CN113413470A - 肿瘤诊疗剂及其制备方法和应用 - Google Patents
肿瘤诊疗剂及其制备方法和应用 Download PDFInfo
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- CN113413470A CN113413470A CN202110600065.XA CN202110600065A CN113413470A CN 113413470 A CN113413470 A CN 113413470A CN 202110600065 A CN202110600065 A CN 202110600065A CN 113413470 A CN113413470 A CN 113413470A
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Abstract
本申请提供了一种肿瘤诊疗剂,包括白蛋白、分散在所述白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在所述白蛋白表面的磁共振造影剂和靶向穿膜肽。该肿瘤诊疗剂可同时实现磁光双模成像和药物治疗,达到诊疗一体化,并且具有良好的靶向性、生物相容性和稳定性,在生物医学领域有广泛的应用前景。本申请还提供了肿瘤诊疗剂的制备方法和应用。
Description
技术领域
本申请涉及生物医学技术领域,尤其涉及肿瘤诊疗剂及其制备方法和应用。
背景技术
分子影像学技术的发展为肿瘤的早期诊断、治疗及预后评价提供了技术支持。目前,围绕肿瘤的早期诊断、治疗及预后评价已经发展了磁、光、声、核素等多种分子影像探针。然而目前分子影像探针的检测深度和分辨率还有待提高,并且目前的分子影像探针仅仅用于成像,作用单一。
发明内容
有鉴于此,本申请提供了一种肿瘤诊疗剂及其制备方法,该肿瘤诊疗剂可同时实现磁光双模成像和药物治疗,达到诊疗一体化,并且具有良好的靶向性、生物相容性和稳定性,在生物医学领域有广泛的应用前景。
第一方面,本申请提供了一种肿瘤诊疗剂,包括白蛋白、分散在所述白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在所述白蛋白表面的磁共振造影剂和靶向穿膜肽。
在本申请中,靶向穿膜肽使得肿瘤诊疗剂能够穿过细胞膜进行肿瘤细胞中;金团簇能够在近红外二区发光实现光学成像,磁共振造影剂实现磁共振成像,实现磁光双模成像;该肿瘤诊疗剂携带有抗肿瘤药物,从而在成像的同时实现药物的精准治疗。
可选的,所述肿瘤诊疗剂的粒径为30nm-200nm。
可选的,所述金团簇的粒径小于2nm。
可选的,所述金团簇包括8个-100个金原子。
可选的,所述靶向穿膜肽和所述白蛋白的摩尔量比值为1-100。
可选的,所述靶向穿膜肽包括iRGD、iNGR、TAT和CTX中的至少一种。
可选的,所述磁共振造影剂和所述白蛋白的摩尔量比值为1-100。
可选的,所述磁共振造影剂包括Gd-DTPA、Gd-DOTA、Gd-DTTA和Gd-HOPO中的至少一种。
可选的,所述抗肿瘤药物和所述白蛋白的摩尔量比值为1-10000。
可选的,所述抗肿瘤药物包括紫杉醇、多西紫杉醇、阿霉素、顺铂、伊立替康、喜树碱、卡莫司汀和姜黄素中的至少一种。
本申请提供的肿瘤诊疗剂可同时实现磁光双模成像和药物治疗,达到诊疗一体化,能够满足临床应用的需求。
第二方面,本申请提供了一种肿瘤诊疗剂的制备方法,包括:
向含第一纳米颗粒的溶液中加入带巯基的还原剂,反应后得到反应液,其中,所述第一纳米颗粒包括白蛋白以及分散在所述白蛋白内的金团簇;
将所述反应液进行超声处理,并向所述反应液中加入含抗肿瘤药物的溶液,反应得到含第二纳米颗粒的溶液,所述第二纳米颗粒包括所述白蛋白以及分散在所述白蛋白内的所述金团簇和所述抗肿瘤药物;
所述含第二纳米颗粒的溶液与靶向穿膜肽和磁共振造影剂反应后,经干燥得到肿瘤诊疗剂,所述肿瘤诊疗剂包括所述白蛋白、分散在所述白蛋白内的所述抗肿瘤药物和所述金团簇,以及通过化学键连接在所述白蛋白表面的所述磁共振造影剂和所述靶向穿膜肽。
可选的,所述第一纳米颗粒的制备包括:氯金酸溶液与白蛋白溶液混合后,加入氢氧化钠溶液和硼氢化钠溶液,反应后过滤得到所述第一纳米颗粒。
可选的,所述带巯基的还原剂的包括谷胱甘肽、半胱氨酸、巯基乙醇和二硫苏糖醇中的至少一种;所述带巯基的还原剂与所述含第一纳米颗粒的溶液中的所述白蛋白的摩尔比为5-30。
可选的,所述含第二纳米颗粒的溶液与靶向穿膜肽反应,包括:含所述靶向穿膜肽的溶液中加入N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐反应后,加入所述含第二纳米颗粒的溶液,反应得到含第三纳米颗粒的溶液,其中,所述第三纳米颗粒包括所述白蛋白、分散在所述白蛋白内的所述抗肿瘤药物和所述金团簇,以及通过化学键连接在所述白蛋白表面的所述靶向穿膜肽。
本申请提供的肿瘤诊疗剂的制备方法操作简单、方便,可以实现工业化生产,有利于肿瘤诊疗剂的广泛使用。
第三方面,本申请提供了第一方面所述的或第二方面所述的制备方法制得的肿瘤诊疗剂在预防、诊断或治疗肿瘤的药物中的应用。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。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。
图1为本申请一实施方式提供的肿瘤诊疗剂的制备方法流程图。
图2为本申请一实施方式提供的肿瘤诊疗剂的制备示意图。
图3为实施例1制得的肿瘤诊疗剂的透射电镜图。
图4为细胞的近红外二区荧光显微镜图。
图5为小鼠的近红外二区光和磁共振成像图。
具体实施方式
下面将结合本申请实施例中的附图,对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。
本申请提供了一种肿瘤诊疗剂,包括白蛋白、分散在所述白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在所述白蛋白表面的磁共振造影剂和靶向穿膜肽。
在预防、诊断和治疗肿瘤过程中,首先需要对肿瘤进行成像,而肿瘤不同程度地吸收和散热入射光,造成入射光衰减,降低成像深度、信背比以及分辨率,使得肿瘤边界模糊不清难以辨认;相较于近红外一区荧光等传统荧光,近红外二区荧光(1000nm-1700nm)具有更纵深的穿透深度、更好的空间分辨率以及低的背景噪声,有利于实现深部组织的高分辨成像,并且对生物组织光损伤和毒性小;本申请提供的肿瘤诊疗剂中具有金团簇,其能够在近红外二区发光,从而可以获得高质量的肿瘤成像结果,并且该肿瘤诊疗剂具有磁共振造影剂,进而可以实现磁共振成像,具有磁光双模成像结果,大幅度提升了成像质量,为诊断提供强有力的技术支持;该肿瘤诊疗剂携带有抗肿瘤药物,肿瘤细胞含有大量谷胱甘肽,可以将肿瘤诊疗剂的二硫键打开,使得抗肿瘤药物释放出来,进而在成像的同时实现抗肿瘤药物的释放和治疗,达到诊疗一体化。
在本申请中,白蛋白是一种生物内源性蛋白,具有可生物降解、无毒等优点,白蛋白作为肿瘤诊疗剂的载体,具有高稳定性和水溶性的性能,可以提高肿瘤诊疗剂的稳定性以及亲水性。
在本申请实施方式中,白蛋白包括人血清白蛋白、牛血清白蛋白、猪血清白蛋白、重组血清白蛋白中的至少一种。上述白蛋白的生物相容性好,有利于在临床使用。在一实施例中,白蛋白为牛血清白蛋白。在本申请实施方式中,白蛋白的粒径为20nm-150nm。进一步的,白蛋白的粒径为25nm-100nm。具体的,白蛋白的粒径可以但不限于为20nm、25nm、40nm、50nm、80nm、90nm、100nm或120nm等。可以理解的,本申请提供的肿瘤诊疗剂中可以包括多个白蛋白。
在本申请中,金团簇均匀分散在白蛋白内部,其能够在近红外二区成像,进而可以获得高质量的成像结果。在本申请实施方式中,金团簇的粒径小于2nm。进一步的,金团簇的粒径小于1.5nm。在本申请实施方式中,金团簇包括8个-100个金原子。在一实施例中,金团簇包括8个-20个金原子。在另一实施例中,金团簇包括30个-50个金原子。在又一实施例中,金团簇包括80个-95个金原子。在本申请中,可以根据需要设置分散在白蛋白中金团簇的量。在本申请一实施例中,肿瘤诊疗剂中金原子与白蛋白的摩尔比为10-1000。从而可以使得肿瘤诊疗剂在近红外二区发光强度大,成像效果好。进一步的,肿瘤诊疗剂中金原子与白蛋白的摩尔比为50-700。在本申请实施方式中,金团簇和白蛋白之间具有Au-S键。通过Au-S键,使得金团簇可以稳定、长期的存在在白蛋白的内部。
在本申请中,抗肿瘤药物分散在白蛋白内部,靶向穿膜肽使得肿瘤诊疗剂进入肿瘤细胞中,从而使得抗肿瘤药物可以进入肿瘤细胞中,同时还提高了疏水性抗肿瘤药物的水溶性,进而使抗肿瘤药物可以精准作用肿瘤细胞,提高治疗效果。在本申请实施方式中,抗肿瘤药物和白蛋白的摩尔量比值为1-10000。从而使得肿瘤诊疗剂携带足够量的抗肿瘤药物,提高肿瘤诊疗剂的治疗效果。进一步的,抗肿瘤药物和白蛋白的摩尔量比值为20-5000。更进一步的,抗肿瘤药物和白蛋白的摩尔量比值为100-1000。具体的,抗肿瘤药物和白蛋白的摩尔量比值可以但不限于为20-100、50-500、100-2000、150-4000或500-5000等。在本申请实施方式中,抗肿瘤药物包括紫杉醇、多西紫杉醇、阿霉素、顺铂、伊立替康、喜树碱、卡莫司汀和姜黄素中的至少一种。上述抗肿瘤药物与白蛋白之间可以形成键能,从而长期稳定分散在白蛋白内部,并且在进入肿瘤细胞后,可以释放并作用在肿瘤细胞中。在一实施例中,抗肿瘤药物包括紫杉醇。
在本申请中,磁共振造影剂通过化学键连接在白蛋白的表面,使得磁共振造影剂可以长期稳定存在,保证磁共振成像的进行。在本申请实施方式中,磁共振造影剂通过共价键连接在白蛋白的表面。进一步的,磁共振造影剂通过酰胺键连接在白蛋白的表面。在本申请实施方式中,磁共振造影剂包括Gd-DTPA、Gd-DOTA、Gd-DTTA和Gd-HOPO中的至少一种。上述磁共振造影剂性能稳定、毒性低、水溶性好,并且所需量少。在本申请实施方式中,磁共振造影剂和白蛋白的摩尔量比值为1-100。进一步的,磁共振造影剂和白蛋白的摩尔量比值为10-80。更进一步的,磁共振造影剂和白蛋白的摩尔量比值为20-65。具体的,磁共振造影剂和白蛋白的摩尔量比值可以但不限于为15、25、30、38、45、50、60、74或85等。在上述摩尔比范围内,磁共振造影剂对肿瘤诊疗剂的结构无影响,并且能够与金团簇共同实现磁光双模态成像功能,提高成像质量。
在本申请中,靶向穿膜肽通过化学键连接在白蛋白的表面,使得靶向穿膜肽可以长期稳定存在,保证肿瘤诊疗剂能够靶向并进入肿瘤细胞内,实现成像和治疗。在本申请实施方式中,靶向穿膜肽通过共价键连接在白蛋白的表面。进一步的,靶向穿膜肽通过酰胺键连接在白蛋白的表面。在本申请实施方式中,靶向穿膜肽和白蛋白的摩尔量比值为1-100。进一步的,靶向穿膜肽和白蛋白的摩尔量比值为15-80。更进一步的,靶向穿膜肽和白蛋白的摩尔量比值为20-70。具体的,靶向穿膜肽和白蛋白的摩尔量比值可以但不限于为15、20、25、30、35、42、55、60、75或80等。在上述摩尔比范围内,肿瘤诊疗剂能够高效、快速地靶向肿瘤细胞并进入肿瘤细胞内,有利于磁光双模成像和药物释放治疗。在本申请实施方式中,靶向穿膜肽包括iRGD、iNGR、TAT和CTX中的至少一种。在本申请中,靶向穿膜肽,如iRGD、iNGR等,能够通过与血管通透性调节分子作用,增强血管的通透性,从而促进肿瘤诊疗剂进入细胞内;iRGD具有RGD结构域,iNGR具有NGR结构域,能够与肿瘤细胞表面以及肿瘤周围血管上的整合素αvβ3、αvβ5特异性结合,靶向到整合素表达较高的肿瘤部位。在一实施例中,iRGD的氨基酸序列为CRGDKGPDC。在另一实施例中,iNGR的氨基酸序列为CRNGRGPDC。
本申请实施方式中,肿瘤诊疗剂的粒径为30nm-200nm。进一步的,肿瘤诊疗剂的粒径为40nm-180nm。更进一步的,肿瘤诊疗剂的粒径为50nm-150nm。具体的,肿瘤诊疗剂的粒径可以但不限于为40nm-60nm、50nm-60nm、70nm-90nm、80nm-110nm、100nm-150nm、110nm-150nm、130nm-160nm或160nm-200nm等。在该粒径范围下肿瘤诊疗剂具有较好的分散性能和稳定性,有利于其使用。
请参阅图1,为本申请一实施方式提供的肿瘤诊疗剂的制备方法流程图,该方法制得上述任一实施方式中的肿瘤诊疗剂,该制备方法包括:
操作101:向含第一纳米颗粒的溶液中加入带巯基的还原剂,反应后得到反应液,其中,第一纳米颗粒包括白蛋白以及分散在白蛋白内的金团簇。
操作102:将反应液进行超声处理,并向反应液中加入含抗肿瘤药物的溶液,反应得到含第二纳米颗粒的溶液,第二纳米颗粒包括白蛋白以及分散在白蛋白内的金团簇和抗肿瘤药物。
操作103:含第二纳米颗粒的溶液与靶向穿膜肽和磁共振造影剂反应后,经干燥得到肿瘤诊疗剂,肿瘤诊疗剂包括白蛋白、分散在白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在白蛋白表面的磁共振造影剂和靶向穿膜肽。
在本申请实施方式中,采用生物矿化法制得第一纳米颗粒。在本申请一实施例中,第一纳米颗粒的制备包括:氯金酸溶液与白蛋白溶液混合后,加入氢氧化钠溶液和硼氢化钠溶液,反应后过滤得到第一纳米颗粒。在一实施例中,氯金酸溶液的溶度为1mM-50mM,氯金酸溶液的体积为0.1mL-3mL。在另一实施例中,白蛋白溶液的溶度为1mg/mL-50mg/mL,白蛋白溶液的体积为0.1mL-5mL。在又一实施例中,氢氧化钠溶液的溶度为0.1M-2M,氢氧化钠溶液的体积为0.1mL-2mL。在又一实施例中,硼氢化钠溶液的溶度为0.01M-0.5M,硼氢化钠溶液的体积为0.01mL-0.5mL。在一具体实施例中,将氯金酸溶液与白蛋白溶液在15℃-30℃下混合,随后依次加入氢氧化钠溶液和预冷的硼氢化钠溶液,溶液变为深棕色;然后将溶液在130rpm-200rpm、25℃-37℃下孵育,制得第一纳米颗粒。在本申请中,第一纳米颗粒可以置于缓冲液中保存备用,具体的,可以但不限于将第一纳米颗粒置于0.1M磷酸盐缓冲液中透析后低温保存。
在本申请实施方式中,在加入带巯基的还原剂之前,还包括将含第一纳米颗粒的溶液的pH调节至7-12。从而有利于后续白蛋白二硫键的打开。在一实施例中,将含第一纳米颗粒的溶液的pH调节至7-9。在另一实施例中,将含第一纳米颗粒的溶液的pH调节至9-12。具体的,可以但不限于将含第一纳米颗粒的溶液的pH调节至7、8、9、10、11或12等。在一具体实施例中,采用氢氧化钠溶液进行pH调节,如采用1mol/L的NaOH溶液调节含第一纳米颗粒的溶液的pH。
在本申请实施方式中,带巯基的还原剂的包括谷胱甘肽、半胱氨酸、巯基乙醇和二硫苏糖醇中的至少一种。通过采用带巯基的还原剂可以打开白蛋白的二硫键,使得白蛋白结构展开,有利于后续抗肿瘤药物的进入和分散。在本申请实施方式中,带巯基的还原剂与含第一纳米颗粒的溶液中的白蛋白的摩尔比为5-30。进一步的,带巯基的还原剂与含第一纳米颗粒的溶液中的白蛋白的摩尔比为10-25。更进一步的,带巯基的还原剂与含第一纳米颗粒的溶液中的白蛋白的摩尔比为12-20。具体的,带巯基的还原剂与含第一纳米颗粒的溶液中的白蛋白的摩尔比可以但不限于为10、12、15、17、20、21、24、28或30等。上述范围有利于白蛋白结构的展开,同时又不会过多破坏白蛋白的结构,使得白蛋白仍然可以负载金团簇以及抗肿瘤药物。在本申请实施方式中,带巯基的还原剂的浓度为0.01mol/L-2mol/L。进一步的,带巯基的还原剂的浓度为0.05mol/L-1.8mol/L。在本申请实施方式中,反应在30℃-60℃进行1min-5min。进一步的,反应在35℃-60℃进行3min-5min。在此反应条件下,有利于白蛋白二硫键的快速打开。
在本申请中,在超声处理的同时加入抗肿瘤药物,从而有利于抗肿瘤药物进入展开的白蛋白的内部,提高白蛋白负载抗肿瘤药物的量,增强肿瘤诊疗剂的疗效,同时还可以防止白蛋白之间聚集,影响纳米诊疗剂的制备。在本申请实施方式中,超声的功率为5W-20W。进一步的,超声的功率为10W-15W。在一实施例中,将反应液在超声细胞破碎仪中进行处理,从而可以进一步使得抗肿瘤药物大量进入白蛋白内部,提高肿瘤诊疗剂中抗肿瘤药物的负载量。在本申请实施方式中,含抗肿瘤药物的溶液的注入速度为30ml/s-80ml/s。具体的,含抗肿瘤药物的溶液的注入速度可以但不限于为30ml/s、40ml/s、50ml/s、60ml/s、70ml/s或80ml/s等。在本申请实施方式中,含抗肿瘤药物的溶液的溶剂包括二甲基亚砜、甲醇、乙醇、丙醇和叔丁醇中的至少一种。采用上述溶剂有利于提高抗肿瘤药物的溶解度,使得抗肿瘤药物与白蛋白之间充分混合和接触。在本申请实施方式中,含抗肿瘤药物的溶液浓度为0.01M-2M。具体的,含抗肿瘤药物的溶液浓度可以但不限于为0.01M、0.05M、0.1M、0.3M、0.7M、1M、1.2M、1.5M、1.8M或2M等。在本申请实施方式中,抗肿瘤药物和白蛋白的摩尔量比值为1-10000。从而使得肿瘤诊疗剂携带足够量的抗肿瘤药物,提高肿瘤诊疗剂的治疗效果。具体的,抗肿瘤药物和白蛋白的摩尔量比值可以但不限于为20-100、50-500、100-2000、150-4000或500-5000等。在操作102中,反应包括在30℃-60℃进行10min-30min。进一步的,反应进行15min-25min。在此反应条件下,有利于抗肿瘤药物与白蛋白充分接触和混合,以使得白蛋白负载足量的抗肿瘤药物,提高肿瘤诊疗剂的疗效。
在本申请中,抗肿瘤药物分散在白蛋白内部。在本申请一实施方式中,采用带巯基的还原剂打开白蛋白的二硫键,使得白蛋白结构展开,抗肿瘤药物加入后,多个白蛋白团聚并包裹抗肿瘤药物。在一实施例中,肿瘤诊疗剂包括多个白蛋白,金团簇分散在白蛋白内,多个白蛋白团聚并包裹抗肿瘤药物,磁共振造影剂和靶向穿膜肽通过化学键连接在白蛋白的表面。进一步的,抗肿瘤药物被包裹在白蛋白的中心。
在操作102后,还包括将含第二纳米颗粒的溶液进行透析处理。通过透析处理可以去除未反应的带巯基的还原剂等杂质,同时也提高第二纳米颗粒的分散效果。在本申请实施方式中,通过将含第二纳米颗粒的溶液置于pH7-12的磷酸盐缓冲液进行透析处理。在一具体实施例中,将含第二纳米颗粒的溶液置于透析袋中,将透析袋置于1L、pH7-12的磷酸盐缓冲液内透析5h-10h,然后再将透析袋置于水中透析1h-3h即可。
在本申请实施方式中,含第二纳米颗粒的溶液与靶向穿膜肽反应,包括:含靶向穿膜肽的溶液中加入N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐反应后,加入含第二纳米颗粒的溶液,反应得到含第三纳米颗粒的溶液,其中,第三纳米颗粒包括白蛋白、分散在白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在白蛋白表面的靶向穿膜肽。在一实施例中,含靶向穿膜肽的溶液中加入N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐在25℃-30℃反应2h-4h。在另一实施例中,加入含第二纳米颗粒的溶液后在25℃-30℃反应12h-14h。在另一实施例中,含靶向穿膜肽的溶液的溶剂包括二甲基亚砜、甲醇、乙醇、丙醇和叔丁醇中的至少一种。在本申请实施方式中,将含第三纳米颗粒的溶液与NHS-磁共振造影剂混合,在在25℃-30℃反应2h-4h,即可得到肿瘤诊疗剂。在本申请中,靶向穿膜肽和磁共振造影剂通过化学反应与白蛋白之间产生化学键合,从而可以长期稳定地负载在白蛋白的表面。
在本申请实施方式中,在干燥之前还包括透析处理;通过透析处理,可以去除溶液中的杂质。在本申请实施方式中,通过将溶液置于pH 7-12的磷酸盐缓冲液进行透析处理。在一具体实施例中,将溶液置于透析袋中,将透析袋置于1L、pH7-12的磷酸盐缓冲液内25℃-30℃透析5h-10h,然后再将透析袋置于水中透析1h-3h即可。在一实施例中,干燥包括在0℃下预冻1h-3h后转移至-20℃下冷冻2h-5h,然后冷冻干燥8h-15h。
请参阅图2,为本申请一实施方式提供的肿瘤诊疗剂的制备示意图,在本申请实施方式中,白蛋白和含金元素的溶液混合,在氢氧化钠和硼氢化钠的作用下,生成了白蛋白金簇,即第一纳米颗粒,所述第一纳米颗粒包括白蛋白以及分散在白蛋白内的金团簇;通过谷胱甘肽处理,并加入紫杉醇溶液,生成了白蛋白金团簇纳米药物,即第二纳米颗粒,所述第二纳米颗粒包括白蛋白以及分散在白蛋白内的金团簇和抗肿瘤药物紫杉醇;再与NHS-iRGD、DTPA-Gd反应,制得白蛋白金团簇靶向纳米药物,即肿瘤诊疗剂,所述肿瘤诊疗剂包括白蛋白、分散在白蛋白内的抗肿瘤药物紫杉醇和金团簇,以及通过化学键连接在白蛋白表面的磁共振造影剂DTPA-Gd和靶向穿膜肽iRGD。
本申请提供了一种以白蛋白为载体,以靶向穿膜肽为靶向配体并负载抗肿瘤药物的磁光双模纳米诊疗剂;通过白蛋白作为载体,采用生物矿化法合成近红外二区发光的金团簇,获得第一纳米颗粒;再通过一步生物还原法制备水溶性的、单分散的第二纳米颗粒;最后在第二纳米颗粒上通过化学键偶连靶向穿膜肽和磁共振造影剂,以实现磁光双模成像。本申请提供的肿瘤诊疗剂的制备方法操作简单、方便,可以实现工业化生产,有利于肿瘤诊疗剂的广泛使用。
本申请提供了上述肿瘤诊疗剂在预防、诊断或治疗肿瘤的药物中的应用。可以理解的,肿瘤可以但不限于为癌症,如脑胶质瘤等。在一实施例中,本申请提供的肿瘤诊疗剂可以应用于预防、诊断或治疗脑胶质瘤中;脑胶质瘤的组织边界不清,还有血脑屏障阻碍成像材料和药物的进入,本申请提供的肿瘤诊疗剂中具有靶向穿膜肽,可以避免血脑屏障的影响,进入脑胶质瘤细胞中,同时通过近红外二区光成像以及磁共振成像,有效识别脑胶质瘤区域,同时携带的抗肿瘤药物可以精准靶向脑胶质瘤,起到治疗作用。
实施例
步骤1:将氯金酸溶液(10mM,1.25mL)与白蛋白溶液(50mg/mL,2.5mL)在25℃下混合均匀,随后依次加入氢氧化钠溶液(1M,0.25mL)和预冷的硼氢化钠溶液(0.1M,0.1mL),溶液变为深棕色;然后将溶液在180rpm、37℃下孵育,制得第一纳米颗粒;将第一纳米颗粒置于0.1M磷酸盐缓冲液中透析后置于4℃保存。
步骤2:取2mL第一纳米颗粒溶液,然后采用1mol/L的NaOH溶液调节第一纳米颗粒溶液的pH值到7;向其中加入谷胱甘肽获得反应液,然后在60℃下轻轻摇动反应0.05h,谷胱甘肽的摩尔数为白蛋白摩尔数的10倍。
步骤3:将步骤2反应后的溶液在60℃的条件下采用超声波细胞破碎仪进行处理,超声波细胞破碎仪的功率为10W,同时以50ml/s的速度向溶液中注入的2mL紫杉醇二甲基亚砜溶液,溶液在60℃的条件下反应20min后得到第二纳米颗粒溶液。
步骤4:将步骤3所得的第二纳米颗粒溶液移入透析袋,保持温度为30℃的条件下,将透析袋置于1L、pH7的PBS缓冲液内透析10h,期间每12h换液1次,每次都采用1L、pH7的PBS缓冲液,然后再将透析袋置于5L双蒸水内透析1h即可获得第二纳米颗粒。
步骤5:将iRGD溶于二甲基亚砜溶液中,然后加入N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,在25℃反应3h,再加入第二纳米颗粒,25℃反应15h;然后向上述溶液中加入NHS-DTPA-Gd,25℃反应3h,获得含肿瘤诊疗剂的溶液。
步骤6:将步骤5所得含肿瘤诊疗剂的溶液移入透析袋,保持温度为30℃的条件下,将透析袋置于1L、pH7的PBS缓冲液内透析10h,期间每12h换液1次,每次都采用1L、pH7的PBS缓冲液,然后再将透析袋置于5L双蒸水内透析1h;然后置于-0℃下预冻1h后,转移至-20℃下冷冻2h,再在冷冻干燥机中冷冻干燥12h,得到肿瘤诊疗剂。将制得的肿瘤诊疗剂进行透射电镜观测,结果如图3所示,可以看出,本申请制得的肿瘤诊疗剂为纳米级别,尺寸均一,颗粒较为分散。
效果实施例
将实施例1制得的肿瘤诊疗剂与C6细胞孵育3h后,通过近红外二区荧光显微镜观测细胞,结果如图4所示。可以看出,本申请提供的肿瘤诊疗剂能够在近红外二区产生荧光信号,有利于成像。将实施例1制得的肿瘤诊疗剂溶于PBS溶液中(浓度为9mg/ml),并通过尾静脉注射注入小鼠体内,在注射24h后,通过近红外二区光以及核磁共振观测小鼠脑部肿瘤部位,结果如图5所示。可以看出,本申请提供的肿瘤诊疗剂具有磁光双模成像效果。
以上所述实施例仅表达了本申请的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本申请专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本申请构思的前提下,还可以做出若干变形和改进,这些都属于本申请的保护范围。因此,本申请专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种肿瘤诊疗剂,其特征在于,包括白蛋白、分散在所述白蛋白内的抗肿瘤药物和金团簇,以及通过化学键连接在所述白蛋白表面的磁共振造影剂和靶向穿膜肽。
2.如权利要求1所述的肿瘤诊疗剂,其特征在于,所述肿瘤诊疗剂的粒径为30nm-200nm。
3.如权利要求1所述的肿瘤诊疗剂,其特征在于,所述金团簇的粒径小于2nm,所述金团簇包括8个-100个金原子。
4.如权利要求1所述的肿瘤诊疗剂,其特征在于,所述靶向穿膜肽和所述白蛋白的摩尔量比值为1-100;所述靶向穿膜肽包括iRGD、iNGR、TAT和CTX中的至少一种;
所述磁共振造影剂和所述白蛋白的摩尔量比值为1-100;所述磁共振造影剂包括Gd-DTPA、Gd-DOTA、Gd-DTTA和Gd-HOPO中的至少一种。
5.如权利要求1所述的肿瘤诊疗剂,其特征在于,所述抗肿瘤药物和所述白蛋白的摩尔量比值为1-10000,所述抗肿瘤药物包括紫杉醇、多西紫杉醇、阿霉素、顺铂、伊立替康、喜树碱、卡莫司汀和姜黄素中的至少一种。
6.一种肿瘤诊疗剂的制备方法,其特征在于,包括:
向含第一纳米颗粒的溶液中加入带巯基的还原剂,反应后得到反应液,其中,所述第一纳米颗粒包括白蛋白以及分散在所述白蛋白内的金团簇;
将所述反应液进行超声处理,并向所述反应液中加入含抗肿瘤药物的溶液,反应得到含第二纳米颗粒的溶液,所述第二纳米颗粒包括所述白蛋白以及分散在所述白蛋白内的所述金团簇和所述抗肿瘤药物;
所述含第二纳米颗粒的溶液与靶向穿膜肽和磁共振造影剂反应后,经干燥得到肿瘤诊疗剂,所述肿瘤诊疗剂包括所述白蛋白、分散在所述白蛋白内的所述抗肿瘤药物和所述金团簇,以及通过化学键连接在所述白蛋白表面的所述磁共振造影剂和所述靶向穿膜肽。
7.如权利要求6所述的制备方法,其特征在于,所述第一纳米颗粒的制备包括:
氯金酸溶液与白蛋白溶液混合后,加入氢氧化钠溶液和硼氢化钠溶液,反应后过滤得到所述第一纳米颗粒。
8.如权利要求6所述的制备方法,其特征在于,所述带巯基的还原剂的包括谷胱甘肽、半胱氨酸、巯基乙醇和二硫苏糖醇中的至少一种;所述带巯基的还原剂与所述含第一纳米颗粒的溶液中的所述白蛋白的摩尔比为5-30。
9.如权利要求6所述的制备方法,其特征在于,所述含第二纳米颗粒的溶液与靶向穿膜肽反应,包括:
含所述靶向穿膜肽的溶液中加入N-羟基琥珀酰亚胺和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐反应后,加入所述含第二纳米颗粒的溶液,反应得到含第三纳米颗粒的溶液,其中,所述第三纳米颗粒包括所述白蛋白、分散在所述白蛋白内的所述抗肿瘤药物和所述金团簇,以及通过化学键连接在所述白蛋白表面的所述靶向穿膜肽。
10.如权利要求1-5任一项所述的或权利要求6-9任一项所述的制备方法制得的肿瘤诊疗剂在预防、诊断或治疗肿瘤的药物中的应用。
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