼酸(化合物6,451.2mg,1.2mmol)、5-溴-2,2'-二噻吩-5'-甲醛(化合物2,273.0mg,1mmol),Pd(PPh3)4(69.3mg,0.06mmol)和K2CO3(828mg,6mmol)装入250mL的两口瓶,抽气10~15分钟,充入氮气2~5分钟,重复抽换气三次。然后将四氢呋喃和水的混合溶剂(v/v=2:1)共60毫升,用注射器注入反应瓶中,80℃反应回流24小时之后,将溶剂旋干,重新溶于二氯甲烷,用水洗涤三次,收集有机相,用无水硫酸镁干燥,过滤旋干。用硅胶柱色谱法分离,洗脱剂用石油醚/乙酸乙酯(PE/EA=10:1),得到化合物7(490.6mg),产率约为78%。
(2)将化合物7(366.9mg,0.7mmol)和化合物4(253.7mg,0.8mmol)装入100mL的两颈瓶中,抽换气三次。之后加入30-50mL的乙醇(里面加入3~5滴的哌啶作为催化剂),80℃反应12小时。最后将溶剂蒸干,用硅胶柱纯化,洗脱剂用二氯甲烷/甲醇(DCM/MeOH=10:1),得到蓝黑色粉末状的TPE-BTIPS(即所述的基于苯并吲哚的I型AIE光敏剂,586mg),产率约为56%。
化合物7的鉴定数据如下:
1H NMR(400MHz,CDCl3)δ9.85(s,1H),7.67(d,J=4.0Hz,1H),7.35(d,J=8.3Hz,2H),7.30(d,J=3.9Hz,1H),7.23(d,J=3.9Hz,1H),7.21(d,J=3.9Hz,1H),7.13(s,3H),7.12(s,3H),7.10(d,J=2.5Hz,2H),7.09(s,1H),7.08(s,1H),7.05(d,J=8.5Hz,7H).
13C NMR(101MHz,CDCl3)δ182.42,147.31,146.15,143.94,143.44,140.04,137.41,134.80,132.13,131.41,131.31,127.89,127.81,127.69,127.18,126.76,126.65,126.59,124.95,124.04,123.97.
TPE-BTIPS的鉴定数据如下:
1H NMR(400MHz,DMSO)δ8.74(d,1H),8.41(d,1H),8.33(d,1H),8.27(d,1H),8.19(t,2H),7.79(t,1H),7.70(dd,2H),7.65(d,1H),7.62-7.58(m,1H),7.52(d,2H),7.16(dt,7.6Hz,9H),7.06-6.95(m,8H),4.91(s,2H),2.69(s,2H),2.24(s,2H),2.01(s,6H).
13C NMR(101MHz,DMSO)δ181.38,146.79,145.53,144.96,143.93,143.54,143.35,141.63,140.39,139.43,139.13,138.45,135.05,133.99,133.56,132.08,131.53,131.16,128.83,128.58,128.43,128.31,127.34,127.07,126.16,125.34,123.56,117.02,114.75,113.61,54.12,47.64,29.33,26.09,14.31.
实施例3DMA-BITPS的合成
(1)将4-二甲氨基苯硼酸(化合物8,363mg,2.2mmol)、5-溴-2,2'-二噻吩-5'-甲醛(化合物2,543.8mg,2mmol),Pd(PPh3)4(150.2mg,0.13mmol)和K2CO3(1.38g,10mmol)装入250mL的两口瓶,抽气10~15分钟,充入氮气2~5分钟,重复抽换气三次。然后将四氢呋喃和水的混合溶剂(v/v=2:1)共80毫升,用注射器注入反应瓶中,80℃反应回流24小时之后,将溶剂旋干,重新溶于二氯甲烷,用水洗涤三次,收集有机相,用无水硫酸镁干燥,过滤旋干。用硅胶柱色谱法分离,洗脱剂用石油醚/乙酸乙酯(PE/EA=10:1),得到化合物9(538.4mg),产率约为86%。
(2)将化合物9(500mg,1.6mmol)和化合物4(662.2mg,2mmol)装入100mL的两颈瓶中,抽换氮气三次。之后加入30-50mL的乙醇(里面加入3~5滴的哌啶作为催化剂),80℃反应12小时。最后将溶剂蒸干,用硅胶柱纯化,洗脱剂用二氯甲烷/甲醇(DCM/MeOH=10:1),得到蓝黑色粉末状的DMA-BTIPS(即所述的基于苯并吲哚的I型AIE光敏剂,681.3mg),产率约为68%。
化合物9的鉴定数据如下:
1H NMR(500MHz,CDCl3)δ9.85(s,1H),7.66(s,1H),7.51(s,2H),7.31(d,1H),7.22(d,1H),7.12(s,1H),6.79(d,2H),3.03(s,6H).
DMA-BITPS的鉴定数据如下:
1H NMR(400MHz,CDCl3)δ8.40(s,2H),8.08(t,3H),7.68(d,4H),7.49(s,2H),7.38(s,1H),7.32(s,1H),7.12(s,1H),6.84(s,2H),5.08-4.97(m,2H),3.15(s,2H),3.05(s,6H),2.47(s,2H),2.01(s,6H).
13C NMR(101MHz,DMSO)δ180.92,150.94,148.08,147.91,145.02,141.26,139.49,139.24,138.72,138.20,133.38,132.50,131.40,130.50,129.09,128.76,127.40,127.05,126.36,123.56,123.25,120.90,113.62,112.81,109.54,100.14,53.50,47.61,46.30,26.20,25.17.
实施例4
将实施例1合成的基于苯并吲哚的I型AIE光敏剂(TPA-BTIPS)溶液与DSPE-PEG2000溶液混合(TPA-BTIPS与表面活性剂DSPE-PEG2000的质量比为1:1),超声的情况下加入到水中,利用共沉淀的方法进行制备纳米颗粒(TPA-BTIPS NPs)。
样品分析
实施例1制得的TPA-BTIPS的紫外吸收光谱、荧光发射光谱和AIE曲线如图1中的A-C所示,TPA-BTIP的紫外吸收波长为630nm,荧光发射峰在960nm处,拖尾至1200nm,具有典型的AIE特性。
将实施例1制得的I型AIE光敏剂利用表面活性剂包裹成实施例4的纳米颗粒之后对其进行分析测试,实施例4制得的TPA-BTIPS NPs的动态光散射粒径分析图如图2中的A所示,平均直径约为52nm,TEM图如图2中的B所示。
用DCFH(活性氧检测剂)测试TPA-BTIPS NPs的活性氧产生能力,如图3中的A所示,激光5分钟后,TPA-BTIPS NPs对照组的荧光强度相较于初始荧光强度提升了500倍;如图3中的B所示,用HPF(羟基自由基检测剂)测试TPA-BTIPS NPs羟基自由基的产生能力,激光5分钟,TPA-BTIPS NPs对照组的荧光强度相较于初始荧光强度提升了17倍;如图3中的C所示,用ABDA试剂(单线态氧检测剂)测试TPA-BTIPS NPs的单线态氧的产生能力,ABDA的吸收基本上没有降低,从而说明TPA-BTIPS NPs几乎不产生单线态氧,以上结果证实TPA-BTIPS为I型AIE光敏剂。
分别利用0μg/mL,0.1μg/mL L,0.2μg/mL,0.4μg/mL,0.8μg/mL,1.6μg/mL,3.2μg/mL,6.4μg/mL,12.8μg/mL浓度的纳米颗粒与4T1细胞共培养,在相应的条件下测试该纳米颗粒在激光和无激光条件下对4T1细胞的毒性测试结果,结果如图4所示,TPA-BTIPS NPs在3.2μg/mL浓度以下没有细胞毒性,但是在660nm,0.1W/cm2的激光下照射5分钟就表现出明显的浓度依赖的细胞毒性。
分别设置空白组、空白加激光对照组、TPA-BTIPS NPs对照组和TPA-BTIPS NPs加激光实验组。利用TPA-BTIPS NPs孵育细胞4小时,分别施加激光和不施加激光。从图5中的D中可以明显观察到细胞周边的“泡泡”存在。而对于空白组(图5中的A)、空白加激光对照组(图5中的B)以及TPA-BTIPS NPs对照组(图5中的C),不存在细胞周边的“泡泡”这种现象。这种现象为细胞焦亡。细胞焦亡现象也通过乳酸脱氢酶(LDH)的释放含量得到了验证,如图6所示,相较于空白组、空白加激光对照组以及TPA-BTIPS NPs对照组,TPA-BTIPS NPs加激光实验组LDH的释放量高达65%。与此同时,蛋白质印迹(WB)结果(图7),证实该焦亡过程是通过激活Caspase 1变成Cleaved-caspase 1,进一步去切断GSDMD,产生Cleaved-GSDMD。Cleaved-GSDMD能在细胞膜上打孔,诱导细胞膜破裂释放内容物。另外,相较于空白组、空白加激光对照组以及TPA-BTIPS NPs对照组,TPA-BTIPS NPs加激光实验组中碱性磷酸酶(ATP)具有明显的释放量(图8),且钙网蛋白明显外翻(图9),高迁移率酯蛋白(HGMB1)明显迁移至细胞膜外(图10)。以上数据证明,TPA-BTIPS NPs在激光条件下,具有明显的诱导细胞焦亡和细胞免疫原性死亡的特性。
将TPA-BTIPS NPs尾静脉注射进入种有皮下瘤的小鼠体内,分别采集0小时、2小时、4小时、8小时、12小时、24小时、48小时的近红外二区荧光图片。从图11可以看出,在12小时时肿瘤部位的富集最大,这为后续的施加激光的时间提供了指导意义。
对实验小鼠尾静脉注射TPA-BTIPS NPs,在12小时时施加激光,相对于对照组,可以有效地抑制肿瘤的生长(图12),且小鼠体重也有缓慢地增加(图13),说明TPA-BTIPS NPs加激光的治疗手段并不影响小鼠的健康,此外,肝功能和肾功能的数据进一步证明了TPA-BTIPS NPs的生物安全性。
以上所述的实施例对本发明的技术方案进行了详细说明,应理解的是以上所述的仅为本发明的具体实施例,并不用于限制本发明,凡在本发明的原则范围内所做的任何修改、补充或类似方式替代等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种基于苯并吲哚的I型AIE光敏剂,其特征在于,结构式如式(I)或(II)所示:
式(I)或(II)中,R1为芳香环衍生物给电子基团,包括芳胺取代的苯基、烷胺取代的苯基、烷氧基取代的四苯基乙烯基或四苯基乙烯基;R2为-CH2CH2OH、-CH2CH2COOH、-CH2CH2CH3或-CH2CH2CH2CH2CH3;X为Cl、Br或I。
2.根据权利要求1所述的基于苯并吲哚的I型AIE光敏剂,其特征在于,所述的芳胺取代的苯基包括式(Ⅲ)所示结构式的任一种:
式(Ⅲ)中,*表示取代位置。
3.根据权利要求1所述的基于苯并吲哚的I型AIE光敏剂,其特征在于,所述的烷胺取代的苯基包括式(Ⅳ)所示结构式的任一种:
式(Ⅳ)中,n为1~10的自然数,*表示取代位置。
4.根据权利要求1所述的基于苯并吲哚的I型AIE光敏剂,其特征在于,所述的烷氧基取代的四苯基乙烯基包括式(V)所示结构式的任一种:
式(V)中,m为1~10的自然数,*表示取代位置。
5.根据权利要求1-4任一所述的基于苯并吲哚的I型AIE光敏剂的制备方法,其特征在于,包括以下步骤:
(1)在钯催化剂、碱性条件下,芳基硼酸和5-溴-2,2'-二噻吩-5'-甲醛为原料以摩尔比1:0.8~1.2发生Suziki偶联反应得到中间体1;
(2)将中间体1和苯并吲哚类化合物为原料以摩尔比1:1~2发生亲和加成反应得到所述的基于苯并吲哚的I型AIE光敏剂;
所述的芳基硼酸的结构式为
所述的苯并吲哚类化合物的结构式为
其中,R1、R2、X的定义同上。
6.根据权利要求5所述的基于苯并吲哚的I型AIE光敏剂的制备方法,其特征在于,步骤(1)的反应过程中,采用四三苯基膦钯催化剂,碳酸钾提供碱性条件,在保护性氛围下反应,反应温度为80~130℃,反应时间为12~24h。
7.根据权利要求5所述的基于苯并吲哚的I型AIE光敏剂的制备方法,其特征在于,步骤(2)的反应过程中,采用哌啶作为催化剂,在保护性氛围下反应,反应温度为80~130℃,反应时间为6~24h。
8.一种纳米颗粒,其特征在于,成分包括权利要求1-4任一所述的基于苯并吲哚的I型AIE光敏剂。
9.根据权利要求8所述的纳米颗粒,其特征在于,所述的纳米颗粒的制备方法包括以下步骤:将所述的基于苯并吲哚的I型AIE光敏剂与表面活性剂混合,共沉淀制备得到所述的纳米颗粒。
10.根据权利要求1-4任一所述的基于苯并吲哚的I型AIE光敏剂在制备肿瘤诊断和/或肿瘤治疗产品中的应用。
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