CN113908273A - 一种核壳结构的金磁纳米簇载药靶向制剂及其制法和应用 - Google Patents
一种核壳结构的金磁纳米簇载药靶向制剂及其制法和应用 Download PDFInfo
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- CN113908273A CN113908273A CN202111117843.6A CN202111117843A CN113908273A CN 113908273 A CN113908273 A CN 113908273A CN 202111117843 A CN202111117843 A CN 202111117843A CN 113908273 A CN113908273 A CN 113908273A
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Abstract
本发明公开了一种核壳结构的金磁纳米簇载药靶向制剂及其制法和应用,包括磁性纳米簇内核和金纳米外壳,在金纳米外壳表面修饰有肿瘤靶向分子和肿瘤治疗药物;所述磁性纳米簇是由超顺磁性氧化铁纳米粒通过交联剂交联形成簇状结构。该制剂可实现肿瘤靶向和肿瘤深部渗透,联合化疗和热疗的作用,利用多模式治疗手段克服单一手段治疗的局限性,实现强效的肿瘤杀伤作用。该制剂还结合了超顺磁性纳米粒和金纳米材料在MRI成像、CT成像和光声(PA)成像方面的优势,结合医学诊断技术,实现肿瘤的精确诊疗。
Description
技术领域
本发明属于医药技术领域,涉及一种核壳结构金磁纳米簇载药靶向制剂,其制备方法及其应用。
背景技术
目前,恶性肿瘤治疗的形势仍然严峻。临床上所使用的化疗药物通常具有较差的水溶性和较强的全身毒性,往往造成体内低生物利用度和严重的不良反应。因此,增加肿瘤局部抑瘤效果,减小全身毒副作用成为了肿瘤治疗中追求的主要目标。纳米技术在肿瘤治疗领域的应用也与肿瘤治疗的这种需求有着密切的关联。尽管大量科学家致力于开发抗癌药的纳米递送系统,但其应用于临床的数量依然非常有限,只有不到10种处于临床Ⅲ期或Ⅳ期临床试验阶段,也仅有10种获批。其临床批准制剂的创新性不足,治疗效果和总生存率提高有限仍是纳米给药系统的重要问题,更提示了人们需要通过研究肿瘤部位的生理特点,寻找并开发具有更加主动靶向作用更强、靶向效率更高的递药系统。
同时,虽然纳米药物能够通过EPR效应和一些主动靶向的机制富集于肿瘤部位,但由于实体瘤肿瘤细胞的周围环境中有大量胶原等基质的存在,其较高的肿瘤间质压力、致密的细胞结构和细胞外基质环境都严重阻碍了药物的有效渗入。因此开发能够促进实体瘤内部渗透的纳米载体成为了实体瘤研究的方向之一。而在提高肿瘤渗透性较差命题中,利用纳米颗粒的尺寸调节能力,将大尺寸纳米颗粒蓄积于肿瘤部位,再利用小尺寸的纳米颗粒渗透进入肿瘤深部,仍然是最为有效的策略之一。
超纯磁性氧化铁纳米粒(Superparamagnetic Iron Oxide Nanoparticles,SPION)即指室温下具备超顺磁性的磁性氧化铁纳米粒。超顺磁性是原本具有多畴结构体相磁性材料,随着材料的尺寸减小至一定程度后,如纳米级,变成具有单畴结构的磁性纳米材料,其磁自旋无序排列后所呈现的特性,表现为其在交变磁场作用下,会被迅速磁化,并可随着磁场发生定向移动,而磁场一旦撤去后,其磁化强度又降为零,即在无外加磁场下,其并不表现出磁性,减少了粒子之间的磁相互作用。超顺磁性氧化铁纳米材料由于其特殊的磁性作用,良好的生物相容性,且能够实现MRI造影、磁热治疗、磁分离、纳米酶、诱导免疫极化等功能而受到了广泛关注,
金纳米材料是研究与应用比较早的一类贵金属纳米,其具有良好的生物相容性、具备独特的光学特性和表面易被修饰等特点,被广泛用于肿瘤诊疗与药物递送的研究。金纳米材料的光学特性主要指表面等离子体共振(Surface plasmon resonance,SPR)现象使之能够将光能高效的转化为热能,产生局部热效应而破坏或消除恶性细胞,被广泛的应用于肿瘤的光热治疗中。此外,由于金具有较高的X射线衰减系数,可作为优良的X射线的造影剂。金纳米材料由于其光热转化能力,还能够应用于肿瘤的光声成像(PAI),即在激光照射后,通过光热转化造成局部温度升高,热膨胀造成压力波获得光声信号。因此,金纳米材料能够由于其特殊的性质,从而可成为集光热治疗、多模式成像于一体的优良诊疗剂。
本发明旨在将超顺磁性氧化铁纳米粒和金纳米材料相结合,使载体兼具两者优异的性能,既可通过超顺磁性氧化铁纳米粒特性实现MRI成像、磁热疗和磁诱导下的药物递送;又可利用金纳米材料的X射线吸收和表面等离子共振作用,分别用于近红外光热疗和光声成像、CT增强成像等方面,可实现多模式一体化诊疗效果。同时金磁纳米簇状结构使其具备一定的降解能力,因而能够实现药物在肿瘤部位深部渗透,联合化疗和热疗,增加抗肿瘤效果;并实现体内的有效代谢,有效减小载体在体内的蓄积毒性。
发明内容
本发明的目的之一在于提供一种核壳结构的金磁纳米簇载药靶向制剂,该制剂多模式能够作为抗肿瘤药物的优良载体,能够靶向肿瘤部位并实现良好的肿瘤部位渗透性,实现肿瘤多模式精准诊疗。
本发明的目的之二在于提供一种核壳结构的金磁纳米簇载药靶向制剂的制备方法。
本发明的目的之三在于提供一种核壳结构的金磁纳米簇载药靶向制剂在肿瘤治疗中的应用。
为了实现上述发明目的,本发明采用以下技术方案:
一种核壳结构的金磁纳米簇载药靶向制剂,包括磁性纳米簇内核和金纳米外壳,在金纳米外壳表面修饰有肿瘤靶向分子和肿瘤治疗药物;所述磁性纳米簇是由超顺磁性氧化铁纳米粒通过交联剂交联形成簇状结构。
进一步的,所述超顺磁性氧化铁纳米粒粒径为3~15nm,电位为-40mV~-20mV;核壳结构金磁纳米簇载药靶向制剂粒径为60~160nm,电位5~30mV,紫外最大吸收波长在600~680nm。
进一步地,所述肿瘤靶向分子选自小分子、糖类分子、蛋白质、多肽、抗体或聚山梨酯类表面活性剂。
更进一步地,所述小分子选自为叶酸、甘草次酸、甘草酸、阿仑膦酸钠或ACUPA;所述糖类分子选自葡萄糖、甘露糖、半乳糖或透明质酸;所述蛋白质选自转铁蛋白、乳铁蛋白、低密度脂蛋白或表皮生长因子(EGF);所述多肽选自RGD肽、iRGD肽、CREKA肽、NGR肽或奥曲肽;所述抗体选自曲妥珠单抗、西妥昔单抗、利妥昔单抗、帕妥珠单抗、维多珠单抗、帕尼单抗或雷珠单抗;所述聚山梨酯类表面活性剂选自聚山梨酯80及聚山梨酯80成分之一聚氧乙烯山梨醇油酸酯。
进一步地,所述肿瘤治疗药物选自小分子化学治疗药物、生物蛋白药物或基因药物。
更进一步地,所述小分子化学治疗药物选自美登素及其衍生物、紫杉醇、阿霉素、柔红霉素、博莱霉素、长春新碱、长春瑞滨、羟基喜树碱、多西他赛、米托蒽醌、氨甲喋呤、5-氟尿嘧啶、卡铂、顺铂、激素类药物或中药单体中的一种或几种;所述生物蛋白药物选自曲妥珠单抗、西妥昔单抗、利妥昔单抗、帕妥珠单抗、维多珠单抗、帕尼单抗、雷珠单抗;所述基因药物选自含报告基因、抗癌基因或细胞因子基因能在真核细胞中重组表达的质粒DNA、寡聚核苷酸或小干扰RNA。
进一步地,所述交联剂选自正电荷聚合物、双端氨基/巯基多肽或半胱氨酸。
更进一步地,所述正电荷聚合物优选壳寡糖。所述双端巯基/氨基多肽优选双端巯基的基质金属蛋白酶敏感的多肽。
上述核壳结构的金磁纳米簇载药靶向制剂通过如下方法制备得到:超顺磁性氧化铁纳米粒和交联剂以一定比例混合后形成磁性纳米簇,磁性纳米簇外层通过氯金酸原位还原形成金纳米外壳,并在表面修饰肿瘤靶向分子以及肿瘤治疗药物。
具体包括以下步骤:
步骤1,将六水合氯化铁溶解于超纯水中,缓慢加入亚硫酸钠将部分三价铁还原成二价铁,缓慢加热至70~80℃后加入含羧基聚合物,剧烈搅拌下快速注入碱溶液,反应10~120min后立即冷却并收取粗产物,粗产物加丙酮或乙醇后用磁铁磁分离洗涤2~3次,用超纯水重分散后透析3天,透析后的产物在3000~5000rpm,20~40min条件下离心两次,倾倒出上层液体即得超顺磁性氧化铁纳米粒;
步骤2,超顺磁性氧化铁纳米粒直接加入或使用活化剂活化后再按照一定比例加入交联剂混合,搅拌2-14h后,通过透析纯化得到磁性纳米簇;
步骤3,磁性纳米簇在搅拌下直接或加入电荷调节剂后再加入氯金酸溶液,并加入聚乙烯吡咯烷酮作为稳定剂,后加入还原剂在磁性纳米簇表面还原金纳米层,搅拌10~120min后取出,3000~5000rpm,10min条件下离心纯化得到核壳结构金磁纳米簇;
步骤4,取步骤3中所制备的核壳结构金磁纳米簇加入肿瘤靶向分子,室温下共孵育0.5~12h,3000~5000rpm离心5~10min,得到核壳结构金磁纳米簇靶向制剂。
步骤5,取步骤4中所制备的核壳结构金磁纳米簇靶向制剂,加入肿瘤治疗药物,室温下共孵育0.5~12h,3000~5000rpm离心5~10min,得到核壳结构金磁纳米簇载药靶向制剂。
进一步地,步骤1中,六水合氯化铁质量为0.95~1.65g,亚硫酸钠质量为0.1~0.3g,含羧基聚合物为聚天冬氨酸或聚丙烯酸,所述碱为氨水、KOH或NaOH。
进一步地,步骤2中,所述活化剂为EDC/NHS,超顺磁性氧化铁纳米粒浓度以Fe3O4计为0.3~0.7mg/mL,交联剂浓度为0.8~1.2mg/mL,超顺磁性氧化铁纳米粒和交联剂溶液的体积比为1:3~1:6,所述透析步骤亦可省略。
进一步地,步骤3中,所述电荷调节剂为聚乙烯亚胺,磁性纳米簇的体积为1~4mL,加入氯金酸的浓度为80~100mM,体积为20~50μL;加入抗坏血酸浓度为300~500mM,体积为30~70μL;聚乙烯吡咯烷酮浓度为0.05~0.1g/mL,加入体积为0.5~1mL。
进一步地,步骤4中所述肿瘤靶向分子和核壳结构金磁纳米簇的质量比为0.5:1~1.5:1。
进一步地,步骤5中所述和肿瘤靶向药物和核壳结构金磁纳米簇靶向制剂的质量比为0.5:1~1:1。
特别地,步骤(4)和步骤(5)顺序可交换,顺序交换后核壳结构金磁纳米簇首先通过原步骤(5)得到核壳结构金磁纳米簇载药制剂,后通过原步骤(4)得到核壳结构金磁纳米簇载药靶向制剂。
本发明还提供了所述核壳结构的金磁纳米簇载药靶向制剂在制备脑胶质瘤、乳腺癌、卵巢癌、肺癌、黑色素瘤或前列腺癌恶性肿瘤治疗药物的应用。
本发明还提供了所述核壳结构的金磁纳米簇载药靶向制剂在制备联合化疗、放疗、光热治疗和磁热治疗试剂中的应用。
本发明还提供了所述的核壳结构金磁纳米簇载药靶向制剂在制备磁共振(MRI)、电子计算机断层扫描(CT)、光声(PA)成像诊断试剂中的应用。
本发明的核壳结构金磁纳米簇载药靶向制剂利用交联剂可降解特性或肿瘤微环境响应型降解特性,从较大的金磁纳米簇颗粒降解成为较小尺寸的纳米颗粒,从而同时利用了大尺寸颗粒的肿瘤蓄积作用和小尺寸颗粒的肿瘤深部渗透作用,改善了制剂的肿瘤蓄积及瘤内分布,为提升肿瘤治疗效果奠定了基础。
本发明提供的核壳结构金磁纳米簇载药靶向制剂在保持完整簇状结构时具备等离子体共振(SPR)效应,从而能够实现光热转化、光声成像等功能,实现针对肿瘤的诊疗作用;而在肿瘤部位簇状结构解体促进了药物的释放,有利于制剂在肿瘤部位的深部渗透,且较小粒径的纳米颗粒易被肾脏清除,从而降低体内的蓄积毒性。该制剂不仅能够联合化疗、光热和光声成像的诊疗作用,还解决了无机载体难以代谢的问题,提高了体内应用的生物安全性。
本发明构建的金磁纳米簇载药靶向制剂通过超顺磁性氧化铁纳米粒用于MRI成像;利用金纳米材料的X射线吸收作用、SPR效应、较高的光学吸收系数,用于CT成像和PA成像,从而通过金磁纳米簇的MRI/CT/PA多模成像实现对恶性肿瘤的精密诊断。
本发明提供的核壳结构金磁纳米簇载药靶向制剂,是集化疗、热疗、放疗效果于一体且能够实现体内降解代谢的可视化靶向肿瘤金磁纳米载体诊疗系统。本制剂能够实现肿瘤部位的靶向与深部渗透,利用多模式治疗手段克服单一手段治疗的局限性,提高肿瘤治疗效果,具有较高的医学诊疗应用价值。
附图说明
图1为本发明中超顺磁性氧化铁纳米粒的透射电镜图;
图2为本发明中超顺磁性氧化铁纳米粒的X射线衍射图谱;
图3为本发明中超顺磁性氧化铁纳米粒的磁滞回线图;
图4为本发明中核壳结构金磁纳米簇的透射电镜(A)和高分辨透射电镜(B)图;
图5为本发明中核壳结构金磁纳米簇在808nm(A)和1064nm(B)近红外激光照射下的升温曲线图;
图6为本发明中核壳结构金磁纳米簇(A)、核壳结构金磁纳米簇靶向制剂(B)和核壳结构金磁纳米簇载药靶向制剂(C)的粒径分布图;
图7为本发明中核壳结构金磁纳米簇(A)、核壳结构金磁纳米簇靶向制剂(B)和核壳结构金磁纳米簇载药靶向制剂(C)的紫外-可见吸收光谱图;
图8为本发明中核壳结构金磁纳米簇靶向制剂(A)和核壳结构金磁纳米簇载药靶向制剂(B)的透射电镜图;
图9为本发明中核壳结构金磁纳米簇载药靶向制剂在U87细胞中的细胞存活率(MNC@Au-DM1为核壳结构金磁纳米簇载药制剂;CREKA-MNC@Au-DM1为核壳结构金磁纳米簇靶向载药制剂);
图10为本发明中金磁纳米簇载药靶向制剂在激光处理后U87细胞的存活率(CREKA-MNC@Au-DM1是核壳结构金磁纳米簇载药靶向制剂,CREKA-MNC@Au-DM+808nm NIR为808nm近红外光处理的核壳结构金磁纳米簇载药靶向制剂;CREKA-MNC@Au-DM+1064nm NIR为1064nm近红外光处理的核壳结构金磁纳米簇载药靶向制剂);
图11为本发明中金磁纳米簇靶向制剂的3D肿瘤球渗透情况(SH-PEG-FITC为巯基聚乙二醇修饰的FITC;FITC-GNPs为FITC标记的实心金纳米颗粒;FITC-MNC@Au为FITC标记的核壳结构金磁纳米簇;FITC-MNC@Au-CREKA为FITC标记的核壳结构金磁纳米簇靶向制剂;FITC-MNC@Au-CREKA+808nm NIR为808nm近红外光照射的FITC标记的核壳结构金磁纳米簇靶向制剂)。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明,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
超顺磁性氧化铁纳米粒的制备与表征
称1.3g FeCl3·6H2O,加20mL超纯水后搅拌,全程氮气保护。再称0.2g Na2SO3,并用5mL的水溶解,缓慢加入FeCl3溶液中,加热至70℃。称取0.2g聚天冬氨酸钠(Mw:7000~8000),用5mL水溶解后,加入反应体系,随后在剧烈搅拌下快速注入2mL氨水(25~28%),反应30min后立即冷却并收取粗产物。粗产物加丙酮或乙醇磁分离洗涤2~3次,再用超纯水重分散后用截留分子量为50kDa的透析袋透析3天。透析后的产物在4000rpm,30min条件下离心两次,倾倒出上层液体作为最终产物,即得超顺磁性氧化铁纳米粒。
取超顺磁性氧化铁纳米粒适量滴于铜网上,室温放置5min后用滤纸吸去多余的液体,后在红外灯下烤干,上覆一层铜网,使用透射电子显微镜观察形貌,结果如图1所示。制备的超顺磁性氧化铁纳米粒不仅受搅拌剪切的影响,其生长空间还受到聚天冬氨酸钠的限制,因而能形成超小的纳米粒,粒径约5nm。
制备的超顺磁性氧化铁纳米粒在60℃真空干燥后取出,研磨成细粉,用于X射线衍射表征,检测波长1.5418A,XRD衍射管电压40kV,电流40mA,扫描速度设置为5°/min,扫描范围20~80°,结果如图2所示。所制备的超顺磁性氧化铁纳米粒含有典型的四氧化三铁晶体的X射线衍射峰,在30.00°,35.38°,43.06°,53.42°,56.96°,62.64°分别对应四氧化三铁的(220),(311),(400),(422),(511),(440)晶面。
制备的超顺磁性氧化铁纳米粒在60℃真空干燥后取出,研磨成细粉,取少量样品使用振动样品磁强计测定磁滞回线,磁场范围±3T,测试温度:300K,结果如图3所示。氧化铁纳米粒表现出较强的磁响应性能。其磁滞回线均过原点,说明当外加磁场为0时几乎无剩磁,表现为超顺磁性。另外,随着磁场增大,磁化强度先提高,而在外加磁场达到一定强度之后磁化强度保持不变,计算得饱和磁化强度为58.22emu/g,能够满足临床作为MRI造影剂的要求。
金磁纳米簇(MNC@Au)的制备与表征
0.5mg/mL超顺磁性氧化铁纳米粒和1.0mg/mL壳寡糖溶液以1:4比例混合后搅拌12h,后使用截留分子量为50kDa的透析袋在pH 4介质中透析48h除去多余杂质,制备得磁性纳米簇(MNCs)。
4mL制备的磁性纳米簇在200~300rpm转速搅拌下加入40μL、浓度为100mM氯金酸,搅拌10min后加入1mL浓度为0.1g/mL聚乙烯吡咯烷酮溶液,2min后加入60μL 500mM抗坏血酸,搅拌30min后取出,4000rpm,10min条件下离心纯化,用超纯水重分散得核壳结构金磁纳米簇(MNC@Au)。
所制备核壳结构金磁纳米簇使用透射电子显微镜观察形貌,并使用高分辨透射电子显微镜得到高分辨结构图像,并计算晶面间距,结果如图4所示。可以看出MNC@Au的大小在60-110nm不等,外层为不规则的花瓣状。高分辨透射照片中测量得到外层晶面间距为0.234nm,对应Au的(111)晶面;内层晶面间距d=0.485nm,对应四氧化三铁的(111)晶面,验证内核为四氧化三铁,外层为金的结构。
金磁纳米簇的光热升温曲线:取1mL的PBS和浓度为0.1、0.2、0.5、1.0mg/mL(以Fe3O4+Au的质量计)的所制备的核壳结构金磁纳米簇,分别使用808nm或1064nm,功率为2W/cm2的近红外光照射10min,用红外热成像仪每隔1min拍照并记录溶液温度,以照射时间为横坐标,溶液温度为纵坐标,绘制温度变化曲线,结果如图5所示,所制备的核壳结构金磁纳米簇在808nm和1064nm的激光照射下均能发生光热转化,且呈现浓度依赖性。
核壳结构金磁纳米簇靶向制剂(CREKA-MNC@Au)和核壳结构金磁纳米簇载药靶向制剂(CREKA-MNC@Au-DM1)的制备与表征
以CREKA肽和所制备的核壳结构金磁纳米簇以质量比0.5:1混合,氮吹后常温振荡孵育3h,取出反应液后在4000rpm条件下离心10min,沉淀为核壳结构金磁纳米簇靶向制剂。沉淀用甲醇-水混合溶液(甲醇:水=75:25)重分散,美登素衍生物DM1与金磁纳米簇靶向制剂以0.8:1的质量比混合后氮吹后常温振荡孵育3h,取出反应液,在4000rpm离心10min,沉淀用超纯水重分散后得核壳结构金磁纳米簇载药靶向制剂。
取所制备的核壳结构金磁纳米簇、核壳结构金磁纳米簇靶向制剂和核壳结构金磁纳米簇载药靶向制剂各3mL,使用粒径电位仪检测定其粒径,结果如图6所示。MNC@Au的载体修饰CREKA多肽之后,水合粒径有了一定的增大,载DM1后粒径水合增大较多,可能与DM1的疏水性有关。
取所制备的核壳结构金磁纳米簇、核壳结构金磁纳米簇靶向制剂和核壳结构金磁纳米簇载药靶向制剂适量,紫外可见分光光度计扫描其在400~1100nm的紫外-可见吸收光谱,结果如图7所示。MNC@Au、CREKA-MNC@Au、CREKA-MNC@Au-DM1最大吸收波长分别为613、621、629nm,相对于MNC@Au均发生了一定的红移。
取所制备的核壳结构金磁纳米簇靶向制剂和核壳结构金磁纳米簇载药靶向制剂适量滴于铜网上,室温放置5min后用滤纸吸去多余的液体,后在红外灯下烤干,上覆一层铜网,使用透射电子显微镜观察形貌,结果如图8所示。两种纳米颗粒的粒径仍在80~120nm之间,外观为花瓣状,可见CREKA短肽的修饰以及DM1的载药过程对于MNC@Au的结构没有发生破坏。
试验例1
金磁纳米簇载药靶向制剂的体外抗肿瘤活性评价
(1)单一化疗作用
对数生长期的U87细胞用0.25%的胰酶消化后收集,以4000-5000/孔的浓度接种于96孔板中,37℃,5%CO2培养至贴壁后弃去旧培养基,分别含不同浓度核壳结构金磁纳米簇载药制剂MNC@Au-DM1,核壳结构金磁纳米簇载药靶向制剂CREKA-MNC@Au-DM1(以DM1浓度计)的培养基100μL,并设空白对照孔和调零孔,每组为6个复孔。共孵育24h或48h后,弃去孔内液体,每孔加入100μL,0.5mg/mL的MTT继续孵育4h。吸去MTT后,每孔加入150μL的DMSO并充分溶解底部的甲瓒结晶,酶标仪检测在490nm处的吸光度值,计算细胞存活率,结果如图9所示。24h时DM1的药效还未完全展现,未能够体现出较强的细胞毒性。两种载药制剂在48h均展现了较强的细胞毒性,随着给药浓度的升高,细胞毒性逐渐增大。
(2)化疗联合热疗作用
对数生长期的U87细胞用0.25%的胰酶消化后收集,以4000-5000/孔的浓度接种于96孔板中,37℃,5%CO2培养至贴壁后弃去旧培养基,分别加入含不同浓度核壳结构金磁纳米簇载药靶向制剂CREKA-MNC@Au-DM1(以Fe3O4+Au计)的培养基100μL,每组为3个复孔,并设空白对照孔和调零孔。其中光热组在37.0±0.5℃的环境中平衡30min后分别使用808nm或1064nm的近红外激光(2W/cm2,5min)照射,继续共孵育至24h,弃去孔内液体,每孔加入100μL,0.5mg/mL的MTT孵育4h。吸去MTT后,每孔加入150μL的DMSO并充分溶解底部的甲瓒结晶,酶标仪检测在490nm处的吸光度值,计算细胞存活率,结果如图10所示。在808nm和1064nm的近红外激光照射下,CREKA-MNC@Au-DM1相较于未光照前均有较大的细胞毒性。在DM1浓度为0.1μg/mL的情况下,由于1064nm的穿透性更佳,且能够使液体(即使是PBS)升温,因此在该浓度下反而产生了比808nm更强的细胞毒性(*p<0.5)。而当DM1浓度为10μg/mL,载体浓度相对升高,808nm的近红外光的照射使制剂产生了相较于1064nm近红外光照射后更显著的细胞毒性(*p<0.05)。
试验例2
金磁纳米簇在3D肿瘤球的渗透性考察
使用悬滴法制备脑胶质瘤细胞U87和TGF-β活化的成纤维细胞HSAS2的混合肿瘤球。甲基纤维素溶解于DMEM基础培养基配制0.24%甲基纤维素溶液,并过0.22μm微孔滤膜除菌,将活化的HSAS2和U87用0.25%胰蛋白酶消化收集,使用0.24%甲基纤维素溶液将其稀释并调整至浓度为8×104/mL,U87和HSAS2以3:1数量比混合。细胞悬液以25μL/drop滴于培养皿盖,同时在培养皿中加入PBS。倒扣悬滴24h后将较小的肿瘤球转移至1.5%琼脂糖包被的96孔板中,每隔1天半量换液,并使用倒置荧光显微镜观察肿瘤球的生长状态,待肿瘤球生长为直径300~400μm时用于肿瘤球渗透性的考察。
肿瘤球与FITC、GNP-FITC、MNC@Au-FITC、CREKA-MNC@Au-FITC,CREKA-MNC@Au-FITC+808nm NIR(SH-PEG-FITC为巯基聚乙二醇修饰的FITC;FITC-GNPs为FITC标记的实心金纳米颗粒,粒径约60~100nm;FITC-MNC@Au为FITC标记的核壳结构金磁纳米簇;FITC-MNC@Au-CREKA为FITC标记的核壳结构金磁纳米簇靶向制剂;FITC-MNC@Au-CREKA+808nm NIR为808nm近红外光照射的FITC标记的核壳结构金磁纳米簇靶向制剂),给药后共孵育6h,其中NIR组给药后在37.0±0.5℃环境中平衡30min后使用808nm,2W/cm2的近红外光照射5min,继续孵育至6h。取出肿瘤球用PBS清洗2遍,用4%的多聚甲醛固定30min后吸去多聚甲醛溶液,并用PBS清洗3遍,使用激光共聚焦显微镜进行Z-stack断层扫描并拍照,结果如图11所示。SH-PEG-FITC难以渗透进入肿瘤深部,而GNP-FITC由于其不可降解的特性,几乎不能渗透进入肿瘤。MNC@Au和CREKA-MNC@Au能够利用尺寸减小的优势和金纳米粒静息逆转成纤维细胞作用渗透进入较深的部位。在CREKAMNC@Au通过808nm近红外光进行照射之后,制剂的渗透性又有一定的提高,在60~80μm处的荧光强度高于了CREKA-MNC@Au组。
Claims (9)
1.一种核壳结构的金磁纳米簇载药靶向制剂,其特征在于:包括磁性纳米簇内核和金纳米外壳,在金纳米外壳表面修饰有肿瘤靶向分子和肿瘤治疗药物;所述磁性纳米簇是由超顺磁性氧化铁纳米粒通过交联剂交联形成簇状结构。
2.根据权利要求1所述的制剂,其特征在于:所述肿瘤靶向分子选自小分子、糖类分子、蛋白质、多肽、抗体或聚山梨酯类表面活性剂。
3.根据权利要求1所述的制剂,其特征在于:所述肿瘤治疗药物选自小分子化学治疗药物、生物蛋白药物或基因药物。
4.根据权利要求1所述的制剂,其特征在于:所述交联剂选自正电荷聚合物、双端氨基/巯基多肽或半胱氨酸。
5.权利要求1所述核壳结构的金磁纳米簇载药靶向制剂的制备方法,其特征在于:通过如下方法制备得到:超顺磁性氧化铁纳米粒和交联剂以一定比例混合后形成磁性纳米簇,磁性纳米簇外层通过氯金酸原位还原形成金纳米外壳,并在表面修饰肿瘤靶向分子以及肿瘤治疗药物。
6.根据权利要求5所述的制备方法,其特征在于:具体包括以下步骤 :
步骤1,将六水合氯化铁溶解于超纯水中,缓慢加入亚硫酸钠将部分三价铁还原成二价铁,缓慢加热至70~80℃后加入含羧基聚合物,剧烈搅拌下快速注入碱溶液,反应10~120min后立即冷却并收取粗产物,粗产物加丙酮或乙醇后用磁铁磁分离洗涤2~3次,用超纯水重分散后透析3天,透析后的产物在3000~5000 rpm,20~40 min条件下离心两次,倾倒出上层液体即得超顺磁性氧化铁纳米粒;
步骤2,超顺磁性氧化铁纳米粒直接加入或使用活化剂活化后再按照一定比例加入交联剂混合,搅拌2-14 h后,通过透析纯化得到磁性纳米簇;
步骤3,磁性纳米簇在搅拌下直接或加入电荷调节剂后再加入氯金酸溶液,并加入聚乙烯吡咯烷酮作为稳定剂,后加入还原剂在磁性纳米簇表面还原金纳米层,搅拌10~120 min后取出,3000~5000 rpm,10 min 条件下离心纯化得到核壳结构金磁纳米簇;
步骤4,取步骤3中所制备的核壳结构金磁纳米簇加入肿瘤靶向分子,室温下共孵育0.5~12 h,3000~5000 rpm离心5~10 min,得到核壳结构金磁纳米簇靶向制剂;
步骤5,取步骤4中所制备的核壳结构金磁纳米簇靶向制剂,加入肿瘤治疗药物,室温下共孵育0.5~12 h,3000~5000 rpm离心5~10 min,得到核壳结构金磁纳米簇载药靶向制剂。
7.权利要求1所述核壳结构的金磁纳米簇载药靶向制剂在制备脑胶质瘤、乳腺癌、卵巢癌、肺癌、黑色素瘤或前列腺癌恶性肿瘤治疗药物的应用。
8.权利要求1所述核壳结构的金磁纳米簇载药靶向制剂在制备联合化疗、放疗、光热治疗和磁热治疗试剂中的应用。
9.权利要求1所述核壳结构的金磁纳米簇载药靶向制剂在制备磁共振、电子计算机断层扫描及光声成像诊断试剂中的应用。
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