CN111039853A - 一种可用于光声成像和光热治疗的铁配合物及其制备方法和用途 - Google Patents
一种可用于光声成像和光热治疗的铁配合物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了一种可用于光声成像和光热治疗的铁配合物及其制备方法和用途,是以磺酸基三苯胺三联吡啶功能配体与Fe配位合成一种配合物FeL2。三联吡啶配体上引入的磺酸基三苯胺,不仅提高了配合物的生物相容性和水溶性,而且增强了分子内推电子能力,同时增大了共轭体系,有利于分子内电荷转移,优化了光学性质。研究结果表明,该配合物具有优异的光声成像效果和较高光热转换效率,是一种可用于光热治疗的光声成像造影剂。
Description
技术领域
本发明涉及一种可用于光声成像和光热治疗的铁配合物及其制备方法和用途,具体为一 种可以进行光声成像和光热治疗的三联吡啶三苯胺磺酸盐铁的配合物及其合成方法。
背景技术
光声成像(PAI)结合了光学成像的高分辨率和声学成像的深部组织穿透性的优势,近年来 已引起广泛关注。优秀的光声成像造影剂应该具备低量子产率、高摩尔消光系数、极好的光 稳定性和生物相容性等特征。可以用作光声成像(PAI)的材料近年来得到较大发展。例如,金 属纳米材料、碳基纳米材料和有机小分子等在光声成像中得到了广泛的应用。然而,纳米材 料制作可重复性差,有机小分子稳定性差难以被修饰。因此,急需研发具有较好的重复性以 及调节性的可用于光声成像的造影剂。
发明内容
本发明针对上述现有技术的不足,提供了一种可用于光声成像和光热治疗的铁配合物及 其制备方法和用途。
金属配合物合成简单,组成易于确定,中心金属与配体之间协同优化,在光学性质方面, 可以通过配体修饰调节推拉电子能力,使吸收和发射波长向所需方向移动,同时改善生物相 容性和水溶性等,也可以选择不同中心金属满足生物光声成像的需要。第4周期、第Ⅷ族的 过渡金属铁,是生物体必须元素,其成本低、无毒性,以铁作为中心体,与光功能配体配位 制备铁配合物。可以预期,该类配合物能作为一种综合性能优秀的光声成像造影剂。
基于以上考虑,本发明用磺酸基三苯胺三联吡啶功能配体与Fe配位合成一种配合物 FeL2。三联吡啶配体上引入的磺酸基三苯胺,不仅提高了配合物的生物相容性和水溶性,而 且增强了分子内推电子能力,同时增大了共轭体系,有利于分子内电荷转移,优化了光学性 质。研究结果表明,该配合物具有优异的光声成像效果和较高光热转换效率,是一种可用于 光热治疗的光声成像造影剂。
本发明中铁配合物简记为FeL2,其结构式如下:
本发明铁配合物的制备方法,包括如下步骤:
步骤1:中间体S的合成
在100mL三口烧瓶周围包裹一层碎冰,将三苯胺甲醛(4.09g,0.015mol)溶解于20mL 精制无水的CH2Cl2并加入到三口烧瓶中,搅拌15min;再用恒压滴液漏斗缓慢滴加氯磺酸 (14.00g,0.120mol,用30mL精制无水CH2Cl2稀释),滴加完毕后,在此条件下继续反应2h;缓慢滴加适量水淬灭反应,升温至40℃反应2h;冷却至室温,再用4mol/L NaOH水溶液 调节pH至7-8,加入乙醇用旋转蒸发仪旋干以除去水,用乙醇重结晶,抽滤,真空干燥24h, 得到5.86g黄色固体,产率81.9%。
步骤2:配体L的合成
250mL三口烧瓶,加入NaOH(2.40g,0.068mol)水溶液和2-乙酰基吡啶(3.03g,0.025 mol),升温到80℃,搅拌30min;将S(4.33g,0.010mol)溶于适量乙醇,加入上述反应体 系中,搅拌30min;恒压滴液漏斗滴加适量NH3·H2O,继续反应6h,静置8-12h,抽滤,用 乙醇淋洗三次,将固体用乙醇重结晶,得到的固体在真空干燥箱干燥24h,得黄色固体4.12g,产率60.1%。
步骤3:目标产物的合成
将配体L(0.6542g,0.0010mol)倒入到250mL圆底烧瓶中,再加入适量的精制乙腈使其完全溶解,在80℃条件下逐滴滴加二氯化铁(0.0811g,0.0005mol)的乙腈(10mL) 溶液,慢慢有固体析出,搅拌2h后,冷却至室温,抽滤得到紫色固体,然后将该固体用乙 醇重结晶,抽滤,将固体放置于真空干燥箱干燥24h,得紫色固体产物0.4712g,产率68%。
本发明合成路线示意如下:
本发明铁配合物的用途,是在光声成像或光热治疗过程中作为造影剂使用。
本发明的有益效果体现在:
1、配合物FeL2中的配体三吡啶引入磺酸三苯胺基团,一方面增加了样品的水溶性,其 油水分离系数LogP为-2.4756(图1a);另一方面较强的推电子能力和较大的共轭体系,使 得吸收峰红移,在PBS缓冲液中,600nm处有一个吸收峰(图1b),能满足光声成像的波长 要求。
2、FeL2具有较高的光热转换效率以及良好的热稳定性。在PBS缓冲液中,其光热转换 效率达到29.6%(图2c),更重要的是四个热循环之后其光热转换效果几乎不变(图2d)。
3、FeL2具有较强的光声信号,1000μM时其光声信号强度能够达到4800a.u(多光谱光 声断层成像单位)(图3b)。
4、FeL2具有优异的活体内光声成像效果及较快的药物清除速率,将FeL2的PBS溶液分 别通过尾静脉和腿部肌肉注射至昆明鼠体内,其在肝脏、肾脏和腿部的信号分别在19分钟、 28分钟和14分钟时达到最强(图4a),在60分钟时几乎消失不见(图4b)。
5、本发明中三联吡啶铁配合物的原料易得、价格低廉、合成路线简短,合成条件温和。 不存在类似的铁配合物光声成像造影剂,具有较强的商业价值。
附图说明
图1(a)是三联吡啶铁配合物的油水分配系数结果,说明FeL2水溶性良好;图1(b)是 三联吡啶铁配合物在PBS缓冲液中的吸收光谱图,说明FeL2在600nm处有一个吸收峰,能满足光声成像的波长要求。
图2是铁配合物的光热性质研究。(a)不同浓度铁配合物在808nm激光照射下的温度变 化情况;(b)0.5mM铁配合物在不同功率激光照射下的温度变化情况;(c)铁配合物光热 转换效率;(d)铁配合物光热“on-off”循环次数。说明了FeL2有较高的光热转换效率同时具 有较好的热稳定性。
图3是铁配合物的体外光声信号强度研究。(a)不同浓度铁配合物归一化条件下的光声 显微照片;(b)不同浓度铁配合物的光声信号强度;(c)光声信号强度与其浓度之间的线性 关系图。说明FeL2在体外具有较强的光声信号,同时其光声信号强度与其浓度之间有较好的 线性关系。
图4是铁配合物的活体成像研究。(a)0.5mM铁配合物200μL分别经尾静脉注射和腿部肌肉注射后,肝,肾和肌肉组织(箭头)不同时间的体内光声图像;(b)0.5mM铁配合物 200μL分别经尾静脉注射和腿部肌肉注射后,肝,肾和肌肉组织光声信号达到最大强度的时 间(0-60min)。说明FeL2在活体内具有优异的成像效果和较快的药物代谢速率。
具体实施方式
以下通过具体的实施例对本发明技术方案作进一步分析说明。
实施例1:中间体S的合成
在100mL三口烧瓶周围包裹一层碎冰,将三苯胺甲醛(4.09g,0.015mol)溶解于20mL 精制无水的CH2Cl2加入到三口烧瓶中,搅拌15min。再用恒压滴液漏斗缓慢滴加氯磺酸(14.00 g,0.120mol,用30mL精制无水CH2Cl2稀释),滴加完毕后,在此条件下继续反应2h。缓慢 滴加适量水淬灭反应,升温至40℃反应2h。冷却至室温,再用4mol/L NaOH水溶液调节pH至7-8。加入乙醇用旋转蒸发仪旋干以除去水,用乙醇重结晶,抽滤,真空干燥24h,得到5.86g黄色固体,产率81.9%。1H NMR(400MHz,DMSO-d6)δppm:9.80(s,1H),7.76(d,J=8.7Hz,2H),7.62(d,J=8.5Hz,4H),7.10(d,J=8.5Hz,4H),6.99(d,J=8.7Hz,2H).ESI-MS m/z:calcd for:(M-Na)+:454.00,found:453.99.
实施例2:配体L的合成
250mL三口烧瓶,加入NaOH(2.40g,0.068mol)水溶液和2-乙酰基吡啶(3.03g,0.025 mol),升温到80℃,搅拌30min。将S(4.33g,0.010mol)溶于适量乙醇,加入上述反应体 系中,搅拌30min。恒压滴液漏斗滴加适量NH3·H2O,继续反应6h,静置一夜。抽滤,用 乙醇淋洗三次,将固体用乙醇重结晶,得到的固体在真空干燥箱干燥24h,得黄色固体4.12g,产率60.1%。1H NMR(400MHz,D2O)δppm:8.22–8.08(m,2H),7.72–7.60(m,2H),7.52–7.34(m,8H),7.10–6.98(m,2H),6.83–6.74(m,2H),6.73–6.60(m,4H),6.41–6.29(m,2H).ESI-MS m/z: calcd for:(M-2Na)/2:317.05,found:317.04.Anal.Calc.for C33H22N4Na2O6S2:C,58.23;H,3.26;N, 8.23%;Found:C,57.98;H,3.46;N,8.01%.N,8.01%.
实施例3:目标产物的合成
将配体L(0.6542g,0.0010mol)倒入到250mL圆底烧瓶中,再加入适量的精制乙腈使其完全溶解,在80℃条件下逐滴滴加二氯化铁(0.0811g,0.0005mol)的乙腈(10mL) 溶液,慢慢有固体析出。搅拌2h后,冷却至室温。抽滤得到紫色固体,然后将该固体用乙 醇重结晶,抽滤,将固体放置于真空干燥箱干燥24h,得紫色固体产物0.4712g,产率68%。 1HNMR(400MHz,d6-DMSO)δ9.52(4H,s),8.95(4H,d,J 7.9),8.38(4H,d,J 8.4),7.96(4H, t,J7.7),7.61(8H,d,J 8.5),7.29(4H,d,J 8.5),7.21(4H,d,J 5.3),7.17–6.74(12H,m).ESI-MS m/z:calcd for:(M-2Na)/2:662.06,found:662.06.Anal.Calc.for C66H44FeN8O12S4:C,46.44;H, 2.60;N,6.56%;Found:C,46.39;H,2.61;N,6.56%.
实施例4:目标分子的生物学研究
1、用PBS缓冲液将FeL2配置成1mM溶液,用功率为1W/cm2,波长为808nm的激光 照射10min,同时使用红外热相仪每分钟记录一次溶液温度。随后遮挡激光器,用红外热像 仪每分钟记录一次溶液温度,记录时间为10min。上述操作进行4个循环。实验结果表明FeL2有较高的光热转换效率,同时具有良好的热稳定性。
2、用光声成像仪测量不同浓度FeL2的光声信号(1000μM,500μM,400μM,300μM,200μM,100μM,50μM),随即吸取用PBS配制的浓度为500μM的FeL2溶液200μL,分别 进行尾静脉和腿部肌肉注射至昆明鼠体内,在光声成像仪下进行成像。实验结果表明FeL2在体外具有较强的光声信号,同时在小鼠体内具有优异的光声成像效果。
Claims (3)
2.一种权利要求1所述的铁配合物的制备方法,其特征在于包括如下步骤:
步骤1:中间体S的合成
将反应器周围包裹一层碎冰,将三苯胺甲醛溶解于精制无水的CH2Cl2后加入到反应器中,搅拌分散均匀;然后向反应器中滴加滴加氯磺酸,滴加完毕后,在此条件下继续反应2h;反应结束后加水淬灭反应,升温至40℃反应2h;冷却至室温,再用NaOH水溶液调节pH至7-8,加入乙醇,用旋转蒸发仪旋干以除去水,乙醇重结晶,抽滤,真空干燥,得到黄色固体,即为中间体S;
步骤2:配体L的合成
向反应器中加入NaOH水溶液和2-乙酰基吡啶,升温至80℃搅拌30min,然后加入中间体S,搅拌分散均匀;随后向反应器中滴加NH3·H2O,继续反应6h,静置,抽滤,用乙醇淋洗,将固体用乙醇重结晶,得到的固体在真空干燥,得黄色固体,即为配体L;
步骤3:目标产物的合成
将配体L加入反应器中,加入适量的精制乙腈使其完全溶解,在80℃条件下滴加二氯化铁的乙腈溶液,慢慢有固体析出,搅拌2h后,冷却至室温,抽滤得到紫色固体,然后将该固体用乙醇重结晶,抽滤,真空干燥,得紫色固体产物即为目标产物。
3.一种权利要求1所述的铁配合物的用途,其特征在于:
所述铁配合物在光声成像或光热治疗过程中作为造影剂使用。
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