CN114805293A - D-π-A化合物、含有该化合物的具有近红外二区发光特性的多功能光疗剂 - Google Patents
D-π-A化合物、含有该化合物的具有近红外二区发光特性的多功能光疗剂 Download PDFInfo
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- CN114805293A CN114805293A CN202210324354.6A CN202210324354A CN114805293A CN 114805293 A CN114805293 A CN 114805293A CN 202210324354 A CN202210324354 A CN 202210324354A CN 114805293 A CN114805293 A CN 114805293A
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Abstract
Description
技术领域
本发明属于光疗技术领域,涉及一种具有近红外二区发光特性的多功能光疗剂,具有近红外二区荧光成像引导的光热和光动力协同癌症治疗的潜力。
背景技术
全球身患癌症的人数在逐年增加,已成为对人类健康的严重威胁。生物医学的发展已经开辟了癌症治疗的新领域,其中光疗可以在诊断的同时进行原位治疗,这已被证明是癌症治疗的卓越方案。在诊断方面,相比于传统的磁共振成像、计算机断层扫描和X光成像,荧光成像技术具有分辨率较高,侵入性小,响应速度快的特点,特别是近红外二区(1000-1700nm)的荧光成像在生物医学领域受到广泛关注,归因于它较深的组织穿透力、较低的组织自发荧光干扰和较少的组织光损伤。在治疗方面,传统的肿瘤治疗手段的缺陷和后遗症比较多,给人们带来了严重的精神负担,开发一种毒副作用小、治疗效果佳的治疗技术被人们所期待。
光疗(光动力/光热)凭借其毒副作用小、治疗效果好等优点步入人们的眼帘,因其高选择性、无创性、良好的可控性和可忽略的耐药性而受到了广泛关注。光动力治疗主要通过形成活性氧(ROS)破坏肿瘤的血管系统,导致癌细胞缺少供能系统,从而间接的杀死癌细胞。光热治疗依靠具有光热效应的材料将光转换为热,从而使细胞膜变松并使各种蛋白质变性,以不可逆转的方式杀死癌细胞。然而,光动力治疗和光热治疗的效率分别受到肿瘤周围缺氧微环境和残留癌细胞获得性耐热特性的严重抑制,导致单独的光动力治疗或光热治疗效果都不令人满意。因此,目前的癌症研究趋势开始转变为光动力治疗和光热治疗的协同治疗模式,以达到相互增效,取长补短的1+1大于2的协同效果。将具有各自特定属性的各种组分组合到一个纳米平台中,是目前最常用的方法。尽管这种多合一的材料在一定程度上可以满足诊断和治疗,但不可避免的会因其成分复杂、加工性困难、重现性低和药代动力学不确定等因素限制了其在临床上的应用。为了达到临床应用的目的,将所有光疗模式巧妙地整合到制备简单、结构明确、生物相容性和重现性好的单个有机小分子中,是癌症治疗的较好选择。然而现有的多功能光疗剂的发射峰大都位于近红外一区,基本还未有发射峰位于近红外二区的光疗剂。
发明内容
本发明的发明目的在于针对现有技术存在的上述问题,提供一种化合物,以及用该化合物制得的同时具有近红外二区荧光成像、光热治疗和光动力治疗的多功能光疗剂。
为实现上述发明目的,本发明通过如下方案实现:D-π-A化合物,所述D-π-A化合物由D、π和A三种基团构成,D为电子供体,π为π桥,A为电子受体,D选自结构式I、II、III所示基团中的一种;π选自结构式IV、V、VI所示基团中的一种;A为VII;I、II、III、IV、V、VI、VII的结构式如下:
作为优选,当D为I时,π为IV,V,VI时,D-π-A结构式为C1、C2、C3中的一种,C1、C2、C3的结构式如下:
作为优选,当D为II时,π为IV,V,VI时,D-π-A结构式为C4、C5、C6中的一种,C4、C5、C6的结构式如下:
作为优选,当D为III时,π为IV,V,VI时,D-π-A结构为C7、C8、C9中的一种,C4、C5、C6的结构式如下:
本发明还提供一种具有近红外二区发光特性的多功能光疗剂,所述的多功能光疗剂为球状核壳结构,以上述D-π-A化合物为核,两亲性聚合物为壳。
在上述具有近红外二区发光特性的多功能光疗剂中,两亲性聚合物包括二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG2000)、聚乳酸-羟基乙酸共聚物(PLGA)、PluronicF127中的一种或多种。
本发明还提供一种上述具有近红外二区发光特性的多功能光疗剂的制备方法,所述的制备方法包括如下步骤:
步骤1:在钯催化剂、无机碱的作用下,在惰性气体保护下,D-B(OH)2和Br-π-CHO进行铃木反应(Suzuki-Miyaura反应)得到化合物D-π-CHO;
步骤2:化合物D-π-CHO和化合物A溶于溶剂,通过缩合反应得固体D-π-A;
步骤3:将溶于有机溶剂的D-π-A和两亲性聚合物倒入水中,超声处理得以D-π-A化合物为核,两亲性聚合物为壳的纳米粒子悬浮液。
在上述具有近红外二区发光特性的多功能光疗剂的制备方法中,步骤1中铃木反应的温度为60-120℃,反应时间为2-24小时。
在上述具有近红外二区发光特性的多功能光疗剂的制备方法中,步骤1中D-B(OH)2、Br-π-CHO、钯催化剂和无机碱的物质的量的比为1:2~5:0.01~0.2:5~20。
作为优选,所述的钯催化剂包括Pd(PPh3)4,、PdCl2,、Pd(OAc)2、Pd(dppf)Cl2中的一种或多种。
作为优选,所述的无机碱包括氢氧化钠、氢氧化钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠中的一种或多种。
作为优选,步骤1具体为:将D-B(OH)2、Br-π-CHO钯催化剂、无机碱溶于有机溶剂和水中,在惰性气体保护下,加热反应,反应完成后降至室温,经萃取,收集有机相,水洗、干燥、分离提纯得到化合物D-π-CHO。
进一步优选,所述的有机溶剂包括甲苯、二氧六环、四氢呋喃中的一种或多种。
在上述具有近红外二区发光特性的多功能光疗剂的制备方法中,步骤2中缩合反应的温度为40-120℃,反应时间为3-12小时。
在上述具有近红外二区发光特性的多功能光疗剂的制备方法中,步骤2中D-π-CHO、化合物A和溶剂的物质的量比为1:1~5:50~200。
作为优选,所述的溶剂包括乙酸酐、乙醇、乙腈、四氢呋喃中的一种或多种。
在上述具有近红外二区发光特性的多功能光疗剂的制备方法中,步骤3中D-π-A与两亲性聚合物的质量比为1:2~6。
与现有技术相比,本发明具有以下优点:
1.本发明在D-π-A结构中引入了双丙二腈取代的1,3-茚二酮电子受体,该电子受体不仅具有较强的吸电子能力,而且其中的四个氰基具有强烈的分子内伸缩振动,伸缩振动的存在有助于将吸收的光能转化为热能。此外,还引入了三苯胺和噻吩类等较强的电子供体,与电子受体一起形成了较强的分子内电荷转移体系,有助于吸收和发射光谱的红移以及活性氧的产生。
2.本发明用以D-π-A化合物为核,两亲性聚合物为壳的光疗剂具有近红外二区(1000~1700nm)荧光发射,同时具有光热和光动力性能,可用于体内成像以及光热和光动力的癌症协同光疗,在生物医学上具有重大意义。
附图说明
图1为本发明光疗剂的结构示意图;
图2为实施例2中多功能光疗剂C2 NPs的粒径分布和电镜图;
图3为实施例1中多功能光疗剂C1 NPs和实施例2中多功能光疗剂C2 NPs在水溶液中的荧光光谱图;
图4为实施例1中多功能光疗剂C1 NPs和实施例2中多功能光疗剂C2 NPs的水溶液在660nm(0.3W/cm2)激光照射下,每2分钟1,3-二苯基异苯并呋喃(DPBF,可以用作单线态氧探针)在410nm处的吸收的变化;
图5为实施例1中多功能光疗剂C1 NPs和实施例2中多功能光疗剂C2 NPs的水溶液在660nm(1W/cm2)激光照射10分钟后,纳米粒子在水中的光热性能,插图为照射10分钟后相应的红外热图像;
图6为4T1细胞在不同浓度C2NPs下的光毒性和暗毒性。
具体实施方式
实施例1
(1)化合物I-π-CHO的合成:
将5-溴噻吩-2-甲醛(670mg,3.5mmol)、4-(二苯基胺基)苯硼酸(1215mg,4.2mmol)、四(三苯基膦)钯(200mg,0.175mmol)和碳酸钾(2415mg,17.5mmol)溶于1,4-二氧六环(25mL)和去离子水(5mL)的混合溶液中,随后混合物在氮气保护下,85℃搅拌5小时。反应体系降至室温,反应液用二氯甲烷和水萃取,收集有机相,水洗,无水硫酸钠干燥,用旋转蒸发仪减压蒸馏除去有机溶剂,得到粗产物。将粗产物通过硅胶柱层析分离提纯,展开剂为石油醚/二氯甲烷(1:1,v/v),得到黄色固体(950mg,产率76%)。1H NMR(300MHz,Chloroform-d)δ9.86(d,J=1.0Hz,1H),7.71(dd,J=4.0,1.1Hz,1H),7.52(dd,J=8.3,1.4Hz,2H),7.36-7.27(m,5H),7.19-7.03(m,8H)。
(2)化合物C1的合成:
将化合物I-π-CHO(100mg,0.2813mmol)和化合物A(70mg,0.2813mmol)溶于3mL乙酸酐中,60℃下搅拌6小时。反应体系降至室温,旋干,并用二氯甲烷溶解,加入石油醚使产物析出,过滤得固体C1(135mg,产率83%)。1H NMR(300MHz,Chloroform-d)δ8.65(s,1H),8.58(dd,J=5.9,3.1Hz,2H),7.78(dd,J=5.9,3.1Hz,2H),7.65(d,J=4.1Hz,1H),7.52(d,J=8.8Hz,2H),7.40-7.28(m,5H),7.22-7.10(m,6H),7.05(d,J=8.7Hz,2H).13C NMR(151MHz,Chloroform-d)δ160.98,157.93,150.25,146.47,143.08,137.31,136.10,135.06,134.56,129.64,127.79,126.36,125.66,125.51,124.83,124.57,124.15,121.50,113.52,113.45。
(3)C1 NPs的合成:
将包含1mg化合物C1和4mg DSPE-PEG2000的1mL四氢呋喃溶液倒入9mL去离子水中,超声处理5分钟。将以上混合物在通风橱中剧烈搅拌24小时,以除去四氢呋喃,并使用0.22μM注射器式过滤器过滤以获得最终的纳米粒子悬浮液,即为多功能光疗剂。
实施例2
(1)化合物II-π-CHO的合成:
将5-溴噻吩[3,2-b]噻吩-2-甲醛(262mg,1.06mmol)、4-(二苯基胺基)苯硼酸(368mg,1.273mmol)、四(三苯基膦)钯(62mg,0.0536mmol)和碳酸钾(732mg,5.304mmol)溶于1,4-二氧六环(25mL)和去离子水(5mL)的混合溶液中,随后混合物在氮气保护下,80℃搅拌5小时。反应体系降至室温,反应液用二氯甲烷和水萃取,收集有机相,水洗,无水硫酸钠干燥,用旋转蒸发仪减压蒸馏除去有机溶剂,得到粗产物。将粗产物通过硅胶柱层析分离提纯,展开剂为石油醚/二氯甲烷(1:1,v/v),得到黄色固体(325mg,产率75%)。1H NMR(600MHz,Chloroform-d)δ9.92(d,J=1.6Hz,1H),7.87(d,J=1.9Hz,1H),7.51-7.46(m,2H),7.40(d,J=1.9Hz,1H),7.29(dd,J=8.5,7.3Hz,4H),7.16-7.11(m,4H),7.08(td,J=8.8,8.1,2.6Hz,4H)。
(2)化合物C2的合成:
将化合物II-π-CHO(50mg,0.1215mmol)和化合物A(33mg,0.1336mmol)溶于2mL乙酸酐中,60℃下搅拌6小时。反应体系降至室温,旋干,并用二氯甲烷溶解,加入石油醚使产物析出,过滤得固体C2(63mg,产率82%)。1H NMR(300MHz,Chloroform-d)δ8.73(s,1H),8.57(dd,J=5.9,3.2Hz,2H),7.87-7.71(m,3H),7.57-7.45(m,2H),7.39(s,1H),7.37-7.27(m,4H),7.23-7.00(m,8H).13C NMR(151MHz,Chloroform-d)δ159.74,155.89,149.41,148.56,145.67,138.05,136.88,136.22,135.70,133.53,132.48,128.54,126.20,125.42,125.02,124.45,123.23,120.80,113.32,112.45。
(3)C2NPs的合成:
将包含1mg化合物C2和4mg DSPE-PEG2000的1mL四氢呋喃溶液倒入9mL去离子水中,超声处理5分钟。将以上混合物在通风橱中剧烈搅拌24小时,以除去四氢呋喃,并使用0.22μM注射器式过滤器过滤以获得最终的纳米粒子悬浮液,即为多功能光疗剂。
实施例2中多功能光疗剂C2 NPs的粒径分布和电镜图如图2所示,从图中可得化合物C2 NPs平均尺寸为72.8nm,TEM图显示C2 NPs的形态为近似球形。
实施例1和实施例2中的多功能光疗剂C1 NPs和C2 NPs在水溶液中的荧光光谱图如图3所示,从图中可得两者的发射峰几乎都位于近红外二区。
实施例1多功能光疗剂C1 NPs和实施例2中多功能光疗剂C2 NPs的水溶液在660nm(0.3W/cm2)激光照射下,每2分钟1,3-二苯基异苯并呋喃(DPBF,可以用作单线态氧探针)在410nm处的吸收的变化如图4所示。从图4中可以看出,C1 NPs和C2 NPs都具有单线态氧产生能力。
实施例1多功能光疗剂C1 NPs和实施例2中多功能光疗剂C2 NPs的水溶液在660nm(1W/cm2)激光照射10分钟后,纳米粒子在水中的光热性能如图5所示,插图为照射10分钟后相应的红外热图像。从图5中可以看出,C1 NPs和C2 NPs均表现出较好的光热效果。
4T1细胞在不同浓度C2 NPs下的光毒性和暗毒性如图6所示。从图6中可以看出,C2NPs具有良好的生物相容性以及在660nm激光照射下具有对癌细胞的杀伤作用。
综上所述,本发明用以D-π-A化合物为核,两亲性聚合物为壳的光疗剂具有近红外二区(1000~1700nm)荧光发射,同时具有光热和光动力性能,可用于体内成像以及光热和光动力的癌症协同光疗,在生物医学上具有重大意义。
以上为本发明所述的具体实施方式,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.一种具有近红外二区发光特性的多功能光疗剂,其特征在于,所述的多功能光疗剂为球状核壳结构,以权利要求1所述的D-π-A化合物为核,两亲性聚合物为壳。
3.根据权利要求2所述的具有近红外二区发光特性的多功能光疗剂,其特征在于,两亲性聚合物包括二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG2000)、聚乳酸-羟基乙酸共聚物(PLGA)、Pluronic F127中的一种或多种。
4.一种如权利要求2所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,所述的制备方法包括如下步骤:
步骤1:在钯催化剂、无机碱的作用下,在惰性气体保护下,D-B(OH)2和Br-π-CHO进行铃木反应(Suzuki-Miyaura反应)得到化合物D-π-CHO;
步骤2:化合物D-π-CHO和化合物A溶于溶剂,通过缩合反应得固体D-π-A;
步骤3:将溶于有机溶剂的D-π-A和两亲性聚合物倒入水中,超声处理得以D-π-A化合物为核,两亲性聚合物为壳的纳米粒子悬浮液。
5.根据权利要求4所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,步骤1中铃木反应的温度为60-120℃,反应时间为2-24小时。
6.根据权利要求4所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,步骤1中D-B(OH)2、Br-π-CHO、钯催化剂和无机碱的物质的量的比为1:2~5:0.01~0.2:5~20。
7.根据权利要求4或6所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,所述的钯催化剂包括Pd(PPh3)4,、PdCl2,、Pd(OAc)2、Pd(dppf)Cl2中的一种或多种。
8.根据权利要求4或6所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,所述的无机碱包括氢氧化钠、氢氧化钾、碳酸钾、碳酸氢钾、碳酸钠、碳酸氢钠中的一种或多种。
9.根据权利要求4所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,步骤2中缩合反应的温度为40-120℃,反应时间为3-12小时。
10.根据权利要求4所述的具有近红外二区发光特性的多功能光疗剂的制备方法,其特征在于,步骤2中D-π-CHO、化合物A和溶剂的物质的量比为1:1~5:50~200,所述的溶剂包括乙酸酐、乙醇、乙腈、四氢呋喃中的一种或多种。
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