CN117800951A - 一种近红外荧光探针及其制备方法与应用 - Google Patents
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Abstract
本发明涉及有机荧光探针分子领域,公开一种近红外荧光探针及其制备方法与应用,制备方法包括将2‑(7‑氮杂苯并三氮唑)‑N,N,N',N'‑四甲基脲六氟磷酸酯、碱和极性溶剂混合,加入克唑替尼和连接分子,反应得到产物a;将其滴入水中,形成混悬液,加入有机溶剂萃取,将萃取物干燥后浓缩,再加入三氟乙酸,反应完全后,柱层析后得到中间体b,加入2‑(7‑氮杂苯并三氮唑)‑N,N,N',N'‑四甲基脲六氟磷酸酯、碱、染料分子和极性溶剂,反应得到混合物c,将其纯化后得到近红外荧光探针。本发明提供的探针可主动靶向细胞间质‑上皮转化因子,在正常组织内能迅速清除,而在肿瘤部位能长时间滞留,从而达到活体诊断的作用。
Description
技术领域
本发明涉及有机荧光探针分子领域,具体涉及一种近红外荧光探针及其制备方法与应用。
背景技术
癌症严重威胁着人类的生命健康,随着人口老龄化程度的加深和人们生活方式的改变,癌症带来的挑战愈加严峻。临床上针对癌症治疗方式主要有外科手术切除、化疗、放疗等,其中手术切除是目前治疗实体肿瘤的首选方案,精准切除肿瘤可有效改善患者预后,延长患者生存期。为了实现肿瘤的精准识别及手术导航,已有包括计算机断层扫描(CT)、磁共振成像(MRI)、正电子发射断层扫描(PET)和超声(US)等技术用于癌组织的成像和诊断。然而,由于空间分辨率或灵敏性低等固有局限性,影响了它们准确识别病变组织边界的能力。光学分子影像手术导航技术具有实时、无创、高分辨率的特点,为肿瘤的精准手术提供了崭新的影像学辅助手段。近红外荧光成像诊断在肿瘤诊断(早、中和晚)、术中导航、预后和复发监测诊断等方面具有优势,该诊断方法主要通过近红外荧光探针(650~1000 nm)来进行具体的检测,其能提供高分辨的组织和器官图像,具有生物毒性小和自发荧光低的优点,有利于最大限度地减少背景干扰。
吲哚菁绿(ICG)是经FDA获批的近红外荧光染料,静脉注射后易于血浆蛋白结合,由肝脏代谢入胆汁中,可经EPR效应滞留于肿瘤组织。但ICG特异性较差,较难区分肿瘤组织和瘤周炎症组织、良性结节等,易导致假阳性结果。具有特异性靶向、经肾脏排泄的近红外荧光探针可有效避免假阳性结果,显著提高肿瘤背景比,使得外科医生在术中能更准确识别肿瘤边界,彻底切除残余肿瘤病灶,最大限度地延长患者生存期,提高患者生存质量。
细胞间质-上皮转化因子(cellular mesenchymalepithelial transitionfactor,c-MET)是一种酪氨酸激酶型受体,而配体生长因子(hepatocyte growth factor,HGF)是c-Met的唯一配体,是间质细胞在发育过程中产生和分泌的一种旁分泌信号分子。正常生理状态下,HGF/c-MET可介导胚胎发育、细胞增殖、受伤组织修复和神经肌肉的形成。参与或涉及到c-MET信号通路的许多靶点大多是多种癌症发生的关键,一旦这些靶点异常激活将会牵动多种癌症发生,由此可见,c-MET靶点在癌症病发中的重要地位。有大量研究表明,c-MET靶点极易过度激活,过度激活后的靶点有可能会使正常细胞病变成癌细胞,并进一步带动其侵袭、转移、扩散等后续事件的发生。
克唑替尼是一种抗肿瘤药物,属于酪氨酸激酶抑制剂,主要作用靶点是c-MET,用于经 CFDA 批准的检测方法确定的间变性淋巴瘤激酶(ALK)阳性的局部晚期或转移性非小细胞肺癌(NSCLC)患者的治疗。克唑替尼能特异性靶向肿瘤组织,激活通路进一步导致肿瘤细胞凋亡,起到肿瘤治疗作用,在开发具有肿瘤特异性的荧光探针过程中,具有肿瘤特异性杀伤作用的抗肿瘤药物具备一定的研究价值,可用于特异性靶向荧光探针的开发,进一步扩大药物的应用价值,用于外科手术导航,切除肿瘤。
公开号为CN116200188A的专利公开了一种基于近红外二区吲哚菁绿纳米粒子特异性肿瘤成像荧光探针及其制备方法和应用,其以十六烷基三甲基溴化铵为模板,使用一锅共缩合法合成单分散的巯基功能化的纳米粒子再将anti-PD-L1抗体通过聚乙二醇连接剂偶联到所得的纳米粒子,分散后得到抗体-聚乙二醇功能化的纳米粒子溶液,向以上溶液中加入吲哚菁绿(ICG)溶液,分散后便形成了基于近红外二区吲哚菁绿纳米粒子特异性肿瘤成像荧光探针,该荧光探针中的巯基功能化的纳米粒子可以防止ICG聚集,减少荧光猝灭,但是问题是容易产生假阳性。
发明内容
本发明目的在于提供一种近红外荧光探针及其制备方法与应用,该探针可主动靶向细胞间质-上皮转化因子,在正常组织内能迅速清除,而在肿瘤部位长时间滞留,从而能达到活体诊断的作用。
为达到上述目的,本发明提供一种近红外荧光探针,其为式(Ⅰ)所示的化合物:
(Ⅰ)
式(Ⅰ)中,X是连接分子,选自无、PEG、聚甘氨酸链中的任一种,Y是在近红外范围内具有荧光激发和发射光谱的染料分子。
优选地,所述Y的结构式为:
结构式中,R1、R2选自(CH2)nSO3H,n=3或4;Z选自3-巯基丙酸或4-羟基苯丙酸。
优选地,所述近红外荧光探针主动靶向细胞间质-上皮转化因子。
本发明还提供一种近红外荧光探针的制备方法,包括以下步骤:
S1:将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱和极性溶剂混合均匀,加入克唑替尼和连接分子,室温反应1~2 h,得到产物a,将产物a滴入水中,形成混悬液;
S2:在混悬液中加入乙酸乙酯萃取,将萃取物干燥后浓缩,再加入三氟乙酸室温反应30~50 min, 柱层析后得到中间体b;
S3:在中间体b中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、在近红外范围内具有荧光激发和发射光谱的染料分子、极性溶剂,室温下搅拌1~2 h得到混合物c;
S4:将混合物c纯化后得到近红外荧光探针。
优选地,所述S1中2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、克唑替尼、连接分子、极性溶剂的摩尔比为(1~2):(1~3):1:1.2:70。
优选地,所述S2中乙酸乙酯、三氟乙酸体积比为1:(1~2)。
优选地,所述S3中中间体b、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、在近红外范围内具有荧光激发和发射光谱的染料分子、极性溶剂的摩尔比为(1~2):2:(1~3):1.1:(90~95)。
优选地,所述碱为三乙胺、二异丙基乙胺中的任一种或多种;所述极性溶剂为二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮中的任一种或多种。
本发明提供一种近红外荧光探针在制备荧光造影剂中的应用。
本发明还提供一种近红外荧光探针在制备肿瘤诊断药物中的应用。
优选地,所述肿瘤为肝癌或结直肠癌。
本发明所达到的有益效果:
1.克唑替尼是一种抗肿瘤药物,主要作用靶点是c-MET,其能够特异性靶向肿瘤组织,激活通路进一步导致肿瘤细胞凋亡,起到肿瘤治疗作用。本发明通过连接分子将克唑替尼和染料分子相连接,在HATU缩合剂的作用下这三种化合物中的羧基和氨基发生反应,生成酰胺键,得以耦联,从而制备成一种近红外荧光探针,这进一步扩大了药物的应用价值,此探针可用于外科手术导航来切除肿瘤。
2. 本发明制备的近红外荧光探针可主动靶向细胞间质-上皮转化因子,其具有肿瘤主动靶向能力、水溶性好、肿瘤滞留时间长、正常组织不蓄积等优点,不仅能应用于制备荧光造影剂或者肿瘤诊断药物,而且在临床外科术中荧光引导肿瘤手术切除等领域具有应用潜力。
附图说明
图1为实施例1~6制备的NY-cMet-01~06的吸收光谱;
图2为实施例1~6制备的NY-cMet-01~06的荧光光谱;
图3为实施例1~5制备的NY- cMet-01~05在肝癌HepG2荷瘤鼠中的体内成像结果;
图4为实施例2和实施例4制备的NY- cMet-02和NY- cMet-04在结直肠癌HCT116荷瘤鼠中的体内成像结果。
具体实施方式
下面结合附图对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
实施例中所用材料及来源见下表1所示:
表1 材料及来源
实施例1
一种近红外荧光探针的制备方法,包括以下步骤:
(1)将克唑替尼(100 mg,1.0 eq)、S0456-Der-01(248 mg,1.1 eq)、2-(7-氮杂苯并三氮唑)-N,N,N', N'-四甲基脲六氟磷酸酯(HATU,169 mg,2.0 eq)、N,N-二异丙基乙胺(86 mg,3.0 eq)、DMSO(1 mL,70.0 eq)混合搅拌,避光室温反应1小时,以液相色谱(HPLC)监测反应,反应完全后得到混合物。
(2)将混合物通过液相纯化得到目标馏分溶液,冻干后得到绿色固体,即为近红外荧光探针NY-cMet-01。
近红外荧光探针NY-cMet-01的合成路线如下:
(3)将NY-cMet-01经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-2H]/2-= 723.4;1H NMR(600 MHz,DMSO-d6)δ 8.17(s,1H),7.98(d,J = 13.5 Hz,2H),7.81–7.71(m,3H),7.63–7.57(m,6H),7.46(td,J = 8.7,5.6 Hz,1H),7.32–7.25(m,4H),7.18(s,1H),7.04(d,J = 8.5 Hz,2H),6.35(td,J = 13.2,6.6 Hz,3H),6.21–6.13(m,2H),4.36(d,J = 10.4 Hz,2H),4.11(s,4H),3.86–3.76(m,1H),3.08(t,J = 11.4 Hz,1H),2.80(dt,J = 20.8,6.8 Hz,2H),2.72–2.51(m,10H),1.99(d,J = 31.4 Hz,2H),1.82(dd,J= 48.5,23.8 Hz,13H),1.66–1.50(m,2H),1.23(d,J = 5.7 Hz,12H);13C NMR(151 MHz,DMSO-d6)δ 172.01,170.14,163.52,158.98,158.72,158.53,158.47,156.55,146.44,145.43,142.56,141.45,141.32,140.77,136.10,135.66,131.26,130.97,129.35,126.59,125.71,125.62,122.51,122.13,121.70,120.07,118.66,118.56,118.10,116.67,116.59,116.45,114.88,114.54,110.78,101.05,73.98,58.42,51.10,48.91,44.06,43.90,34.56,32.84,32.64,32.07,31.85,30.17, 27.61,27.58,27.52,27.47,26.32,24.18,22.75,21.16,18.89。
实施例2
一种近红外荧光探针的制备方法,包括以下步骤:
(1)将克唑替尼(100 mg,1.0 eq)、BOC-NH-PEG4酸(98 mg,1.2 eq)、2-(7-氮杂苯并三氮唑)-N,N,N', N'-四甲基脲六氟磷酸酯(169 mg,2.0 eq)、N,N-二异丙基乙胺(86mg,3.0 eq)、DMSO(1 mL,70.0 eq),室温反应1小时,使用薄层色谱法(TLC)监测反应,待反应完全后,将反应液滴入水中,形成混悬液。
(2)在混悬液中加入10 mL乙酸乙酯萃取,合并有机层浓缩后,再加入10 mL三氟乙酸室温反应30 min,以薄层色谱法(TLC)监测反应,反应完全后,蒸干后再使用柱层析法纯化,得到克唑替尼-PEG4中间体。
(3)将克唑替尼-PEG4中间体(100 mg,1.0 eq)、S0456-Der-01(160 mg,1.1 eq)、2-(7-氮杂苯并三氮唑)-N,N,N', N'-四甲基脲六氟磷酸酯(110 mg,2.0 eq)、N,N-二异丙基乙胺(56 mg,3.0 eq)、DMSO(1mL,93.3 eq)混合搅拌,避光室温反应1小时,以液相色谱(HPLC)监测反应,反应完全后得到混合物。
(4)将混合物通过液相纯化得到目标馏分溶液,冻干后得到绿色固体,即为近红外荧光探针NY-cMet-02。
近红外荧光探针NY-cMet-02的合成路线如下:
(5) 将NY-cMet-02经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-2H]/2-= 845.8;1H NMR(600 MHz,DMSO-d6)δ 8.16(s,1H),8.05(s,2H),7.87(t,J =5.5 Hz,1H),7.77(d,J = 14.0 Hz,2H),7.71(s,1H),7.60(ddd,J = 14.1,11.0,7.3 Hz,6H),7.46(t,J = 8.7 Hz,1H),7.31(d,J = 8.3 Hz,2H),7.20(d,J = 8.6 Hz,2H),7.14(d,J = 0.9 Hz,1H),6.99(d,J = 6.7 Hz,2H),6.29(q,J = 6.7 Hz,1H),6.20(d,J = 14.2Hz,2H),4.45(d,J = 10.9 Hz,2H),4.12(s,4H),4.00(d,J = 12.9 Hz,1H),3.67–3.59(m,2H),3.49(s,4H),3.46–3.40(m,8H),3.33(t,J = 5.8 Hz,2H),3.19(t,J = 12.7 Hz,1H),3.12(q,J = 5.6 Hz,2H),2.79–2.66(m,7H),2.65–2.54(m,6H),2.29–2.21(m,2H),2.09–1.98(m,2H),1.94–1.81(m,6H),1.81–1.66(m,9H),1.23(d,J = 7.1 Hz,12H);13C NMR(151MHz,DMSO-d6)δ 172.05,171.74,169.30,163.50,158.97,158.72,158.46,146.54,145.41,142.58,141.49,141.31,140.73,135.88,135.65,135.61,130.54,129.27,126.62,125.73,122.51,122.13,120.08,118.58,118.51,118.43,117.98,116.70,114.82,110.84,101.08,74.00,70.26,70.21,70.17,69.99,69.53,67.39,58.69,51.11,48.94,44.28,44.04,38.97,37.68,33.28,33.05,32.11,30.69,27.56,26.32,24.19,22.74,21.18,18.91。
实施例3
一种近红外荧光探针的制备方法,包括以下步骤:
与实施例2不同之处在于:以BOC-GLY-GLY-GLY-OH替换实施例2中的BOC-NH-PEG4酸进行反应。
该红外荧光探针NY- cMet-03的结构式如下:
将NY-cMet-03经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-3H]/3-= 539.5;1H NMR(600 MHz,DMSO-d6)δ 8.24-8.15(m,3H),8.02(s,2H),7.91-7.86(m,1H),7.79(t,J = 15.1 Hz,2H),7.69(dd,J = 23.8,12.6 Hz,1H),7.64-7.55(m,6H),7.46(q,J = 8.7 Hz,1H),7.31(dd,J = 17.3,9.0 Hz,2H),7.22(d,J = 8.6 Hz,2H),7.15(s,1H),7.03(dd,J = 22.8,7.1 Hz,2H),6.37–6.27(m,1H),6.20(d,J = 14.2 Hz,2H),4.21–3.86(m,8H),3.78–3.60(m,4H),3.19(t,J = 12.5 Hz,1H),2.94–2.54(m,12H),2.35(s,2H),2.07–1.96(m,2H),1.87(t,J = 12.4 Hz,6H),1.79–1.63(m,9H),1.28–1.13(m,12H);13C NMR(151 MHz,DMSO-d6)δ 172.07,169.38,167.08,163.48,158.96,146.51,145.35,142.60,141.36,140.73,135.65,130.63,126.60,125.69,122.49,120.08,118.02,116.78,116.51,114.81,114.59,110.79,101.08,73.99,58.64,51.11,48.91,44.06,42.50,37.44,27.57,27.54,27.50,26.33,24.17,22.78,21.19,18.91。
实施例4
一种近红外荧光探针的制备方法,包括以下步骤:
与实施例2不同之处在于:以BOC-GLY-GLY-GLY-OH替换实施例2中的BOC-NH-PEG4酸进行反应、S0456-Der-02替换S0456-Der-01进行反应。
该红外荧光探针NY- cMet-04的结构式如下:
将NY-cMet-04经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-2H]/2-= 764.9;1H NMR(600 MHz,DMSO-d6)δ 8.70(d,J = 13.9 Hz,2H),8.28(t,J =5.7 Hz,1H),8.19(d,J = 8.4 Hz,2H),7.99(s,2H),7.88(t,J = 5.2 Hz,1H),7.76(dd,J =11.7,1.1 Hz,3H),7.63(ddd,J = 13.9,8.2,3.0 Hz,4H),7.48(t,J = 8.7 Hz,1H),7.41(d,J = 8.4 Hz,2H),7.16(d,J = 0.9 Hz,1H),6.50(d,J = 14.1 Hz,2H),6.30(q,J = 6.7Hz,1H),4.49–4.26(m,6H),4.02(dd,J = 16.5,5.0 Hz,1H),3.88(dd,J = 16.3,4.9 Hz,2H),3.77–3.65(m,4H),3.14(t,J = 12.3 Hz,1H),3.00(t,J = 7.1 Hz,2H),2.69(dt, J =13.6,9.5 Hz,9H),2.44(t,J = 7.3 Hz,2H),2.07–1.97(m,6H),1.86(d,J = 6.6 Hz,3H),1.79(s,3H),1.68(s,12H);13C NMR(151 MHz,DMSO-d6)δ 172.48,170.70,169.73,169.30,167.04,158.98,158.72,156.59,155.62,146.49,145.36,142.82,141.58,140.92,135.61,135.53,134.37,131.30,129.29,126.61,125.56,122.28,121.66,121.53,120.27,118.62,118.52,118.02,116.75,110.74,102.47,74.06,58.61,49.23,48.32,43.34,43.25,42.61,42.40,40.90,35.93,33.03,32.83,32.16,27.85,26.32,23.71,21.07,18.90。
实施例5
一种近红外荧光探针的制备方法,包括以下步骤:
与实施例2不同之处在于:以BOC-GLY-GLY-GLY-OH替换实施例2中的BOC-NH-PEG4酸、S0456-Der-03替换S0456-Der-01进行反应。
该红外荧光探针NY- cMet-05的结构式如下:
将NY-cMet-05经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-2H]/2-= 779.2;1H NMR(600 MHz,DMSO-d6)δ 8.68(d,J = 13.8 Hz,2H),8.29(t, J =5.3 Hz,1H),8.19(d,J = 7.9 Hz,2H),8.00(s,2H),7.90(d,J = 5.2 Hz,1H),7.78-7.70(m,3H),7.67-7.57(m,4H),7.47(t,J = 8.6 Hz,1H),7.37(t,J = 7.1 Hz,2H),7.15(d,J =9.8 Hz,1H),6.40–6.26(m,3H),4.43(ddd,J = 15.1,11.3,3.8 Hz,1H),4.18(s,4H),4.04(d,J = 13.7 Hz,1H),3.87(d,J = 12.4 Hz,2H),3.76–3.64(m,4H),3.15(t,J = 12.5 Hz,1H),3.00(dd,J = 16.2,9.1 Hz,2H),2.75(t,J = 11.9 Hz,1H),2.70–2.56(m,8H),2.44(t,J = 7.2 Hz,2H),2.02(s,2H),1.86(d,J = 6.6 Hz,3H),1.84–1.72(m,11H),1.66(dd,J= 10.2,6.6 Hz,12H);13C NMR(151 MHz,DMSO-d6)δ 172.39,170.71,169.73,169.28,167.07,158.96,158.71,155.55,146.49,145.49,145.21,142.75,141.52,140.81,135.65,135.56,134.06,129.28,126.65,125.54,122.20,121.55,120.23,118.58,118.02,116.78,110.86,102.23,74.02,58.60,51.15,49.24,44.16,43.38, 42.63,42.40,40.97,35.82,32.83,27.86,27.82,26.41,26.21,22.82,20.99,18.91。
实施例6
一种近红外荧光探针的制备方法,包括以下步骤:
与实施例2不同之处在于:以BOC-GLY-GLY-GLY-OH替换实施例2中的BOC-NH-PEG4酸、S0456-Der-04替换S0456-Der-01进行反应。
该红外荧光探针NY- cMet-06的结构式如下:
将NY-cMet-06经质谱和核磁氢谱、核磁碳谱进行结构表征,结构测定结果如下:[M-H]-= 1590.3;1H NMR(600 MHz,DMSO-d6)δ 8.21(s,1H),8.15(dd,J = 14.4,8.4 Hz,2H),7.99(s,2H),7.87(t,J = 5.2 Hz,1H),7.80(d,J = 13.9 Hz,2H),7.75(d,J = 4.1Hz,1H),7.60(dd,J = 19.0,8.8 Hz,6H),7.48(td,J = 8.7,3.6 Hz,1H),7.35(d,J = 8.3Hz,2H),7.23(d,J = 8.6 Hz,2H),7.16(d,J = 1.1 Hz,1H),7.04(d,J = 8.5 Hz,2H),6.36(d,J = 14.1 Hz,2H),6.30(q,J = 6.6 Hz,1H),4.44(td,J = 11.4,5.7 Hz,1H),4.38(s,1H),4.28(s,4H),4.06–3.85(m,3H),3.71(d,J = 5.7 Hz,2H),3.64(d,J = 5.2 Hz,2H),3.17(dd,J = 15.0,9.3 Hz,1H),2.82–2.65(m,7H),2.60(t,J = 6.7 Hz,4H),2.36(dt,J =15.4,4.7 Hz,2H),2.08–1.93(m,6H),1.86(d,J = 6.6 Hz, 6H),1.67(dd,J = 14.4,5.8Hz,1H),1.26(d,J = 10.0 Hz,12H);13C NMR(151 MHz,DMSO-d6)δ 172.12,169.90,169.36,167.06,163.53,158.97,158.71,158.55,146.49,145.31,142.63,141.57,140.84,135.84,135.62,135.51,130.65,129.30,126.57,125.55,122.80,122.28,121.67,121.54,120.10,118.61,118.03,116.77,114.87,110.71,101.36,74.05,58.68,48.90,48.26,43.38,43.12,42.73,42.49,37.54,30.39,27.57,24.29,23.65,21.30,18.90。
测试例1 光谱测试
将NY-cMet-01~06系列探针配置成约1nmol的水溶液,先使用紫外分光光度计(HITACHI,3J1-0015)检测各探针在500-900 nm范围内的吸收光谱,结果如图1所示,NY-cMet-01、NY-cMet-02 、NY-cMet-03、NY-cMet-05的最大吸收约在775 nm,NY-cMet-04和NY-cMet-06的最大吸收约在790 nm,进而在酶标仪(Molecule devices,D1524R)检测各探针在750-850nm范围内的荧光发射光谱,结果如图2所示,NY-cMet-01、NY-cMet-02 、NY-cMet-03、NY-cMet-05的最大发射光谱约在800 nm,NY-cMet-04和NY-cMet-06的最大发射光谱约在820 nm。
测试例2 皮下瘤HepG2荷瘤鼠模型(人源肝癌细胞)活体成像
在皮下瘤HepG2荷瘤鼠模型中,分别尾静脉给药NY-cMet-01~05系列探针(5 nmol/只,葡萄糖注射液100 μL),以吲哚菁绿(ICG,1.0 mg/kg,注射用水100 μL)为对照,给药后以手术荧光影像系统(南京诺源医疗器械有限公司,10B)进行荧光成像,依次是0 h(给药前)、6 h、12 h、24 h、48 h,结果如图3所示。从该图可知,在皮下瘤HepG2荷瘤鼠中,与ICG相比,NY-cMet-02~05具有更强的肿瘤荧光信号,NY-cMet-01肿瘤部位荧光信号较弱;NY-cMet-02和NY-cMet-03给药后在肝脏滞留时间长达48 h;NY-cMet-04和NY-cMet-05不仅展现出良好的体内代谢特性(肾排泄),同时还具有良好的肿瘤靶向能力,给药24 h后基本上只剩肿瘤有荧光信号,成像时间超过48 h;NY-cMet-02~05探针具有潜在的肝癌肿瘤显影能力,可做进一步研究开发,以期应用于临床荧光引导肿瘤手术切除。
测试例3 结直肠癌(HCT116)荷瘤鼠模型活体成像
在结直肠癌(HCT116)荷瘤鼠模型中,分别尾静脉给药探针NY-cMet-02和NY-cMet-04(5 nmol /只,葡萄糖注射液100 μL),给药后以手术荧光影像系统(南京诺源医疗器械有限公司,10B)进行荧光成像,依次是0 h(给药前)、6 h、12 h、24 h、48 h,结果如图4所示。从该图可知,探针NY-cMet-02和NY-cMet-04在结直肠癌(HCT116)荷瘤鼠上同样具有良好的肿瘤靶向能力,具备潜在的临床应用前景,需做进一步研究开发,以期应用于临床外科。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变形,这些改进和变形也应视为本发明的保护范围。
Claims (8)
1.一种近红外荧光探针,其特征在于:其为式(Ⅰ)所示的化合物:
;
式(Ⅰ)中,X是连接分子,选自无、PEG、聚甘氨酸链中的任一种,Y是在近红外范围内具有荧光激发和发射光谱的染料分子;所述Y的结构式为:
;
结构式中,R1、R2选自(CH2)nSO3H,n=3或4;Z选自3-巯基丙酸或4-羟基苯丙酸。
2.一种如权利要求1所述的一种近红外荧光探针的制备方法,其特征在于,包括以下步骤:
S1:将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱和极性溶剂混合均匀,加入克唑替尼和连接分子,室温反应1~2 h,得到产物a,将产物a滴入水中,形成混悬液;
S2:在混悬液中加入乙酸乙酯萃取,将萃取物干燥后浓缩,再加入三氟乙酸室温反应30~50 min,柱层析后得到中间体b;
S3:在中间体b中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、在近红外范围内具有荧光激发和发射光谱的染料分子、极性溶剂,室温下搅拌1~2 h得到混合物c;
S4:将混合物c纯化后得到近红外荧光探针。
3.根据权利要求2所述的一种近红外荧光探针的制备方法,其特征在于,所述S1中2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、克唑替尼、连接分子、极性溶剂的摩尔比为(1~2):(1~3):1:1.2:70;所述S2中乙酸乙酯、三氟乙酸体积比为1:(1~2)。
4.根据权利要求2所述的一种近红外荧光探针的制备方法,其特征在于,所述S3中中间体b、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、碱、在近红外范围内具有荧光激发和发射光谱的染料分子、极性溶剂的摩尔比为(1~2):2:(1~3):1.1:(90~95)。
5.根据权利要求2所述的一种近红外荧光探针的制备方法,其特征在于,所述碱为三乙胺、二异丙基乙胺中的任一种或多种;所述极性溶剂为二甲基甲酰胺、二甲基亚砜、N-甲基吡咯烷酮中的任一种或多种。
6.权利要求1所述的一种近红外荧光探针在制备荧光造影剂中的应用。
7.权利要求1所述的一种近红外荧光探针在制备肿瘤诊断药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述肿瘤为肝癌或结直肠癌。
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