CN107417734A - 一种具有双光子吸收特性的铂配合物及其制备方法和应用 - Google Patents
一种具有双光子吸收特性的铂配合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种具有双光子吸收特性的三脚架结构的铂(II)配合物,其化学式为{[Pt(dien)]3L}(NO3)6(配合物1),其中,L为三(4‑吡啶基苯基)胺,dien为二乙烯三胺,结构式如式(I)所示。本发明还公开上述铂配合物的合成与潜在的抗肿瘤光动力治疗应用,本发明所述铂配合物在体外抗肿瘤筛选中表现出暗毒性低、光动力活性强的特点,并且在裸鼠肿瘤模型中,在430 nm光照作用下显著抑制肿瘤生长,具备良好光动力治疗抗肿瘤药物开发潜能。式(I)。
Description
技术领域
本发明属于抗肿瘤药物制备技术领域,更具体地,涉及一种具有双光子吸收特性的铂配合物及其制备方法和应用。
背景技术
铂类配合物在抗肿瘤方面取得了很大的成功,顺铂、卡铂和奥沙利铂是美国FDA批准用于临床治疗的抗肿瘤药物。这三个铂配合物的抗肿瘤作用靶点是DNA,它们进入细胞后,能与DNA发生交联反应,导致DNA结构折叠和扭曲,抑制DNA的复制和转录,最终诱导肿瘤细胞凋亡。这三个铂配合物在膀胱癌,卵巢癌,头颈癌,睾丸癌和肺癌等治疗中都表现出良好的效果,但由于它们具有严重的毒副作用,如肾毒性,肝毒性和心脏毒性等,同时存在一定的耐药性,限制了它们在临床上的进一步发展。这些年来,科学家们在这些临床抗肿瘤的铂类药物的基础上进行了多种多样的结构修饰和改进,希望能揭示新的抗肿瘤机制、降低毒副作用和耐药性,扩大铂类药物的抗肿瘤谱。在铂类药物的基础上引入靶向基团,使之能特异的靶向肿瘤细胞,或者将具有生物活性的功能基团与铂配合物偶联在一起发挥它们的协同作用是其中两个设计新型铂类抗肿瘤药物的可行的策略。
光动力疗法(Photodynamic therapy, PDT)相对于传统的放疗和化疗来说,具有较高的选择性和较低的毒副作用,是一类非常具有吸引力的癌症治疗方法。在光照作用下,光敏剂能够被激发随后把能量传递给周围的三线态氧分子 (3O2),从而产生单线态氧(1O2),或者把能量转移给细胞内其他物质从而产生其他具有细胞毒性的活性氧物种(Reactive oxygen species, ROS),最终导致肿瘤细胞遭受不可逆的氧化损伤。
研究表明,铂基光敏剂具有增强光动力治疗的效果。铂由于重原子效应,能促进光敏剂从第一激发单重态 (S1) 到第一激发三重态 (T1) 的系间窜越,从而提高单线态氧量子产率,而光照产生的活性氧物种能破坏细胞膜和核膜,促进铂配合物进入细胞与靶点DNA相互作用。
发明内容
本发明的目的在于根据现有技术中的不足,提供了一种具有双光子吸收特性的铂配合物。
本发明的另一目的在于提供上述铂配合物的制备方法。
本发明的再一目的在于提供上述铂配合物作为光敏剂在制备光动力疗法抗肿瘤药物中的应用。
本发明所述铂配合物具备很好的光动力治疗活性,在光照作用下能够显著抑制肿瘤的生长。
本发明通过以下技术方案实现上述技术目的:
本发明提供了一种具有双光子吸收特性的铂配合物,所述铂配合物的化学式为{[Pt(dien)]3L}(NO3)6,其中L为三(4-吡啶基苯基)胺,dien为二乙烯三胺,所述铂配合物的结构式如式(I)所示,
式(I)。
本发明同时提供所述的具有双光子吸收特性的铂配合物的制备方法,包括如下步骤:将铂前体配合物[Pt(dien)Cl]Cl和硝酸银溶于溶剂中,氮气保护下避光55~65℃反应38~42 h,反应结束后低温离心得到上清液,然后加入配体L,氮气保护下避光85~95℃反应45~50 h;反应结束后加入过量乙醇,析出的沉淀即为具有双光子吸收特性的铂配合物;
其中,配体L为三(4-吡啶基苯基)胺,dien为二乙烯三胺。
优选地,是在氮气保护下避光60℃反应40 h,反应结束后低温离心得到上清液,然后加入配体L,氮气保护下避光90℃反应48 h。
优选地,所述的溶剂为纯水。
优选地,铂前体配合物[Pt(dien)Cl]Cl和硝酸银的摩尔比为1:2,[Pt(dien)Cl]Cl和配体L的摩尔比为3:1。
铂前体配合物[Pt(dien)Cl]Cl的结构式为:。
本发明同时保护所述的具有双光子吸收特性的铂配合物在制备抗肿瘤药物中的应用。
进一步地,是保护上述铂配合物在制备光动力治疗抗肿瘤药物中的应用。
其中,肿瘤为良性或恶性肿瘤。
更进一步地,所述的肿瘤为对顺铂、卡铂或奥沙利铂中的一种或多种具有耐药性的肿瘤。
本发明所述的具有光动力治疗抗肿瘤活性的化合物为金属铂配合物,包含金属离子,其本身带电荷,相对于传统的有机小分子来说,增加了一定的水溶性,而且这类金属配合物具有平面构型,可以通过多种不同的修饰实现其与抗肿瘤靶点的特异性结合。
实验结果显示本发明提供的铂配合物具有双光子吸收特性。在体外抗肿瘤筛选中发现配合物1在黑暗条件下对肿瘤细胞基本没有暗毒性,但在425nm可见光照射下表现出很高的光毒性,而且比顺铂的毒性要高。进一步的机制研究表明,配合物1在光照作用下能产生大量的活性氧,导致DNA损伤,引起细胞周期阻滞,最后诱导细胞凋亡。配合物1在裸鼠肿瘤模型中也表现出良好的光动力治疗抗肿瘤效果。
与现有技术相比,本发明具有如下优点和有益效果:
本发明所提供的铂配合物水溶性好,可实现与抗肿瘤靶点的特异性结合,且为具有双光子吸收特性的配合物,其在体外抗肿瘤筛选中表现出暗毒性低、光动力活性强的特点,在光照作用下比顺铂的细胞毒性要高,能够显著抑制肿瘤生长,具备良好光动力治疗抗肿瘤药物开发潜能。
附图说明
图1是实施例1中配合物1的双光子吸收截面图。
图2是实施例1中配合物1的双光子激发的荧光强度对激发光功率二次方的依赖性。
图3是实施例3中配合物1在黑暗和光照条件下对裸鼠肿瘤的生长抑制作用图(生理盐水作为阴性对照,顺铂作为阳性对照)。
图4是实施例3中实验结束后各组小鼠的肿瘤照片。
具体实施方式
以下结合具体实施例和附图来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,本发明所用试剂和材料均为市购。
实施例1:制备配合物1
将[Pt(dien)Cl]Cl (110.7 mg, 0.30 mmol) 和 AgNO3 (101.9 mg, 0.60 mmol) 置于带支管的单颈瓶中,加入15 mL水,搅拌,N2保护下避光60 oC反应40 h。反应结束后低温高速离心除去AgCl沉淀。上清液转移到另外一个带支管的单颈瓶中,加入配体L (42.9 mg,0.09 mmol), 搅拌,N2保护下避光90 oC反应48 h。反应完之后加入乙醇直至有沉淀生成,低温高速离心得到黄色固体,用乙醇洗3次,真空干燥即得配合物1,产率73.2%。
铂前体配合物[Pt(dien)Cl]Cl可按文献合成:C. F. Weber, R. van Eldik,Eur. J. Inorg. Chem. 2005, 4755-4761,配体L可按文献合成:M. D. Zhang, C. M. Di,L. Qin, X. Q. Yao, Y. Z. Li, Z. J. Guo, H. G. Zheng, Cryst. Growth Des. 2012,12, 3957-3963。
反应式如下:
。
配体L为三(4-吡啶基苯基)胺,dien为二乙烯三胺。
配合物1的元素分析C45H63N19O18Pt3•6H2O(分子量为1851.4),理论值:C 29.19%,H4.08%,N 14.37%;实验值:C 29.30%,H 4.08%,N 14.22%。1H-NMR(400 MHz, D2O): δ = 8.74(d, J = 6.0 Hz, 6H), 7.93‒7.90 (m, 12H), 7.45 (d, J = 8.5 Hz, 6H), 3.40 (dd,J = 14.1, 5.0 Hz, 6H), 3.20‒2.96 (m, 18H); 13C-NMR (126 MHz, D2O): δ = 151.97,149.53, 148.42, 129.74, 128.33, 124.59, 123.06, 53.85, 50.27 ppm; 195Pt-NMR(107 MHz, D2O): δ = -2836.00 ppm (K2PtCl4 作为内标,δ = 0).
实施例2:配合物1的双光子吸收特性表征
配合物的双光子吸收截面是用纳秒脉冲激光器OpoletteTM 355II (激光脉宽≤ 100fs,频率80 MHz)测定的。双光子激发波长为800~880 nm, 罗丹明6G作为参照。双光子激发的荧光强度与激光能量之间的二次方关系是在激发光波长为810 nm处确定的。双光子吸收截面 (δ) 通过以下公式计算得到。,其中I为积分荧光强度,c为浓度,n为折射率,Φ为荧光量子产率,下标“r”为参照物,“s”为待测物。
实验结果如图1所示,可以看出,配合物1在波长约为810 nm处具有最大的双光子吸收截面,为383.8 GM。另外,对配合物1的双光子激发的荧光强度对激发光功率的依赖性研究如图2所示,当激发波长为810 nm时,配合物1的荧光强度大约与激发光功率的二次方成正比,表明以上测试发生的是一个双光子过程,证明配合物1具有双光子吸收的特性。
实施例3:配合物1对多种肿瘤细胞株的光动力治疗活性
细胞毒性采用四唑盐(MTT)比色法测定。细胞用胰酶消化收集并用培养基重悬成单细胞悬液,通过细胞计数将细胞浓度调整为5×104/mL并接种于96孔培养板,每孔160 µL。在37oC,含5% CO2的培养箱中培养24 h后,再分别加入不同浓度的药物,继续孵育48 h,在结束前4 h于每孔加入20 µL MTT (5 mg/mL),4 h后小心除去上清液,每孔加入150 µL DMSO,于室温振荡10 min,再用酶标仪测定每孔在波长为595 nm处的OD值。细胞存活率通过以下公式进行计算,然后再通过作图求得半数杀伤浓度 (IC50)。细胞存活率% = 加药孔平均OD值/对照孔平均OD值×100%。受试细胞株分别为HeLa(人宫颈癌细胞株)、HepG2(人肝癌细胞株)、A549(人肺癌细胞株)、A549cisR(耐顺铂人肺癌细胞株)。
光毒性测试:细胞加入不同浓度的药物处理后在黑暗条件下孵育12 h,然后用波长为425 nm的LED光源 (40 mW cm-2) 照射15 min (36 J cm-2)。然后在黑暗条件下继续孵育32 h,接着加入MTT。后续处理同上段所述。
所得配合物对多种肿瘤细胞株的光毒性和暗毒性如表1所示。
表1:配合物1在黑暗条件及425 nm光照条件下对不同细胞中的IC50值
aPI (Phototoxicity index)表示配合物在黑暗条件下和光照条件下所得到的IC50值的比值。
由实验结果可以看出,配合物1在黑暗条件下几乎没有细胞毒性,但在425 nm可见光照射下,毒性明显增强,而且比顺铂的细胞毒性要高。
实施例4:配合物1对裸鼠肿瘤模型中的光动力治疗效果
SPF级的4‒5周龄的雌性裸鼠购自中山大学实验动物中心,所有的实验操作都严格按照中山大学动物关爱和使用协会制定的操作规范进行。
于小鼠背部右侧靠后皮下注射约1×106个HeLa细胞建立小鼠体内肿瘤模型。当肿瘤体积长到约200 mm3时,将小鼠随机分成5组(每组5只)然后进行如下给药:
组1(生理盐水):瘤内注射与加药组体积相同的生理盐水。
组2(生理盐水+光照):瘤内注射与加药组体积相同的生理盐水。
组3(配合物1):瘤内注射剂量为10 mg/kg小鼠体重的配合物1。
组4(配合物1+光照):瘤内注射剂量为10 mg/kg小鼠体重的配合物1。
组5(顺铂):瘤内注射剂量为10 mg/kg小鼠体重的顺铂。
加药时,配合物1和顺铂都先溶于生理盐水配置成一定浓度的储备液,再注射到小鼠肿瘤中,加完药5 h后,组2和组4的所有小鼠都要用430 nm激光(360 mW cm-2)照射肿瘤部位15 min。每6天加一次药,一共加两次,观察13天。每2天用数字卡尺测量肿瘤长径(a)和短径(b)和称体重一次。肿瘤体积(V)用公式V = ab2/2 进行计算,结果如图3所示。实验结束后将各组小鼠的肿瘤解剖出来,拍照,结果如图4所示。
实验结果表明,光照条件下配合物1能有效抑制肿瘤的生长,其效果与顺铂相当。
Claims (10)
1.一种具有双光子吸收特性的铂配合物,其特征在于,所述铂配合物的化学式为{[Pt(dien)]3L}(NO3)6,其中L为三(4-吡啶基苯基)胺,dien为二乙烯三胺,所述铂配合物的结构式如式(I)所示,
式(I)。
2.一种铂配合物,其特征在于,中心配体为三苯胺衍生物,配位金属为二价铂离子,辅助配体为二乙烯三胺及其衍生物,或氨基类饱和胺,几何结构为三脚架或三叉型。
3.权利要求1所述的具有双光子吸收特性的铂配合物的制备方法,其特征在于,将铂前体配合物[Pt(dien)Cl]Cl和硝酸银溶于溶剂中,氮气保护下避光55~65℃反应38~42 h,反应结束后低温离心得到上清液,然后加入配体L,氮气保护下避光85~95℃反应45~50 h;反应结束后加入过量乙醇,析出的沉淀即为具有双光子吸收特性的铂配合物;
其中,配体L为三(4-吡啶基苯基)胺,dien为二乙烯三胺。
4.根据权利要求3所述的制备方法,其特征在于,是在氮气保护下避光60℃反应40 h,反应结束后低温离心得到上清液,然后加入配体L,氮气保护下避光90℃反应48 h。
5.根据权利要求3所述的制备方法,其特征在于,所述的溶剂为纯水。
6.根据权利要求3所述的制备方法,其特征在于,铂前体配合物[Pt(dien)Cl]Cl和硝酸银的摩尔比为1:2,[Pt(dien)Cl]Cl和配体L的摩尔比为3:1。
7.权利要求1所述的具有双光子吸收特性的铂配合物在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用,其特征在于,是在制备光动力治疗抗肿瘤药物中的应用。
9.根据权利要求8所述的应用,其特征在于,肿瘤为良性或恶性肿瘤。
10.根据权利要求9所述的应用,其特征在于,所述的肿瘤为对顺铂,卡铂或奥沙利铂中的一种或多种具有耐药性的肿瘤。
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