CN107308462B - 一种海胆状纳米金的制备方法及其在肿瘤成像及治疗中的应用 - Google Patents
一种海胆状纳米金的制备方法及其在肿瘤成像及治疗中的应用 Download PDFInfo
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Abstract
本发明公开了一种海胆状纳米金的绿色制备方法及其在肿瘤成像及治疗中的应用。主要是以氯金酸为金源,依次加入稳定剂、还原剂、生长抑制剂,采用一步合成法制备而成。该方法简单温和、绿色环保。合成的海胆状纳米金可作为造影剂应用于光声成像(PA)、正电子发射计算机断层成像(PET)和红外热成像(TI)等多种医学影像模式,患者只需要承受一种造影剂给药,即可达到多种诊断效果,且可以降低造影剂用量,进一步减轻毒副作用。此外,该材料在808nm近红外光照射下,可实现光与热的转换,并可吸收大量X射线,具有较高的光热转换效率,可以用于制备肿瘤细胞的光热治疗(PTT)、放射治疗(RT)、或PTT/RT联合疗法的治疗剂。
Description
技术领域
本发明涉及一种海胆状纳米金的绿色合成方法,及其在肿瘤的多模态成像和联合治疗中的应用。
背景技术
恶性肿瘤严重危害人类健康,纳米材料技术的发展为恶性肿瘤的诊疗带来新思路。利用纳米材料实现肿瘤的诊断和治疗相结合(诊疗结合),近年来已经受到了越来越多的关注。纳米材料独特的物理化学性质,赋予其能够在单一平台上整合成像诊断和药物治疗的巨大潜质。因此,成像和治疗一体化制剂的开发成为目前的研究热点,此类制剂在癌症的准确诊断和有效治疗方面具有很大的潜在优势,并且为疾病的“可视化治疗”提供了新的契机。
分子影像学技术可作为早期诊断方法,它是在临床症状还未出现时就检测到肿瘤的早期生物学特性。近年来非侵入式分子影像技术受到越来越多的关注,通常造影剂被广泛用于非侵入成像,特别是用于肿瘤诊断。常见的非侵入成像手段包括光声成像(Photoacoustic Imaging,PA)、正电子发射计算机断层成像(Positron EmissionTomography,PET)和红外热成像(Thermal Infrared Imaging,TI)。目前临床上使用的大部分造影剂,其灵敏度均有待于进一步提高;低灵敏度将导致高剂量注射,增加毒副作用。同时,这些临床使用的造影剂只局限于一种特定的成像技术,而不能实现多模态,多角度成像;而现代医学通常需要综合不同影像学数据进行疾病的诊断;基于这种情况,患者可能需要多次承受不同的造影剂注射给药,方可达到最终确诊,这将增加患者所承受的造影剂毒副作用,可能导致患者健康的损坏,并会加重患者的经济负担。因此,迫切需要开发一种高灵敏度的多模态分子影像造影剂,以提高诊断的灵敏度、特异性,并期望能够实现多种临床影像的同时获取。
传统的肿瘤治疗手段有手术切除,化学治疗和放射治疗等,但这几种肿瘤治疗方法都存在毒副作用大和给药效率低等不足。光热治疗属于物理疗法,较强光吸收的材料能在近红外光下将光能转化为热能从而杀死癌细胞,达到肿瘤治疗的效果。其具有治疗时间短、疼痛少、副作用小和治疗特异性好等特点,是一种具有潜在广泛应用前景的肿瘤治疗方法。因此,开发研制新型安全的能够诱导肿瘤光热治疗的生物材料是当前推广光热治疗的必要前提。近年来纳米技术在生物医学领域尤其是在癌症的早期诊断和治疗方面得到了广大研究。通过对纳米材料的合理设计,开发一种集多模态成像和治疗为一体的新型、高效、多功能纳米平台成为可能,从而实现肿瘤的诊断和治疗的时空统一。
用于光热治疗的纳米试剂种类繁多,包括有机物、聚合物、碳材料、无机物以及他们的复合物。其中最常见的无机纳米材料主要由贵金属材料和铜与氧族化合物组成。以贵金属金为例,金能制备出各种不同的形貌,比如金棒、片状金、星形金以及笼状金,他们对近红外光具有良好的吸收,因而被广泛的进行光热性能的测试,然而这些不同形貌的金纳米粒子制备过程复杂,制备条件苛刻,并且在长时间的激光照射下会出现金属“熔融效应”,结构不稳定,这些都限制了他们作为光热试剂的应用。
检索国内外有关多模态成像和联合治疗一体化纳米平台方面的文献和专利结果表明:目前还没有发现基于海胆状纳米金的 PA/PET/TI多模态成像和PTT/RT联合疗法为一体的多功能纳米粒子绿色制备方法和应用的报道。
发明内容
本发明的目的在于针对现有技术的不足,提供一种绿色环保、易操作、易规模化的海胆状纳米金的绿色制备方法及其在肿瘤成像及治疗中的应用,该方法制备得到的纳米粒子具有优异的PA/PET/TI多模态成像功能和实现PTT/RT联合治疗的效果。为多模态成像造影剂和诊疗一体化平台的开发提供了一种新方法,应用前景广阔。
本发明的一种海胆状纳米金的绿色合成方法具体包括如下步骤:
将氯金酸溶液分散到稳定剂中,获得由稳定剂稳定的氯金酸溶液,向其中加入还原剂,使氯金酸与还原剂的摩尔比为1:(50~100),室温下搅拌,再加入生长抑制剂,搅拌,得到海胆状纳米金悬浮液。
上述技术方案中,所述的稳定剂通常为聚乙烯吡咯烷酮、柠檬酸钠、聚乙二醇、壳聚糖、无机盐、或石墨烯。
所述的还原剂为硼氢化钠、过氧化氢、抗坏血酸、或柠檬酸钠。
所述的生长抑制剂可以为KOH、NaOH、K2CO3、Na2CO3、或NaHCO3。
本发明方法获得的纳米金呈海胆状,其表面类似海胆毛刺,通过调节氯金酸和还原剂的浓度可控制海胆状纳米金的尺寸及等离子共振峰,海胆状纳米金的直径约20~200nm。
本发明所述的海胆状纳米金在制备用于肿瘤多模态成像造影剂中的应用。海胆状纳米金表面具有类似海胆状毛刺,该材料在近红外区具有较强的吸收特性,因而具有光声成像的功能;同时其优良的光热转换效率可以用于红外热成像;该材料同样可以通过标记多种同位素,进而具有核医学成像功能(包括PET,SPECT等)。
本发明涉及的海胆状纳米金在制备用于肿瘤光热治疗和放射治疗药物中的应用。所述的海胆状金纳米颗粒具有优异的光热转换效率,在808nm的激光照射下,经过几分钟便可以将局部温度快速提升至 70℃以上,满足肿瘤细胞被杀灭的条件,可以用于肿瘤的光热治疗;同时,元素金的分子量较大(Z=79,高于医用碘海醇)、X射线吸收能力强,经X射线照射后可产生较强的光电吸收效应和二次电子加速 DNA的断裂,可以使放射治疗作用增强,因此可以作为放射治疗的增敏剂,实现X射线辐射剂量的降低,减少辐射损伤。
本发明所涉及的海胆状纳米金可通过不同的剂量给药,这取决于早期成像诊断的肿瘤细胞,组织及肿瘤患者的临床状况。本发明的造影剂和光热、放射增敏药物的给药剂量和浓度,可由临床医生例行确定。用药方案取决于各种因素,例如成像的肿瘤细胞,组织或肿瘤是分散还是局部,患者的健康程度,年龄等。通过参照其他造影剂的用药方案,本领域技术人员能够确定本发明药物的最佳有效剂量及浓度。
本发明的海胆状纳米金颗粒可通过任何已知的递送方法方式给药:全身递送(静脉注射),动脉内,肿瘤内,胃肠外,肺腔内,局部、或局部给药的区域递送形式。如动脉内注射能够被用来“局域效果”成像及特定区域的光热治疗、放射治疗。
本发明的海胆状纳米金可以用于肿瘤的光声成像、正电子发射计算机断层成像和红外热成像等多种成像模式,患者只需接受一种造影剂给药,即可达到多种诊断效果;而且由于造影剂灵敏度的提高,使得造影剂的用量降低,进一步减轻诊断过程的毒副作用。
本发明的海胆状纳米金在808nm激光照射下,能有效地将光能转化成热能,产生70℃以上的过高热,进而热杀伤肿瘤细胞;而且元素金具有较高的X射线的吸收能力,可以增强放射治疗的效果,可以作为放射治疗的增敏剂,实现放射剂量的降低,减少辐射损伤;因此该纳米金不仅可以实现肿瘤的光热治疗,还可以作为放射治疗的增敏剂,实现光热/放疗的联合治疗方法,提高治疗效果。
附图说明
图1为装载拉曼探针的海胆状纳米金的透射电镜图片;
图2为海胆状纳米金的紫外可见近红外吸收光谱曲线图;
图3为海胆状纳米金及对照组(水)的升温曲线;
图4为海胆状纳米金、拉曼探针和装载拉曼探针的海胆状纳米金的拉曼增强(SERS)光谱图;
图5为海胆状纳米金肿瘤细胞的细胞光热杀伤效果的荧光显微镜图像;
图6为海胆状纳米金颗粒注射到小鼠体内,利用Raman光谱仪扫描得到的小鼠肿瘤部位的拉曼增强(SERS)信号图;
图7为不同浓度的海胆状纳米金和医用碘海醇的CT成像图(a)和 CT信号值(b);
图8为海胆状纳米金颗粒注射到小鼠体内,利用红外热成像仪得到的红外热成像图。
具体实施方式
下面结合附图和具体实施例对本发明做进一步的详细说明,以下实施例是对本发明的解释,本发明并不局限于以下实施例。
实施例1:
(1)将100μL,10mM氯金酸溶液加到20mL的稳定剂中,此例中所采用的稳定剂为柠檬酸钠(也可以采用聚乙烯吡咯烷酮、聚乙二醇、壳聚糖等),室温搅拌5~30min得到由稳定剂稳定的氯金酸分散液。向氯金酸分散液中加入一定量的还原剂(1mL,此例中采用硼氢化钠),室温下搅拌5~30min,再加入氢氧化钠(或者氢氧化钾、碳酸钠、碳酸氢钠等),调节混合液的pH值为碱性,室温下搅拌5~30min,直到气泡基本消失,得到海胆状纳米金颗粒悬浮液。
(2)将步骤(1)中得到的悬浮液,先在3000~4000rpm下离心,弃去沉淀;将上层液体在6000~8500rpm下离心15min后,收集海胆状纳米金颗粒(Au-Ur)备用。
取海胆状纳米金颗粒悬液10ml,向其中加入浓度为1μg/ml~ 1mg/ml的拉曼探针(如Dox、DTTC、DTDC、CV、ICG等)溶液1~15ml 避光孵育12~48h,然后用去离子水漂洗2~3遍,去除游离的拉曼探针;6000~8500rpm下离心15min,得到装载拉曼探针的海胆状纳米金备用。
上述制备得到的纳米金颗粒,直径约80±15nm,并具备了光声成像、PET成像、拉曼增强成像、CT成像、近红外热成像,放射增敏、光热治疗功能。
使用透射电子显微镜(TEM)、紫外-可见分光光度计(UV-Vis)、光声成像系统、PET成像系统、Raman成像系统、CT成像系统对Au-Ur 纳米粒子进行表征;并利用808nm近红外激光照射Au-Ur纳米粒子,以及孵育完Au-Ur纳米粒子的肿瘤细胞,用于验证其放射增敏作用和光热治疗的优势和效果。具体测试结果如下:
(1)透射电子显微镜(TEM)
透射电子显微镜照片表明装载有拉曼探针的Au-Ur的形貌和纳米尺寸,结果参照图1。
(2)紫外—可见分光光度计(UV-Vis)
紫外—可见近红外光谱,表明该方法合成得到的Au-Ur纳米粒子的特征光谱。结果参照图2,通过调控稳定剂的加入量,可以得到吸收峰在不同位置的具有不同光学性能的Au-Ur纳米粒子。
(3)光热转化能力
Au-Ur纳米粒子的光热转化能力利用808nm近红外激光进行测试,结果如图3所示,Au-Ur纳米粒子可以将光能转换成热能。在相同的功率2W/cm2,180s激光照射下,Au-Ur纳米粒子相对于水有明显的升温性能。表明Au-Ur纳米粒子可以有效的将光能转化成热能,可通过高温杀伤肿瘤细胞。
(4)显微拉曼光谱仪
表面装载有拉曼探针的Au-Ur纳米粒子,具有表面增强拉曼信号的效果,通过显微拉曼光谱仪可以检测到增强的拉曼信号;结果参照图4,以单纯Au-Ur和拉曼探针作为对照,比较其与装载有拉曼探针的Au-Ur的表面拉曼增强(SERS)效果。
(5)Au-Ur纳米粒子对肿瘤细胞杀伤效果的实验
利用Calxein-AM/PI试剂盒对经过Au-Ur纳米粒子以及激光处理过的细胞进行染色处理,通过荧光倒置显微镜观察Au-Ur纳米粒子对细胞的杀伤效果。如图5所示,绿色区域(图中左下侧)为活细胞,红色区域(图中右上侧)为死细胞。
(6)显微拉曼光谱检测拉曼增强作用及拉曼成像
将载有拉曼探针的Au-Ur纳米粒子用无菌PBS缓冲液配制成金浓度为0.02M的Au-Ur溶液,取200μL溶液注射进体重为22g的小鼠体内,24h后通过拉曼光谱仪扫描获得小鼠肿瘤部位的拉曼信号值(图 6)。拉曼增强成像图表明,本方法合成得到的载有拉曼探针的Au-Ur 纳米粒子具有较好的拉曼增强效果。
(7)CT成像
将制备得到的Au-Ur纳米粒子用无菌PBS缓冲液配制成不同浓度的Au-Ur溶液,分别取一定量溶液置于小EP管内,通过CT扫描仪扫描获得不同浓度Au-Ur溶液的CT信号图和信号值,并以医用碘海醇作为对照(图7)。CT成像图表明,本方法合成得到的Au-Ur纳米粒子具有较好的CT成像效果。
(8)红外热成像
将制备得到的Au-Ur纳米粒子用无菌PBS缓冲液配制成金浓度为 0.02M的Au-Ur溶液,取200μL溶液通过尾静脉注射的方式注射进体重为22g的小鼠体内。经过体循环后的小鼠利用808nm的近红外激光照射肿瘤部位(照射时间5min),并通过红外热像仪记录小鼠肿瘤部位的温度变化。如图8所示,在808nm近红外激光照射下,肿瘤部位温度升高较明显,说明本合成方法制备得到的Au-Ur纳米粒子具有优异的光热转化效率,进而可以实现光热治疗效果。
以上对本发明的描述是说明性的,而非限制性的,本专业技术人员理解,在权利要求限定的精神与范围之内可对其进行许多修改、变化或等效,但是它们都将落入本发明的保护范围内。
Claims (2)
1.一种海胆状纳米金的制备方法,其特征在于,包括如下步骤:
将氯金酸溶液分散于稳定剂中,获得由稳定剂稳定的氯金酸溶液,向其中加入还原剂,使氯金酸与还原剂的摩尔比为1:(50~100),室温下搅拌,再加入生长抑制剂,搅拌,得到海胆状纳米金悬浮液;所述的稳定剂为聚乙烯吡咯烷酮、柠檬酸钠、聚乙二醇或壳聚糖,所述的还原剂为硼氢化钠、抗坏血酸或柠檬酸钠,所述的生长抑制剂为KOH、NaOH、Na2CO3或NaHCO3。
2.一种如权利要求1所述方法制备 的海胆状纳米金的应用,其特征在于:海胆状纳米金用于制备光声成像或正电子发射型计算机断层成像的造影剂。
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