CN110935039A - pH敏感的131I标记金纳米星及其制备方法和应用 - Google Patents
pH敏感的131I标记金纳米星及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种pH敏感的131I标记金纳米星及其制备方法和应用。本发明通过表面修饰pH敏感两性离子APAS,进一步与修饰有3‑(4‑羟基苯基)丙酸N‑羟基琥珀酰亚胺酯(HPAO)的功能化聚乙烯亚胺结合,最后在功能化聚乙烯亚胺表面标记131I以构建兼具SPECT/CT成像及光热/放射性治疗的纳米诊疗试剂,可实现其在癌细胞内的高量摄取进而实现精准诊疗。
Description
技术领域
本发明属于功能化金纳米星材料技术领域,特别涉及一种pH敏感两性离子功能化的131I标记金纳米星颗粒及其制备方法和应用。
背景技术
癌症基于其局部浸润性及远端转移特性,目前已成为危害人类健康的头号杀手。癌症的治愈程度与其发现的时期密切相关,因此及早发现、及早治疗成为治愈癌症、减少癌症后期转移隐患的有效方法。随着纳米技术在近年来的发展,多种纳米诊疗体系已被设计用于癌症的早期精确诊断及高效治疗,包括:脂质体、硅纳米材料、放射性核素标记物、聚合物、树状大分子、贵金属基纳米材料等,主要是通过在体内传输递送至肿瘤部位发挥诊疗功效。在众多的纳米诊疗材料中,贵金属基纳米材料基于其能在近红外光照射下实现光热转换,通过高温烧蚀癌细胞以达到DNA及RNA不可逆的损伤,具有高效的肿瘤光热治疗作用。其中,金纳米星基于其较高的X-射线衰减系数、高光热转换效率及稳定性,可用于肿瘤的电子计算机断层扫描(Computed Tomography,CT)及光热治疗。但其在体内生物医学应用中,经体内循环传输至肿瘤处的金纳米星含量较低,使其成像及光热治疗效果受限。因此,为提高金纳米星功能材料的诊疗效率,提高癌细胞对其的摄取量极为关键。
近年来,两性离子的发展为提高癌细胞对纳米颗粒的摄取提供了思路。尤其对于pH敏感两性离子,在血液及正常组织的微环境(pH 7.0-7.4)下,两性离子由于自身带有负电荷及正电荷功能基团,使其达到电荷平衡呈现电中性;在肿瘤微酸性(pH 5.5-6.5)环境下,两性离子可结合质子转变为正电性,实现电荷翻转,进而实现其在癌细胞内的高量摄取。目前已有相关研究报道,将两性离子4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐(APAS)修饰在金纳米颗粒表面,基于APAS在微酸性条件下通过电荷翻转使功能化金纳米颗粒表面转变为正电荷(15mV),可实现其在人宫颈癌HeLa细胞的高量摄取,细胞摄取量可达到每孔细胞45ng(Mizuhara,T.K.et al.Angew.Chem.,Int.Ed.2015,54,6567)。
因此,可通过将pH敏感两性离子APAS与金纳米星结合,从而在肿瘤微酸性环境下实现金纳米星在癌细胞的高量摄取,以达到癌症早期诊断及治疗的效果。
发明内容
本发明的目的是提供一种pH敏感两性离子功能化的131I标记金纳米星颗粒及其制备方法和应用,通过将pH敏感两性离子APAS与金纳米星结合,同时修饰131I以构建兼具SPECT/CT成像及光热/放射性治疗的纳米诊疗试剂,可实现其在癌细胞内的高量摄取进而实现精准诊疗。
为了实现上述发明目的,本发明采用以下技术方案:
一种pH敏感的131I标记金纳米星,包括金纳米星颗粒,在金纳米星颗粒表面修饰有4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和功能化载体聚乙烯亚胺,所述4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和功能化载体聚乙烯亚胺通过巯基共价键与金纳米星颗粒连接;
所述功能化载体聚乙烯亚胺上还连接有放射性核素131I和异硫氰酸荧光素。
上述金纳米星的制备方法,包括以下步骤:
步骤1,将超支化聚乙烯亚胺PEI.NH2溶解于水中,加入巯基乙酸甲酯MTG,60-70℃加热反应制得修饰有巯基的聚乙烯亚胺PEI.NH2-SH,将PEI.NH2-SH和3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯HPAO混合,搅拌反应制得PEI.NH2-SH-HPAO,然后将PEI.NH2-SH-HPAO和异硫氰酸荧光素FI混合,搅拌反应,制得PEI.NH2-SH-HPAO-FI;
步骤2,将氯金酸溶液加热煮沸,再加入柠檬酸钠,继续煮沸15-25min,冷却得到金种子水溶液,将金种子水溶液加至氯金酸溶液中,然后加入AgNO3溶液和抗坏血酸溶液,搅拌,得到金纳米星Au NSs;
步骤3,将4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐APAS溶解于水中,加入到步骤2得到的金纳米星Au NSs中,搅拌反应得到修饰有APAS的Au NSs金纳米星APAS-Au NSs;
步骤4,将步骤1制得的PEI.NH2-SH-HPAO-FI和步骤3制得的APAS-Au NSs混合,搅拌反应得到APAS-Au-PEI-HPAO-FI NSs;
步骤5,向步骤4的APAS-Au-PEI-HPAO-FI NSs中,加入三乙胺和乙酸酐进行乙酰化以中和聚乙烯亚胺表面多余的氨基,得到乙酰化APAS-Au-PEI-HPAO-FI NSs;
步骤6,向步骤5得到的乙酰化APAS-Au-PEI-HPAO-FI NSs中,加入氯胺T及放射性Na131I,搅拌反应并加入Na2S2O5及KI,反应结束后分离纯化,得到131I标记的功能化金纳米星材料APAS-Au-131I-PEI-HPAO-FI NSs。
进一步地,步骤1中,巯基乙酸甲酯与超支化聚乙烯亚胺的摩尔比为30-32:1,3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯与超支化聚乙烯亚胺的摩尔比为4-7:1,异硫氰酸荧光素与超支化聚乙烯亚胺的摩尔比为4-7:1。
进一步地,步骤2中柠檬酸钠和氯金酸的摩尔比为5-6:1,金种子、HAuCl4、AgNO3与抗坏血酸的摩尔比为2:50:4-6:1。
进一步地,步骤3中4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和金纳米星的摩尔比为8-12:1。
进一步地,步骤5中三乙胺、乙酸酐和APAS-Au-PEI-HPAO-FI NSs的摩尔比为120-660:100-550:1。
进一步地,步骤6中,Na131I的放射性活性为190-360MBq;才用PD-10脱盐柱进行分离纯化,以pH 7.0-7.4的PBS为流动相。
上述pH敏感的131I标记金纳米星在制备肿瘤诊疗试剂中的应用。
本发明的pH敏感两性离子功能化的131I标记金纳米星颗粒,其具有良好的pH响应电荷翻转性能,体外细胞实验证明其在微酸性环境下可增强癌细胞对其的摄取量。在标记放射性核素131I后,其具有良好的放射性稳定性,可作为性质优良的纳米诊疗试剂,实现在肿瘤的高量摄取,可进行肿瘤精准SPECT/CT成像及光热/放射性治疗。
附图说明
图1为本发明中APAS-Au-131I-PEI-HPAO-FI NSs的合成示意图。
图2为本发明中氢核磁共振谱图,其中(a)为PEI.NH2-SH、(b)为PEI.NH2-SH-HPAO、(c)为PEI.NH2-SH-HPAO-FI。
图3为本发明中APAS-Au-PEI-HPAO-FI NSs的紫外可见吸收光谱图。
图4为本发明中TEM测试结果,其中(a)为金种子的TEM图片、(b)为金种子的粒径分布直方图、(c)为APAS-Au-PEI-HPAO-FI NSs的TEM图片、(d)为APAS-Au-PEI-HPAO-FI NSs的粒径分布直方图。
图5为本发明中不同pH条件下的Au-PEI-HPAO-FI NSs及APAS-Au-PEI-HPAO-FINSs溶液的电势曲线图。
图6为本发明中不同pH条件下HeLa细胞分别经Au-PEI-HPAO-FI NSs及APAS-Au-PEI-HPAO-FI NSs孵化3h的细胞摄取图。
具体实施方式
基于金纳米星可进行CT成像及光热治疗的优势,本发明设计通过在金纳米颗粒表面修饰pH敏感两性离子4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐(APAS),进一步再与修饰有3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯(HPAO)的功能化聚乙烯亚胺结合,最后在功能化聚乙烯亚胺表面标记131I以构建兼具SPECT/CT成像及光热/放射性治疗的纳米诊疗试剂,可实现其在癌细胞内的高量摄取进而实现精准诊疗。131I作为兼具单光子发射计算机断层成像(SPECT)及放射性治疗的核医学药物,在自身衰减过程中可同时发射出γ射线及β射线,可在分子层面上实现肿瘤部位的监控、治疗,常作为辅助成像及治疗试剂以弥补金纳米星进行CT成像灵敏度低等缺点。
如图1所示,pH敏感两性离子APAS可通过其分子结构中的巯基与金纳米星以共价键合修饰在金纳米星表面,实现在微酸性环境下通过电荷翻转表面呈现正电荷以实现癌细胞的高量摄取。同时,在聚乙烯亚胺表面通过共价键连接有巯基乙酸甲酯MTG,使得聚乙烯亚胺表面部分氨基转变为巯基,表面巯基基团可通过Au-S键修饰在金纳米星表面。进一步地,使用功能化聚乙烯亚胺作为载体,将其修饰在金纳米星表面时,由于功能化聚乙烯亚胺表面修饰有HPAO,其可用于放射性核素131I的标记,赋予该诊疗体系SPECT成像及放射性治疗功能。此外,异硫氰酸荧光素FI也修饰在功能化聚乙烯亚胺表面,其作为小分子荧光物质,可实现功能化金纳米星在体内的荧光示踪。
本发明所提供的pH敏感两性离子功能化的131I标记金纳米星颗粒,其制备过程简单,易于操作,其制备方法可用于多种功能化金纳米星材料的制备,如:可将金纳米星颗粒作为载体平台构建基因递送体系,将超支化聚乙烯亚胺或者树状大分子类高分子化合物修饰在金纳米星颗粒表面,再以该类高分子化合物作为载体负载特定基因以实现基因递送,构建多种纳米诊疗复合体系,具有良好的生物医学应用前景。
本发明所制备功能化金纳米星复合材料可作为良好的诊疗试剂,有望用于癌症的精准诊疗,以期实现肿瘤的精确SPECT/CT成像及高效的光热/放射性治疗,其为构建新型智能纳米诊疗试剂奠定基础。
以下实施例进一步说明本发明的内容,但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下,对本发明方法、步骤或条件所作的修改或替换,均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
实施例1
步骤1,称取干重为100mg超支化聚乙烯亚胺(PEI.NH2,Mw=25000)溶于20mL水中,边搅拌边逐滴滴加10.73mL巯基乙酸甲酯(MTG),并在60~70℃水浴条件下反应48h,其中MTG与PEI.NH2的摩尔比为30:1,将所得的溶液用纤维素透析膜MWCO=14000在磷酸盐缓冲溶液和蒸馏水中透析3天,冷冻干燥处理得到PEI.NH2-SH。用5mL的DMSO溶解干重为80mg的PEI.NH2-SH,边搅拌边逐滴滴加溶于5mL DMSO溶液的干重为4.14mg的3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯(HPAO),其中HPAO与PEI.NH2-SH的摩尔比为5:1,反应24h,将所得的溶液用纤维素透析膜MWCO=14000在磷酸盐缓冲溶液和蒸馏水中透析3天,冷冻干燥处理得到PEI.NH2-SH-HPAO。随后,再用5mL的DMSO溶解干重为66.28mg的PEI.NH2-SH-HPAO,边搅拌边逐滴滴加溶于5mL DMSO溶液的干重为3.94mg的异硫氰酸荧光素(FI),其中FI与PEI.NH2-SH-HPAO的摩尔比为4:1,反应24h,将所得的溶液用纤维素透析膜MWCO=14000在磷酸盐缓冲溶液和蒸馏水中透析3天,冷冻干燥处理得到PEI.NH2-SH-HPAO-FI。
步骤2,称取干重为8.24mg的氯金酸HAuCl4,并溶解于20mL的蒸馏水中配制浓度为1mM的溶液,加热煮沸。再称取干重为200mg的柠檬酸钠,将其溶于19.8mL的蒸馏水中,配成质量分数1%的柠檬酸钠水溶液。将配好的3mL柠檬酸钠溶液加入到煮沸的HAuCl4溶液中,保持加热沸腾状态反应20min,反应结束后,经冷却纯化得到柠檬酸钠稳定的金种子水溶液,其中柠檬酸钠与HAuCI4的摩尔比为5:1。称取干重为2.06mg的HAuCI4,将其溶于20mL蒸馏水中,配制为浓度0.25mM的HAuCI4溶液,边搅拌边逐滴滴加200μL的金种子溶液,搅拌反应2-4分钟后加入200μL的AgNO3溶液(2.5mM)和100μL的抗坏血酸(1mM),溶液颜色转变为蓝色时持续搅拌反应2h,通过离心纯化得到金纳米星(Au NSs),其中金种子、HAuCI4、AgNO3与抗坏血酸的摩尔比为2:50:5:1。
步骤3,称取干重为1.68g的4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐(APAS),将其溶于15mL水中配成溶液,加入到50mg的Au NSs水溶液(5mL)中,持续快速搅拌反应3天得到APAS-Au NSs,其中APAS与Au NSs的摩尔比为10:1。
步骤4,称取干重为79.4mg的PEI.NH2-SH-HPAO-FI,将其溶解于20mL水中配制其溶液,并加入到溶解于2mL蒸馏水的APAS-Au NSs(5mg)中,搅拌反应3天得到APAS-Au-PEI-HPAO-FI NSs溶液,其中PEI.NH2-SH-HPAO-FI与Au NSs的摩尔比为5:1。
步骤5,将得到的APAS-Au-PEI-HPAO-FI NSs溶液中,加入1.43mL三乙胺N(C2H5)3和811.1μL乙酸酐Ac2O进行乙酰化以中和PEI表面多余的氨基得到乙酰化的APAS-Au-PEI-HPAO-FI NSs,其中三乙胺N(C2H5)3、乙酸酐Ac2O和APAS-Au-PEI-HPAO-FINSs的摩尔比为600:500:1。
步骤6,将得到的乙酰化的APAS-Au-PEI-HPAO-FI NSs溶液中,加入150μg氯胺T及放射性350MBq的Na131I(1mL),搅拌反应并加入Na2S2O5(150μg)及KI(100μg),反应5分钟,最后通过PD-10脱盐柱分离纯化,以pH=7.0-7.4的PBS为流动相,通过收集分离出来的放射性活性液体得到131I标记的功能化金纳米星材料APAS-Au-131I-PEI-HPAO-FINSs。
对比例1
步骤1,称取实施例1的步骤2中合成的中间产物Au NSs(4mg)并溶解于5mL水中,向其中加入溶于15mL水中的63.5mg的PEI.NH2-SH-HPAO-FI,搅拌反应3天得到Au-PEI-HPAO-FI NSs溶液,其中PEI.NH2-SH-HPAO-FI与Au NSs的摩尔比为5:1。
步骤2,将得到的Au-PEI-HPAO-FI NSs溶液中,加入1.15mL三乙胺N(C2H5)3和648.7μL乙酸酐Ac2O进行乙酰化以中和PEI表面多余的氨基得到乙酰化的Au-PEI-HPAO-FI NSs,其中三乙胺N(C2H5)3、乙酸酐Ac2O和Au-PEI-HPAO-FI NSs的摩尔比为600:500:1。
步骤3,将得到的乙酰化的Au-PEI-HPAO-FI NSs溶液中,加入150mg氯胺T及放射性350MBq的Na131I(1mL),搅拌反应并加入Na2S2O5(150mg)及KI(100mg),反应5分钟,最后通过PD-10脱盐柱分离纯化,以pH=7.0-7.4的PBS为流动相,通过收集分离出来的放射性活性液体得到131I标记的功能化金纳米星材料Au-131I-PEI-HPAO-FI NSs。
使用1HNMR(氢核磁共振)、UV-Vis(紫外可见光谱)、TEM(透射电子显微镜)、Zeta电势测试、癌细胞摄取测试、放射性稳定性测试对上述实施例制得的金纳米颗粒进行表征。
(1)1HNMR测试
如图2所示,通过对功能化PEI进行氢核磁共振表征可知:每个PEI分子上修饰了25.6个巯基、2.8个HPAO、2.4个FI。表明已经成功将PEI表面部分基团转变为巯基,且成功在其表面修饰了功能分子HPAO和FI。
(2)UV-Vis测试结果
如图3所示,金纳米星颗粒APAS-Au-PEI-HPAO-FI NSs的表面等离子体共振(SPR)峰在780nm处,证明了金纳米星颗粒的形成。
(3)TEM测试结果
制备得到的金种子及功能化金纳米星的尺寸及尺寸分布情况如图4所示,金种子纳米颗粒的平均直径约14.02nm,为球形结构,尺寸较为均一、分布较窄;金纳米星颗粒的平均直径约58.10nm,为星形结构,尺寸较为均一、分布较窄。
(4)Zeta电势测试结果
对实施例1制备得到的APAS-Au-PEI-HPAO-FI NSs和对比例1制备得到的Au-PEI-HPAO-FI NSs进行Zeta电势测量以测试APAS-Au-PEI-HPAO-FI NSs在不同pH条件下的表面电荷。分别将APAS-Au-PEI-HPAO-FI NSs和Au-PEI-HPAO-FI NSs溶解于不同pH(5.0,5.5,6.0,6.5,7.0,7.5)的磷酸盐缓冲液中,使APAS-Au-PEI-HPAO-FI NSs和Au-PEI-HPAO-FINSs的浓度均为1μM,进行Zeta电势测量。如图5所述,结果表明,在pH7.0-7.5之间,本发明中制备得到的APAS-Au-PEI-HPAO-FI NSs和Au-PEI-HPAO-FI NSs的Zeta电势均接近电中性;然而在pH 5.0-6.5时,APAS-Au-PEI-HPAO-FI NSs的Zeta电势呈现正电性,且随着酸性增强而增强,而Au-PEI-HPAO-FI NSs的Zeta电势仍然保持电中性。说明基于APAS的修饰,使功能化的金纳米星颗粒在酸性条件下表面发生了电荷翻转,由电中性转变为正电性。
(5)癌细胞摄取测试结果
为验证pH敏感两性离子功能化的131I标记金纳米星颗粒在不同pH条件下的细胞摄取情况,选用人宫颈癌HeLa细胞作为模型细胞进行体外验证。将HeLa细胞首先种板种于12孔板中,细胞密度为2×105细胞/孔,在过夜孵化后,细胞贴壁。将APAS-Au-PEI-HPAO-FINSs(终浓度为1μM)和Au-PEI-HPAO-FI NSs(终浓度为1μM)分别孵化不同pH(5.0,5.5,6.0,6.5,7.0,7.5)条件下的HeLa细胞,待孵化3h后,将各孔中的材料倒掉并用PBS洗涤2次,用胰蛋白酶处理细胞使其悬浮,再将其悬浮于1mL培养基中,进行细胞计数。之后,将各个细胞样离心并溶于300μL王水(浓盐酸与浓硝酸体积比为3:1)中,待裂解完全再加入2.7mL的蒸馏水中将其稀释至3mL,利用电感耦合等离子体原子发射光谱仪(ICP-AES)来测量各细胞样品中金元素含量。
如图6所示,本发明中制备得到的APAS功能化的金纳米星颗粒在弱酸性环境下,人宫颈癌HeLa细胞对其摄取量提高,且随着酸性的增强,人宫颈癌HeLa细胞摄取量逐渐增大,而非APAS功能化的金纳米星颗粒在不同pH条件下细胞摄取量未发生明显增加。说明了本发明的APAS功能化的金纳米星颗粒在微酸性环境中发生了电荷翻转,基于表面带有的正电荷可与癌细胞细胞膜表面发生静电作用,以实现其在癌细胞内的高量摄取。
(6)放射性稳定性测试结果
以薄层色谱法对得到的pH敏感两性离子功能化的131I标记金纳米星颗粒进行放射性稳定性测试。具体是将200μL的放射性标记物APAS-Au-131I-PEI-HPAO-FI NSs与2mL0.9%的生理盐水混合,之后利用薄层色谱法测试37℃下APAS-Au-131I-PEI-HPAO-FI NSs在1h、2h、5h及24h的放射性化学纯度。结果如下表所示:
时间(h) | 1 | 2 | 5 | 24 |
放射性化学纯度(h) | 99.25 | 98.51 | 97.32 | 95.53 |
从上表可知,在不同时间点(1h、2h、5h、24h)下,APAS-Au-131I-PEI-HPAO-FI NSs的放射性化学纯度均在90%以上。说明APAS-Au-131I-PEI-HPAO-FI NSs具有良好的放射性稳定性,未有大量的131I从金纳米星颗粒上脱落。
Claims (8)
1.一种pH敏感的131I标记金纳米星,其特征在于:包括金纳米星颗粒,在所述金纳米星颗粒表面修饰有4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和功能化载体聚乙烯亚胺;
所述4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和功能化载体聚乙烯亚胺通过巯基共价键与金纳米星颗粒连接;
所述功能化载体聚乙烯亚胺上还连接有放射性核素131I和异硫氰酸荧光素。
2.权利要求1所述的金纳米星的制备方法,其特征在于:包括以下步骤:
步骤1,将超支化聚乙烯亚胺PEI.NH2溶解于水中,加入巯基乙酸甲酯MTG,60-70℃加热反应制得修饰有巯基的聚乙烯亚胺PEI.NH2-SH,将PEI.NH2-SH和3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯HPAO混合,搅拌反应制得PEI.NH2-SH-HPAO,然后将PEI.NH2-SH-HPAO和异硫氰酸荧光素FI混合,搅拌反应,制得PEI.NH2-SH-HPAO-FI;
步骤2,将氯金酸溶液加热煮沸,再加入柠檬酸钠,继续煮沸15-25min,冷却得到金种子水溶液,将金种子水溶液加至氯金酸溶液中,然后加入AgNO3溶液和抗坏血酸溶液,搅拌,得到金纳米星Au NSs;
步骤3,将4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐APAS溶解于水中,加入到步骤2得到的金纳米星Au NSs中,搅拌反应得到修饰有APAS的AuNSs金纳米星APAS-Au NSs;
步骤4,将步骤1制得的PEI.NH2-SH-HPAO-FI和步骤3制得的APAS-Au NSs混合,搅拌反应得到APAS-Au-PEI-HPAO-FI NSs;
步骤5,向步骤4的APAS-Au-PEI-HPAO-FI NSs中,加入三乙胺和乙酸酐进行乙酰化以中和聚乙烯亚胺表面多余的氨基,得到乙酰化APAS-Au-PEI-HPAO-FI NSs;
步骤6,向步骤5得到的乙酰化APAS-Au-PEI-HPAO-FI NSs中,加入氯胺T及放射性Na131I,搅拌反应并加入Na2S2O5及KI,反应结束后分离纯化,得到131I标记的功能化金纳米星材料APAS-Au-131I-PEI-HPAO-FI NSs。
3.根据权利要求2所述的制备方法,其特征在于:步骤1中,巯基乙酸甲酯与超支化聚乙烯亚胺的摩尔比为30-32:1, 3-(4-羟基苯基)丙酸N-羟基琥珀酰亚胺酯与超支化聚乙烯亚胺的摩尔比为4-7:1,异硫氰酸荧光素与超支化聚乙烯亚胺的摩尔比为4-7:1。
4.根据权利要求2所述的制备方法,其特征在于:步骤2中柠檬酸钠和氯金酸的摩尔比为5-6:1,金种子、HAuCl4、AgNO3与抗坏血酸的摩尔比为2:50:4-6:1。
5.根据权利要求2所述的制备方法,其特征在于:步骤3中4-(1,1,1-三苯基-14,17,20,23,26-五氧杂-2-硫杂)苯磺酰基三甲胺丁酰盐和金纳米星的摩尔比为8-12:1。
6.根据权利要求2所述的制备方法,其特征在于:步骤5中三乙胺、乙酸酐和APAS-Au-PEI-HPAO-FI NSs的摩尔比为120-660:100-550:1。
7.根据权利要求2所述的制备方法,其特征在于:步骤6中,Na131I的放射性活性为190-360 MBq;才用PD-10脱盐柱进行分离纯化,以pH 7.0-7.4的PBS为流动相。
8.权利要求1所述的金纳米星在制备肿瘤诊疗试剂中的应用。
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TSUKASA MIZUHARA等: "Acylsulfonamide-Functionalized Zwitterionic Gold Nanoparticles for Enhanced Cellular Uptake at Tumor pH", 《ANGEW. CHEM.》 * |
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