CN112870381B - 一种以核酸适配体为模板合成的双模态纳米羟基磷灰石的方法 - Google Patents
一种以核酸适配体为模板合成的双模态纳米羟基磷灰石的方法 Download PDFInfo
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Abstract
本发明公开了一种以核酸适配体为模板合成的双模态纳米羟基磷灰石的方法,该方法以核酸适配体为模板合成纳米羟基磷灰石的过程中掺入具有成像功能的稀土离子,核酸适配体为AS1411,具有成像功能的稀土离子是具有荧光成像功能的Tb3+以及具有MRI成像能力的Gd3+。本发明采用以核酸适配体为模板的仿生合成方法,简单快速地实现了具有特异性识别细胞/组织的nHAp的合成,并在合成过程中掺杂具有不同成像功能的稀土离子,实现了荧光/MRI纳米成像探针的制备(AS1411‑nHAp:Gd/Tb),纳米材料具有生物相容性良好、理化性能优良、稀土离子掺杂率高、功能多元化等特性。
Description
技术领域
本发明涉及的是一种以核酸适配体为模板一步合成稀土离子共掺杂的双模态纳米羟基磷灰石的方法。
背景技术
纳米羟基磷灰石(nano-Hydroxyapatite,nHAp)为人体和动物矿化组织如骨骼、牙齿和钙化肌腱中无机相的主要组成,具有优异的生物相容性、生物活性和生物亲和性,可诱导骨组织再生,已广泛应用于骨缺损修复及骨组织工程领域。其晶体结构及表面特性赋予其强大的离子交换能力、络合能力和吸附能力。作为药物载体,已被广泛应用于癌症、骨质疏松、骨膜炎等疾病的治疗。此外,nHAp还具有抗肿瘤活性,对肿瘤细胞如肝癌细胞、肠癌细胞、骨肉瘤细胞、黑色素瘤细胞等活性具有抑制作用,能抑制癌细胞增殖,促进癌细胞凋亡,在高热治疗癌症方面也引起了广泛关注。
近年来,以nHAp为生物相容性载体构建生物成像探针用于细胞及活体成像已成为研究热点之一。特别是利用nHAp独特的晶体结构和较强的离子交换能力,将荧光稀土离子(Eu3+、Sm3+、Tb3+)、顺磁性金属离子(Gd3+、Mn2+)或放射性同位素(18F、64Cu)通过离子掺杂的方式取代Ca2+即可获得不同模式的成像探针。然而,单一模态的成像方式在成像灵敏度、分辨率以及穿透深度等方面的优缺点各有不同。比如核磁共振成像(MRI)具有高的空间分辨率,但成像灵敏度低,成像时间长、成本高;计算机断层扫描成像(CT)具有高的空间分辨率,却无法分辨密度接近的软组织。基于此,近年来,将两种成像功能互补的生物成像技术结合,构建双模态生物成像探针已成为疾病的早期诊断和治疗的重要研究方向之一。如ChenFeng等(Chen Feng,et al."The photoluminescence,drug delivery and imagingproperties of multifunctional Eu3+/Gd3+dual-doped hydroxyapatite nanorods."Biomaterials 2011.32(34):9031-9039.)以Eu3+作为荧光标记离子,Gd3+为磁共振成像标记离子,将二者共掺杂到nHAp晶体中,成功实现了小鼠体内MRI和体内光学成像示踪。Annemarie等(Tesch Annemarie,et al.,Luminomagnetic Eu3+-and Dy3+-dopedhydroxyapatite for multimodal imaging.Mater Sci Eng C Mater Biol Appl,2017.81:p.422-431.)则利用共沉淀法合成Eu3+/Dy3+共掺杂nHAp构建荧光/核磁双模态纳米成像探针,并获得较好的荧光/核磁成像信号。然而,nHAp本身对细胞及组织不具备特异性识别能力,限制了其在生物体内的应用。
常用的解决方法是在其表面耦联核酸适配体、蛋白质受体或者抗体等靶向分子赋予其生物识别能力。例如Zeng等人(Zeng Shuli,et al.,Mono-dispersed Ba2+-dopedNano-hydroxyapatite conjugated with near-infrared Cu-doped CdS quantum dotsfor CT/fluorescence bimodal targeting cell imaging.Microchemical Journal,2017.134:p.41-48.)通过水热法高温合成Ba2+掺杂nHAp,通过三乙醇胺修饰,进一步耦联近红外量子点及透明质酸实现靶向双模态成像。同样,Syamchand等人(Syamchand,S.S.,etal.,Hydroxyapatite nanocrystals dually doped with fluorescent andparamagnetic labels for bimodal(luminomagnetic)cell imaging.MicrochimicaActa,2015.182(5-6):p.1213-1221.)用Ho3+标记nHAp,并通过聚乙烯胺的修饰成功耦联叶酸分子实现靶向CT成像。但是,这种后修饰以及纯化过程较为繁琐,易导致nHAp粒径聚集增大进而降低其入胞能力,难以获取高灵敏成像效果。
发明内容
本发明的目的在于提供一种以核酸适配体为模板一步合成具有靶向识别能力的双模态纳米羟基磷灰石。其合成方法与传统稀土掺杂羟基磷灰石的合成方法相比具有步骤简单、合成条件温和(室温反应)、稀土掺杂效率高等特性,解决现有纳米羟基磷灰石成像探针在构建上的复杂性以及材料团聚等因素对成像灵敏度的限制。该双模态纳米成像探针可通过模板分子AS1411的生物活性,以及Gd3+和Tb3+的MRI及荧光造影能力,实现对癌细胞的靶向双模态示踪分析,并探究其在疾病诊断中的应用前景。在此基础上,可望促进其它纳米生物医用材料的研制和开发。本发明采用以下技术方案:
本发明提供一种以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,该方法以核酸适配体为模板合成纳米羟基磷灰石的过程中掺入具有成像功能的稀土离子,所述核酸适配体为AS1411,所述具有成像功能的稀土离子是具有荧光成像功能的Tb3+以及具有MRI成像能力的Gd3+。该方法所得到的材料简称AS1411-nHAp:Gd/Tb。
以核酸适配体为模板合成纳米羟基磷灰石的过程包括:室温下,通过核酸适配体AS1411具有的负电荷性质与Ca2+离子通过静电吸附作用结合后,加入PO4 3-离子,并以AS1411的核酸链结构为导向形成AS1411功能化的纳米羟基磷灰石。通过在含有核酸适配体AS1411的反应体系中添加Ca2+溶液使Ca2+离子参与静电吸附作用和离子交换作用。Ca2+溶液是由硝酸钙(Ca(NO3)2·4H2O)固体溶于双蒸水(ddH2O)中配制而成,对其浓度不进行严格的控制,但为了使得到的AS1411-nHAp:Gd/Tb具有较小的粒径以获得更好的入胞效果,反应体系中AS1411与Ca2+摩尔浓度比应当大于或等于1/1000。
掺入具有成像功能的稀土离子的方法是:利用纳米羟基磷灰石的离子交换特性,通过与Ca2+交换,在纳米羟基磷灰石的晶格中掺入稀土离子Gd3+和Tb3+,从而获得具有MRI及荧光成像能力的双模态纳米羟基磷灰石。稀土离子Gd3+和Tb3+的掺杂是通过将Gd3+溶液和Tb3+溶液添加到合成纳米羟基磷灰石的反应体系中来实现的。Gd3+溶液是由硝酸钆(Gd(NO3)3·6H2O)溶于ddH2O中配制而成,建议浓度为1mol/L,Tb3+溶液是由硝酸铽(Tb(NO3)3·5H2O)溶于ddH2O中配制而成,建议浓度为1mol/L,根据反应体系中纳米羟基磷灰石中掺杂的Ca2+量调节Gd3+溶液和Tb3+溶液的使用量,两种溶液的溶度也可以根据使用需求进行调整。但合成体系中总阳离子浓度与总阴离子浓度的摩尔比应当大于或等于1.67。
在合成纳米羟基磷灰石的过程中加入F-离子以提高纳米羟基磷灰石形貌的均一性。通过NaF为反应体系提供F-离子。NaF的加入比例是体系中Ca2+摩尔浓度的6%-20%。
以核酸适配体为模板合成纳米羟基磷灰石的过程中,反应体系的pH值为8-10。调节pH的过程中可以使用氢氧化钠溶液为pH调节剂。
以核酸适配体为模板合成纳米羟基磷灰石的过程是将PO4 3-溶液滴加到含有核酸适配体AS1411以及Ca2+、Gd3+、Tb3+的溶液中得到合成体系,并将合成体系进行搅拌反应。PO4 3-溶液是由磷酸钠(Na3PO4·12H2O)溶于ddH2O中配制而成,优选其浓度是体系中Ca2+摩尔浓度的60%。
下面对本发明的技术方案进行进一步的说明。
以核酸适配体为模板合成的双模态纳米羟基磷灰石是具有靶向性双模态的nHAp成像探针(简称AS1411-nHAp:Gd/Tb),其合成方法的具体操作步骤是:用无酶水溶解合成体系中所需的AS1411,在磁力搅拌作用下,向反应容器中加入Ca2+溶液(优选摩尔浓度比AS1411/Ca2+≥1/1000),依靠AS1411与Ca2+的强静电吸附作用,实现AS1411配体与Ca2+的结合,依次加入Gd3+溶液和Tb3+溶液,通过Gd3+/Tb3+与Ca2+的离子交换作用实现Gd3+离子和Tb3+离子的共掺杂(调节三种离子浓度以优化稀土离子掺杂浓度);加入NaOH调节合成反应体系溶液pH为8-10,加入NaF替代OH-,室温下混合搅拌均匀(通常搅拌10min左右即可)后以2mL/min的速度逐滴加入PO4 3-溶液(逐滴加入以使产物粒径更小和均匀),反应体系中总阳离子与总阴离子的摩尔浓度比大于或等于1.67,在室温下继续混合搅拌2-24h(优选6-12h),实现AS1411-nHAp:Gd/Tb的合成。该方法可以获得粒径105nm左右的针状纳米nHAp粒子,它在紫外激发光照射下,能发出强绿光,具有4个荧光发射峰,在发射波长543nm处有最大的荧光发射强度。
与现有技术相比,本发明至少具有以下有益效果:
本发明采用以核酸适配体为模板的仿生合成方法,简单快速地实现了具有特异性识别细胞/组织的nHAp的合成,并在合成过程中掺杂具有不同成像功能的稀土离子,实现了荧光/MRI纳米成像探针的制备(AS1411-nHAp:Gd/Tb),可以制成粒径105nm左右的针状晶体探针。以核酸适配体为模板的仿生合成方法省去了传统合成方法中的高温条件、反应步骤繁琐、先合成后修饰等缺点,使所合成的纳米材料具有生物相容性良好(毒性小、入胞效率高)、理化性能优良(晶体粒径小,成像清晰)、稀土离子掺杂率高、功能多元化(双模态成像)等特性。对nHAp和其它纳米生物医用材料的安全性评价提供相关技术基础,可望促进其它纳米生物医用材料的研制和开发。
附图说明
图1是AS1411-nHAp:Gd/Tb的透射电镜(A)及晶格照片(B)。
图2是AS1411-nHAp:Gd/Tb的EDS(A)及XPS(B)图谱。
图3是AS1411-nHAp:Gd/Tb在AS1411与Ca2+的不同摩尔浓度比下的Zeta电位值。
图4是AS1411-nHAp:Gd/Tb在不同合成条件下的粒径大小。
(A)AS1411与Ca2+的摩尔浓度比;(B)反应时间。
图5是AS1411-nHAp:Gd/Tb在不同合成条件下,在285nm激发波长下的荧光强度的变化。(A)AS1411与Ca2+的摩尔浓度比;(B)反应时间。
图6是AS1411-nHAp:Gd/Tb在人口腔鳞癌细胞系(SCC-25)和小鼠成纤维细胞系(L929)中的CCK-8实验结果。
图7是AS1411-nHAp:Gd/Tb在不同Gd离子含量共掺杂下的MRI T1加权下的弛豫值及成像图。
图8是AS1411-nHAp:Gd/Tb与人口腔鳞癌细胞系(SCC-25)和小鼠成纤维细胞系(L929)分别共培养6h和12h后的细胞荧光成像图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1:
本实施例通过以核酸适配体为模板简单快速合成纳米羟基磷灰石,并在其中掺杂具有成像功能的稀土离子,从而获得具有癌细胞靶向识别功能的双模态纳米羟基磷灰石。我们通过核酸适配体AS1411与Ca2+的静电吸附作用,使得以AS1411为模板合成nHAp得以实现,并通过nHAp的离子交换特性,掺杂具有荧光成像功能和MRI成像功能的稀土离子。简单快速实现以核酸适配体为模板合成双模态纳米羟基磷灰石的具体过程如下(反应体系总容积1mL,体系中AS1411的摩尔浓度为50μmol/L,Ca2+的摩尔浓度50mmol/L,PO4 3-的摩尔浓度30mmol/L,Gd3+的摩尔浓度7.5mmol/L,Tb3+的摩尔浓度7.5mmol/L,F-的摩尔浓度3mmol/L):
1)将AS1411用无酶水溶解成100mmol/L,振荡混匀,得到AS1411溶液。
2)加入500μL上述步骤1)得到的AS1411溶液于EP管中,在磁力搅拌下,依次在EP管中加入50μL、1mol/L的Ca2+溶液(由Ca(NO3)2·4H2O配制),7.5μL、1mol/L的Gd3+溶液(由Gd(NO3)3·6H2O配制),7.5μL、1mol/L的Tb3+溶液(由Tb(NO3)3·5H2O配制),用1mol/L的NaOH溶液调节反应体系溶液pH为10,之后加入3μL、1mol/L的F-溶液(由NaF配制),混合搅拌10min后逐滴加入50μL、0.6mol/L的PO4 3-溶液(由Na3PO4·12H2O配制),加入去离子水,使反应体系总容积为1mL,反应体系中总阳离子与总阴离子的摩尔浓度比大于1.67,室温下继续混合搅拌反应12h。
3)将上述步骤2)反应结束后的水层分散液在8000rpm离心5min,吸去上清液,沉淀物用去离子水清洗三次后离心即获得以AS1411为模板合成的双模态nHAp(AS1411-nHAp:Gd/Tb),其透射电镜图及晶格照片如图1所示,从图1(A)可以看出所合成的AS1411-nHAp:Gd/Tb呈单分散均匀的针状形貌,从图1(B)可以看出该材料的晶面间距约为0.30nm。
实施例2:
对实施例1所合成的AS1411-nHAp:Gd/Tb的元素组成进行考察,通过透射电子显微镜(EDS)和X射线光电子能谱仪(XPS)对合成材料的元素组成进行测定,结果如图2所示。
从图2可以看出,所合成的AS1411-nHAp:Gd/Tb中包含元素Ca、O、P、F、Gd、Tb,即证明了双模态nHAp的成功合成。
实施例3:
采用实施例1相同的方法,仅调整AS1411与Ca2+的摩尔浓度比分别为1:500、1:1000、1:2000、1:5000、1:10000以及无AS1411,其他与实施例1相同,制备得到对应的AS1411-nHAp:Gd/Tb样品及无AS1411的对照样品。考察AS1411-nHAp:Gd/Tb及对照样品在不同AS1411与Ca2+的摩尔浓度比下的Zeta电位及粒径大小,通过纳米粒度电位仪对合成材料进行测定,结果如图3及图4(A)所示。从图3可以看出,随着AS1411摩尔浓度的增加,电位由正变负,可证明AS1411的成功修饰;Zeta电位的绝对值越大,纳米材料稳定性越好,当AS1411与Ca2+的摩尔浓度比为1:1000时,nHAp已处于较稳定状态;如图4(A)所示,当AS1411与Ca2+的摩尔浓度比为1:1000和1:500时,nHAp的粒径最小,约为105nm。
采用实施例1相同的方法,仅调整步骤2)在室温下继续混合搅拌反应的时间分别为0h、2h、6h、12h、24h,其他与实施例1相同,制备得到对应的AS1411-nHAp:Gd/Tb样品,考察AS1411-nHAp:Gd/Tb在不同搅拌反应时间下的粒径大小,通过纳米粒度电位仪对合成材料进行测定,结果如图4(B)所示。从图4(B)可以看出,反应时间在6h时,nHAp的粒径最小,其次为12h时。
实施例4:
采用实施例1相同的方法,仅调整AS1411与Ca2+的摩尔浓度比分别为1:500、1:1000、1:2000、1:5000、1:10000以及无AS1411,其他与实施例1相同(Gd3+/Ca2+=3:20、Tb3+/Ca2+=3:20、反应时间12h),制备得到对应的AS1411-nHAp:Gd/Tb样品及无AS1411的对照样品。考察AS1411-nHAp:Gd/Tb及对照样品在不同AS1411与Ca2+的摩尔浓度比下的荧光强度。通过荧光光谱仪对所合成材料在最佳激发波长285nm下测定荧光发射强度,结果如图5(A)所示。采用实施例1相同的方法,仅调整步骤2)在室温下继续混合搅拌反应的时间分别为0h、2h、6h、12h、24h,其他与实施例1相同,制备得到对应的AS1411-nHAp:Gd/Tb样品,考察AS1411-nHAp:Gd/Tb在不同搅拌反应时间下的荧光强度。通过荧光光谱仪对所合成材料在最佳激发波长285nm下测定荧光发射强度,结果如图5(B)所示。
结果表明,在激发波长285nm激发下,当合成材料中无AS1411存在时,nHAp:Gd/Tb的荧光发射强度很低,不发出绿光;在发射波长543nm处,随着AS1411摩尔浓度的增加,nHAp的荧光强度逐渐增强,即在体系中AS1411/Ca2+摩尔浓度比为1:500时荧光发射强度最高(图5A);随着反应时间增加,nHAp的荧光发射强度逐渐增强,反应时间在12h时,荧光发射强度达到峰值,随后下降(图5B)。
实施例5:
按实施例1制备荧光/MRI纳米成像探针AS1411-nHAp:Gd/Tb(AS1411/Ca2+=1:1000、Gd3+/Ca2+=3:20、Tb3+/Ca2+=3:20、反应时间12h),将其与人口腔鳞癌细胞系(SCC-25)和小鼠成纤维细胞系(L929)分别共培养24h后,用CCK-8法考察该荧光/MRI纳米成像探针的细胞毒性。分别测定了10~150μg/mL该材料对细胞的生物毒性。测定结果见图6。
结果表明,经AS1411-nHAp:Gd/Tb处理后,L929细胞的存活率与nHAp:Gd/Tb作用后结果无明显差异,对细胞无明显细胞毒性(见图6(A));对于SCC-25细胞,AS1411-nHAp:Gd/Tb浓度增加到100μg/mL及以上时,对细胞表现出明显的细胞毒性,并与nHAp:Gd/Tb的细胞毒性产生明显差异(见图6(B))。这与SCC-25细胞中AS1411的靶向蛋白核仁素比L929细胞中的核仁素表达量较多有关。
实施例6:
按实施例1制备AS1411-nHAp:Gd/Tb(AS1411/Ca2+=1:1000、Gd3+/Ca2+=3:20、Tb3+/Ca2+=3:20、反应时间12h),我们采用磁共振成像(MRI)设备测定G d离子含量在0.2mM、0.4mM、0.6mM、0.8mM、1mM和2mM下的AS1411-nHAp:Gd/Tb(Gd3+的含量是通过调节溶液中AS1411-nHAp:Gd/Tb的总含量以获得含不同浓度的Gd3+溶液)的MRI弛豫值。并采用激光共聚焦显微镜测定AS1411-nHAp:Gd/Tb与两种细胞系(SCC25和L929)分别共培养6h和12h后的材料入胞情况,测定结果如图7和图8所示。
从图7(A)可以看出,MRI在T1加权下的弛豫值与AS1411-nHAp:Gd/Tb的共掺杂的Gd离子浓度具有较好的线性关系,从图7(B)可以看出,AS1411-nHAp:Gd/Tb具有良好的MRI成像能力,且成像能力与Gd离子浓度具有一定的关系,在图示浓度范围内,Gd离子浓度越高,成像能力越好。如图8所示,单独采用FITC荧光标记SCC25、L929两种细胞系,细胞显示红色荧光;单独采用AS1411-nHAp:Gd/Tb与两种细胞系(SCC25和L929)共培养,细胞显示绿色荧光,采用FITC、AS1411-nHAp:Gd/Tb合并与两种细胞系(SCC25和L929)共培养,细胞显示红色和绿色荧光,并且在6h和12h时,AS1411-nHAp:Gd/Tb在人舌鳞癌细胞系SCC25中的入胞都显著多于小鼠成纤维细胞系(L929),从而证明了材料具有较好的靶向能力,且该材料发出绿色荧光。
尽管这里参照本发明的解释性实施例对本发明进行了描述,但是,应该理解,本领域技术人员可以设计出很多其他的修改和实施方式,这些修改和实施方式将落在本申请公开的原则范围和精神之内。
Claims (6)
1.一种以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,用无酶水溶解核酸适配体AS1411,搅拌条件下,加入Ca2+溶液,AS1411与Ca2+的摩尔浓度比大于或者等于1/1000,依靠AS1411与Ca2+的强静电吸附作用,实现AS1411与Ca2+的结合,依次加入Gd3+溶液和Tb3+溶液,通过Gd3+、Tb3+与Ca2+的离子交换作用实现Gd3+离子和Tb3+离子的共掺杂;调节合成反应体系溶液pH为8-10,加入F-离子,搅拌均匀后逐滴加入PO4 3-溶液,室温下搅拌2-24h,得到双模态纳米羟基磷灰石AS1411-nHAp:Gd/Tb。
2.根据权利要求1所述的以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,所述的合成体系中总阳离子浓度与总阴离子浓度的摩尔比大于或等于1.67。
3.根据权利要求1所述的以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,所述Gd3+由Gd(NO3)3•6H2O提供,所述Tb3+由Tb(NO3)3•5H2O提供,所述Ca2+由Ca(NO3)2•4H2O提供,所述PO4 3-由Na3PO4·12H2O提供。
4.根据权利要求1所述的以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,所述逐滴加入的滴加速度为2mL/min。
5.根据权利要求1所述的以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,所述F-离子由NaF提供。
6.根据权利要求5所述的以核酸适配体为模板合成双模态纳米羟基磷灰石的方法,其特征在于,使用NaOH调节合成反应体系溶液的pH。
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