CN112142721A - 一种可靶向线粒体的近红外二区噻喃盐荧光化合物及其制备方法与应用 - Google Patents
一种可靶向线粒体的近红外二区噻喃盐荧光化合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种可靶向线粒体的近红外二区噻喃盐荧光化合物及其制备方法与应用。经过对噻喃盐杂环结构改造,引入不同的修饰基团,其发射波长可红移至近红外二区(1000‑1200nm)。该类化合物光稳定性好,易后修饰,可以通过化学键合连接不同的生物标记物(多肽、抗体、PEG、叶酸等),改善其水溶性、靶向性,降低其生物毒性,提高其生物利用度。可用于线粒体成像、药物药效评估、乳腺癌、骨肉瘤、脑胶质瘤等实体瘤肿瘤成像、血管成像,同时还可以用于手术导航、疾病的早期诊断、术中实时监控、光热治疗、光动力治疗等生物应用。具有很好的工业生产价值以及生物医学应用前景。
Description
技术领域
本发明属于荧光染料制备技术领域,并涉及生物医学领域中的肿瘤成像、光热及化疗联合治疗,具体涉及一种具有近红外二区荧光发射的噻喃盐荧光化合物的制备方法与应用。
背景技术
急性髓系白血病(AML)是一种异质性和复杂的血液恶性肿瘤,每年影响全球约100万人,目前分子靶向化疗、异基因造血干细胞移植(HSCT)等多种治疗手段已广泛应用于临床治疗急性髓系白血病。然而,20岁以上的AML患者的5年生存率仍然很低(~25%),与传统的实体瘤相比,急性髓系白血病由于肿瘤细胞在免疫系统中不断循环,易造成药物耐药及逃逸,导致治疗效果不理想。AML 的治疗仍是临床研究中最艰巨的挑战之一,开发新型的诊疗手段显得尤为重要。
线粒体作为一种重要的亚细胞细胞器,调节许多细胞行为,如细胞信号、分化、生长、凋亡、代谢和死亡,在能量的产生和细胞的存活中起着至关重要的作用。因此,基于线粒体靶向的小分子药物显示出广泛的应用前景,可以从亚细胞水平抑制肿瘤细胞的生长,然而,小分子亚细胞器官靶向药物仍然是人们梦寐以求的。近红外二区荧光成像作为一种新型的光学显影手段,具有背景干扰小,组织穿透深度深,高的时空分辨率等特点,目前在肿瘤早期诊断、药物药效评估、血管成像、肿瘤示踪、手术导航、肿瘤治疗等方面显示出巨大的优势。大量的近红外二区光学材料如碳纳米管(SWNTs)、量子点(QDs)、有机小分子染料、有机共聚物等已经被成功开发,而小分子染料由于结构明晰,质量可控,易修饰,低毒易代谢等优点具有很好的临床转化潜力。最具典型代表就是有机小分子 CH1055,其通过化学键连接PEG构筑了第一个近红外二区探针CH1055-PEG,其具有很好的光学稳定性及很快的肝肾清除率(90%,24h),在肿瘤成像、血管成像等方面应用很广。然而,大多数二区荧光染料结构后修饰难,水溶性差,生物利用度相对较低,且基于近红外二区的线粒体靶向的小分子荧光探针报道仍然很少。
发明内容
为了解决现有近红外二区染料合成工艺复杂,后修饰难,生物利用度差等不足,本发明提供了一种可靶向线粒体的噻喃盐的近红外二区荧光分子,该类分子合成工艺简单、产率高、光稳定性好,易后修饰连接各种生物标记物构筑功能性的分子探针。基于此,本发明利用其线粒体靶向的特点成功实现了白血病的活体成像及成像介导的光热及化疗协同治疗。
为了实现上述目的,本发明采用如下技术方案:
第一方面,提供一种可修饰的近红外二区噻喃盐荧光分子,其结构通式(1) 如下:
n=0,1;
R1选自:
R2选自:
R3选自:
R4选自:
优选地,上述可修饰的近红外二区噻喃盐荧光分子具体为:
第二方面,提供上述噻喃盐荧光分子的制备方法,具体路线如下:
n=0,1;
R1选自:
R2选自:
R3选自:
R4选自:
(1)、将化合物2溶于20mL乙醇中,冰浴下加入20%KOH溶液并在室温下反应10分钟,然后将化合物1加入到混合物中,并将反应在室温下搅拌12小时,反应完毕后,用2M HCl溶液将反应溶液调节至pH=3,过滤收集形成的黄色中间体化合物3;
(2)、将化合物4和四氢吡咯溶于50mL苯中,并加热至100℃反应4小时,形成烯胺中间体,冷却至室温后,减压除去苯,接着往反应体系中加入50mL 1,4- 二氧六环溶解,并加入化合物3,加热回流反应6小时,反应完全后,冷却至室温,将上述反应体系倒入100mL水中,并用乙酸乙酯萃取3次,有机层用100mL 饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩得到粗产物,粗产物进一步经过柱层析纯化,得到中间体化合物5;
(3)、将化合物5溶于乙醚中并搅拌10分钟,接着加入硫代乙酸和三氟化硼醚并加热回流反应3小时,冷却至室温后,将反应混合物用水淬灭,向溶液中加入过量的乙醚,然后在室温下搅拌混合物以沉淀得到浅黄色中间体化合物6;
(4)、在反应容器中加入化合物6,原料7和乙酸酐,微波500℃下反应2小时,反应完毕后,加入大量乙醚,析出粗产物,粗产物进一步通过柱层析纯化分离得到最终荧光化合物(1)。
优选地,上述步骤(1)中,化合物1及化合物2的摩尔比为1:1.5,整个反应体系溶液的浓度为0.5-1mol/L,反应温度为0-25℃。
优选地,上述步骤(2)中,化合物4、四氢吡咯和中间体3三者的物质的量之比为5:5:1,反应体系溶液浓度为0.5-1mol/L。
优选地,上述步骤(3)中,硫代乙酸和三氟化硼乙醚及化合物5的反应比例为10:10:1,反应温度为100℃,溶液浓度为0.1-1mol/L。
优选地,上述步骤4)中,上述反应在10mL封管中进行,微波压力为15-20 个大气压,温度为75℃,化合物6与原料7物质的量之比为1:3-5。
第三方面,提供一种近红外二区荧光成像探针,为上述通式(I)所示的荧光化合物可修饰位点修饰聚乙二醇、多肽、蛋白、核酸适配体、叶酸及其衍生物。
优选地,上述近红外二区荧光成像探针的结构式为:
第四方面,提供上述近红外二区噻喃盐荧光成像探针在制备用于细胞线粒体成像的试剂中的应用。
第五方面,提供上述近红外二区噻喃盐荧光成像探针在制备用于肿瘤诊断的试剂中的应用。
第六方面,提供上述近红外二区噻喃盐荧光成像探针在制备用于急性髓系白血病成像的试剂中的应用。
第七方面,提供上述近红外二区噻喃盐荧光成像探针在制备用于急性髓系白血病光热治疗及化疗的药物中的应用。
第八方面,提供上述近红外二区噻喃盐荧光成像探针在制备用于在生物体内成像的试剂中的应用。
本发明改造了吡喃盐结构母核,将吡喃盐改造为噻喃盐,并于旁边并一六元环,通过将吡喃盐改造为噻喃盐,可以有效降低分子的能隙值,同时旁边的噻喃盐六元环可以通过缩合反应引入不同的电子受体(噻吩、并噻吩、苯、吡啶)等,构筑一系列不同波长范围的噻喃盐分子,本发明筛选出不同发射波长(850~1100 nm)的近红外二区荧光分子LQQ-1~LQQ-5,另外,右侧的炔基反应位点可以通过化学反应引入可修饰基团,增加的可修饰位点可选择性连接不同的生物活性官能团或者靶向基团,拓宽该类荧光探针的应用前景、改善其水溶性和生物相容性以及提高对不同肿瘤的靶向性。急性髓系白血病是一种恶性血液肿瘤,其对葡萄糖具有高的摄取,因此葡萄糖可以作用其靶向单元,为了解决分子的生物相容性,本发明借助化学方法将噻喃盐分子L1通过N3-PEG8-NHS与葡萄糖盐酸盐连接起来形成对急性髓系骨髓瘤具有特异靶向的近红外二区探针L1-PEG-Glu。随后对其细胞毒性及体外光学特性进行了研究,发现其对THP-1及Molm-13细胞具有浓度依赖性的细胞毒性,且细胞毒性在808nm激光照射下明显增强,表现出一定程度的化疗及光热治疗协同治疗效果,通过流式、共聚焦、凋亡等途径对其机理进行了验证,证明了L1-PEG-Glu是通过线粒体靶向引起细胞凋亡。另外,在生物医学荧光成像中发现该荧光探针具有较高的组织穿透深度,较高的时空分辨率,在肿瘤诊断与治疗上具有很好的应用前景。
附图说明
图1为实施例1所述荧光分子LQQ-1的氢谱、碳谱核磁谱图,
A为LQQ-1的氢谱核磁谱图,B为LQQ-1的碳谱核磁谱图。
图2为实施例2所述荧光分子LQQ-1~LQQ-5在二氯甲烷中的吸收发射波谱。
图3为实施例3所述PEG-Glu的合成路线。
图4为实施例4所述近红外二区荧光探针L1-PEG-Glu的合成路线。
图5为实施例4所述近红外二区荧光探针L1-PEG-Glu的高分辨质谱。
图6为实施例5所述荧光探针L1-PEG-Glu和ICG在血清中的光稳定性。
图7为实施例6所述为正常细胞293T及hFOB1.19正常细胞与急性髓系白血病细胞THP-1及Molm-13对荧光探针L1-PEG-Glu的摄取能力。
图8为实施例7所述荧光探针L1-PEG-Glu对正常细胞293T及hFOB1.19正常细胞与急性髓系白血病细胞THP-1及Molm-13的细胞毒性。
图9为实施例8所述不同浓度的L1-PEG-Glu血清溶液在808nm激光下的升温曲线。
图10为实施例9所述荧光探针L1-PEG-Glu在不同情况下的Molm-13及 THP-1细胞倒置荧光显微成像图。
图11为实施例10所述荧光探针L1-PEG-Glu对THP-1及Molm-13细胞不同处理下的细胞凋亡流式分析图。
图12为实施例11所述荧光探针L1-PEG-Glu对急性髓系白血病细胞THP-1 及Molm-13的细胞线粒体共聚焦成像图。
图13为实施例12所述荧光探针L1-PEG-Glu对白血病小鼠模型的体内近红外二区成像图。
图14为实施例13所述荧光探针L1-PEG-Glu对白血病小鼠模型治疗后与正常小鼠骨髓及外周血CD34+细胞表达情况。
图15为实施例13所述荧光探针L1-PEG-Glu对白血病模型鼠治疗后骨髓免疫组化分析图。
具体实施方式
通过以下详细说明结合附图可以进一步理解本发明的特点和优点。所提供的实施例仅是对本发明方法的说明,而不以任何方式限制本发明揭示的其余内容。实施例1】噻喃类化合物LQQ-1、LQQ-2、LQQ-3、LQQ-4及LQQ-5的合成及表征
噻喃类化合物LQQ-1、LQQ-2、LQQ-3、LQQ-4及LQQ-5(如下所示),所有化合物均通过核磁及高分辨质谱进行表征确定,
其中,噻喃类化合物LQQ-1合成路线及步骤如下
化合物3的合成:在冰浴中,将KOH水溶液(50%w/w,70mL)加入到 4-羟基苯乙酮2(100mmol,13.6g)的200mL MeOH溶液中。搅拌10分钟后,在1小时内滴加苯甲醛1(100mmol,10.6g)的30mL MeOH溶液。然后,将反应混合物在室温搅拌过夜。减压除去MeOH后,将混合物用3M HCl水溶液中和。将沉淀物过滤并用水洗涤。用MeOH重结晶,得到18.8g浅黄色结晶固体。产率: 84%。1H NMR(400MHz,MeOD):δ7.97(dd,J=9.2,2.3Hz,2H),7.71–7.62 (m,4H),7.40–7.32(m,3H),6.88–6.81(dd,2H)。
化合物4的合成:将化合物3(20mmol,4.48g),炔丙基溴(80%的甲苯溶液)(30mmol,3.34mL)和K2CO3(60mmol,4.15g)的丙酮(40mL)混合物回流。5小时,然后冷却至室温并过滤。减压除去滤液的溶剂后,得到粗产物。用MeOH重结晶,得到4.85g白色固体。产率:92%。1H NMR(400MHz, CDCl3):δ8.05(d,J=8.9Hz,2H),7.81(d,J=15.6Hz,1H),7.64(dd,J=6.5, 3.1Hz,2H),7.54(d,J=15.6Hz,1H),7.45–7.36(m,3H),7.06(d,J=8.9Hz, 2H),4.77(d,J=2.4Hz,2H),2.57(t,J=2.4Hz,1H)。13C NMR(101MHz,CDCl3):δ188.8、161.3、144.3、135.1、131.9、130.8、130.5、129.0、128.5、121.9、114.8、 77.9、76.3、56.0。
化合物5的合成:在装有分水器的圆底烧瓶中,将环己酮(20mmol,1.7mL) 和吡咯烷(20mmol,1.65mL)的苯(20mL)混合物回流4h。除去溶剂,并将剩余的混合物溶解在二氧六烷中。将化合物2(10mmol,2.62g)加入到混合物中并回流2小时。冷却至室温后,加入水(60mL)以淬灭反应,然后用EtOAc (3×20mL)萃取。合并的有机层用无水Na2SO4干燥并浓缩,得到粗产物,将其通过快速色谱纯化(硅胶,己烷/EtOAc:5:1,v/v)得到无色油状化合物5(2.2g)。产率:64%。1H NMR(400MHz,氯仿-d3):δ7.98(d,J=9.0Hz,1H),7.31–7.17 (m,4H),7.00(d,J=9.0Hz,1H),4.74(d,J=2.4Hz,1H),3.84–3.68(m, 2H),3.41(dd,J=18.8,9.3Hz,1H),2.55(t,J=2.4Hz,1H),2.50(dd, J=10.6,2.4Hz,2.4Hz,1H),2.29–2.19(m,1H),2.17–2.08(m,1H),1.98–1.86 (m,1H),1.82–1.74(m,2H),1.69–1.59(m,1H));13C NMR(101MHz, CDCl3):δ220.8,197.7,161.4,142.5,131.0,130.5,128.6,128.6,126.8,114.7,77.9, 76.3,55.9,53.2,41.3,40.7,39.8,27.2,20.7;1H NMR(400MHz,氯仿-d3):δ7.91 (d,J=8.7Hz,2H),7.30–7.14(m,5H),6.97(d,J=8.7Hz,2H),4.73(d,J =2.4Hz,2H),3.79(dd,J=16.4,6.2Hz,1H),3.69(q,J=7.4Hz,1H),3.31 (dd,J=16.4,7.4Hz,1H),2.54(t,J=2.4Hz,1H),2.45(q,J=8.2Hz,1H), 2.29–2.17(m,1H),2.06(dt,J=18.3,9.0Hz,1H),1.89(dp,J=12.6,4.5Hz,1H), 1.69(dt,J=13.4,7.2Hz,1H),1.53(tt,J=9.7,5.7Hz,1H);13C NMR(101MHz, CDCl3):δ220.1、193、161.2、142.6、131.0、130.4、128.5、128.4、126.7、114.6、 77.9、76.2、55.9、53.1、42.7、41.1、38.9、28.0、20.4。
化合物6的合成:将硫代乙酸(12.7mmol,0.9mL)加入到化合物5(5.8mmol, 2.0g)的乙醚(10mL)溶液中。在所有试剂完全溶解后,将三氟化硼醚化物(34.7 mmol,4.4mL)滴加到混合物中,然后回流6h。然后,将反应混合物冷却至室温,并用水(1mL)淬灭。然后将其倒入乙醚(100mL)中,并且出现大量黄色固体。滤出后,用乙醚洗涤并干燥,得到1.44g黄色固体。产率:59%。1H NMR (400MHz,CDCl3):δ8.31(s,1H),7.85(d,J=8.3Hz,2H),7.68–7.65(m,2H), 7.59–7.57(m,4H),7.15(d,J=8.3Hz,2H),4.77(d,J=2.2Hz,2H),3.71(t, J=6.6Hz,2H),3.32(t,J=6.8Hz,2H),2.60(t,J=2.2Hz,1H),2.42-2.29(m, 2H);13C NMR(101MHz,CDCl3):δ175.0、166.2、162.0、159.6、149.5、137.2、 132.1、131.7、130.3、129.6、129.0、127.3、116.9、77.4、76.9、56.3、38.6、34.4、24.9。
化合物7的合成:取250mL圆底烧瓶,抽无水无氧,充氩气保护,加化合物4-碘二甲基苯胺(1.57g,6.35mmol),5-醛基-2-噻吩硼酸(1.19g,7.62mmol), Pd(PPh3)4(0.37g,0.3175mmol),加甲苯/乙醇(30mL/30mL)溶解,加2M K2CO3 (6mL),85℃反应3h。反应完成后,二氯甲烷萃取,无水Na2SO4干燥,旋干溶剂,得黄色固体粗品。经柱层析纯化得化合物7纯品。1H NMR(400MHz, Chloroform-d)δ9.84(s,1H),7.70(d,J=3.9Hz,1H),7.58(d,J=8.7Hz,2H),7.26 (d,J=3.9Hz,1H),6.73(d,J=8.7Hz,2H),3.04(s,6H).13C NMR(101MHz,Chloroform-d)δ182.6,156.2,151.2,140.2,138.2,127.6,121.6,120.9,112.2,40.3.
化合物LQQ-1合成:取10mL封管,加化合物6(30mg,0.07mmol),化合物7(24mg,0.1mmol),3mL乙酸酐溶解,微波反应(100W,75℃)反应2h。反应完成后,加乙醚析出产物,DCE:MeCN(5:1)过硅胶柱,得化合物LQQ-1。荧光分子LQQ-1的氢谱、碳谱核磁谱图如图1所示。其结构表征数据如下:1H NMR(400MHz,Acetonitrile-d3)δ8.12(s,1H),7.95(s,1H),7.92(d,J=8.7Hz, 2H),7.90(d,J=8.7Hz,2H),7.71-7.67(m,3H),7.58(d,J=3.8Hz,1H),7.56(d,J= 8.7Hz,2H),7.44(d,J=4.0Hz,1H),7.25(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,2H),4.91(d,J=2.4Hz,2H),3.41(m,2H),3.27–3.09(m,2H),2.95(s,6H),2.92(t, J=2.4Hz,1H),1.62(t,J=2.4Hz,3H)13C NMR(126MHz,CD3CN)δ169.7, 162.2,158.8,156.0,152.1,151.9,149.1,144.7,138.8,138.0,134.1,131.8,130.4, 129.9,129.7,128.0,127.9,124.2,123.8,121.5,120.9,117.1,112.9,79.0,78.7,56.9, 32.8,30.4,21.3.HRMSCalcd for:C37H32NOS2 +([M-BF4]+):570.1925, found:570.1938.
本发明通过与上述合成LQQ-1类似的方法获得LQQ-2、LQQ-3、LQQ-4 及LQQ-5,
噻喃盐LQQ-2的结构表征数据如下:
1H NMR(400MHz,Acetonitrile-d3)δ8.48(s,1H),7.95(s,1H),7.92(d,J=8.7Hz,2H),7.90~7.70(m,2H),7.70~7.67(m,3H),7.66~7.58(m,5H),7.56(d,J=8.7 Hz,2H),7.44(d,J=4.0Hz,1H),7.43~7.24(d,J=8.8Hz,2H),7.08~7.07(d,J= 8.8Hz,2H),5.23(d,J=2.4Hz,2H),3.42~3.40(m,3H),3.17–3.16(m,3H),2.95 (s,6H),2.92(t,J=2.4Hz,1H),1.62(t,J=2.4Hz,3H).13C NMR(101MHz, CD3CN)δ172.2,168.9,166.0,162.1,161.9,159.1,154.7,148.8,148.0,144.1,141.8, 140.4,140.0,139.7,138.0,137.9,134.2,133.8,131.5,130.9,127.1,122.9,109.2, 89.0,88.8,78.0,67.0,42.4,41.5,31.3.
HRMS Calcd for:C43H34NOS2 +([M-BF4]+):644.2082,found:644.2048.
噻喃盐LQQ-3的结构表征数据如下:
1H NMR(400MHz,Acetonitrile-d3)δ8.48(s,1H),7.95(s,1H),7.92~7.90(d,J=8.7Hz,1H),7.70(m,2H),7.67(m,2H),7.58(d,J=3.8Hz,3H),7.56(d,J=8.7Hz, 2H),7.44(d,J=4.0Hz,1H),7.25(d,J=8.8Hz,2H),6.68(d,J=8.8Hz,1H),6.44 (d,J=8.8Hz,1H),3.41(m,2H),3.27–3.09(m,2H),2.95(s,6H),2.92(t,J=2.4 Hz,1H),1.61(t,J=2.4Hz,3H),1.18(t,J=2.4Hz,3H).13C NMR(101MHz, CD3CN)δ172.2,168.8,166.0,162.1,162.0,159.1,154.7,148.8,148.0,144.1,141.8, 140.4,140.0,138.0,137.9,134.2,133.8,131.5,130.9,127.1,122.9,109.2,101.3, 99.9,89.0,88.8,78.0,67.0,42.4,41.5,31.3.
HRMS Calcd for:C41H34NOS3 +([M-BF4]+):652.1803,found:652.1864.
噻喃盐LQQ-4的其结构表征数据如下:
1H NMR(400MHz,Acetonitrile-d3)δ8.43(s,1H),8.30(s,1H),8.27~8.12(d,J=8.7Hz,1H),7.70(m,2H),7.67~7.66(m,2H),7.58(d,J=3.8Hz,3H),7.56(d,J=8.7Hz,2H),7.44(d,J=4.0Hz,1H),7.25(d,J=8.8Hz,2H),6.68(d,J=8.8Hz, 1H),6.48(d,J=8.8Hz,1H),4.80(d,J=2.4Hz,2H),3.42~3.41(m,3H),3.27– 3.09(m,2H),2.95(s,6H),2.92(t,J=2.4Hz,1H).13C NMR(101MHz,CD3CN)δ 172.2,167.8,165.0,162.1,162.0,154.7,148.8,148.0,144.1,141.8,140.4,140.0, 139.7,138.0,137.9,134.2,133.8,127.1,122.9,109.2,101.3,99.9,89.0,88.8,83.7, 78.0,60.9,42.4,31.3.
HRMS Calcd for:C41H32NOS3 +([M-BF4]+):650.1646,found:650.1672.
噻喃盐LQQ-5的结构表征数据如下:
1H NMR(400MHz,Acetonitrile-d3)δ8.48(s,1H),8.35(s,1H),8.27(d,J=8.7Hz,1H),8.12~8.10(m,2H),7.70~7.69(m,2H),7.67~7.58(d,J=3.8Hz,3H),7.56(d, J=8.7Hz,2H),7.44(d,J=4.0Hz,1H),7.25(d,J=8.8Hz,2H),6.75(d,J=8.8Hz, 1H),6.48(d,J=8.8Hz,1H),4.52(d,J=2.4Hz,2H),3.42~3.41(m,3H),3.27– 3.09(m,3H),2.95(s,6H),2.92(t,J=2.4Hz,1H).13C NMR(101MHz,CD3CN)δ 179.2,172.2,167.8,165.1,162.5,154.7,148.8,148.0,144.1,141.8,140.4,140.0, 139.7,138.0,137.9,134.2,133.8,127.1,122.9,109.2,101.3,99.9,89.0,88.8,83.7, 78.0,61.0,42.4,31.3.
HRMS Calcd for:C42H33N2OS2 +([M-BF4]+):645.2034,found:645.2086.
【实施例2】染料LQQ-1~LQQ-5的紫外吸收发射波谱
称取染料LQQ-1~LQQ-5溶于DCM溶剂中,浓度为0.1~1mol/L,置于岛津紫外光谱仪下测量不同染料的吸收波谱,然后进行归一化作图。然后将对应样品置于荧光光谱仪下测量各自的发射波谱,激发波长选择808nm,分别对其jinx归一化,得到图2,根据谱图可以看出,随着在分子上引入的供电子基团越多,其对应的吸收发射谱图较蓝移,引入的吸电子基越多,对应的染料对应的吸收发射谱图红移。
【实施例3】近红外二区探针PEG-Glu的制备方案
称取葡萄糖盐酸盐(2.35mg,0.01mmol)和N3-PEG8-NHS(6mg,0.01mmol) 并将其溶于1mL无水DMF,随后加入DIPEA(14mg,0.1mmol),室温反应过夜,反应结束后,将反应液加入至50mL乙醚中置于-80℃冰箱中析出沉淀,接着离心除去上层乙醚清液即可获得粗产物PEG-Glu,获得的粗产物不经纯化直接投下一步。其合成路线见附图3。
【实施例4】近红外二区探针L1-PEG-Glu的制备方案
称取LQQ-1(15mg,0.023mmol)及PEG-Glu(29mg,0.046mmol)溶于1mL 无水DMF溶剂中,加入催化量的CuSO4·5H2O,TBTA和抗坏血酸钠NaVc,混合物在25℃下反应2小时,反应通过高效液相色谱检测,反应完毕后,将上述反应液加入50mLEt2O中置于-80℃析出沉淀,离心,沉淀进一步通过高效液相色谱纯化,得到目标产物L1-PEG-Glu(15.5mg,收率52.5%)。其合成路线见附图4。产物通过MALDI-TOF-MS表征确定。其高分辨质谱图参见附图5。
【实施例5】近红外二区探针L1-PEG-Glu与ICG光稳定性比较
取等体积的实施例4的探针L1-PEG-Glu与ICG的血清溶液,调节其起始荧光强度一致,置于近红外二区成像仪下持续808nm激光照射1小时,每隔一分钟进行拍照,最后作荧光变化曲线图,对比其光稳定性。见附图6,近红外二区探针L1-PEG-Glu光照1小时,其荧光信号强度无明显衰减,相反ICG荧光信号衰减明显,说明探针L1-PEG-Glu的光稳定性要优于ICG。
【实施例6】正常细胞系293T和hFOB1.19及急性髓系白血病细胞THP-1和 Molm-13对探针L1-PEG-Glu摄取能力比较
取6孔板培养上述4种细胞,每孔1×106个细胞,在孵育箱中培养过夜,次日加入20μM探针L1-PEG-Glu,培养24h,收集每孔细胞,离心,弃去培养基,加入PBS洗涤三次(5mL×3),收集细胞沉淀,置于近红外二区成像仪下成像,定性分析其对探针L1-PEG-Glu的摄取能力。见附图7,THP-1及Molm-13细胞沉淀的荧光强度较正常细胞293T及hFOB1.19要强,表明,THP-1及Molm-13 细胞对探针L1-PEG-Glu的摄取能力要强于正常细胞。
【实施例7】探针L1-PEG-Glu对实施例6的四种细胞的细胞毒性评价。
将实施例6的四种细胞接种在96孔板中(每孔约5000个细胞)。12h后,用含不同浓度L1-PEG-Glu的新鲜培养基替代。然后孵育24小时,然后进行细胞计数kit-8(CCK-8)测定细胞活力。见附图8,不同浓度培养上述4种细胞24小时后,肿瘤细胞THP-1及Molm-13表现出一定的细胞毒性,而正常细胞293T 及hFOB1.19则显示出较高的成活率,表明探针L1-PEG-Glu对肿瘤细胞具有细胞毒性,对骨髓瘤细胞具有一定的化疗作用。
【实施例8】探针L1-PEG-Glu的体外光热升温曲线。
取不同浓度的探针L1-PEG-Glu血清溶液20μL,置于808nm激光下持续激光照射5分钟,激光功率密度为1.2W/cm2,用光热相机记录每个样品的升温,绘制升温曲线。见附图9,1.2W/cm2的激光照射下,探针L1-PEG-Glu的温度随着浓度的增加而增大,在60μM的浓度下,其温度可以升至60℃,具有一定的光热效果,可以用作光热协同治疗。
【实施例9】探针L1-PEG-Glu对癌细胞THP-1及Molm-13不同处理下的细胞显微成像
取6孔板将癌细胞THP-1及Molm-13接种其中,分别予以空白处理,808nm 激光照射5min、加入L1-PEG-Glu(20μM)及加入L1-PEG-Glu(20μM)和808nm 激光照射5min处理,培养24小时后,置于倒置荧光显微镜下成像,观察其细胞形态。见附图10,可以看出在空白组及单独激光组下,细胞呈现出良好的细胞形态,在药物组及药物加激光照射下,肿瘤细胞的形态发生明显变化,呈现出凋亡形态,直观的证明了探针L1-PEG-Glu对骨髓瘤细胞具有一定的化疗及光热协同治疗效果。
【实施例10】探针L1-PEG-Glu对癌细胞THP-1及Molm-13不同处理情况下的凋亡流式分析。
取6孔板将癌细胞THP-1及Molm-13接种其中,分别予以空白处理,808nm 激光照射5min,加入L1-PEG-Glu(20μM)及加入L1-PEG-Glu(20μM)和808nm 激光照射5min处理,培养24小时后,收集细胞悬浮液,用凋亡试剂盒避光染色10分钟,接着,离心,PBS洗涤细胞沉淀,1小时内通过流式细胞仪对其进行凋亡分析。见说明书附图11,可以看出随着治疗程度的加深,两种肿瘤细胞的凋亡细胞百分比在增加,定量的证明了探针L1-PEG-Glu对骨髓瘤细胞THP-1 及Molm-13的具有一定的化疗及光热协同治疗效果。
【实施例11】探针L1-PEG-Glu对癌细胞THP-1及Molm-13线粒体共聚焦成像
在培养瓶中培养癌细胞THP-1及Molm-13,取0.5mL细胞悬浮液于EP管中,加入1.5mL新鲜培养基稀释;涡旋,使细胞分散均匀,在荧光小皿中加入1mL 细胞悬浮液;培养24h后,加入荧光探针L1-PEG-Glu(10nM~100μM),孵育 6h;6h后,弃去含有化合物的培养基,用PBS反复清洗细胞3次;配好100nM 的Mito-Tracker Green溶液,取1μL至1mL培养基中,摇匀加入荧光小皿中,染色30min;染色结束后,再次用PBS清洗细胞3次,加入新鲜培养基,接着将上述细胞加入至载玻片上进行共聚焦成像,通过用Mito-Tracker Green和 L1-PEG-Glu分别对细胞的线粒体染色,发现两者几乎完全重合,证明了探针 L1-PEG-Glu对线粒体的靶向。见附图12。
【实施例12】探针L1-PEG-Glu对白血病模型鼠(PDX)活体成像。
通过尾静脉将近红外二区荧光探针L1-PEG-Glu(200μg in 200μL PBS)注入到白血病模型鼠体内,对照组尾静脉注射200μLPBS溶液,并对其进行不同时间点的近红外二区活体荧光成像。见附图13,由图可以看出,随着注射探针时间的推移,探针在模型鼠的骨髓处的富集明显增加,6小时达到最大,在正常小鼠体内,骨髓处无明显荧光信号,全部在肝脏富集,说明探针L1-PEG-Glu对骨髓瘤具有很好的靶向性,能用于活体骨髓瘤成像。
【实施例13】探针L1-PEG-Glu对白血病模型鼠(PDX)进行活体光热及化疗联合治疗
取9只PDX模型鼠随机分为三组,每组3只,分别给与空白对照、 L1-PEG-Glu(20μM)、L1-PEG-Glu(20μM)及808nm激光照射5分钟,一周后将小鼠模型处死,收集外周血及骨髓,对CD34表达水平进行分析,同时对骨髓进行免疫组化分析,结果见附图14-15所示,给药激光组的CD34+的比例较空白组及单独L1-PEG-Glu要低,结果与骨髓的免疫组化分析一致,上述结果表明该近红外二区探针L1-PEG-Glu对急性髓性白血病具有线粒体介导的光热及化疗联合治疗作用,在临床上具有潜在的应用价值。
Claims (10)
3.权利要求1或2所述的噻喃盐荧光分子的制备方法,其特征在于,具体路线如下:
n=0,1;
R1选自:
R2选自:
R3选自:
R4选自:
(1)、将化合物2溶于20mL乙醇中,冰浴下加入20%KOH溶液并在室温下反应10分钟,然后将化合物1加入到混合物中,并将反应在室温下搅拌12小时,反应完毕后,用2M HCl溶液将反应溶液调节至pH=3,过滤收集形成的黄色中间体化合物3;优选地,化合物1及化合物2的摩尔比为1:1.5,整个反应体系溶液的浓度为0.5-1mol/L,反应温度为0-25℃;
(2)、将化合物4和四氢吡咯溶于50mL苯中,并加热至100℃反应4小时,形成烯胺中间体,冷却至室温后,减压除去苯,接着往反应体系中加入50mL 1,4-二氧六环溶解,并加入化合物3,加热回流反应6小时,反应完全后,冷却至室温,将上述反应体系倒入100mL水中,并用乙酸乙酯萃取3次,有机层用100mL饱和盐水洗涤,无水硫酸钠干燥,过滤并浓缩得到粗产物,粗产物进一步经过柱层析纯化,得到中间体化合物5;优选地,化合物4、四氢吡咯和中间体3三者的物质的量之比为5:5:1,反应体系溶液浓度为0.5-1mol/L;
(3)、将化合物5溶于乙醚中并搅拌10分钟,接着加入硫代乙酸和三氟化硼醚并加热回流反应3小时,冷却至室温后,将反应混合物用水淬灭,向溶液中加入过量的乙醚,然后在室温下搅拌混合物以沉淀得到浅黄色中间体化合物6;优选地,硫代乙酸、三氟化硼乙醚及化合物5的物质的量之比为10:10:1,反应温度为100℃,溶液浓度为0.1-1mol/L;
(4)、在反应容器中加入化合物6,原料7和乙酸酐,微波500℃下反应2小时,反应完毕后,加入大量乙醚,析出粗产物,粗产物进一步通过柱层析纯化分离得到最终荧光化合物(1);优选地,上述反应在10mL封管中进行,微波压力为15-20个大气压,温度为500℃,化合物6与原料7物质的量之比为1:3-5。
4.一种近红外二区噻喃盐荧光成像探针,其特征在于,所述探针为权利要求1的通式(I)所示的荧光化合物可修饰位点修饰聚乙二醇、多肽、蛋白、核酸适配体、叶酸及其衍生物。
6.权利要求4或5所述的近红外二区噻喃盐荧光成像探针在制备用于细胞线粒体成像的试剂中的应用。
7.权利要求4或5所述的近红外二区噻喃盐荧光成像探针在制备用于肿瘤诊断的试剂中的应用。
8.权利要求4或5所述的近红外二区噻喃盐荧光成像探针在制备用于急性髓系白血病成像的试剂中的应用。
9.权利要求4或5所述的近红外二区噻喃盐荧光成像探针在制备用于急性髓系白血病光热治疗及化疗的药物中的应用。
10.权利要求4或5所述的近红外二区噻喃盐荧光成像探针在在制备用于在生物体内成像的试剂中的应用。
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