CN113384696A - 一种纳米光敏剂、制备方法及其应用 - Google Patents
一种纳米光敏剂、制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及一种纳米光敏剂、制备方法及其应用,通过采用金属有机框架ZIF8作为载体,将光敏剂部花青540装载到ZIF8上,同时在所述ZIF8表面修饰生物可溶性配体DSPE‑mPEG‑FA,由于ZIF8在正常的生理环境,例如血液等中性条件保持稳定,而在肿瘤微酸性环境条件下缓慢分解,因此以ZIF8结构为载体的光敏剂可以有效代谢,同时,ZIF8表面所修饰的生物可溶性配体能够使光敏剂富集到肿瘤组织并发挥PDT效应。并且光敏剂分子在激发光的照射下的荧光发射可以作为生物成像指示,实现在肿瘤靶向的PDT治疗。
Description
技术领域
本发明属于生物医学技术领域,具体涉及一种纳米光敏剂、制备方法及其应用。
背景技术
光动力治疗(PDT)在癌症的治疗方法中是一种非侵害的治疗方法,对于癌症的局部治疗具有时间和空间的可操作性。PDT不可缺少的三个要素包括激发光,氧气和光敏剂。PDT通过激发光激活光敏剂(PS)并与氧分子作用产生活性氧,活性氧对周围小于0.2微米的生物大分子包括DNA、蛋白和脂质细胞膜等产生不可逆的氧化损伤,从而直接导致基本的新陈代谢障碍,导致肿瘤细胞的调亡坏死。
大量的研究表明,单独的PDT治疗或者结合其他诊疗模式的PDT治疗在早期的抗肿瘤治疗中具有潜在的应用。然而,在PDT的治疗中,光敏剂药物在PDT中会出现,非特异性的分布到其他的组织器官而没有在肿瘤部位富集,小分子光敏剂药物在体内代谢过快而没有富集到肿瘤组织。
因此,现有技术还有待于进一步的提升和改进。
发明内容
本发明提供了一种纳米光敏剂、制备方法及其应用,旨在解决现有的光敏剂药物在体内代谢快,不能富集到肿瘤组织的问题。
本发明的技术方案如下:
第一方面,本发明提供一种纳米光敏剂,其中,包括:金属有机框架、附着在所述金属有机框架的腔体或通道中的部花青540以及与所述金属有机框架表面结合的生物相溶性靶向配体。
可选地,所述的纳米光敏剂,其中,所述生物相溶性靶向配体包括二硬脂酰基磷脂酰乙醇胺-甲氧基聚乙二醇-叶酸;所述金属有机框架包括ZIF8类框架材料。
第二方面,本法提供一种纳米光敏剂的制备方法,其中,包括步骤:
提供一金属有机框架,所述金属有机框架的腔体或通道中的部花青540;
将所述金属有机框架溶解在去离子水中,得到金属有机框架溶液,将包含生物相溶性靶向配体的溶液分散在所述金属有机框架溶液中,得到纳米光敏剂。
可选地,所述的制备方法,其中,所述金属有机框架由六水硝酸锌和部花青540分散到2-甲基咪唑溶液中得到;所述六水硝酸锌和2-甲基咪唑的摩尔比为1:5。
可选地,所述的制备方法,其中,所述部花青540为溶液,所述部花青540溶液的浓度为1-3mg/mL。
可选地,所述的制备方法,其中,所述金属有机框架由六水硝酸锌和部花青540分散到2-甲基咪唑溶液中得到,具体包括:
将六水硝酸锌溶解在甲醇中,得到六水硝酸锌甲醇溶液;将部花青540溶解在乙醇中,得到部花青540乙醇溶液;
在搅拌条件下,将所述六水硝酸锌甲醇溶液和所述部花青540乙醇溶液加入到所述2-甲基咪唑溶液中,得到混合溶液;
将所述混合溶液避光保存,得到沉淀产物。
可选地,所述的制备方法,其中,所述将所述混合溶液避光保存,得到沉淀产物之后还包括:
将所述沉淀产物放入离心设备进行离心分离,对离心后得到的固态物真空干燥;其中,离心分离的条件包括离心转速7500-8500rpm,离心时间5-10min。
可选地,所述的制备方法,其中,所述将包含生物相溶性靶向配体的溶液分散在所述金属有机框架溶液中,得到纳米光敏剂的步骤,具体包括:
将生物相溶性靶向配体溶解在去离子水中,得到所述包含生物相溶性靶向配体的溶液;
将所述包含生物相溶性靶向配体的溶液滴加到所述金属有机框架溶液中,在避光环境下搅拌反应,得到纳米光敏剂。
第三方面,本发明提供一种上述所述的纳米光敏剂的应用,其中,用于肿瘤靶向的光动力治疗。
有益效果:本发明所提供的纳米光敏剂,通过将光敏剂分子(部花青540)装载在金属有机框架结构中并修饰生物相溶性靶向配体,可使纳米光敏剂有效的富集到肿瘤组织并发挥PDT效应。并且光敏剂分子在激发光的照射下的荧光发射可以作为生物成像指示,实现在肿瘤靶向的PDT治疗。
附图说明
图1为本发明实施例提供的MC540-ZIF8-DSPE-mPEG-FA构建示意图;
图2为本发明实施例提供的MC540-ZIF8纳米光敏剂的透射电镜照片;
图3为本发明实施例提供的MC540-ZIF8-DSPE-mPEG-FA吸收光谱;
图4为本发明实施例提供的MC540-ZIF8-DSPE-mPEG-FA的细胞生物毒性测试;
图5为本发明实施例提供的MC540-ZIF8-DSPE-mPEG-FA的靶向光动力细胞存活率测试。
具体实施方式
本发明提供一种纳米光敏剂、制备方法及其应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
如图1所示,图1为本发明实施例提供一种纳米光敏剂构建示意图,即利用2-甲基咪唑和Zn2+进行反应生成以Zn2+为中心,以2-甲基咪唑为骨架组成的一种MOF结构(ZIF8),该材料拥有很高的比表面积。MOF结构在正常的生理环境,例如血液等中性条件下保持稳定,而在肿瘤微酸性的肿瘤环境(PH=6.5或者PH=5.5)条件下缓慢分解,因此以MOF结构装载药物的体系可以有效代谢,对生物的毒副作用小。
将部花青540(MC540)装载到MOF上,并修饰生物相溶性靶向配体,形成具有肿瘤微环境可降解的纳米光敏剂。
在本实施例中,所述部花青540(MC540)是一种光敏剂,能吸收波长为540nm的可见光,从而改变自身结构,使光能转化为化学能,并将能量传递给周围的O2,生成活性很强的单线态氧(1O2),单线态氧能够破坏细胞内的生物大分子如磷脂、蛋白质、核酸等,进而导致细胞死亡。
在本实施例中,生物相溶性配体可以是二硬脂酰基磷脂酰乙醇胺-甲氧基聚乙二醇-叶酸(DSPE-mPEG-FA),通过修饰生物性相容的靶向配体可以使纳米光敏剂更好的靶向到肿瘤组织中,在肿瘤部位富集,实现在肿瘤靶向的PDT治疗。
在本实施例中,通过将MC540装载到ZIF8上,并采用DSPE-mPEG-FA对MOF表面进行修饰,所得到的MC540-ZIF8-DSPE-mPEG-FA,可有效靶向肿瘤组织发挥光动力效应,并在肿瘤的微酸性的条件下逐渐代谢降解。
在本实施例中,六水硝酸锌和2-甲基咪唑的浓度低于1:5时,所形成的纳米粒子不稳定,容易聚沉;高于1:5时,形成的纳米粒子尺寸过大,不利于生物血液循环。
基于相同的发明构思,本发明中的纳米光明剂可以用于肿瘤靶向的光动力治疗。
下面通过具体的实施例对本发明所提供的纳米光敏剂及其制备方法做进一步的解释说明。
实施例1
称量58.5mg六水硝酸锌放入50ml甲醇中,搅拌溶解;称量3240mg 2-甲基咪唑放入50ml甲醇中,充分搅拌溶解;称量20mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存24小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8000rpm,10min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体。如图2所示,图2为MC540-ZIF8的透射电镜照片,从照片中可以看出MC540-ZIF8成颗粒状分布。
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。MC540-ZIF8-DSPE-mPEG-FA的吸收光谱如图3所示。
实施例2
称量58.5mg六水硝酸锌放入50ml甲醇中,搅拌溶解;称量4860mg 2-甲基咪唑放入60ml甲醇中,充分搅拌溶解;称量20mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应1小时,将反应结束的溶液避光保存20小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(7000rpm,15min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体。
称取3mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应40小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(12000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例3
称量11.7mg六水硝酸锌放入10ml甲醇中,搅拌溶解;称量3240mg 2-甲基咪唑放入50ml甲醇中,充分搅拌溶解;称量20mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应1.5小时,将反应结束的溶液避光保存22小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(7500rpm,20min),去离子水离心四次,产物真空干燥,得到MC540-ZIF8固体。
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应35小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例4
称量58.5mg六水硝酸锌放入50ml甲醇中,搅拌溶解;称量3240mg 2-甲基咪唑放入50ml甲醇中,充分搅拌溶解;称量2mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存22小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8500rpm,10min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例5
称量58.5mg六水硝酸锌放入50ml甲醇中,搅拌溶解;称量3240mg 2-甲基咪唑放入50ml甲醇中,充分搅拌溶解;称量1mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存22小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8500rpm,10min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例6
称量58.5mg六水硝酸锌放入50ml甲醇中,搅拌溶解;称量3240mg 2-甲基咪唑放入50ml甲醇中,充分搅拌溶解;称量5mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存22小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8500rpm,10min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例7
称量117mg六水硝酸锌放入80ml甲醇中,搅拌溶解;称量6480mg 2-甲基咪唑放入100ml甲醇中,充分搅拌溶解;称量10mg MC540光敏剂分子溶解在1ml乙醇中,
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存24小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8500rpm,15min),去离子水离心三次,产物真空干燥,得到MC540-ZIF8固体
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
实施例8
称量117mg六水硝酸锌放入100ml甲醇中,搅拌溶解;称量6480mg 2-甲基咪唑放入100ml甲醇中,充分搅拌溶解;称量2mg MC540光敏剂分子溶解在1ml乙醇中;
将六水硝酸锌甲醇溶液和光敏分子逐渐缓慢加入到2-甲基咪唑溶液中,一边加入一边搅拌,完全加入后,继续搅拌反应半小时,将反应结束的溶液避光保存24小时,过滤后得到沉淀产物MC540-ZIF8。
将沉淀产物MC540-ZIF8离心(8500rpm,20min),去离子水离心五次,产物真空干燥,得到MC540-ZIF8固体
称取2mg DSPE-mPEG-FA溶解在去离子水中;称量2mg MC540-ZIF8溶解在去离子水中,并持续不断搅拌。将DSPE-mPEG-FA缓慢滴加入MC540-ZIF8溶液中,避光搅拌反应36小时;将MC540-ZIF8-DSPE-mPEG-FA的产物离心(10000rpm,10min),并分散在磷酸盐缓冲溶液中,备用。
下面对实施例1所制备得到的纳米光敏剂MC540-ZIF8-DSPE-mPEG-FA的生物毒性进行测试
将小鼠乳腺癌细胞4T1细胞消化后接种在96孔板中,每孔约为1X104个。96孔板中培养24小时,更换新鲜培养基,加入不同浓度的纳米光敏剂。分别孵育24小时和48小时,然后加入10微升CCK8检测试剂盒,在细胞培养箱中继续培养1小时,然后测定450nm波长处的吸收,测试结果如图4所示。
对纳米光敏剂MC540-ZIF8-DSPE-mPEG-FA的PDT效应进行测试
将小鼠乳腺癌细胞4T1细胞消化后接种在96孔板中,每孔约为1X104个。96孔板中培养24小时,更换新鲜培养基,分别加入最佳浓度的纳米光敏剂MC540-ZIF8-DSPE-mPEG-FA,ZIF8,MC540-ZIF8和PBS溶液。分别孵育6小时,然后用540nm激光照射10分钟,继续培养12小时,然后加入10微升CCK8检测试剂盒,在细胞培养箱中继续培养1小时,然后测定450nm波长处的吸收,测试结果如图5所示。
综上所述,本发明所提供的一种纳米光敏剂、制备方法及其应用,通过采用金属有机框架ZIF8作为载体,将光敏剂部花青540装载到ZIF8上,同时在所述ZIF8表面修饰生物可溶性配体DSPE-mPEG-FA,由于ZIF8在正常的生理环境,例如血液等中性条件保持稳定,而在肿瘤微酸性环境条件下缓慢分解,因此以ZIF8结构为载体的光敏剂可以有效代谢,同时,ZIF8表面所修饰的生物可溶性配体能够使光敏剂富集到肿瘤组织并发挥PDT效应。并且光敏剂分子在激发光的照射下的荧光发射可以作为生物成像指示,实现在肿瘤靶向的PDT治疗。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
1.一种纳米光敏剂,其特征在于,包括:金属有机框架、附着在所述金属有机框架的腔体或通道中的部花青540以及与所述金属有机框架表面结合的生物相溶性靶向配体。
2.根据权利要求1所述的纳米光敏剂,其特征在于,所述生物相溶性靶向配体包括:二硬脂酰基磷脂酰乙醇胺-甲氧基聚乙二醇-叶酸。
3.根据权利要求1所述的纳米光敏剂,其特征在于,所述金属有机框架包括ZIF8类框架材料。
4.一种纳米光敏剂的制备方法,其特征在于,包括步骤:
提供一种金属有机框架,所述金属有机框架的腔体或通道中的部花青540;
将所述金属有机框架溶解在去离子水中,得到金属有机框架溶液,将包含生物相溶性靶向配体的溶液分散在所述金属有机框架溶液中,得到纳米光敏剂。
5.根据权利要求4所述的制备方法,其特征在于,所述金属有机框架由六水硝酸锌和部花青540分散到2-甲基咪唑溶液中得到;所述六水硝酸锌和2-甲基咪唑的摩尔比为1:5。
6.根据权利要求5所述的制备方法,其特征在于,所述部花青540为溶液,所述部花青540溶液的浓度为1-3mg/mL。
7.根据权利要求5所述的制备方法,其特征在于,所述金属有机框架由六水硝酸锌和部花青540分散到2-甲基咪唑溶液中得到,具体包括:
将六水硝酸锌溶解在甲醇中,得到六水硝酸锌甲醇溶液;将部花青540溶解在乙醇中,得到部花青540乙醇溶液;
在搅拌条件下,将所述六水硝酸锌甲醇溶液和所述部花青540乙醇溶液加入到所述2-甲基咪唑溶液中,得到混合溶液;
将所述混合溶液避光保存,得到沉淀产物。
8.根据权利要求7所述的制备方法,其特征在于,将所述混合溶液避光保存,得到沉淀产物之后还包括:
将所述沉淀产物放入离心设备进行离心分离,对离心后得到的固态物真空干燥;其中,离心分离的条件包括离心转速7500-8500rpm,离心时间5-10min。
9.根据权利要求4所述的制备方法,其特征在于,所述将包含生物相溶性靶向配体的溶液分散在所述金属有机框架溶液中,得到纳米光敏剂的步骤,具体包括:
将生物相溶性靶向配体溶解在去离子水中,得到所述包含生物相溶性靶向配体的溶液;
将所述包含生物相溶性靶向配体的溶液滴加到所述金属有机框架溶液中,在避光环境下搅拌反应,得到纳米光敏剂。
10.一种权利要求1所述的纳米光敏剂在肿瘤靶向的光动力治疗中的应用。
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CN111494339A (zh) * | 2020-04-24 | 2020-08-07 | 东南大学 | 癌细胞膜仿生纳米反应器agz@cm在制备抗癌药物中的应用 |
CN111643673A (zh) * | 2020-07-08 | 2020-09-11 | 福建医科大学孟超肝胆医院(福州市传染病医院) | 一种同时包载光敏剂和蛋白质的肿瘤靶向纳米药物及其应用 |
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