CN110124060A - 一种双模式光学示踪纳米药物载体及其制备方法 - Google Patents
一种双模式光学示踪纳米药物载体及其制备方法 Download PDFInfo
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- CN110124060A CN110124060A CN201910494725.3A CN201910494725A CN110124060A CN 110124060 A CN110124060 A CN 110124060A CN 201910494725 A CN201910494725 A CN 201910494725A CN 110124060 A CN110124060 A CN 110124060A
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- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
本发明公开了一种双模式光学示踪纳米药物载体及其制备方法,该药物载体包括芯层、包层和涂敷层,包层为空心碳纳米管,芯层设置在包层内腔,涂敷层设在在包层外壁;芯层为温度相变特性的吲哚,涂敷层为吸附有SERS标记物的金核银壳纳米粒子和荧光探针;药物模型Ⅰ通过吲哚封装在包层内腔,药物模型Ⅱ通过空心碳纳米管化学特性装载在包层外壁,实现温度控制药物模型Ⅰ释放和pH控制药物模型Ⅱ释放。该药物载体利用碳纳米管和金属纳米粒子复合结构实现了多种药物协同运输并控制释放,表面增强拉曼散射(SERS)和荧光双模式光学示踪。
Description
技术领域
本发明涉及纳米材料制备技术,尤其涉及一种新型双模式光学示踪纳米药物载体及其制备方法,该结构的双模光学示踪纳米药物载体将表面增强拉曼散射(SERS)信号、荧光信号和碳纳米管载体结构集于一体,具备荧光和SERS双光学示踪能力和多药物运输功能。
背景技术
近年来,随着纳米材料制备、表征等技术的高速发展,基于纳米材料的多功能纳米药物载体以其独特的药物运输特性、小尺寸以及靶向和示踪的特点在生物诊断和生物医学领域具有重大的应用前景。
在光学示踪技术中,荧光探测技术快速且简单,是一种常用的生物检测手段,在生物传感、药物研发、肿瘤诊断治疗等领域中得到广泛应用。表面增强拉曼散射(SERS)技术由于其超高的灵敏度以及独特的“指纹”光谱特性,其谱线窄、检测条件温和、对生物样品损伤小、不易光漂白等特点被广泛地应用在环境检测、细胞成像和病原体/蛋白质检测等领域。
在生物医学方面,纳米药物载体系统是目前研究肿瘤治疗的热点之一。纳米药物载体是一种尺寸较小的纳米级药物输送系统,可以将高浓度的抗肿瘤药物、DNA或一些大分子运输到肿瘤部位。这种纳米药物载体的具有的屏蔽作用不仅可以将水溶性较差的药物运输到细胞内部还可以在血液循环系统中流动时对药物起到保护作用。这种纳米药物载体主要由三个部分组成:(1)载体材料;(2)负载物包括药物或者生物活性分子;(3)表面功能化修饰。
然而,随着研究的不断深入,人们对纳米药物载体的要求不断提高通常,已有的药物载体很难实现药物的运输和检测同时进行。若能实现载体在运输的过程中同时药物分子或肿瘤标记物的检测,在运送药物到达病灶的同时还能获得更加丰富的肿瘤相关信息,这将为癌症诊断和肿瘤治疗效果的评估提供更可靠的判据。通常用于纳米药物载体光学示踪主要是基于荧光信号,以量子点为例,在药物载体上标记上量子点可以实现对载体的荧光示踪,但是合成量子点所用到的原料一般都是重金属,毒性很大,不利于生物体内应用,此外对于没有荧光特性的药物也很难实现药物的示踪。而拉曼信号较弱,在生物体内实现药物载体的示踪则需要进行增强形成SERS光谱信号。此外,药物载体还需要具有可控释放的功能,避免药物在到达肿瘤患处前提前释放,从而增加肿瘤患处的药物浓度,提高药物的治疗效率。
因而,如果能在一个光学探针体系中同时集成荧光与SERS信号部分,使该探针具备荧光与SERS联合成像的能力。集成荧光和SERS双模式光学示踪、载药特性、操作简便、药物可控释放等诸多优点于一体的多功能纳米药物载体,以满足肿瘤早期诊断和治疗一体化的要求。
发明内容
发明目的:为了克服现有技术中存在的不足,本发明提供一种新型双模式光学示踪纳米药物载体,该纳米药物载体将SERS、荧光技术和纳米药物载药技术结合在一起,具备优异的光学双模成像和出色的药物运输能力,这种新型的双模光学示踪纳米药物载体不仅可以监测生物环境内载体的分布和动态过程,还可以实现同时监测生物环境内多种药物的示踪和控制药物释放功能。本发明同时提供一种碳纳米管和SERS、荧光技术相结合的多功能药物载体的制备方法,该方法制备出来的载体的光学信号强、稳定性好、操作简单、载药量大,并且可重复性好、成本低廉。
技术方案:为实现上述目的,本发明采用的技术方案为:
本发明的双模式光学示踪纳米药物载体结合大内径空心碳纳米管和SERS、荧光技术,主要包括分散于水溶液中的纳米药物载体,每个纳米药物载体包括芯层、包层和涂敷层,载体的芯层装载药物模型Ⅰ,并利用温度相变特性将药物模型Ⅰ封装在包层内部,实现温度控制药物模型Ⅰ的释放;并利用载体的包层,即碳纳米管管壁化学特性装载药物模型Ⅱ,实现pH控制药物模型Ⅱ的释放。载体的涂敷层吸附有表面增强拉曼散射标记物(SERS标记物)的金核银壳纳米粒子和荧光分子。在激发光照射下,能够产生较强的SERS和荧光信号。
一种双模式光学示踪纳米药物载体,包括芯层、包层和涂敷层,包层为大内径空心碳纳米管,芯层设置在包层内腔,涂敷层设在在包层外壁;芯层为温度相变特性的吲哚,涂敷层为吸附有表面增强拉曼散射SERS标记物的金核银壳纳米粒子和荧光探针;药物模型Ⅰ通过吲哚封装在包层内腔,药物模型Ⅱ通过空心碳纳米管化学特性装载在包层外壁,实现温度控制药物模型Ⅰ释放和pH控制药物模型Ⅱ释放,该药物载体在细胞溶酶体内或近红外光照射下能够实现药物的可控释放。
一种上述双模式光学示踪纳米药物载体的制备方法,包括如下步骤:
S1、对空心碳纳米管进行功能化修饰,确保空心碳纳米管内腔贯通不封堵,空心碳纳米管长度和空心碳纳米管水溶性均满足设定要求,并在空心碳纳米管外壁修饰羧基官能团;
S2、使用柠檬酸钠还原法制备金核银壳纳米粒子,该方法制备的金核银壳纳米粒子的尺寸可调且稳定性好,SERS增强效果亦良好;
S3、在S1得到的空心碳纳米管外壁包裹一层聚合物,完成空心碳纳米管外壁氨基功能团的修饰;
S4、在S3得到的包裹聚合物的碳纳米管外壁修饰吸附有SERS标记物的金核银壳纳米粒子和荧光探针,得到具有SERS和荧光双模示踪的纳米药物载体;
S5、在S4得到的纳米药物载体的腔体内装载药物模型Ⅰ并使用温度相变特性的吲哚作为塞子将药物模型Ⅰ封装在纳米药物载体的腔体内不泄露,在不同的温度下吲哚会呈现出液态和固态两种状态,从而起到腔体塞子的开关作用;
S6、在S5得到的纳米药物载体外壁装载药物模型Ⅱ。
具体的,所述S1中,在空心碳纳米管外壁修饰羧基官能团的方法为:首先使用浓硫酸和浓硝酸混合超声处理方法制备稳定的碳纳米管水溶液,然后采用具有水溶性的羧基功能团修饰得到的碳纳米管水溶液,最后通过0.22μm孔径的滤膜过滤和透析袋处理使得最终得到溶液的pH达到中性。
具体的,使用浓硫酸和浓硝酸混合超声处理方法制备稳定的碳纳米管水溶液,所述浓硫酸和浓硝酸的摩尔比为1:3。
具体的,所述药物模型Ⅰ通过近红外光照导致的温度响应释放,药物模型Ⅱ通过pH值控制释放。
具体的,所述S4中,SERS标记物为易于通过化学键方式标记到金属表面的拉曼分子,该类SERS标记物具有较大拉曼散射截面,链接到金属表面后产生的SERS信号较强;荧光探针为易于通过化学键方式标记到氨基功能团上的荧光探针,该类荧光标记物具有较强的发射光谱和较高的光稳定性。
具体的,所述药物模型Ⅰ为6-巯基鸟嘌呤,药物模型Ⅱ为盐酸阿霉素。
具体的,所述SERS标记物为4-巯基苯甲酸,荧光探针为异硫氰酸荧光素。
具体的,所述大内径空心碳纳米管的长度约0.5~1μm,外径为30-60nm,内径为20-50nm范围内。
有益效果:本发明提供的双模式光学示踪纳米药物载体及其制备方法,与现有技术相比,具有如下优点:1、本发明的制备方法操作简单、可重复性好、成本低廉并且环境友好,大内径碳纳米管、合金纳米粒子和SERS、荧光标记物也只需要极少的量就可以完成纳米粒子的制备;制备出来的纳米药物载体稳定性好,对生物体的毒性小。2、本发明的光学可示踪纳米药物载体使用大内径碳纳米管做作为载体,其内部呈中空形,表面的可功能化修饰的富勒烯结构,可以应用于装载各类药物分子。3、本发明的光学可示踪纳米药物载体外部塞子具有温度相变特性,可以在较低温度下打开塞子释放被装载在纳米药物载体空心结构内部的药物分子。4、本发明的光学可示踪纳米药物载体具有近红外光吸收特性,在近红外激光照射下可以将近红外光转化为热能。5、本发明的纳米药物载体主要具有SERS-荧光双模光学信号、载药特性和光热的特点,在药物装载运输、瘤细胞光热治疗、生物传感及探测等应用领域具有重要的潜在应用价值。
附图说明
图1本发明的双模式光学示踪纳米药物载体的结构示意图;
图2以4-巯基苯甲酸(4MBA)分子为SERS标记物,将4MBA分子标记在金核银壳纳米粒子表面,激发SERS光谱,激发波长为633nm;
图3以异硫氰酸荧光素(FITC)分子为荧光标记物,将FITC分子标记在碳纳米管外壁上,激发荧光光谱,激发波长为488nm;
图4以盐酸阿霉素(DOX)作为药物模型Ⅱ,将DOX装载在碳纳米管外壁上,激发荧光光谱,激发波长为633nm;
图5以6-巯基鸟嘌呤(6-TG)为药物模型Ⅰ和异硫氰酸荧光素(FITC)混合(为了方便使用荧光手段观测药物模型Ⅰ的释放过程,在实际应用时可以不封装荧光分子),装载到碳纳米管的空心腔体内并用吲哚封闭,然后通过加热实现FITC和6-TG的控制释放并测得溶液中载体释放FITC的荧光光谱强度,结果显示碳纳米管空心腔内装载FITC和6-TG后释放的荧光强度远强于FITC标记载体的荧光强度,间接证明了腔内药物的释放过程;发波长为488nm。
图6该双模式光学示踪纳米药物载体的近红外光热测试结果,激光照射波长为808nm。
具体实施方式
下面结合附图对本发明作更进一步的说明。
本发明的双模式光学示踪纳米药物载体是一种多功能的复合纳米粒子,以大内径碳纳米管作为模板和支撑物,在其表面修饰了标记SERS标记物的金核银壳纳米粒子和荧光探针,同时在最外层上修饰靶向分子实现肿瘤细胞靶向功能。该双模式光学示踪纳米药物载体在激发光照射下,能产生荧光和SERS信号,具备荧光、SERS联合示踪能力;该双模式光学示踪纳米药物载体在碱中性和高温条件下能实现药物的装载与运输功能,并具有在肿瘤细胞组织处、肿瘤细胞溶酶体和近红外激光照射下实现药物的控制释放能力。该本发明中采用一种拉曼分子、一种荧光标记物及两种抗肿瘤药物来制备双模式光学示踪纳米药物载体。拉曼分子为4-巯基苯甲酸(4-Mercaptobenzoic acid,4MBA),荧光探针为异硫氰酸荧光素(FITC)。两种抗肿瘤药物分别为盐酸阿霉素(Doxorubicin,DOX)和6-巯基鸟嘌呤(6-Thioguanine,6-TG)。
下面结合附图和实施例对本发明作更进一步的说明。
实施例1以Au@Ag纳米粒子作为SERS基底,以大内径碳纳米管为载体,以4MBA作为SERS标记物,以FITC为荧光分子,制备双模式光学示踪纳米药物载体粒子;实施例2以Au@Ag纳米粒子作为SERS基底,以大内径碳纳米管为载体,以6-TG和DOX作为抗肿瘤药物,制备双模式光学示踪纳米药物载体粒子。
实施例1
以大内径碳纳米管为载体,以Au@Ag纳米粒子为SERS基底,以4MBA作为SERS标记物,以FITC为荧光分子,制备双模式光学示踪纳米药物载体粒子,该方法包括如下步骤:
(1)制备水溶性大内径碳纳米管,首先对碳纳米管剪切短化修饰。取10mg通过乙炔经过镍基催化剂催化裂解方式制备得到的大内径薄壁多壁碳纳米管(LNCNTs),LNCNTs的内径一般大于20nm,外径为30-60nm,长度1~10μm。将LNCNTs和50mL浓硫酸-浓硝酸混合液(摩尔比3:1)混合后加入玻璃烧瓶中,并烧瓶置于将水温为50°的超声波清洗仪中超声处理12h,然后用大量的去离子水对混合溶液进行稀释。接着,通过0.22μm的滤膜过滤1次,通过离心机5000转/分钟转速离心清洗2次,最后取10mL浓缩液体加入到透析袋中透析12小时至溶液为中性。所制得剪切短的大内径碳纳米管长度约为0.5-1μm左右。
(2)制备金纳米球粒子(Au NPs)。取2mL 1%的氯金酸溶液加入到200mL去离子水中,加热至沸腾,然后加入8mL 1%的柠檬酸三钠溶液加热搅拌至再次沸腾,待溶液颜色变为酒红色后,冷却溶液以备用。所制得的Au NPs尺寸约为15nm左右。
(3)制备金核银壳纳米球粒子(Au@Ag NPs)。在步骤(2)得到的Au NPs溶液中加入16mL 1%的氯金酸溶液,加热至沸腾,然后将20mL 10mM硝酸银(AgNO3)溶液逐滴加入上述沸腾的Au NPs溶液中持续加热并剧烈搅拌,反应溶液随着AgNO3的加入而逐渐由酒红色变成棕黄色,再持续搅拌加热0.5h后,将溶液冷却并常温保存腾,待溶液颜色变为酒红色后,冷却溶液以备用。所制得的Au@Ag NPs尺寸约为28nm左右。
(4)制备金核银壳纳米/碳纳米管复合纳米药物载体(LNCNTs/Au@Ag NPs)。首先将2mg剪切短的LNCNTs分散到10mL 10mg/mL的聚丙烯胺盐酸盐(PAH)溶液中:超声30分钟后,高速离心洗涤,重新分散到2ml的去离子水中,即得包裹PAH的LNCNTs。金核银壳纳米/碳纳米管复合纳米粒子由于PAH的包裹,因此其表面存在氨基使粒子表现为正,而Au@Ag NPs使用柠檬酸钠作为粒子稳定剂,故Au@Ag NPs表面为负电性。取200μL所制的包裹PAH的LNCNTs溶液加入到40mL的Au@Ag NPs溶液中,常温超声15min后,3500转/分钟转速离心2次清洗以去除上清游离的Au@Ag NPs,并重新分散到10mL的去离子水中,即得LNCNTs/Au@Ag NPs。
(5)在步骤(4)得到的纳米粒子溶液中依次加入20μL 10-3M 4MBA,缓慢搅拌3小时以上,然后将溶液以4000转/分钟,10分钟离心清洗并收集反应液中的纳米粒子,最终将该纳米粒子分散在10mL去离子水中。
(6)金核银壳纳米/碳纳米管复合纳米药物载体表面修饰荧光染料。金核银壳纳米/碳纳米管复合纳米粒子由于PAH的包裹,因此其表面存在氨基,取1mL 0.5mg/mL FITC水溶液加入到10mL步骤(4)中得到的复合纳米粒子水溶液并缓慢搅拌1h。然后以4000转/分钟,10分钟离心清3次过量的FITC并分散至10mL去离子水中即得同时具有荧光及SERS信号的双模式纳米药物载体粒子。
如图1所示,该双模式光学示踪药物载体,包括分散于水溶液中的纳米粒子,每个纳米粒子呈多层结构,芯层为药物模型Ⅰ1和吲哚2混合物,包层为大内径薄壁碳纳米管3并修饰荧光标记物7,涂敷层为附着在大内径空心碳纳米管3表面上的标记有SERS标记物5的金核银壳纳米粒子6。
该金核银壳纳米/碳纳米管复合纳米载体粒子的SERS信号探测是通过将该光学探针滴于硅片上,并固定在共焦拉曼光谱仪上测得。激光源为633nm的氩离子激光器,样品上的照射功率为1.5mW,积分时间为10s。荧光信号通过荧光光谱仪探测,激发波长为488nm。该载体粒子既有信噪比很高的SERS信号(图2)又具有荧光示踪特性(图3),可以实现荧光与SERS联合成像的功能,适用于的生物成像和靶分子探测。
实施例2
制备以Au@Ag核壳结构纳米材料修饰大内径碳纳米管为载体,以盐酸阿霉素(DOX)分子和6-巯基鸟嘌呤(6-TG)分子为药物模型的光学示踪药物载体,该方法包括如下步骤:
(1)制备水溶性大内径碳纳米管,首先对碳纳米管剪切短化修饰。取10mg通过乙炔经过镍基催化剂催化裂解方式制备得到的大内径薄壁多壁碳纳米管(LNCNTs),LNCNTs的内径一般大于20nm,外径为30-60nm,长度1~10μm。将LNCNTs和50mL浓硫酸-浓硝酸混合液(摩尔比3:1)混合后加入玻璃烧瓶中,并烧瓶置于将水温为50°的超声波清洗仪中超声处理12h,然后用大量的去离子水对混合溶液进行稀释。接着,通过0.22μm的滤膜过滤1次,通过离心机5000转/分钟转速离心清洗2次,最后取10mL浓缩液体加入到透析袋中透析12小时至溶液为中性。所制得剪切短的大内径碳纳米管长度约为0.5-1μm左右。
(2)制备金纳米球粒子(Au NPs)。取2mL 1%的氯金酸溶液加入到200mL去离子水中,加热至沸腾,然后加入8mL 1%的柠檬酸三钠溶液加热搅拌至再次沸腾,待溶液颜色变为酒红色后,冷却溶液以备用。所制得的Au NPs尺寸约为15nm左右。
(3)制备金核银壳纳米球粒子(Au@Ag NPs)。在步骤(2)得到的Au NPs溶液中加入16mL 1%的氯金酸溶液,加热至沸腾,然后将20mL 10mM硝酸银(AgNO3)溶液逐滴加入上述沸腾的Au NPs溶液中持续加热并剧烈搅拌,反应溶液随着AgNO3的加入而逐渐由酒红色变成棕黄色,再持续搅拌加热0.5h后,将溶液冷却并常温保存腾,待溶液颜色变为酒红色后,冷却溶液以备用。所制得的Au@Ag NPs尺寸约为28nm左右。
(4)制备金核银壳纳米/碳纳米管复合纳米药物载体(LNCNTs/Au@Ag NPs)。首先将2mg剪切短的LNCNTs分散到10mL 10mg/mL的聚丙烯胺盐酸盐(PAH)溶液中:超声30分钟后,高速离心洗涤,重新分散到2ml的去离子水中,即得包裹PAH的LNCNTs。金核银壳纳米/碳纳米管复合纳米粒子由于PAH的包裹,因此其表面存在氨基使粒子表现为正,而Au@Ag NPs使用柠檬酸钠作为粒子稳定剂,故Au@Ag NPs表面为负电性。取200μL所制的包裹PAH的LNCNTs溶液加入到40mL的Au@Ag NPs溶液中,常温超声15min后,3500转/分钟转速离心2次清洗以去除上清游离的Au@Ag NPs,并重新分散到10mL的无水乙醇溶液中,即得LNCNTs/Au@Ag NPs纳米药物载体溶液。
(5)将在步骤(4)得到的复合纳米药物载体溶液中加入20mg吲哚,然后将混合溶液密封在取样瓶内,70℃环境下搅拌8小时。然后将混合溶液使用4℃含15%的乙醇溶液清洗三次,除去没有装载入纳米载体的多余吲哚分子。最后将得到的装载了吲哚的纳米药物载体重新分散到10mL去离子水溶液中并4℃保存。
(6)使用三乙胺溶液将在步骤(5)得到的装载吲哚的纳米药物载体溶液pH值调整为8.0,然后加入10μL 0.5mg/mL的DOX溶液,常温暗室条件下缓慢搅拌12小时以上装载DOX,然后将反应溶液3500转/分钟,5分钟离心清洗二次,去除上清溶液并收集沉淀物,最终将装载DOX的纳米药物载体重新分散在10mL的水溶液中即得同时DOX和吲哚两种药物的纳米药物载体。
如图1所示,该双模示踪纳米药物为分散于水溶液中的纳米粒子,每个纳米粒子包括芯层、包层和涂覆层,芯层大内径碳纳米管内径中的吲哚分子2和药物模型Ⅱ,包层为大内径空心碳纳米管3,涂覆层为碳纳米管管壁3外层修饰荧光分子7、吸附拉曼分子5标记的金核银壳纳米粒子6和药物模型Ⅱ4。
该双模式光学示踪纳米药物载体是通过大内径碳纳米管的管壁上π-π化学键和空心结构装载药物。空心关口的封闭塞是利用吲哚(Indole)温度相变特性,当温度在52℃以上时,吲哚由固态变为液态,液态吲哚可以进入到大内径CNTs的内壁中并在常温情况下变成固态对大内径碳纳米管空心进行封闭。
该双模式光学示踪纳米药物载体的SERS信号探测是通过该药物载体植入活细胞内,并固定在共焦拉曼光谱仪上测得。激光源波长为633nm,细胞样品上的照射功率为1.2mW,积分时间为10s。荧光信号探测是通过将药物载体溶液植入活细胞体内,在搭配探测器和光谱仪的共聚焦显微镜上测得,激发光源为波长488nm,该标记具有信噪比很高的SERS和荧光信号,适用于的生物光学成像和靶分子检测。
综上,本发明提供的药物载体利用碳纳米管和金属纳米粒子复合结构实现了多种药物协同运输并控制释放,表面增强拉曼散射(SERS)和荧光双模式光学示踪。该药物载体以Au@Ag核壳结构纳米粒子为SERS基底;以荧光分子作为荧光标记物,以大内径空心碳纳米管为药物载体形成特定结构的SERS和荧光双模光学示踪的纳米药物载体,以碳纳米管空心结构和碳纳米管管壁作为药物运输载体,以温度相变的吲哚作为封闭物;该药物载体在可见波段的激发光照射下,产生具有较高信噪比的SERS和荧光信号,在酸性环境和近红外激光照射下实现药物模型的控制释放。采用大内径碳纳米管和金核银壳纳米复合物作为药物载体,实现荧光和SERS双模式光学示踪、载药特性、操作简便、药物可控释放等诸多优点于一体的多功能纳米药物载体,以满足肿瘤早期诊断和治疗一体化中队药物载体的多功能要求。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种双模式光学示踪纳米药物载体,其特征在于:包括芯层、包层和涂敷层,包层为空心碳纳米管,芯层设置在包层内腔,涂敷层设在在包层外壁;芯层为温度相变特性的吲哚,涂敷层为吸附有SERS标记物的金核银壳纳米粒子和荧光探针;药物模型Ⅰ通过吲哚封装在包层内腔,药物模型Ⅱ通过空心碳纳米管化学特性装载在包层外壁,实现温度控制药物模型Ⅰ释放和pH控制药物模型Ⅱ释放。
2.一种权利要求1所述的双模式光学示踪纳米药物载体的制备方法,其特征在于:包括如下步骤:
S1、对空心碳纳米管进行功能化修饰,确保空心碳纳米管内腔贯通,空心碳纳米管长度和空心碳纳米管水溶性均满足设定要求,并在空心碳纳米管外壁修饰羧基官能团;
S2、使用柠檬酸钠还原法制备金核银壳纳米粒子;
S3、在S1得到的空心碳纳米管外壁包裹一层聚合物,完成空心碳纳米管外壁氨基功能团的修饰;
S4、在S3得到的包裹聚合物的碳纳米管外壁修饰吸附有SERS标记物的金核银壳纳米粒子和荧光探针,得到具有SERS和荧光双模示踪的纳米药物载体;
S5、在S4得到的纳米药物载体的腔体内装载药物模型Ⅰ并使用温度相变特性的吲哚作为塞子将药物模型Ⅰ封装在纳米药物载体的腔体内不泄露;
S6、在S5得到的纳米药物载体外壁装载药物模型Ⅱ。
3.根据权利要求2所述的制备方法,其特征在于:所述S1中,在空心碳纳米管外壁修饰羧基官能团的方法为:首先使用浓硫酸和浓硝酸混合超声处理方法制备稳定的碳纳米管水溶液,然后采用具有水溶性的羧基功能团修饰得到的碳纳米管水溶液,最后通过0.22μm孔径的滤膜过滤和透析袋处理使得最终得到溶液的pH达到中性。
4.根据权利要求3所述的制备方法,其特征在于:使用浓硫酸和浓硝酸混合超声处理方法制备稳定的碳纳米管水溶液,所述浓硫酸和浓硝酸的摩尔比为1:3。
5.根据权利要求2所述的制备方法,其特征在于:所述药物模型Ⅰ通过近红外光照导致的温度响应释放,药物模型Ⅱ通过pH值控制释放。
6.根据权利要求2所述的制备方法,其特征在于:所述S4中,SERS标记物为通过化学键方式标记到金属表面的拉曼分子;荧光探针为通过化学键方式标记到氨基功能团上的荧光探针。
7.根据权利要求2所述的制备方法,其特征在于:所述药物模型Ⅰ为6-巯基鸟嘌呤,药物模型Ⅱ为盐酸阿霉素。
8.根据权利要求2所述的制备方法,其特征在于:所述SERS标记物为4-巯基苯甲酸,荧光探针为异硫氰酸荧光素。
9.根据权利要求2所述的制备方法,其特征在于:所述空心碳纳米管的长度为0.5~1μm,外径为30-60nm,内径为20-50nm。
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