CN114806546A - 基于荧光分子的有机框架材料及其制备方法和应用 - Google Patents
基于荧光分子的有机框架材料及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种基于荧光分子的有机框架材料，所述有机框架材料NP1‑Zr‑MOF是NP1与锆离子簇配位形成的多孔材料，每个锆离子簇在三维空间上配位12个NP1分子，其中在X‑Y轴上配位四个NP1分子，Y‑Z轴上配位四个NP1分子，X‑Z轴上配位四个NP1分子。本发明的NP1‑Zr‑MOF材料具有良好的肿瘤靶向作用，可以作为靶向给药系统或可视化药物载体，安全可靠，在肿瘤的治疗领域具有非常广阔的应用前景。
Description
技术领域
本发明涉及生物医学材料领域，具体涉及一种基于荧光分子的有机框架材料及其制备方法和应用。
背景技术
金属有机框架材料(metal-organic framework，MOF)是以金属离子簇为结点，与有机桥接分子通过配位键作用形成的多孔功能性材料。通过调整反应条件，可将MOF材料的尺寸控制在纳米级，形成nMOF。与传统纳米材料相比，nMOF具有自身独特的优势，例如合成方法简单多样，如溶剂热法、反向微乳法、超声法、机械化学法等，能够适合于大规模工业化生产。同时，MOF材料的比表面积大，可作为优良载体递送不同类别的分子。MOF材料易于表面修饰，物化性质和功能多样且可调节，具备有机和无机材料各自的特点。
nMOF材料应用到疾病诊断和治疗中已有尝试，在生物医学中的应用已成为一个迅速发展的热点。由于它们具有大小合适并且均一的孔道，可以将小分子药物、治疗性核酸、诊断性分子高效包裹在内。通过选择自身荧光性或者治疗性有机配体，结合具有影像特性的金属离子，可赋予nMOF特别的诊疗特性。通过共价或者非共价作用引入功能性靶向基团(例如多肽、抗体、适配体、小分子等)可以使材料特异性到达病灶，改善诊断的准确率和治疗的靶向效果，以及降低材料可能的毒副作用。
荧光分子NP1，四[4-(4'-羧基苯基)苯基]乙烯，其化学式为C54H36O8，为一种多芳基乙烯化合物，具有高度的分子对称性，由于乙烯基与苯环是以单键相连接，单个NP1分子荧光发光很弱，当分子发生聚集或者溶液温度降低以后，苯环的旋转受限，激发态的电子辐射衰减增强，可出现聚集诱导发光(Aggregates induced emission，AIE)现象。
发明内容
本发明的目的是利用荧光分子NP1和锆离子合成一种具有极强的荧光稳定性的肿瘤靶向多模态成像有机框架材料。
为了解决现有技术的问题，本发明提供了如下技术方案：一种基于荧光分子的有机框架材料，其特征在于：所述有机框架材料NP1-Zr-MOF是NP1与锆离子簇配位形成的多孔材料，每个锆离子簇在三维空间上配位12个NP1分子，其中在X-Y轴上配位四个NP1分子，Y-Z轴上配位四个NP1分子，X-Z轴上配位四个NP1分子；或者多孔材料的酰胺、酯或盐，或该多孔材料形成的活性衍生物。NP1-Zr-MOF整体呈现出立体网格状的结构。
2、根据权利要求1所述的基于荧光分子的有机框架材料，其特征在于：所述NP1的分子式是C54H36O8，化学结构式如式(I)所示：
优选的，所述有机框架材料NP1-Zr-MOF的锆离子簇是8-16个锆离子形成的聚合体。
优选的，所述有机框架材料NP1-Zr-MOF中部分锆离子为89Zr，89Zr在NP-Zr-MOF中的质量含量为0.01％至0.1％之间。
优选的，所述有机框架材料NP1-Zr-MOF表面修饰有Py-PAA-PEG分子，并通过Py-PAA-PEG偶联肿瘤靶向分子。
本发明还公开了上述的基于荧光分子的有机框架材料的制备方法，其特征在于包括如下步骤:
(1)将ZrOCl2·8H2O和NP1溶解在有机溶剂DMF中；
(2)将反应体系的pH调节到1-5，在80-110℃反应24-72小时，反应产物洗涤后，再经凝胶阻滞层析，得到NP1-Zr-MOF。
优选的，步骤(1)中还加入89ZrCl4，剂量为300-1000MBq之间，质量为10-100微克，制得荧光/PET双成像的NP1-Zr-MOF。
优选的，步骤(1)具体为将90mg的ZrOCl2·8H2O和30mg的NP1溶于9ml DMF中，室温搅拌数小时；
步骤(2)具体为加入6ml甲酸，超声至分散完全后，将反应混合物放入反应釜中，并将反应釜置于120℃反应三天，将反应液取出并用去离子水和无水乙醇交替洗涤3-5次，同时离心分离，离心转速为10000-12000r/min；经凝胶阻滞柱进行纯化，冻干，制得NP1-Zr-MOF。
本发明还公开了上述基于荧光分子的有机框架材料在作为靶向肿瘤的药物输送载体中的应用。
本发明还公开了一种肿瘤靶向连接的药物输送系统，包括上述的NP1-Zr-MOF、肿瘤靶向分子和至少一种活性物质。
优选的，所述的肿瘤靶向分子偶联至NP1-Zr-MOF，所述肿瘤靶向分子为多肽、小蛋白、抗体、纳米抗体、核酸、医用同位素、适配体中的一种或几种的组合；所述的活性物质为显像剂或药物；所述的显像剂为放射性核素、放射性核素标记物或分子影像剂中的一种或几种的组合，药物为能杀伤癌细胞的化学药物、生物药物、光热治疗或光动力治疗药物中的一种或几种的组合。
优选的，所述的肿瘤为乳腺癌、肺癌、胃癌、结肠直肠癌、胰腺癌、前列腺癌、宫颈癌、头颈癌或卵巢癌。
有益效果：本发明合成的MOF材料具有极强的荧光稳定性，尺寸和孔径可控，毒性低，且能够进行双模态成像，可以特异性结合不同类型肿瘤细胞，灵敏度高，可以应用于肿瘤的筛查、诊断。该MOF材料在肿瘤靶向给药、癌症诊断等方面彰显出较强的优越性，为基于荧光分子的多能生物材料的开发和设计提供有效的开发途径。
与现有技术相比，本发明具有如下优点：
(1)本发明借助于荧光分子NP1和锆离子的稳定配位，利用溶剂热法得到了性质稳定且荧光特性好的MOF材料，该设计方法简单易操作，能大规模高效合成MOF材料。
(2)本发明合成的MOF材料具有良好的肿瘤靶向作用，可以作为靶向给药系统或可视化药物载体，安全可靠，在肿瘤的治疗领域具有非常广阔的应用前景。
(3)本发明NP1-Zr-MOF材料经过晶体结构分析对比，利用剑桥晶体数据中心(CCDC)数据库的已知MOF材料结构无同源性，且国内外文献也均未见报道，由此可以得出利用本发明的方法获得的MOF材料结构新颖，具有潜在的应用价值。
(4)本发明的MOF材料可在结构中添加或连接其他有机MOF配体，引入新的诊断、影像特性。另外，本发明的MOF材料也涉及材料表面进行有机分子修饰，例如聚乙二醇、其他聚合物分子、蛋白或者多肽衍生物。本发明NP1-Zr-MOF可用芘-聚丙烯酸-聚乙二醇(Py-PAA-PEG)进行表面修饰，偶联肿瘤靶向多肽c(RGDfC)。
(5)本发明所述的MOF材料或其衍生物与能杀伤癌细胞的制剂相缀合或混合，形成靶向连接的药物输送系统，可以缀合的制剂包括：小分子、多肽、核酸(DNA和RNA)、蛋白质(包括抗体类蛋白)、医用同位素等。
附图说明
图1为NP1-Zr-MOF的晶体结构图。
图2为利用动态光散射法(DLS)测定的本发明的NP1-Zr-MOF的水合粒径图。
图3为利用透射电子显微镜(TEM)测定的本发明的NP1-Zr-MOF材料形貌图。
图4是本发明的NP1-Zr-MOF的荧光发射光谱(激发光为405nm)图。
图5是利用X射线衍射光谱(XRD)测定的本发明的NP1-Zr-MOF晶体结构图。
图6是利用热重分析(TGA)测定的本发明的NP1-Zr-MOF有机成分图。
图7是利用氮气吸附-解吸分析(BET)测定本发明的NP1-Zr-MOF材料比表面积图。
图8是本发明的NP1-Zr-MOF被三阴性乳腺肿瘤细胞MDA-MB-231摄取的荧光显微镜照片。
图9是本发明的NP1-Zr-MOF在三阴性乳腺肿瘤小鼠肺转移模型中的荧光成像图。
图10是本发明的NP1-Zr-MOF在三阴性乳腺肿瘤小鼠原位模型中的PET成像结果图。
具体实施方式
下面结合具体试验例，进一步阐述本发明。这些试验例仅用于说明本发明而不用于限制本发明的范围。
试验例1
NP1-Zr-MOF的溶剂热法合成
将90mg的ZrOCl2·8H2O和30mg的NP1溶于9ml DMF中，室温搅拌数小时；之后加入6ml甲酸，超声至分散完全后，将反应混合物放入反应釜中，并将反应釜置于120℃反应三天，将反应液取出并用去离子水和无水乙醇交替洗涤3-5次，同时离心分离，离心转速为10000-12000r/min。经凝胶阻滞柱进行纯化，冻干得到目标产物。产物NP1-Zr-MOF的结构式如图1所示，为NP1与锆离子簇配位形成的多孔材料，锆离子簇通常是8-16个锆离子形成的聚合体，平均值在12左右，在三维空间上配位12个NP1分子，其中在X-Y轴上配位四个NP1分子，Y-Z轴上配位四个NP1分子，X-Z轴上配位四个NP1分子。产物可用粒径仪测出其粒径(图2)或用TEM测定其尺寸和形貌(图3)，并用测定其荧光性质(图4)，晶体结构(图5)，材料组分(图6)以及比表面积与孔径(图7)。
试验例2
利用表面聚乙二醇修饰和多肽修饰，实现肿瘤细胞靶向
NP1-Zr-MOF的结构中含有大量的苯环结构，利用苯环与苯环之间的π-π相互作用力，能够将Py-PAA-PEG分子稳定修饰于NP1-Zr-MOF的表面。在Py-PAA-PEG分子末端连接马来酰亚胺基团，可在pH值7.5左右高效偶联肿瘤靶向多肽c(RGDfC)。c(RGDfC)多肽是一种靶向整合素(integrin)αvβ3蛋白的强力多肽配体，能够把NP1-Zr-MOF导向αvβ3蛋白高表达的三阴性乳腺肿瘤细胞MDA-MB-231中。
利用c(RGDfC)多肽的导向，100μg/mL的NP1-Zr-MOF在MDA-MB-231乳腺肿瘤细胞中具有很强的细胞摄取，展现出较强且稳定的细胞荧光，实现特异的肿瘤细胞荧光检测。这种强的细胞荧光可以稳定存在超过12小时(图8)。同时，在作为对照的成纤维细胞L929中，NP1-Zr-MOF不呈现特异性摄取，证明了其肿瘤细胞靶向的特异性。
试验例3
NP1-Zr-MOF的体内肿瘤靶向荧光检测
在雌性裸鼠(6-10周龄)中建立MDA-MB-231细胞静脉注射后的乳腺肿瘤肺部转移模型。利用每只小鼠静脉注射2百万MDA-MB-231肿瘤细胞，在28-40天的时间可在小鼠的肺部形成1-3mm左右的肿瘤结节。在肿瘤细胞注射后30天，通过静脉注射可给予5mg/kg体重量的实施例1获得的NP1-Zr-MOF，在注射后1小时进行荷瘤小鼠的解剖。通过在IVIS Illumina3活体光学成像仪中进行观测，可利用NP1-Zr-MOF的荧光清晰鉴别小鼠肺部小至1-2mm的乳腺肿瘤结节灶(图9)，证明了NP1-Zr-MOF在体内肿瘤靶向的特异性和灵敏性。
试验例4
掺入锆-89的NP1-Zr-MOF的合成
在试验例1的溶剂热法合成过程中，在90mg的ZrOCl2·8H2O和30mg的NP1的反应体系中(9mL DMF)，加入300-1000MBq 89ZrCl4，质量为10-100微克，室温搅拌1-2小时，加入6ml甲酸，超声至分散完全后，将反应混合物放入反应釜中，并将反应釜置于120℃反应72小时，将反应液取出并用去离子水和无水乙醇交替洗涤3-5次，同时离心分离，离心转速为10000-12000r/min。最终将产物NP1-Zr(89Zr)-MOF重新悬浮在去离子水中，采用质量比1：1与Py-PAA-PEG在超声状态下复合12-24小时，复合后的PEG-NP1-Zr(89Zr)-MOF可以与c(RGDfC)多肽按照质量比10：1在磷酸缓冲液中反应2-16小时，并利用梯度溶剂洗涤法得到可以用于PET影像的NP1-Zr-MOF材料。
试验例5
NP1-Zr-MOF的体内肿瘤靶向PET影像检测
在雌性裸鼠(6-10周龄)中建立MDA-MB-231原位肿瘤模型。每只小鼠在乳腺脂肪块注射5百万MDA-MB-231肿瘤细胞，当肿瘤直径达到6-10mm之间(通常生长4周左右)，利用试验例4中获得的锆-89标记的NP1-Zr-MOF进行荷瘤小鼠的尾静脉注射(材料注射剂量为5mg/kg，放射剂量为每只小鼠100-200μCi，3.7-7.4MBq)。在注射后2小时与24小时，使用西门子的Inveon小动物活体PET成像仪，进行PET成像，并用Amide影像处理软件进行图像处理以及器官定量。通过图像分析，可确认NP1-Zr-MOF能够靶向富集于MDA-MB-231，主要通过肝胆代谢排出体外，且在血液中的半衰期较短，意味着优越的肿瘤检测信噪比(图10)。
在PET影像结束后，对荷瘤小鼠进行处死，取主要器官/组织(心、肝、肺、脾、肾、肿瘤、骨、肌肉、血液、脑)，利用Perkin-Elmer的Wizard2伽玛射线检测器进行组织/器官放射定量，精确测量NP1-Zr-MOF在荷瘤小鼠中的分布、代谢情况，具体结果显示于表1。NP1-Zr-MOF在MDA-MB-231荷瘤小鼠中器官分布情况(注射后24小时，单位：％总注射剂量/克体重)如表1所示：
表1
结果表明，NP1-Zr-MOF在MDA-MB-231肿瘤的摄取较高(4％总注射剂量/克体重)，肿瘤/肌肉的信噪比在7.2±0.8(每组5只小鼠测试)，肿瘤检测特异性较佳。
上述试验例仅为本发明的优选实施方式，不以任何形式限制本发明，应当指出，对于本技术领域的普通技术人员来说，采用等同替换或等效变换方式所获得的技术方案，或在不脱离本发明原理的前提下，做出的若干改进和润饰，均在本发明的保护范围内。
Claims (12)
1.一种基于荧光分子的有机框架材料，其特征在于：所述有机框架材料NP1-Zr-MOF是NP1与锆离子簇配位形成的多孔材料，每个锆离子簇在三维空间上配位12个NP1分子，其中在X-Y轴上配位四个NP1分子，Y-Z轴上配位四个NP1分子，X-Z轴上配位四个NP1分子。
2.根据权利要求1所述的基于荧光分子的有机框架材料，其特征在于：所述NP1的分子式是C54H36O8，化学结构式如式(I)所示：
3.根据权利要求1所述的基于荧光分子的有机框架材料，其特征在于：所述有机框架材料NP1-Zr-MOF的锆离子簇是8-16个锆离子形成的聚合体。
4.根据权利要求1所述的基于荧光分子的有机框架材料，其特征在于：所述有机框架材料NP1-Zr-MOF中部分锆离子为89Zr，89Zr在NP-Zr-MOF中的质量含量为0.01％至0.1％之间。
5.根据权利要求1-4中任一项所述的基于荧光分子的有机框架材料，其特征在于：所述有机框架材料NP1-Zr-MOF表面修饰有Py-PAA-PEG分子，并通过Py-PAA-PEG偶联肿瘤靶向分子。
6.权利要求1-5中任一项所述的基于荧光分子的有机框架材料的制备方法，其特征在于包括如下步骤:
(1)将ZrOCl2·8H2O和NP1溶解在有机溶剂DMF中；
(2)将反应体系的pH调节到1-5，在80-110℃反应24-72小时，反应产物洗涤后，再经凝胶阻滞层析，得到NP1-Zr-MOF。
7.根据权利要求6所述的基于荧光分子的有机框架材料的制备方法，其特征在于：步骤(1)中还加入89ZrCl4，制得荧光/PET双成像的NP1-Zr-MOF。
8.根据权利要求6所述的根据基于荧光分子的有机框架材料的制备方法，其特征在于：步骤(1)具体为将90mg的ZrOCl2·8H2O和30mg的NP1溶于9ml DMF中，室温搅拌数小时；
步骤(2)具体为加入6ml甲酸，超声至分散完全后，将反应混合物放入反应釜中，并将反应釜置于120℃反应三天，将反应液取出并用去离子水和无水乙醇交替洗涤3-5次，同时离心分离，离心转速为10000-12000r/min；经凝胶阻滞柱进行纯化，冻干，制得NP1-Zr-MOF。
9.根据权利要求8所述的根据基于荧光分子的有机框架材料的制备方法，其特征在于：步骤(1)中还加入10-100微克的89ZrCl4。
10.权利要求1-5所述的基于荧光分子的有机框架材料在作为靶向肿瘤的药物输送载体中的应用。
11.一种肿瘤靶向连接的药物输送系统，其特征在于：包括权利要求1-5中任一项所述的NP1-Zr-MOF、肿瘤靶向分子和至少一种活性物质。
12.根据权利要求11所述的肿瘤靶向连接的药物输送系统，其特征在于：所述的肿瘤靶向分子偶联至NP1-Zr-MOF，所述肿瘤靶向分子为多肽、小蛋白、抗体、纳米抗体、核酸、医用同位素、适配体中的一种或几种的组合；所述的活性物质为显像剂或药物；所述的显像剂为放射性核素、放射性核素标记物或分子影像剂中的一种或几种的组合，药物为能杀伤癌细胞的化学药物、生物药物、光热治疗或光动力治疗药物中的一种或几种的组合。
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