CN107213475A - 一种双模式靶向成像功能纳米复合材料的制备和应用 - Google Patents
一种双模式靶向成像功能纳米复合材料的制备和应用 Download PDFInfo
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Abstract
本发明属于多功能纳米生物医药材料领域,具体涉及一种具有核磁共振和荧光双模式靶向成像和光热转换功能的纳米复合材料的制备方法和应用。纳米复合材料为核壳型结构;其中,内核为具有强磁敏感性的超顺磁性Fe3O4纳米颗粒与掺杂荧光分子的SiO2层组装形成复合纳米核,外壳为具有较强的光热转换能力的偶联特异性配体的金纳米粒子靶向探针。所得纳米核壳材料可同时作为核磁共振成像和荧光成像的造影剂。通过调节复合纳米材料的吸收峰至近红外区域,并通过酰胺键将复合材料与SW620细胞特异性配体融合pVIII蛋白实现偶联。本发明所制得的复合材料通过核磁共振和荧光双模式成像功能实现了对肿瘤细胞的特异性检测和高效的光热现象。
Description
技术领域
本发明属于多功能纳米生物医药材料领域,具体涉及一种具有核磁共振和荧光双模式靶向成像和光热转换功能的纳米复合材料的制备方法和应用。
背景技术
具备多重模式结合、高效特异性主动靶向的生物探针能够集成靶向识别、超灵敏检测和高效治疗于一体,为肿瘤的早期诊断和治疗带来了新的契机,具有重要的生物医学应用价值。目前,核磁共振成像和光学成像是最具发展潜力的诊断方式。光学成像是目前发展起来的新兴研究领域。其突出特点是非侵入性地对活体内参与生理和病理过程的分子事件进行可视化观察,是目前公认的开展活体内分子事件研究的主流手段之一,在生命科学研究领域具有重大应用前景。但光学成像同时也具有分辨率低、背景干扰大、清晰度不高等缺点。另外一种成像模式核磁共振成像在影像的采集过程中可以自由选择,它对于体内的部位几乎都可以进行扫描,甚至可以做到只针对某些组织区域显像,这个优势对于癌细胞的早期发现和诊疗是有益的。更重要的是核磁共振成像具有高灵敏性、高分辨率和无电离辐射等优点,能够弥补光学成像的不足,是目前临床上精确监控组织病变的一种无创三维立体成像模式。若将二者进行有效地结合,将对癌症的诊断和治疗具有非常重要的意义。
超顺磁性的过渡金属氧化物是一种重要的核磁共振成像造影剂,在外磁场存在的情况下能够表现极大的磁敏感性,通过缩短T2弛豫时间使得T2加权图像变暗,表现出负增强效果,可有效提高MRI成像的对比度。
目前,基于Fe3O4纳米颗粒与Au组装形成核壳纳米结构主要依赖于种子介导法,在此过程中,带有大量负电荷的金纳米球通过静电作用吸附于纳米颗粒表面并生长为完整金壳。但由于静电作用不稳定,被吸附的金纳米球易脱落,导致金壳的制备过程重复性不好。因此提高复合纳米材料的核磁共振造影效果、可控调节其近红外吸收峰、增强特异性识别能力、提高分散性和可重复性等仍然是其在肿瘤诊疗应用中亟需解决的难题。
发明内容
本发明的目的是提供一种新型的具有核磁共振和荧光双模式靶向成像和光热转换功能的纳米复合材料。
为实现上述目的,本发明采用技术方案为:
一种双模式靶向成像和光热转换功能的纳米复合材料,纳米复合材料为核壳型结构;其中,内核为具有强磁敏感性的超顺磁性Fe3O4纳米颗粒与掺杂荧光分子的SiO2层组装形成复合纳米核,外壳为具有较强的光热转换能力的偶联特异性配体的金纳米粒子靶向探针。
所述具有较强的光热转换能力的偶联特异性配体的金纳米粒子靶向探针为能够特异性识别肿瘤细胞的多肽配体。
所述具有较强的光热转换能力的金纳米粒子偶联特异性配体的探针为融合pVIII蛋白。
一种双模式靶向成像和光热转换功能的纳米复合材料的制备方法,
1)复合纳米粒子:将溶剂热法合成的Fe3O4纳米颗粒分散于0.1M盐酸中,超声处理、离心,洗涤得沉淀,沉淀再溶于去离子水中,超声分散;加入无水乙醇并混匀,随后在搅拌条件下加入正硅酸乙酯,条件保持弱碱性,室温下搅拌均匀,而后加入活化的荧光分子,继续搅拌、经离心,洗涤,干燥,制得复合纳米粒子Fe3O4@RhB/SiO2;
2)复合材料进行巯基化:将上述获得Fe3O4@RhB/SiO2纳米颗粒的溶液中逐滴加入3-巯丙基三甲氧基硅烷,室温下搅拌混合均匀;
3)纳米金连接:将纳米金溶液与上述表面巯基功能化的Fe3O4@RhB/SiO2纳米颗粒混匀,超声振荡,然后室温静置;利用磁铁将偶联有纳米金的Fe3O4@RhB/SiO2纳米颗粒分离,洗涤沉淀即为Fe3O4@RhB/SiO2-AuNPs,并将其重悬于水中,待用;
4)将碳酸钾溶液与氯金酸溶液室温搅拌混匀,混匀后与上述Fe3O4@RhB/SiO2-AuNPs纳米球混匀,再次混匀后加入抗坏血酸溶液,振荡产物经磁铁分离,洗涤,洗涤后再次重复步骤4)的操作,产物记为Fe3O4@RhB/SiO2@Au;
5)将采用蛋白活化剂和羧基端活化剂活化的融合pVIII蛋白与上述合成的Fe3O4@RhB/SiO2@Au纳米球连接,即可得到Fe3O4@RhB/SiO2@Au@fusion-pVIII多功能纳米复合材料。
所述经无水乙醇混匀后加入正硅酸乙酯使体系为弱碱性,室温下搅拌6小时,搅拌后加入适量的3-氨丙基三乙氧基硅烷,继续搅拌,而后加入浓度为1mM活化的荧光分子,继续搅拌8小时,再次逐滴加入与3-氨丙基三乙氧基硅烷等量的正硅酸乙酯并搅拌6小时,经离心,洗涤,干燥,制得复合纳米粒子Fe3O4@RhB/SiO2。
所述步骤4)经磁铁分离后检测其近红外吸收光谱,经反复操作后检测其近红外吸收光谱范围605-747nm。
一种双模式靶向成像功能的纳米复合材料的应用,所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII用于靶向荧光共聚焦成像。
一种双模式靶向成像功能的纳米复合材料的应用,所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII用于靶向核磁共振成像。
一种双模式靶向成像功能的纳米复合材料的应用,所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII在用于肿瘤细胞的光热中的应用。
所述肿瘤细胞为结肠癌细胞。
本发明所具有的优点:本发明纳米复合材料同时具有双模式靶向成像与光热功能,其具有典型的内核和双外壳层的核壳结构;制备过程中采用溶剂热法制备具有强磁敏感性的超顺磁性Fe3O4纳米颗粒并与荧光分子组装形成复合纳米核;合成蔗糖稳定的单分散的金纳米球,利用Au-S键将其组装于纳米核表面并生长,构筑稳定且重复性高的金壳结构;所形成的纳米核壳材料可同时作为核磁共振成像和荧光成像的造影剂。通过调节复合纳米材料的吸收峰至近红外区域,并通过酰胺键将复合材料与SW620细胞特异性配体融合pVIII蛋白实现偶联。本发明所制得的材料通过核磁共振和荧光双模式具有可提高核磁共振造影效果、可控调节其近红外吸收峰、增强特异性识别能力、提高分散性和可重复性等优点实现对肿瘤细胞的特异性检测和高效的光热治疗。
附图说明
图1为本发明实施例制得Fe3O4@RhB/SiO2@Au纳米颗粒的UV-vis-NIR吸收光谱变化图;
图2为本发明实施例Fe3O4@RhB/SiO2@Au纳米颗粒的透射电镜图;
图3为本发明实施例中所制得Fe3O4、Fe3O4@RhB/SiO2和Fe3O4@RhB/SiO2@Au纳米颗粒的磁滞回线;
图4为本发明实施例制得的不同浓度Fe3O4@RhB/SiO2@Au@融fusion-pVIII纳米复合材料的MRI图像(A),T2弛豫效率与不同铁浓度的关系(B)。
图5为本发明实施例制得的Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米颗粒与SW620细胞、HEK293T细胞和HepG2细胞孵育4h后的激光共聚焦图片;
图6为本发明实施例制得的Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米颗粒与SW620细胞、HepG2细胞和HEK293T细胞孵育6h,采用功率为3W/cm2的808nm激光器照射不同时间细胞的存活率。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整的描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
本发明采用溶剂热法制备具有强磁敏感性的超顺磁Fe3O4纳米颗粒并与荧光分子组装形成复合纳米核;将稳定的单分散金纳米球,利用Au-S键将其组装于纳米核表面并生长,构筑稳定且重复性高的金壳结构;所形成的纳米核壳材料可同时作为核磁共振成像和荧光成像的造影剂。通过调节复合纳米材料的吸收峰至近红外区域,并通过酰胺键将复合材料与SW620细胞特异性配体融合pVIII蛋白实现偶联。本发明所制得的复合材料通过核磁共振和荧光双模式成像功能实现了对肿瘤细胞的特异性检测和高效的光热现象。
实施例1
取20mg溶剂热法合成的Fe3O4纳米颗粒,加入10mL浓度为0.1M的盐酸,超声处理10min,然后倒入50mL离心管中,9000rpm离心20min,除去上清,用去离子水洗涤沉淀三次,最终所得沉淀溶于4mL去离子水中,超声分散。向含有Fe3O4纳米颗粒的水溶液中加入16mL无水乙醇并混匀,然后逐滴加入200μl浓氨水,搅拌5min,在搅拌条件下逐滴加入200μL TEOS,于室温下搅拌6h,即可得到Fe3O4@SiO2纳米颗粒。
吸取20μL APTES加入至溶液中,继续搅拌反应12h,然后将20μL浓度为1mM活化的RhB荧光分子加入至溶液中,继续搅拌8h,再次逐滴加入200μL TEOS并搅拌6h,然后将纳米材料转移至50ml离心管中,9000rpm离心20min,除去上清,沉淀用无水乙醇和去离子水洗涤多次,最终溶于水中,置于60℃真空干燥箱中干燥过夜,所得固体粉末表征后备用。
Fe3O4@RhB/SiO2纳米颗粒表面巯基化:向上述所得Fe3O4@RhB/SiO2纳米颗粒的溶液中按照MPTMS:TEOS=1:5的比例逐滴加入MPTMS,室温搅拌24h。
将纳米金球负载于Fe3O4@RhB/SiO2纳米颗粒表面,并生长为金壳,最终得到Fe3O4@RhB/SiO2@Au纳米结构。取15mL金纳米球溶液,与1mL表面功能化的Fe3O4@RhB/SiO2纳米颗粒混匀,超声10min,然后室温静置2h。利用磁铁将偶联有金纳米球的Fe3O4@RhB/SiO2纳米颗粒分离,并用水洗涤三次,去除多余的金纳米球,沉淀重悬于1mL水中。配制8mL浓度为10mgmL-1的K2CO3溶液,与300μL浓度为10mM HAuCl4溶液混匀,室温搅拌30min,然后加入上述得到的Fe3O4@RhB/SiO2-AuNPs纳米颗粒并混匀,向溶液中加入75μL浓度为0.1M的抗坏血酸,振荡反应2h,所得产物经磁铁分离洗涤,检测其吸收光谱。多次重复此操作,至Fe3O4@RhB/SiO2@Au纳米颗粒的吸收峰移动至近红外区,如图1所示,显示了在合成过程中,随着表面金纳米颗粒的生长,Fe3O4@RhB/SiO2@Au的吸收峰逐渐红移,当第一次以Fe3O4@RhB/SiO2-AuNPs表面附着的金纳米颗粒为种子,在其表面还原HAuCl4时,其吸收峰红移至605nm,四次重复此操作以后,吸收峰红移至747nm。最终产物的电镜表征如图2所示,完整的Au壳包裹于Fe3O4@RhB/SiO2纳米颗粒表面形成了单一分散的Fe3O4@RhB/SiO2@Au纳米复合材料。X-射线能量色散谱分析结果显示Fe、Si和Au的同时存在,进一步证明我们已成功获得Fe3O4@RhB/SiO2@Au多层核壳纳米结构。
活化已分离的SW620细胞特异性融合pVIII蛋白。称取0.5mg融合pVIII蛋白至10mL离心管中并加入50μL dH2O,逐渐滴加THF至溶液澄清,总体积约150μL。向溶液中加入二碳酸二叔丁酯(BOC),使其终浓度为2mM,冰上振荡20min,转移至室温振荡3h,于4℃冰箱中静置过夜。将50mM的EDC和30mM的NHS混匀,然后取15μL加入至上述融合pVIII蛋白溶液中,室温避光静置5h,使融合pVIII蛋白的羧基端活化。
将活化的融合pVIII蛋白与合成的Fe3O4@RhB/SiO2@Au纳米颗粒连接。向上述制备的1mL含有Fe3O4@RhB/SiO2@Au纳米颗粒溶液中加入30μL浓度为1mM的半胱氨酸,超声混匀,然后避光搅拌5h。将已活化的pVIII蛋白与半胱氨酸修饰的Fe3O4@RhB/SiO2@Au纳米颗粒混合,置于4℃冰箱中过夜反应。然后按照TFA:BOC=5:1的比例向上述体系中加入0.175μLTFA,冰浴条件下振荡10min,转移至室温,继续搅拌5h,即可得到Fe3O4@RhB/SiO2@Au@fusion-pVIII多功能纳米复合材料。
图3为所制得Fe3O4、Fe3O4@RhB/SiO2和Fe3O4@RhB/SiO2@Au纳米颗粒的磁滞回线。在室温条件下,测量所得Fe3O4@RhB/SiO2@Au纳米颗粒的磁饱和强度。与Fe3O4和Fe3O4@SiO2纳米颗粒相比,Fe3O4@RhB/SiO2@Au纳米颗粒的Ms值显著降低,减小至10.837emu/g,但依然能被外部磁铁吸附并分离。对磁滞回线的局部放大,Fe3O4@RhB/SiO2@Au纳米颗粒的磁滞回线仍然经过原点,无矫顽力和剩磁力,是一种超顺磁纳米材料。因此,最终构筑的多功能核壳结构Fe3O4@RhB/SiO2@Au仍然具有一定强度的Ms,能被磁铁吸附分离,具备超顺磁性的特点,是临床肿瘤核磁共振成像的理想造影剂。
图4为不同浓度Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米复合材料的核磁共振图像(A),T2弛豫效率与不同铁浓度的关系(B)。Fe3O4@RhB/SiO2@Au@fusion-pVIII复合纳米材料水溶液的图像随着材料浓度的增加而逐渐变暗,推测是由于纳米材料有效缩短了其周围水中氢质子的弛豫时间,表现出显著的负增强效果。Fe3O4@RhB/SiO2@Au@fusion-pVIII复合纳米材料的r2值高达176.2mM-1s-1(图B),可作为一种理想的T2加权造影剂应用于肿瘤核磁共振检测。
图5为制得的Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米颗粒与SW620肿瘤细胞、HEK293T细胞和HepG2细胞孵育4h后的激光共聚焦图片。在550nm激光照射下,结肠肿瘤细胞SW620呈现红色荧光,而对照组HEK293T细胞和HepG2细胞未呈现荧光信号。因此,推测SW620细胞的荧光信号是由进入细胞的RhB分子在激发光下产生红色荧光,而对照组细胞中不存在荧光分子,所以没有出现荧光信号。由于荧光分子RhB包裹于SiO2壳中,在实验过程中不存在泄露进入细胞产生假阳性的情况,因此SW620细胞中的RhB荧光信号能够准确说明Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米材料与靶标特异性结合并进入图6为制得的Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米颗粒与SW620细胞、HepG2细胞和HEK293T细胞孵育6h,采用功率为3W/cm2的808nm激光器照射不同时间细胞的存活率。由于细胞和细胞培养液中的组分对近红外光无吸收,而Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米材料具有近红外光吸收的特性,当808nm激光照射时,能够有效地将吸收的光能通过电子的震动转化为热量,一定照射时间后,纳米材料产生的过高热能够导致细胞死亡。据此,SW620细胞的死亡是由于其吸收Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米材料产生的过高热引起,而对照细胞没有吸收纳米材料,对入射光无吸收且不能产生热量,其生存状态不受影响。这充分说明Fe3O4@RhB/SiO2@Au@fusion-pVIII纳米复合材料能够特异性识别并在3W/cm2的激光照射下杀伤肿瘤细胞,对肿瘤的靶向光热治疗具有重要价值。
由以上技术方案可知,本发明同时具有双模式靶向成像与光热功能的纳米复合材料,所述的纳米复合材料具有典型的内核和双外壳层的核壳结构。其制备采用溶剂热法制备具有强磁敏感性的超顺磁性Fe3O4纳米颗粒并与荧光分子组装形成复合纳米核;将稳定的单分散金纳米球,利用Au-S键将其组装于纳米核表面并生长,构筑稳定且重复性高的金壳结构;所形成的纳米核壳材料可同时作为核磁共振成像和荧光成像的造影剂。通过调节复合纳米材料的吸收峰至近红外区域,并通过酰胺键将复合材料与SW620细胞特异性配体融合pVIII蛋白实现偶联。本发明所制得的造影剂通过核磁共振和荧光双模式成像功能实现了对肿瘤细胞的特异性检测和高效的光热治疗。
上面结合附图对本发明优选的具体实施方式和实施例作了详细的说明,但是本发明并不限于上述实施方式和实施例,靶向探针也不限于特异性配体融合pVIII蛋白,其可能能够和待检测的肿瘤细胞特异性结合的抗体、靶向多肽配体或适配体等,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
本领域技术人员在考虑说明书及实践这里公开的发明后,将容易想到本发明的其它实施方案。本申请旨在涵盖本发明的任何变型、用途或者适应性变化,这些变型、用途或者适应性变化遵循本发明的一般性原理并包括本发明未公开的本技术领域中的公知常识或惯用技术手段。说明书和实施例仅被视为示例性的,本发明的真正范围和精神由权利要求指出。
Claims (10)
1.一种双模式靶向成像和光热转换功能的纳米复合材料,其特征在于:纳米复合材料为核壳型结构;其中,内核为具有强磁敏感性的超顺磁性Fe3O4纳米颗粒与掺杂荧光分子的SiO2层组装形成复合纳米核,外壳为具有较强的光热转换能力的偶联特异性配体的金纳米粒子靶向探针。
2.根据权利要求1所述的双模式靶向成像和光热转换功能的纳米复合材料,其特征在于:所述具有较强的光热转换能力的偶联特异性配体的金纳米粒子靶向探针为能够特异性识别肿瘤细胞的多肽配体。
3.根据权利要求2所述的双模式靶向成像和光热转换功能的纳米复合材料,其特征在于:所述具有较强的光热转换能力的金纳米粒子偶联特异性配体的探针为融合pVIII蛋白。
4.一种权利要求1所述的双模式靶向成像和光热转换功能的纳米复合材料的制备方法,其特征在于:
1)复合纳米粒子:将溶剂热法合成的Fe3O4纳米颗粒分散于0.1M盐酸中,超声处理、离心,洗涤得沉淀,沉淀再溶于去离子水中,超声分散;加入无水乙醇并混匀,随后在搅拌条件下加入正硅酸乙酯,条件保持弱碱性,室温下搅拌均匀,而后加入活化的荧光分子,继续搅拌、经离心,洗涤,干燥,制得复合纳米粒子Fe3O4@RhB/SiO2;
2)复合材料进行巯基化:将上述获得Fe3O4@RhB/SiO2纳米颗粒的溶液中逐滴加入3-巯丙基三甲氧基硅烷,室温下搅拌混合均匀;
3)纳米金连接:将纳米金溶液与上述表面巯基功能化的Fe3O4@RhB/SiO2纳米颗粒混匀,超声振荡,然后室温静置;利用磁铁将偶联有纳米金的Fe3O4@RhB/SiO2纳米颗粒分离,洗涤沉淀即为Fe3O4@RhB/SiO2-AuNPs,并将其重悬于水中,待用;
4)将碳酸钾溶液与氯金酸溶液室温搅拌混匀,混匀后与上述Fe3O4@RhB/SiO2-AuNPs纳米球混匀,再次混匀后加入抗坏血酸溶液,振荡产物经磁铁分离,洗涤,洗涤后再次重复步骤4)的操作,产物记为Fe3O4@RhB/SiO2@Au;
5)将采用蛋白活化剂和羧基端活化剂活化的融合pVIII蛋白与上述合成的Fe3O4@RhB/SiO2@Au纳米球连接,即可得到Fe3O4@RhB/SiO2@Au@fusion-pVIII多功能纳米复合材料。
5.根据权利要求4所述的双模式靶向成像和光热转换功能的纳米复合材料的制备方法,其特征在于:所述经无水乙醇混匀后加入正硅酸乙酯使体系为弱碱性,室温下搅拌6小时,搅拌后加入适量的3-氨丙基三乙氧基硅烷,继续搅拌,而后加入浓度为1mM活化的荧光分子,继续搅拌8小时,再次逐滴加入与3-氨丙基三乙氧基硅烷等量的正硅酸乙酯并搅拌6小时,经离心,洗涤,干燥,制得复合纳米粒子Fe3O4@RhB/SiO2。
6.根据权利要求4所述的双模式靶向成像和光热转换功能的纳米复合材料的制备方法,其特征在于:所述步骤4)经磁铁分离后检测其近红外吸收光谱,经反复操作后检测其近红外吸收光谱范围605-747nm。
7.一种权利要求1所述的双模式靶向成像和光热转换功能的纳米复合材料的应用,其特征在于:所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII用于靶向荧光成像。
8.一种权利要求1所述的双模式靶向成像和光热转换功能的纳米复合材料的应用,其特征在于:所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII用于靶向核磁共振成像。
9.一种权利要求1所述的双模式靶向成像和光热转换功能的纳米复合材料的应用,其特征在于:所述纳米复合材料Fe3O4@RhB/SiO2@Au@fusion-pVIII用于肿瘤细胞的光热治疗中的应用。
10.根据权利要求9所述的双模式靶向成像和光热转换功能的纳米复合材料的应用,其特征在于:所述肿瘤细胞为结肠癌细胞。
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