CN107118767B - 一种放射性核素碘标记的荧光碳点、合成方法和应用 - Google Patents
一种放射性核素碘标记的荧光碳点、合成方法和应用 Download PDFInfo
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Abstract
本发明公开了一种放射性核素碘标记的荧光碳点、其合成方法和应用，属于纳米医学、分子影像领域，具体涉及一种可直接用于放射性核素碘标记的荧光碳点及其合成方法、肿瘤成像的应用。该碳点一步合成，可直接标记上放射性核素碘，标记产物具有优越的放射化学稳定性和物理化学稳定性，可直接用于肿瘤区域的基于124I的正电子发射断层成像(PET)，基于125I的单光子发射计算机断层成像(SPECT)成像以及131I放疗。该荧光碳点合成方法简单、原料价格低廉、荧光效率高、生物相容性好、既具有类似小分子体内代谢快的优势，又可利用纳米颗粒的高渗透长滞留效应很好地在肿瘤区域富集，从而进行肿瘤诊断和治疗。
Description
技术领域
本发明属于纳米医学、分子影像、核医学领域，具体涉及一种可直接用于放射性核素碘标记的荧光碳点及其合成方法、肿瘤成像的应用。
背景技术
纳米医学是借助纳米科技在分子水平上开展疾病预防、诊治及改善健康状况等医学应用的一门新型科学技术。由于纳米材料有着较小的尺寸、较大的比表面积、可精确调控的形貌和独特的物理化学性质，在多个生物学及医学领域(如生物荧光标记、活体多模态显像、药物和基因运输、肿瘤多功能治疗等方面)，均具有广泛的应用前景。
荧光碳量子点作为一种新型的超小碳纳米颗粒，具有优异的光电学性、良好的生物相容性及安全性、媲美小分子药物的活体代谢能力和较低的制备成本等特点，所以在光学成像、金属离子的生化分析检测和光催化等领域都体现出重要的应用价值。与传统半导体量子点相比，碳量子点不含任何重金属元素，细胞毒性小，易被细胞摄取，表面易进行各种修饰，更具有临床应用的潜力。
分子影像主要包含光学成像、磁共振成像、超声成像、光声成像、基于放射性核素的PET成像和SPECT成像等。相比其他成像手段来说，基于放射性核素的显像主要具有以下优势：其对探针的灵敏度可以达到纳克级别、无组织穿透深度限制，能适时地对体内药物的分布和代谢进行无损定量/半定量分析。
核素碘(包括124I,125I,131I)是较常用于临床诊疗的核素。其中124I半衰期4.1天，可用作PET成像；125I半衰期60天，可发射俄歇电子及低能量的γ射线，是优秀的内照射治疗用放射性核素并可用作SPECT成像；131I半衰期8.4天，可发射364keV的γ射线用于SPECT显像诊断，并可发射192keV的β射线用于治疗。碘标记化合物通常受到温度和时间的影响而脱碘，因而需要低温或冷冻干燥等条件保存。针对不同的靶向分子，通常需要根据被标记分子的结构和生化性质来选择不同的标记方法，不仅操作复杂，而且提纯有一定的难度。
发明内容
本发明的目的在于提供一种荧光碳点及其制备方法，该纳米材料合成简单，荧光效率高，生物相容性好，具有小分子的代谢特性。自身含有一定酪氨酸结构，可高效地标记上核素碘，不用修饰其他可标碘的配体，并可进一步修饰各种靶向分子，有针对性地用于各种肿瘤的SPECT/PET成像和放射性治疗。
本发明采用的技术方案包括以下步骤：
(1)将柠檬酸和酪氨酸溶解在酸性水溶液中，搅拌均匀后，高温反应数小时，降至常温后，纯化处理反应液，即得碳点。
(2)将步骤(1)中所得纯化后的碳点与靶向分子耦连上。
(3)将步骤(2)中所得样品取出少量，加入到含有氯胺T/氯甘脲的EP管中，加入核素碘反应一段时间，即得标记上碘的荧光碳点。
进一步的，所述步骤(1)中柠檬酸与酪氨酸质量比为1：1～5：1，水溶液pH为0～3(例如pH值为1、2)，反应温度为160～220℃，反应时间为4～12h。纯化方法优选为透析或硅胶柱分离。
进一步的，所述步骤(2)碳点:表面配体:EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐):NHS(N-羟基琥珀酰亚胺)的摩尔比1:1～3:1～5:1～5,在DMF(二甲基甲酰胺)中反应过夜，透析后即得最终样品，表面配体可以为叶酸、多肽、适配子、抗体等靶向分子，PEG、 PAA等高分子。
进一步的，所述步骤(3)中碳点用量为10～100微克，氯胺T/氯甘脲的量为20～200微克，核素碘可以为124I、125I、131I，反应时间为5～120min。
本发明的优点和特点在于：
1、本发明采用极为简单的水热法一步合成出荧光碳量子点，有很高的荧光产率，有很好的水溶性和生物相容性，可用于细胞层面的标记。
2、本发明合成的碳点可以直接标记上核素碘，不用外接其他配体，标记率高，放射化学稳定性强，表面更可以修饰各种靶向配体，针对不同肿瘤做靶向诊疗。
3、本发明合成的碳点在体内有很好的物理稳定性和放射化学稳定性。不仅具有小分子类似的药代动力学，可以很快从体内代谢，具有很好的生物安全性，而且由于纳米材料的高渗透长滞留效应，能够很好地在肿瘤区域富集，从而进行肿瘤显像。
附图说明
下面结合附图和实施例对本发明作进一步说明。
附图1为本发明实施例1荧光碳点的TEM图
附图2为本发明实施例1荧光碳点的荧光光谱图
附图3为本发明实施例1标记核素碘后的碳点的HPLC图，标记率高达100％
附图4为本发明实施例1 125I标记的碳点在肿瘤鼠内的SPECT显像(左右图分别为尾静脉给药后2h时间点时，老鼠不同横切面的SPECT图)
具体实施方式
现将本发明的具体实施例叙述如下，但本发明的实施方式不限于此。
实施例1
取0.5g柠檬酸和0.1g酪氨酸溶解于水中，调节pH＝1，使溶液呈澄清状态，搅拌均匀后，置于高压反应釜中，在180℃温度下反应6h，待冷却后，将所得碳点溶液用分子量为500的透析袋透析24h纯化。
取10mg碳点溶于DMF中，加入20mg EDC和20mg NHS进行活化两小时，然后加入100mg甲氧基PEG2000氨基，反应过夜后，用分子量为2000的透析袋透析一天。
取10微克PEG修饰的碳点(溶解在100微升水中)加入到涂有100微克氯甘脲的EP管中，然后向其中加入1mCi的Na125I溶液，振荡反应半小时后，将溶液取出即得核素125I标记的碳点。
荧光碳点的TEM图、荧光碳点的荧光光谱图、标记核素碘后的碳点的HPLC图，标记的碳点在肿瘤鼠内的SPECT显像分别如图1至图4所示。
实施例2
取0.6g柠檬酸和0.3g酪氨酸溶解于水中，调节pH＝1.5，使溶液呈澄清状态，搅拌均匀后，置于高压反应釜中，在160℃温度下反应12h，待冷却后，将所得碳点溶液用硅胶柱进行纯化。
取15mg碳点溶于DMF中，加入30mg EDC和30mg NHS进行活化两小时，然后加入150mg叶酸-PEG2000-氨基，避光反应过夜后，用分子量为2000的透析袋透析两天。
取20微克叶酸修饰的碳点(溶解在100微升水中)加入到含有200微克氯胺T的EP管中，然后向其中加入1mCi的Na131I溶液，振荡反应10min后，将溶液取出即得核素131I标记的碳点。
实施例3
取0.4g柠檬酸和0.4g酪氨酸溶解于水中，调节pH＝1.5，使溶液呈澄清状态，搅拌均匀后，置于高压反应釜中，在200℃温度下反应4h，待冷却后，将所得碳点溶液用分子量为500的透析袋透析24h纯化。
取12mg碳点溶于DMF中，加入25mg EDC和25mg NHS进行活化两小时，然后加入10mg c(RGDfk)多肽，避光反应过夜后，用分子量为1000的透析袋透析两天。
取15微克RGD修饰的碳点(溶解在120微升水中)加入到涂有150微克氯甘脲的EP管中，然后向其中加入1mCi的Na124I溶液，振荡反应1h后，将溶液取出即得核素124I标记的碳点。
实施例4
取0.5g柠檬酸和0.25g酪氨酸溶解于水中，调节pH＝1.2，使溶液呈澄清状态，搅拌均匀后，置于高压反应釜中，在200℃温度下反应4h，待冷却后，将所得碳点溶液用硅胶柱分离纯化。
取10mg碳点溶于DMF中，加入30mg EDC和30mg NHS进行活化两小时，然后加入10mg EGFR糖蛋白，避光反应过夜后，用分子量为1000的透析袋透析两天。
取15微克EGFR修饰的碳点(溶解在120微升水中)加入到涂有100微克氯甘脲的EP管中，然后向其中加入1mCi的Na125I溶液，振荡反应0.1h后，将溶液取出即得核素125I标记的碳点。
Claims (6)
1.一种放射性核素碘标记的荧光碳点的合成方法，该方法包括以下步骤：
(1) 将柠檬酸和酪氨酸溶解在酸性水溶液中，搅拌均匀后，160-220℃反应数小时，降至常温后，纯化处理反应液，即得碳点；
(2) 将步骤(1)中所得纯化后的碳点与靶向分子耦连上；
(3) 将步骤(2)中所得样品取出少量，加入到含有氯胺T/氯甘脲的EP管中，加入核素碘反应一段时间，即得标记上碘的荧光碳点。
2.根据权利要求1所述的一种放射性核素碘标记的荧光碳点的合成方法，其特征在于：步骤(1)中所述柠檬酸与酪氨酸质量比为1：1-5：1，水溶液pH为0-3，反应时间为4-12 h；纯化方法包括透析或硅胶柱分离。
3.根据权利要求1所述的一种放射性核素碘标记的荧光碳点的合成方法，其特征在于：步骤(2) 中，碳点: 表面配体: EDC: NHS的摩尔比1: 1-3: 1-5: 1-5, 在DMF中反应过夜，透析后即得最终样品，表面配体为包括叶酸、多肽、适配子、抗体在内的靶向分子，或包括PEG, PAA在内的高分子。
4.根据权利要求1所述的一种放射性核素碘标记的荧光碳点的合成方法，其特征在于：所述步骤(3)中碳点用量为10-100微克，氯胺T/氯甘脲的量为20-200微克，核素碘为124I、125I、131I中的至少一种，反应时间为5-120 min。
5.一种放射性核素碘标记的荧光碳点，其是由权利要求1至4任一项方法制备而得。
6.如权利要求5所述的一种放射性核素碘标记的荧光碳点在肿瘤精准靶向制剂或是在核医学肿瘤成像制剂方面的应用。
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