CN112704685A - 一种顺铂配位体及其在制备肿瘤纳米诊疗剂中的应用 - Google Patents

一种顺铂配位体及其在制备肿瘤纳米诊疗剂中的应用 Download PDF

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CN112704685A
CN112704685A CN202110080714.8A CN202110080714A CN112704685A CN 112704685 A CN112704685 A CN 112704685A CN 202110080714 A CN202110080714 A CN 202110080714A CN 112704685 A CN112704685 A CN 112704685A
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张越
时令
姚勇
汪洋
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Nantong University
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Abstract

本发明公开了一种顺铂配位体及其在制备肿瘤纳米诊疗剂中的应用，属于医药技术领域。通过金属配位将荧光基元和产生单线态氧的基元连接在一个分子上，组装体外部用甘醇链保护，使其在体内循环过程稳定存在，同时金属配位抑制了卟啉之间的致密堆积，使得其光照产生单线态氧的能力大大提高，从而提高了抗肿瘤效率。

Description

一种顺铂配位体及其在制备肿瘤纳米诊疗剂中的应用
技术领域
本发明属于医药技术领域，具体涉及一种顺铂配位体及其在制备肿瘤纳米诊疗剂中的应用。
背景技术
目前，肿瘤是对人类健康威胁最大的疾病之一，传统的药物治疗是肿瘤治疗的首选，但药物治疗具有靶向性差，毒副作用大；药物的溶解性和稳定性差；细胞易产生耐药性；以及药物在体内传输和治疗过程难以检测等缺点，超分子化学由于其动态可逆的特点，可以很好的解决以上的问题。
Pt(II)配位组装体作为典型超分子载体，其在超分子肿瘤治疗方面也取得了一些进展，但是，基于Pt(II)配位组装体的具有靶向性、高载药率、低毒副作用(体内循环稳定)，同时集化疗和光热/光动力治疗等协同治疗于一体的超分子智能肿瘤治疗体系还未系统开展过，这严重制约了超分子化学以及肿瘤治疗研究的发展。
发明内容
本发明的目的是提供一种顺铂体及其在制备纳米诊疗剂中的应用，通过Pt(II)配位自组装，简洁高效的构筑了一类可用于肿瘤靶向性的光热、光动力治疗的纳米诊疗剂。
为了实现上述发明目的，本发明采用以下技术方案：
一种顺铂配位体，其结构式如下式所示：
Figure BDA0002909173550000011
具体地，上述顺铂配位体采用下式的方法合成得到：
Figure BDA0002909173550000021
由于上述顺铂配位体含有四苯乙烯荧光基团，卟啉单元在光照下能够产生单线态氧，三乙基膦能够靶向线粒体，顺铂是一种良好的抗肿瘤药物，而水溶性甘醇链则将这些功能基团包裹在里面，使其在体内循环过程中能够稳定存在，因此该顺铂配位体是一种两亲化合物，能够在水中自组装形成纳米胶束，作为肿瘤纳米诊疗剂。自组装过程如下式所示：
Figure BDA0002909173550000022
有益效果：本发明的新型纳米诊疗剂通过金属配位将荧光基元和产生单线态氧的基元连接在一个分子上，组装体外部用甘醇链保护，使其在体内循环过程稳定存在，同时金属配位抑制了卟啉之间的致密堆积，使得其光照产生单线态氧的能力大大提高，从而提高了抗肿瘤效率。
附图说明
图1为顺铂配位体的核磁共振氢谱图(常温,400MHz,丙酮-d6)。
图2为顺铂诊疗剂的扫描电镜图。
图3为Hela细胞和DAPI、线粒体指示剂、顺铂诊疗剂共同培养30分钟后的激光共聚焦图片。其中：(a)为DAPI，(b)为线粒体指示剂，(c为)顺铂诊疗剂，(d)为a,b,c叠加后的图片，标尺20微米。
图4为纳米诊疗剂在正常细胞和肿瘤细胞中分别在光照和不光照条件下的细胞毒性(光照时间5分钟)。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的修改或替换，均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
实施例1
四苯乙烯卟啉顺铂配位体的制备
称取63.78mg单吡啶四苯乙烯、61.5mg单吡啶卟啉、145.8mg 90°Pt、93.49mg甘醇链间苯二甲酸，加至10mL圆底烧瓶中，加入4mL丙酮和1mL水，加热至60℃反应过夜，TLC监测至反应物消失，过滤除去不溶性物质，用氮气吹干溶剂后重新溶解在0.5mL丙酮中，加8mL无水乙醚重结晶三次，得到四苯乙烯卟啉顺铂配位体。产率：83％。
顺铂配位体的核磁共振氢谱如图1所示。
1H NMR(400MHz,Acetone-d6)δ:9.50(s,1H),8.78(d,J＝4.00Hz,2H),8.71(d,J＝4.00Hz,2H),8.38(s,1H),8.10(s,2H),7.70(d,J＝4.00Hz,2H),7.60-7.53(m,18H),7.46-7.41(m,20H),7.38-7.31(m,10H),7.04(s,2H),6.65(s,2H),6.44(s,2H),6.11(s,2H),6.00(d,J＝4.00Hz,2H),5.11(s,2H),4.17(t,J＝4.00Hz,6H),3.81(t,J＝4.00Hz,6H),3.60(t,J＝4.00Hz,30H),3.53(t,J＝4.00Hz,6H),3.36(s,4H),1.42-1.38(m,24H),1.00(d,J＝8.00Hz,36H).
13C NMR:(100MHz,Acetone-d6)δ；169.70,159.70,154.66,150.03,147.70,147.67,147.42,145.28,144.52,143.20,143.02,141.45,139.71,139.59,139.22,139.16,139.10,138.97,137.70,137.38,135.30,132.53,131.38,129.38,128.86,128.51,127.71,127.68,127.58,126.99,124.90,124.71,122.56,121.97,121.40,120.42,118.28,116.12,106.65,71.58,70.68,70.49,69.93,69.09,58.89,17.97,8.49.
MS(m/z):HRMS(ESI)Calcd.for C158H188N6O20P4Pt2([M–2OTf]2+):1501.6060,found:1501.6054.
实施例2
顺铂配位体纳米诊疗剂的制备
在10mL的圆底烧瓶中加入180mg的顺铂配位体，0.1mL DMF，剧烈搅拌下1个小时内滴加10mL水，搅拌1小时候，离心后透析除去DMF得到顺铂配位体纳米诊疗剂。真空干燥后通过扫描电镜对所制备的纳米诊疗剂进行了表征。
结果如图2所示，从图中可以看出最终制得的纳米诊疗剂是球状的，直径在250nm左右。
实施例3
纳米诊疗剂的抗肿瘤效果测试
1、线粒体靶向细胞成像。将人类宫颈癌细胞(HeLa细胞)接种在6孔板中(5×104个mL–1，每孔2mL)，在37℃、5％CO2培养箱中培养24小时。将细胞在相应的溶液孵育4小时。然后除去培养基，并用磷酸盐缓冲液洗涤细胞3次。最后，通过共聚焦激光扫描显微镜观察细胞。
结果如图3所示，该纳米诊疗剂都进入细胞中的线粒体内。由于纳米诊疗剂中含有四苯乙烯单元，其在聚集状态下会产生强烈的荧光发射，同时三乙基膦具有线粒体靶向的作用，因此当纳米诊疗剂进入细胞后会将细胞内线粒体“点亮”，从而起到细胞成像的作用。
2、细胞毒性。将人类宫颈癌细胞(HeLa细胞)在Dulbecco改良的Eagle培养基(DMEM)中孵育。该培养基含有10％的胎牛血清和1％的青霉素-链霉素。将HeLa细胞接种到96孔板(5×104个mL–1，每孔0.1mL)中，在37℃、5％CO2培养箱中培养24h。然后细胞在我们制备的纳米诊疗剂中孵育24小时。利用MTT法测定相应细胞的生存率。
结果如图4所示，该纳米诊疗剂在光照下对肿瘤细胞具有较高的杀伤率。该纳米诊疗剂在正常细胞中由于外部水溶性甘醇链的保护稳定存在，没有细胞毒性，光照时其中的卟啉基元能够产生单线态氧会杀死细胞。而在肿瘤细胞中，由于肿瘤细胞的酸性微环境，会破坏金属配位，从而释放出顺铂药物，同时，光照加剧药物的释放和单线态氧的产生，杀死肿瘤细胞的效率大大增加。由于该纳米诊疗剂中含有卟啉单元，同时金属配位抑制卟啉之间的芳香堆积，使得其在光照条件下产生单线态氧的能力大大提高，此外，Pt金属配位在酸性条件下不稳定，能够释放出顺式铂药物，二者协同作用大大提高杀死癌细胞的效率。

Claims (4)

1.一种顺铂配位体，其结构式如下式所示：
Figure DEST_PATH_IMAGE001
。
2.权利要求1所述的顺铂配位体的合成方法，其特征在于：将单吡啶四苯乙烯、单吡啶卟啉、90 oPt、甘醇链间苯二甲酸，加入丙酮和水，加热反应，反应结束后过滤除去不溶性物质，用氮气吹干溶剂后重新溶解在丙酮中，用无水乙醚重结晶，即可得到四苯乙烯卟啉顺铂配位体。
3.权利要求1所述的顺铂配位体在制备肿瘤纳米诊疗剂中的应用。
4.一种肿瘤纳米诊疗剂，由权利要求1所述的顺铂配位体在水中自组装形成。
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CN110917348A (zh) * 2019-12-09 2020-03-27 南京邮电大学 荧光/光声成像及光疗一体化靶向纳米诊疗剂及其构建与应用
CN111494411A (zh) * 2020-05-21 2020-08-07 中国医学科学院放射医学研究所 一种原位自组装四价铂药物及其制备方法与应用

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CN111494411A (zh) * 2020-05-21 2020-08-07 中国医学科学院放射医学研究所 一种原位自组装四价铂药物及其制备方法与应用

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