CN114129726B - 一种靶向肽修饰的金簇氧化铁组装材料放疗增敏剂 - Google Patents
一种靶向肽修饰的金簇氧化铁组装材料放疗增敏剂 Download PDFInfo
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Abstract
本发明公开了一种金簇氧化铁组装材料放疗增敏剂，属于纳米材料化学和生物化学的交叉领域。本发明以Au4簇溶液在细胞培养液中与氧化铁组装，然后在其表面修饰环精氨酸‑甘氨酸‑天冬氨酸‑苯丙氨酸半胱氨酸（cRGD）肽，得到Au4‑IO NP‑cRGD。该金簇氧化铁组装材料在室温下具有较强的绿色荧光，其具有良好的分散性和肿瘤靶向性，可以用于高品质细胞成像。该金簇氧化铁组装材料可以作为放疗增敏剂起到放疗增敏效果，减少X射线剂量，具备杀死肿瘤细胞的高效性。
Description
技术领域
本发明属于纳米材料化学和生物化学的交叉领域，具体涉及一种金簇组装材料放疗增敏剂，尤其涉及一种靶向肽修饰的金簇氧化铁组装材料放疗增敏剂。
背景技术
放疗已应用于全球超过一半的癌症患者，大约40％的癌症治疗涉及放疗，有时与其他治疗相结合。高效放疗的一个重大而紧迫的挑战是如何最大限度地杀死癌细胞，同时最大限度地减少对周围健康组织的损害。在影响放疗疗效的众多药物中，金基纳米材料由于其高质量衰减系数和低细胞毒性成为癌症治疗的主要候选材料。与此同时，一系列基于芬顿反应的治疗系统也被开发出来。例如，超顺磁性氧化铁纳米粒子可以在酸性条件下释放Fe2+/Fe3+并进入细胞质，进一步影响细胞内的活性氧稳态。然而，由于H2O2浓度和离子释放速率有限，这些单一的癌症治疗策略通常不足以有效遏制肿瘤。因此，开发联合疗法非常必要。目前急需研发新型的放疗增敏剂。
发明内容
本发明目的在于提供一种新型金簇氧化铁组装材料放疗增敏剂。
为实现本法发明目的，本发明以Au4簇溶液在细胞培养液中与氧化铁组装，然后在其表面修饰环精氨酸-甘氨酸-天冬氨酸-苯丙氨酸半胱氨酸(cRGD)肽，得到金簇氧化铁组装材料(Au4-IO NP-cRGD)。
具体通过如下步骤制备而成：
(1)将氯化铁(FeCl3·6H2O)和油酸钠溶解在由乙醇、蒸馏水和正己烷组成的混合溶剂中。将所得溶液加热反应。反应完成后，上层含有油酸铁络合物的有机层在分液漏斗中用蒸馏水洗涤。洗涤后，得到蜡状固体形式的油酸铁络合物。然后将油酸铁络合物和油醇溶解在二苯醚中，将反应混合物加热反应。得到含有氧化铁纳米晶体的溶液，将其冷却至室温，并向溶液中加入过量丙酮以沉淀纳米晶体。通过离心分离纳米晶体，在油相中产生氧化铁。最后，将制备的氧化铁分散在四氢呋喃中，与含有马来酰亚胺功能化聚乙二醇(PEG，MW＝2000)的四氢呋喃溶液混合，加热搅拌反应，得到PEG修饰的氧化铁。
(2)将配体4-异丙基噻唑烷-2-硫酮溶解于二氯甲烷(DCM)和乙腈(CH3CN)混合溶液中，室温搅拌溶解澄清；加入三乙胺，室温搅拌反应；然后加入Me2SAuCl，室温继续搅拌，反应结束以后，将反应液避光挥发，得晶体，过滤，洗涤，室温晾干，得到Au4簇。
(3)将Au4簇溶解在DMF中，然后用乙醇稀释。将细胞培养液中PEG修饰的氧化铁加入到Au4簇的乙醇溶液中振荡均匀，得到Au4-IO NP。
(4)将环精氨酸-甘氨酸-天冬氨酸-苯丙氨酸半胱氨酸(cRGD)肽加入到Au4-IO NP的水悬浮液中，振荡均匀，得到金簇氧化铁组装材料，简写为：Au4-IO NP-cRGD。
步骤(3)所述PEG修饰的氧化铁溶液:Au4簇体溶液的体积比优选6:4。
所述金簇氧化铁组装材料具有良好的分散性(图1和2所示)。在室温条件下具有强烈的绿色荧光，其发射谱表现出宽的吸收带(λem＝510nm)(图3所示)。该材料对细胞具有良好的靶向性(图4所示)。将其用于细胞克隆实验，实验过程中对其进行不同条件的处理，Au4-IO NP-cRGD+X射线实验组细胞坏死最为显著(图5所示)。
本发明有益效果：该金簇氧化铁组装材料在室温下具有较强的绿色荧光，具有聚集诱导发光性质，且具有良好的分散性、肿瘤靶向性和良好的生物相容性，可以用于高品质细胞成像，作为放疗增敏剂起到放疗增敏效果，实现芬顿效应辅助的放疗增敏。减少X射线剂量，具备杀死肿瘤细胞的高效性。在基于聚集诱导发光构建肿瘤联合治疗平台方面有很好的理论依据和参考价值。
附图说明
图1为本发明金簇氧化铁组装材料的透射电镜图。
图2为本发明金簇氧化铁组装材料的动态光散射图。
图3为本发明金簇氧化铁组装材料的发射曲线图。
图4为本发明金簇氧化铁组装材料的细胞成像图。
图5为本发明金簇氧化铁组装材料作为放疗增敏剂用于细胞克隆实验结果图。
具体实施方式
下面通过实例对本发明做进一步的说明：
实施例1：本发明金簇氧化铁组装材料的合成
(1)将氯化铁(FeCl3·6H2O)和油酸钠溶解在由乙醇、蒸馏水和正己烷组成的混合溶剂中。将所得溶液加热至70℃，反应4小时。反应完成后，上层含有油酸铁络合物的有机层在分液漏斗中用蒸馏水洗涤。洗涤后，得到蜡状固体形式的油酸铁络合物。然后将油酸铁络合物和油醇溶解在二苯醚中。将反应混合物加热至220℃，反应30分钟。将所得含有氧化铁纳米晶体的溶液冷却至室温，并向溶液中加入过量丙酮以沉淀纳米晶体。通过离心分离纳米晶体，在油相中产生氧化铁。最后。将制备的氧化铁分散在四氢呋喃中，与含有马来酰亚胺功能化聚乙二醇(PEG，MW＝2000)的四氢呋喃溶液混合，60℃下剧烈搅拌10-12小时，最终得到PEG稳定的氧化铁。
(2)将配体4-异丙基噻唑烷-2-硫酮溶解于二氯甲烷(DCM)和乙腈(CH3CN)混合溶液中，室温搅拌溶解澄清；加入三乙胺，室温搅拌反应；然后加入Me2SAuCl，室温继续搅拌，反应结束以后将反应液置于4℃下避光挥发，得晶体，过滤，用乙腈洗涤，室温晾干，得到Au4簇。
(3)将Au4簇溶解在DMF中，然后用乙醇稀释。将细胞培养液中PEG修饰的氧化铁加入到Au4簇的乙醇溶液中(体积比为6:4)振荡均匀，得到Au4-IO NP。
(4)将环精氨酸-甘氨酸-天冬氨酸-苯丙氨酸半胱氨酸(cRGD)肽加入到Au4-IO NP的水悬浮液中，振荡均匀，得到金簇氧化铁组装材料，简写为：Au4-IO NP-cRGD。
实施例2：本发明金簇氧化铁组装材料作为放疗增敏剂
取实施例1制得的本发明金簇氧化铁组装材料加入到培养基里面超声均匀，将含有此材料的培养基用于细胞克隆实验，对不同组别进行不同剂量的X射线处理。结果见图5，可以看出，Au4-IO NP-cRGD+X射线实验组细胞坏死最为显著。
以上实施例仅用于说明本发明的内容，除此之外，本发明还有其它实施方式。但是，凡采用等同替换或等效变形方式形成的技术方案均落在本发明的保护范围内。
Claims (3)
1.一种金簇氧化铁组装材料，其特征在于，通过如下步骤制备而成：
（1）将氯化铁和油酸钠溶解在由乙醇、蒸馏水和正己烷组成的混合溶剂中，将所得溶液加热反应；反应完成后，上层含有油酸铁络合物的有机层用蒸馏水洗涤，得到油酸铁络合物；然后将油酸铁络合物和油醇溶解在二苯醚中，将反应混合物加热反应，得到含有氧化铁纳米晶体的溶液，将其冷却至室温，并向溶液中加入过量丙酮，离心分离得到氧化铁；将制备的氧化铁分散在四氢呋喃中，与含有马来酰亚胺功能化聚乙二醇的四氢呋喃溶液混合，加热搅拌反应，得到PEG修饰的氧化铁；
（2）将配体4-异丙基噻唑烷-2-硫酮溶解于二氯甲烷和乙腈混合溶液中，室温搅拌溶解澄清；加入三乙胺，室温搅拌反应；然后加入Me2SAuCl，室温继续搅拌，反应结束以后，将反应液避光挥发，得晶体，过滤，洗涤，室温晾干，得到Au4簇；
（3）将Au4簇溶解在DMF中，然后用乙醇稀释；将细胞培养液中PEG修饰的氧化铁加入到Au4簇的乙醇溶液中振荡均匀，得到Au4-IO NP；
（4）将环精氨酸-甘氨酸-天冬氨酸-苯丙氨酸半胱氨酸肽加入到Au4-IO NP的水悬浮液中，振荡均匀，得到金簇氧化铁组装材料，简写为：Au4-IO NP-cRGD。
2.如权利要求1所述的金簇氧化铁组装材料，其特征在于，步骤（3）所述PEG修饰的氧化铁溶液:Au4簇溶液的体积比优选 6:4。
3.如权利要求1或2所述的金簇氧化铁组装材料在制备放疗增敏剂或细胞成像剂中的应用。
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