CN108175859B - 一种多模磁光热诊疗一体化纳米探针及其制备方法和应用 - Google Patents
一种多模磁光热诊疗一体化纳米探针及其制备方法和应用 Download PDFInfo
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Abstract
本本发明涉及一种多模磁光热诊疗一体化纳米探针及其制备方法和应用。所述探针AuNRs@nSiO2@mSiO2(Gd2O3)通过纳米金棒AuNRs、实心型氧化硅nSiO2、介孔型氧化硅mSiO2和氧化钆纳米颗粒Gd2O3组装而成;其中,AuNRs的长径比为1.5~4.5:1,nSiO2的厚度为5~15 nm,mSiO2的厚度为10~40 nm,所述探针中Gd2O3的装载量为10~30%。本发明提供的多模磁光热诊疗一体化纳米探针AuNRs@nSiO2@mSiO2(Gd2O3)兼具高分辨率的磁共振成像和高灵敏度的光成像的优势,可实现多模磁光热诊疗一体化。
Description
技术领域
本发明属于纳米生物材料技术领域,更具体地,涉及一种多模磁光热诊疗一体化纳米探针及其制备方法和应用。
背景技术
多模态分子影像结合磁共振成像的高分辨率和光学成像的高灵敏度能够准确诊断出早期肿瘤,并对活体的病理生理过程进行更为详细的定量分析。以肿瘤靶向纳米探针作为成像造影剂,能够增强成像对比度和灵敏度,具有实时、动态、可视化的分子信息。
钆类纳米颗粒型造影剂因其较高的弛豫效率和被动靶向性能成为新一代磁共振造影剂的重点研发对象。纳米金棒作为一种可视的纳米分子探针,由于其在近红外区独特的表面等离共振,具有较高的双光子吸收截面以及近红外光热转换效率,能够用于双光子荧光成像和光热治疗。
然而,由于金棒的热不稳定性以及制备工艺的特殊性,这两种生物纳米材料一直未被有效组装。因此,如何将钆类纳米颗粒与纳米金棒组装在一起,并作为新型靶向纳米探针能够同时实现磁共振与光学成像的复合,并有效引导光热治疗真正实现诊疗一体化效果,这是所属领域技术人员急需解决的技术难题。
因此,研究一种钆类纳米颗粒与纳米金棒组装而成的新型靶向纳米探针具有重要的研究意义和应用价值。
发明内容
本发明的目的在于克服现有技术中无法将钆类纳米颗粒与纳米金棒组装的缺陷,提供一种多模磁光热诊疗一体化纳米探针。本发明提供的探针将钆类纳米颗粒与纳米金棒成功组装成探针,能够同时实现磁共振与光学成像的复合,并有效引导光热治疗真正实现诊疗一体化效果。
本发明的另一目的在于提供上述探针的制备方法。
本发明的另一目的在于提供上述探针在光热治疗领域中的应用。
为实现上述发明目的,本发明采用如下技术方案:
一种多模磁光热诊疗一体化纳米探针AuNRs@nSiO2@mSiO2(Gd2O3),所述探针AuNRs@nSiO2@mSiO2( Gd2O3)通过纳米金棒AuNRs、实心型氧化硅nSiO2、介孔型氧化硅mSiO2和氧化钆纳米颗粒Gd2O3组装而成;其中,AuNRs的长径比为1.5~4.5,nSiO2的厚度为5~15nm,mSiO2的厚度为10~40 nm,所述探针中Gd2O3的装载量为0~30%。
本发明所指的装载量为行业内常规对于质量分数的表述。
本发明提供的多模磁光热诊疗一体化纳米探针AuNRs@nSiO2@mSiO2(Gd2O3)通过纳米金棒AuNRs、实心型氧化硅nSiO2、介孔型氧化硅mSiO2和氧化钆纳米颗粒Gd2O3组装而成,兼具高分率的磁共振成像和高灵敏度的光成像的优势,可实现多模磁光热诊疗一体化。
AuNRs的长径比,nSiO2、mSiO2的厚度和Gd2O3的装载量是影响三者能否组装成功及是否可实现磁共振与光学成像复合的关键因素。当AuNRs长径比变化时,探针的最佳吸收峰位也会随之变化,随着金棒长径比的增加,金棒的等离吸收峰会发生红移。本发明的发明人经过多次试验发现,当控制AuNRs长径比为1.5~4.5时,探针的最佳吸收峰位可控制在650~900 nm,从而使得探针实现磁共振与光学成像的复合。
nSiO2的沉积可为后续mSiO2的沉积提供可能。nSiO2的沉积厚度太薄,难以保证二氧化硅沉积的均匀性;nSiO2的沉积厚度太厚,一方面会增大颗粒的尺寸,另外一方面减弱金棒与其他物质间的相互作用,故当nSiO2的沉积的沉积厚度控制在5~15nm时,可保证钆金或金棒与光敏剂之间具有较好的相互作用。
mSiO2的沉积是作为氧化钆和光敏剂的媒介载体。
优选地,所述AuNRs的长径比为2.5。
优选地,所述nSiO2的厚度为10 nm;所述mSiO2的厚度为30nm;所述Gd2O3的负载量为20%。
为了进一步提高有效的下转换及上转换发光,可向氧化钆纳米颗粒Gd2O3中掺杂稀土元素,如Yb3+和Er3+等。
优选地,所述探针中的Gd2O3还掺杂有Yb3+和Er3+,所述掺杂有Yb3+和Er3+的探针为AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+),所述Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为为5~40%,Er3+的掺杂的摩尔分数为1~4%。
更为优选地,所述Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为10 %, Er3+的掺杂的摩尔分数为2 %。
为了进一步增强光敏特性,可在探针表面修饰锌酞菁ZnPcS2P2;为了进一步增强靶向性,可在探针表面修饰叶酸;为了使其具备长循环特性,可在探针表面修饰PEG二乙酸。
优选地,所述探针表面修饰有ZnPcS2P2、叶酸或PEG二乙酸中的一种或数种。
上述探针的制备方法,包括如下步骤:
S1:制备长径比为15~4.5的AuNRs溶液;
S2:将AuNRs溶液离心取上清液后超声分散于水中,加入碱性溶液,并在搅拌条件下加入TEOS 乙醇溶液,搅拌,离心,洗涤后得AuNRs@nSiO2;
S3:将S2所得AuNR@nSiO2超声分散于CTAB溶液中,加入碱性溶液,搅拌条件下加入TEOS 乙醇溶液,搅拌,离心,洗涤后得AuNRs@nSiO2@mSiO2;
S4:去除AuNRs@nSiO2@mSiO2中的CTAB;
S5:将S4所得AuNRs@nSiO2@mSiO2与激光烧蚀法得到的Gd2O3胶体溶液混合,搅拌、超声、离心、洗涤即得所述探针AuNRs@nSiO2@mSiO2( Gd2O3)。
可通过常规的方法制备S1中特定长径比的AuNRs溶液。本发明提供一种制备该特定长径比的AuNRs溶液的较好方法。
优选地,S1中AuNRs由如下方法制备得到:将氯金酸溶液分散于CTAB溶液中,加入NaBH4冰水溶液,搅拌后得金棒种子溶液,待用;将氯金酸溶液分散于CTAB溶液中,加入AgNO3溶液,并在搅拌过程中加入抗坏血酸,静置条件下加入金棒种子溶液,离心后分散于水中即得所述AuNRs溶液,所述AgNO3与氯金酸的摩尔比为0.1~0.4:1。
本发明选用还原性很强的NaBH4冰水溶液作为还原剂来制备金棒种子,可利于小颗粒金种的快速成核,使得产生的金种只有1~1.5nm左右,同时保证操作的安全性。
本发明选用还原性较弱的抗环血酸来进一步将金离子还原到金种上,实现金种的缓慢生长。
另外控制硝酸银的用量是调控金棒的长径比的关键因素。
常规的碱性溶液如氢氧化钠溶液、氨水溶液等均可应用于本发明中,作为S2和S3中的碱性溶液。
本领域制备介孔二氧化硅时一般采用加热(500℃)的方法就可完全去除CTAB。但是当介孔二氧化硅沉积在金棒上时,金棒在100~200℃的温度下就会变形,故本发明提供了一种合适的可完全去除CTAB的方法,可使得CTAB去除得更彻底且不损害AuNRs@nSiO2@mSiO2。
优选地,S4中去除CTAB的方法为:S3所得AuNRs@nSiO2@mSiO2超声分散于醇溶液中,加入浓酸,回流,离心、洗涤即将CTAB去除。此时的回流温度根据CTAB的沸点可进行合理选择,如50~80℃。更为优选地,所述回流的温度为60℃,回流的时间为24h。
现有技术中通过nSiO2的沉积从而实现介孔二氧化硅mSiO2包裹金棒(AuNRs@nSiO2@mSiO2)是没有很大的难度的;本发明的发明人曾尝试在mSiO2里面掺杂Gd2O3来实现金棒上mSiO2和Gd2O3的组装,其主要方法是:AuNR@nSiO2超声分散于CTAB溶液,加入碱性溶液(氢氧化钠溶液或浓氨水溶液)、硝酸钆(提供钆离子)和TEOS 乙醇溶液,理论上TEOS 乙醇溶液水解反应得到SiO2,硝酸钆将和碱性溶液反应得到氢氧化轧,并且氢氧化轧和CTAB将一同包裹进 SiO2中,沉积到金棒表面;再加热将CTAB去除,同时氢氧化钆脱水生成Gd2O3,即可实现金棒、mSiO2和Gd2O3的组装。但经过多次试验发现,硝酸钆单独与碱性溶液生成颗粒很大的氢氧化钆,介孔二氧化硅也因为溶液碱性度不合适和难以调节的原因无法生成,使得组装难以进行。
故本发明尝试采用先沉积mSiO2,再装载Gd2O3的方法。
一般情况下,通过常规的化学合成方法和激光烧蚀法都可将Gd2O3纳米颗粒制备成Gd2O3胶体溶液,再得到氧化钆纳米颗粒Gd2O3。但选用化学合成方法来制备Gd2O3胶体溶液时杂质离子及有机试剂会污染氧化钆纳米晶体的表面,一旦这些杂质复合到颗粒表面,降低其表面不饱和悬挂键的数量。经过研究发现,氧化钆纳米颗粒Gd2O3的纯度及其晶体表面是否富含大量的不饱和悬挂键是影响Gd2O3能否组装成功的关键。若其纯度不高或表面的不饱和悬挂键少,将致使Gd2O3颗粒难以与介孔二氧化硅mSiO2的表面氧成键,无法实现Gd2O3的组装。故选用激光烧蚀法来得到纯度高且表面富含不饱和悬挂键的Gd2O3胶体溶液。在原料中掺杂稀土元素,如Yb3+和Er3+,可得到掺杂有Yb3+和Er3+的Gd2O3:Yb3+/Er3+胶体溶液。
优选地,探针中的Gd2O3还掺杂有Yb3+和Er3+时,Gd2O3:Yb3+/Er3+胶体溶液通过如下制备方法得到:氧化钆、氧化铕和氧化铒研磨混合均匀后加入聚乙烯醇水溶液造粒、烘干、过筛,压片,煅烧得固体靶材;将固体靶材进行激光烧蚀即可得到所述Gd2O3:Yb3+/Er3+胶体溶液。
本发明可通过常规的方法将ZnPcS2P2、叶酸或PEG二乙酸中的一种或数种修饰在探针表面以使其功能化。
优选地,在探针表面修饰ZnPcS2P2的方法如下:将探针AuNRs@nSiO2@mSiO2( Gd2O3)超声分散于醇溶液,加入3-氨丙基三乙氧基硅烷乙醇溶液,回流,离心,洗涤;然后分散于水中,加入ZnPcS2P2,避光搅拌后即得修饰有ZnPcS2P2的探针AuNRs@nSiO2@mSiO2( Gd2O3)-ZnPcS2P2。
优选地,在探针表面修饰叶酸的方法如下:将探针AuNRs@nSiO2@mSiO2( Gd2O3)分散形成纳米胶体溶液后,加入叶酸, 在40℃下搅拌6h,即可实现在探针表面修饰叶酸。
优选地,在探针表面修饰PEG二乙酸的方法如下将探针AuNRs@nSiO2@mSiO2(Gd2O3)分散形成纳米胶体溶液后,加入PEG二乙酸,在40℃下搅拌6h,即可实现在探针表面修饰PEG二乙酸。
如选用掺杂有稀土元素和/或表面修饰有ZnPcS2P2的探针进行分散后,再加入叶酸和/或PEG二乙酸,可得到多种功能化的探针。
上述探针在光热治疗领域中的应用也在本发明的保护范围内。
与现有技术相比,本发明具有如下有益效果:
本发明提供的多模磁光热诊疗一体化纳米探针AuNRs@nSiO2@mSiO2(Gd2O3) 通过纳米金棒AuNRs、实心型氧化硅nSiO2、介孔型氧化硅mSiO2和氧化钆纳米颗粒Gd2O3组装而成,兼具高分辨率的磁共振成像和高灵敏度的光成像的优势,可实现多模磁光热诊疗一体化。
附图说明
图1为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)及各组分的形貌图和能谱图,其中a为金棒的形貌图,b为实心的二氧化硅包裹金棒AuNRs@nSiO2的形貌图,c为介孔的二氧化硅包裹金棒AuNRs@nSiO2@mSiO2的形貌图,d为液相激光烧蚀法制备得到的氧化钆纳米颗粒Gd2O3的形貌图,e为氧化钆纳米颗粒Gd2O3的暗场成像图,f氧化钆纳米颗粒Gd2O3的高分辨电镜图,g为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)的电子衍射图,h为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)的EDX能谱图,i~n为单个颗粒的电镜(i)、暗场成像(j)以及各个元素的Mapping图(k~n);
图2为AuNRs@nSiO2@mSiO2中介孔二氧化硅mSiO2的孔径分布图;
图3为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2的磁共振成像性能图;a为核磁弛豫性能图,b为小鼠体内磁共振成像图,c为小鼠各组织部位(肾脏、肝脏和移植瘤部位)的磁共振信号强度的变化图;
图4为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)的吸光能力图;
图5为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)的光热转换图;
图6为探针光热治疗的肿瘤细胞变化情况图;
图7为肿瘤鼠光动力-光热协同治疗效果图。
具体实施方式
下面结合实施例进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。下例实施例中未注明具体条件的实验方法,通常按照本领域常规条件或按照制造厂商建议的条件;所使用的原料,试剂等,如无特殊说明,均为可从常规市场等商业途径得到的原料和试剂。本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
实施例1
本实施例提供了一种修饰有ZnPcS2P2、叶酸和PEG二乙酸的探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,该探针中AuNRs的长径比为2.5,nSiO2的厚度为10nm,mSiO2的厚度为30nm,Gd2O3:Yb3+/Er3+的负载量为20%,Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为10 %, Er3+的掺杂的摩尔分数为2%。
该探针由如下制备方法制备得到:
(1)纳米金棒AuNRs的制备
0.36 g CTAB溶入8.34 mL去离子水,然后加入0.5 mL 0.006 mmol/L氯金酸溶液,加入1.16 mL 0.01 mol/L NaBH4冰水溶液,较快速搅拌两分钟,搅拌完放置于27 ℃水浴中放置4 h后获得金棒种子溶液。
3.6 g CTAB溶入82.86 mL 去离子水,再向其中加入12.5 mL氯金酸溶液,再加入0.005 mol/L的AgNO3溶液2.24 mL,搅拌中加入2.4 mL 0.05 mmol/L 抗坏血酸,此时溶液由黄色变为无色,静止过程中加入0.2 mL上一步制备的金棒种子溶液,在静置中放入27 ℃水浴中放置12 h,用9000 r/min 离心20分钟收集得纳米金棒AuNRs,分散于70 mL去离子水中。
如图1a所示,为所得到的金棒的形貌图。从图中可知,得到的金棒长短均一,长径比约为2.5,具有较好的分散性能。
通过调整AgNO3与氯金酸的摩尔比可得到其它长径比的均一的纳米金棒AuNRs,如当AgNO3与氯金酸的摩尔比为0.4时,得到的纳米金棒AuNRs的长径比为4.5;当AgNO3与氯金酸的摩尔比为0.1时,得到的纳米金棒AuNRs的长径比为1.5。
(2)AuNR@nSiO2@mSiO2的制备
取上一步所制备得到的纳米金棒溶液10 mL,用9000 r/min 离心一次,去除上清液,超声分散于20 mL去离子水中,加入0.025 mol/L NaOH溶液 0.4 mL。在缓慢搅拌过程中每隔30 min 加入25%(体积分数)的TEOS 乙醇溶液 72μL,共加入4次,继续搅拌12 h。离心,用水洗一次再用酒精洗一次,如此反复,重复三次,即得AuNR@SiO2。如图1b所示,为实心的二氧化硅包裹金棒AuNRs@nSiO2的形貌图。
将0.029 g CTAB溶入40 mL去离子水中,将所得到的AuNR@SiO2超声分散于此CTAB溶液中,加入0.025 mol/L NaOH溶液 0.8 mL,在缓慢搅拌过程中每隔30 min 加入25%(体积分数)的TEOS 乙醇溶液 72μL,共加入4次。离心,用水洗一次再用酒精洗一次,如此反复,重复三次,即得AuNR@nSiO2@mSiO2,且该AuNR@nSiO2@mSiO2中含有毒性的CTAB,待去除。
(3)CTAB的去除
将AuNR@nSiO2@mSiO2超声分散于100 mL乙醇溶液中,加入2 mL浓盐酸,在60 ℃下回流24 h,离心收集,用水洗一次,乙醇洗涤一次,如此反复,重复2次,得AuNR@nSiO2@mSiO2(如图1c),并将其分散于去离子水当中。
如图2所示,为AuNRs@nSiO2@mSiO2中介孔二氧化硅mSiO2的孔径分布图,该mSiO2的孔径大约为3.2nm。
(4)Gd2O3:Yb3+/Er3+的制备
采用两步法制备稀土掺杂氧化钆纳米颗粒:
第一步,采用固相烧结法制备固体陶瓷靶材。首先将氧化钆和氧化镱和氧化铒按摩尔比例88:10:2配比称量后,用玛瑙研钵中研磨30分钟,使其稀土氧化物粉末混合均匀;然后在粉末中加入适量(3~5滴)质量分数为7.0%的聚乙烯醇(polyvinyl alcohol, PVA)水溶液对其进行造粒,经造粒后的粉末在50 ℃下烘干,接着用40目筛过筛;用粉末压片机在15 MPa压力下将过筛后的粉末干压成型,得到直径约15 mm的圆柱状样品;最后将样品置于密闭坩埚中以10 ℃/min升温速率升至1500 ℃后保温10小时,样品随炉冷却至室温后取出,即得到固体靶材。
接着,采用液相脉冲激光烧蚀法制备纳米材料。首先将固体靶材置于容器底部,加入液体,使液面距靶材的高度约为3 mm,然后将激光聚焦于靶材表面烧蚀,即可得到纳米颗粒胶体溶液。将得到的胶体溶液静置24小时,取上层液体。拟采用的激光器是钇铝石榴石晶体激光器(Nd:YAG),波长为1064 nm,脉宽为6s,脉冲能量为70 mJ/pulse,工作频率为100Hz。
将该胶体溶液进行离心分离,取液体,即可得到超微氧化钆纳米颗粒Gd2O3,如图1d~f所示,该颗粒的粒径约为2~3nm。
通过调控第一步中氧化钆和氧化镱和氧化铒按摩尔比例可得到不同发射峰强度的Gd2O3:Yb3+/Er3+。如氧化钆和氧化镱和氧化铒按摩尔比例为88:10:2,675nm的红光发射峰最强,如氧化钆和氧化镱和氧化铒按摩尔比例为89:10:1,675nm的红光发射峰强度只有原来的一半。当然,如不添加氧化铕和氧化铒,则可得到Gd2O3胶体溶液。
(5)AuNR@SiO2@mSiO2( Gd2O3:Yb3+/Er3+)的制备
将所得的5mL Au@nSiO2@mSiO2水溶液与上一步制得的25 mL Gd2O3:Yb3+/Er3+胶体溶液混合于平底烧瓶中。加入搅拌子高速搅拌30 min,取出搅拌子,置于超声水浴槽中进行超声,功率设为100%,超声12h后,离心除去多余的氧化钆,用水和酒精各洗两遍,分散于酒精中,即得AuNR@SiO2@mSiO2( Gd2O3:Yb3+/Er3+),如图1f。从该图可知,相对于图1c介孔二氧化硅包裹金棒,掺杂氧化钆后,该探针的整体形貌没有发生明显的变化。
(6)AuNR@SiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2的制备
将制备所得到的AuNR@SiO2@mSiO2( Gd2O3:Yb3+/Er3+) 超声分散于50 mL乙醇溶液中,加入0.5 mL 5%(体积比)的3-氨丙基三乙氧基硅烷(APTES)乙醇溶液,在60 ℃下回流12h,离心,使其表面挂接上氨基,用乙醇洗涤两次去除未反应的APTES。将氨基化的AuNR@SiO2@mSiO2( Gd2O3:Yb3+/Er3+)超声分散在20 mL 去离子水中,加入0.125 mg 两亲性磺酸基邻苯二甲酰亚氨甲基酞菁锌(ZnPcS2P2)光敏剂分子,避光搅拌12 h,即可成功实现光敏剂分子ZnPcS2P2的挂接。离心收集去除未挂接的锌酞菁衍生物。
如图1g~n所示,为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2的电子衍射图和EDX能谱图,从该图可知,探针中金和钆的含量都比较高。
(7)叶酸及PEG二乙酸的在线表面修饰:
向AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2的纳米颗粒胶体溶液中加入0.1mg 叶酸,超声搅拌5min后,在40℃下搅拌6h,离心去除多余的叶酸分子,再在同样的方法下加入0.05mg PEG二乙酸分子,超声搅拌5min后,在40℃下搅拌6h,离心后用乙醇和水各清洗一次,保存于去离子水中用于其他表征检测。
实施例2
本实施例提供一种修饰有ZnPcS2P2、叶酸和PEG二乙酸的探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,该探针中AuNRs的长径比为1.5,nSiO2的厚度为15nm,mSiO2的厚度为40nm,Gd2O3:Yb3+/Er3+的质量分数为30 %,Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为40 %, Er3+的掺杂的摩尔分数为1 %。
该探针可按实施例1中的制备方法及调节相关的控制条件制备得到。
实施例3
本实施例提供一种修饰有叶酸和PEG二乙酸的探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3 +/Er3+)-ZnPcS2P2,该探针中AuNRs的长径比为4.5,nSiO2的厚度为5nm,mSiO2的厚度为10nm,Gd2O3:Yb3+/Er3+的质量分数为10 %,Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为5 %, Er3+的掺杂的摩尔分数为4 %。
性能测试
以实施例1提供的探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2为例,对其性能进行测试。
(1)磁共振成像性能
体内核磁共振成像是在中山大学附属肿瘤医院完成,采用了 Balb/c 裸鼠移植瘤模型,使用的设备是西 门子公司生产的 3.0 T 临床商用核磁共振成像系统。具体步骤如下:(1) 4~6 周大的 Balb/c 裸鼠若干只( 购自中山大学医学院动物实验中心),用 来皮下移植肿瘤细胞:于裸鼠后肢腹侧,经皮下注射 100 μL 含有鼻咽癌 CNE2 细 胞( 5×106)的 PBS 溶液,观察肿瘤生长; (2) Balb/c 裸鼠经喂养十天左右,待其移植瘤尺寸增大到~60 mm3,尾静脉注 射 0.1%戊巴比妥钠将其麻醉,然后尾静脉注射一定浓度的纳米颗粒 PBS 溶液, 再放入核磁共振成像系统观察。扫描参数: T1轴位: FOV = 64 mm, slicethickness = 2.0 mm, TR = 600 ms, TE = 12 ms, averages = 6.。
如图3所示,为探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2的磁共振成像性能图。从图3a可知,该探针(MPNs)的核磁弛豫性能大约是临床使用的MRI造影剂Gd-DTPA的6倍左右,具有很高的对比度。从图3b可知,小鼠体内磁共振成像图可以看到在1h左右,小鼠肿瘤部位的信号最强。图3c为小鼠各组织部位(肾脏、肝脏和移植瘤部位)的磁共振信号强度的变化情况,注射药物半小时后在肾脏部分信号最强,之后逐渐递减,而肿瘤部位由于通透增强和高渗透性能够不断积累纳米探针,在注射药物一小时后仍然保持较高的信号,在6小时信号减弱,但比肾脏和肝脏部位的信号都要强。
(2)吸光性能和光热转换性能
多功能诊疗分子探针的吸光能力检测是采用紫外-可见-近红外光谱仪(UV-3150)进行记录的, 超纯水为空白对照, 在400~1000nm波长范围内扫描。图4分别为金棒,介孔硅包金棒以及钆掺介孔硅包金棒的等离吸收峰,可以看到随着包裹和掺杂的进行,吸收峰的最佳峰位发生了红移,这是因为金棒表面的介电常数越来越大。纳米探针的最佳吸收峰位为795nm,与我们使用的800nm激光器波长匹配度最高,会产生良好的等离吸收共振。与此同时,我们对纳米探针的光热转换性能进行了评估,采用800nm激光分别照射含探针的PBS溶液和纯的PBS溶液,可以看到含纳米探针的PBS溶液在激光的辐照下持续升温,(图5a)而纯的PBS溶液温度变化非常小,表明所制备纳米探针展现出良好光热转换性能。将纳米探针与人宫颈癌细胞HeLa细胞共同培养一段时间,在近红外800nm激光照射下,可以看到超过80%的肿瘤细胞失去活性(图5b),而对照组展现可忽略的细胞毒性。图6展现的是经纳米探针处理后的肿瘤细胞在激光照射前和激光照射后的状态,可以看到有大量的细胞死亡,表明我们制备的纳米探针对肿瘤细胞具有良好的光热致死能力。
(3)肿瘤鼠光动力-光热协同治疗活体实验
建立两种4T1乳腺癌皮下移植瘤小鼠模型,一种是早期肿瘤(3-5mm),另外一种为中晚期肿瘤(8-11mm),二十只肿瘤鼠随机分成两组,每组含早期肿瘤鼠和中晚期肿瘤鼠各5只,对照组小鼠注射100μL的PBS溶液,实验组小鼠注射含纳米探针的PBS溶液(0.1 μmol L−1 Au),1h后先使用980nm(0.5 W cm−2)连续波激光照射小鼠肿瘤部位五分钟,再使用800nm连续波激光(0.5 W cm−2)照射小鼠肿瘤部位五分钟,同时采用红外热像仪检测肿瘤部位温升情况。早期肿瘤鼠经过一次治疗,中晚期肿瘤鼠第二天再进行一次光治疗。
采用4T1乳腺癌皮下移植瘤小鼠。结果如图7所示:图7a与c相对应,是在尾静脉 注射小鼠后,用激光照射小鼠肿瘤部位,图7a为实验示意图,图7c为红外热像图,可以看 到,温度高达53℃,足以杀灭肿瘤组织。图7b与d分别是两只经过光动力-光热协同治疗后 的小鼠,图7b中的这只小鼠是中晚期小鼠(肿瘤大小约10~12mm),可以看到,经过治疗 后,肿瘤部位出现淤肿,有坏死迹象,能够抑制肿瘤的生长。图7d为中早中期肿瘤鼠(约 3~5nm大小肿瘤),小鼠一次治疗,便成功治愈。
Claims (8)
1.一种多模磁光热诊疗一体化纳米探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,所述探针通过纳米金棒AuNRs、实心型氧化硅nSiO2、介孔型氧化硅mSiO2和氧化钆纳米颗粒Gd2O3组装而成;其中,AuNRs的长径比为1.5~4.5,nSiO2的厚度为5~15 nm,mSiO2的厚度为10~40 nm,所述探针中Gd2O3的装载量为10~30%;Gd2O3颗粒与介孔二氧化硅mSiO2的表面氧成键;
Gd2O3掺杂有Yb3+和Er3+,Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为5~40%,Er3+的掺杂的摩尔分数为1~4%;
所述探针表面修饰有ZnPcS2P2。
2.根据权利要求1所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,所述AuNRs的长径比为2.5。
3.根据权利要求1所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,所述nSiO2的厚度为10 nm;所述mSiO2的厚度为30 nm;所述探针中Gd2O3的装载量为20%。
4.根据权利要求1所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,所述Gd2O3:Yb3+/Er3+中Yb3+的掺杂的摩尔分数为10 %,Er3+的掺杂的摩尔分数为2 %。
5.根据权利要求1所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,所述探针表面修饰有叶酸或PEG二乙酸中的一种或两种。
6.根据权利要求1~5任一所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,AuNRs@nSiO2@mSiO2(Gd2O3)通过如下过程制备得到:
S1:制备长径比为1.5~4.5的AuNRs溶液;
S2:将AuNRs溶液离心取上清液后超声分散于水中,加入碱性溶液,并在搅拌条件下加入TEOS乙醇溶液,搅拌,离心,洗涤后得AuNRs@nSiO2;
S3:将S2所得AuNR@nSiO2超声分散于CTAB溶液中,加入碱性溶液,搅拌条件下加入TEOS乙醇溶液,搅拌,离心,洗涤后得AuNRs@nSiO2@mSiO2;
S4:去除AuNRs@nSiO2@mSiO2中的CTAB;
S5:将S4所得AuNRs@nSiO2@mSiO2与激光烧蚀法得到的Gd2O3胶体溶液混合,搅拌、超声、离心、洗涤即得所述AuNRs@nSiO2@mSiO2( Gd2O3)。
7.根据权利要求6所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,S1中AuNRs由如下方法制备得到:将氯金酸溶液分散于CTAB溶液中,加入NaBH4冰水溶液,搅拌后得金棒种子溶液,待用;将氯金酸溶液分散于CTAB溶液中,加入AgNO3溶液,并在搅拌过程中加入抗坏血酸,静置条件下加入金棒种子溶液,离心后分散于水中即得所述AuNRs溶液,所述AgNO3与氯金酸的摩尔比为0.1~0.4:1。
8.根据权利要求6所述探针AuNRs@nSiO2@mSiO2( Gd2O3:Yb3+/Er3+)-ZnPcS2P2,其特征在于,S4中去除CTAB的方法为:将S3所得AuNRs@nSiO2@mSiO2超声分散于醇溶液中,加入酸溶液,回流,离心、洗涤即将CTAB去除。
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