CN106474493B - 用于体内细菌感染的诊疗一体化纳米探针及其制备方法 - Google Patents
用于体内细菌感染的诊疗一体化纳米探针及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种用于体内细菌感染的诊疗一体化纳米探针,包括硅纳米颗粒,硅纳米颗粒外包裹有聚阳离子电解质层,聚阳离子电解质层外侧修饰有近红外有机荧光染料,且交联有聚乙二醇和细菌靶向分子;本发明还公开了其制备方法:制备粒径为60‑80nm的硅纳米颗粒;将硅纳米颗粒加入到聚阳离子电解质的盐溶液中,搅拌反应后得到聚阳离子电解质包裹的硅纳米颗粒;将近红外有机荧光染料溶于有机溶剂中,加入共价偶联剂进行活化,再加入聚阳离子电解质包裹的硅纳米颗粒,反应后得到表面修饰有近红外有机荧光染料的硅纳米颗粒;将聚乙二醇和细菌靶向分子进行活化后交联到硅纳米颗粒表面的聚阳离子电解质上,得到用于体内细菌感染的诊疗一体化纳米探针。
Description
技术领域
本发明涉及医用纳米材料领域,尤其涉及一种用于体内细菌感染的诊疗一体化纳米探针及其制备方法。
背景技术
细菌是一类重要的病原体,它们侵入机体后会分泌产生大量的生物毒素,从而破坏机体的结构和功能,造成宿主感染。近年来,由于抗生素的滥用,抗药性细菌(如耐甲氧西林金黄色葡萄球菌MRSA)大量出现,病原细菌引起的感染疾病已成为危害人类身体健康的重要杀手,引起了全球性的广泛关注。因此为开展细菌感染疾病的早期诊断与治疗,研究病原细菌的快速检测和治疗技术具有非常重要的意义。
目前,临床上主要通过对组织或血液样本进行凃板培养,然后根据长出的细菌菌落的形态及生理生化反应特征来完成细菌感染的分析诊断。然而这种基于细菌培养法的诊断策略耗时较长(几天时间)、操作繁琐,且只能用于体外环境。因此,如何实现对体内细菌感染的快速、非侵入检测已成为近年来的研究热点,这其中尤以近红外荧光成像技术得到了广泛关注,且一系列近红外荧光探针已被成功用于体内细菌感染的分析诊断。然而,这些探针存在着诸如检测灵敏度低、准确性差、应用面较窄等缺点。另外,如何实现对体内细菌感染诊断同时的有效治疗,尤其对抗药性细菌的有效诊断和杀灭是如今细菌感染研究的难点。因此,构建一种针对体内细菌感染的诊疗一体化探针具有广泛的临床应用前景。
有鉴于上述的缺陷,本设计人,积极加以研究创新,以期创设一种新型的用于体内细菌感染的诊疗一体化纳米探针及其制备方法,使其更具有产业上的利用价值。
发明内容
为解决上述技术问题,本发明的目的是提供一种用于体内细菌感染的诊疗一体化纳米探针及其制备方法,本发明能够实现对体内细菌感染的快速、非侵入、高灵敏度诊断和高效治疗。
本发明的一种用于体内细菌感染的诊疗一体化纳米探针,包括硅纳米颗粒,硅纳米颗粒外包裹有聚阳离子电解质层,聚阳离子电解质层外侧修饰有近红外有机荧光染料,且交联有聚乙二醇和细菌靶向分子。
进一步的,近红外有机荧光染料为碳菁类荧光染料。
进一步的,硅纳米颗粒的粒径为60-80nm,这一范围的纳米颗粒不宜被血液清除,一定程度上延长了其体内滞留时间。
进一步的,硅纳米颗粒为实心二氧化硅纳米颗粒或介孔二氧化硅纳米颗粒。
进一步的,聚阳离子电解质选自聚丙烯氯化铵、聚二烯丙基二甲基氯化铵或聚乙烯亚胺中的一种。
进一步的,聚阳离子电解质的分子量为10000-20000g/mol,这一分子量范围的聚电解质修饰一方面既可以增强硅纳米颗粒的稳定性,另一方面在细菌存在条件下也易于从硅纳米颗粒表面脱落。
进一步的,近红外有机荧光染料选自吲哚菁绿或Cypate。
进一步的,聚乙二醇的分子量为3000-5000g/mol,这一分子量范围的聚乙二醇修饰可以增强纳米探针在体内的稳定性和滞留时间。
进一步的,细菌靶向分子选自万古霉素和/或细菌特异性抗体,细菌特异性抗体为大肠杆菌K99抗体或耐甲氧西林金黄色葡萄球菌MRSA抗体。
本发明还公开了一种用于体内细菌感染的诊疗一体化纳米探针的制备方法,包括以下步骤:
(1)制备粒径在60-80nm的硅纳米颗粒;
(2)将步骤(1)得到的硅纳米颗粒加入到聚阳离子电解质的盐溶液中,搅拌反应后得到聚阳离子电解质包裹的硅纳米颗粒;
(3)将近红外有机荧光染料溶于有机溶剂中,加入共价偶联剂进行活化,再加入步骤(2)得到的聚阳离子电解质包裹的硅纳米颗粒,搅拌反应后得到表面修饰有近红外有机荧光染料的硅纳米颗粒;
(4)将聚乙二醇和细菌靶向分子进行活化后与步骤(3)得到的硅纳米颗粒表面的聚阳离子电解质交联,得到用于体内细菌感染的诊疗一体化纳米探针。
进一步的,在步骤(3)中,有机溶剂为N,N-二甲基甲酰胺、氯仿或二甲亚砜中的一种。
进一步的,在步骤(3)中,共价偶联剂为EDC(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)和NHS(N-羟基琥珀酰亚胺)。
进一步的,在步骤(3)中,搅拌反应后进行离心,水洗后将表面修饰有近红外有机荧光染料的硅纳米颗粒分散在水中或PBS缓冲液中。
进一步的,在步骤(4)中,将聚丙烯酸溶于水中,加入EDC和NHS共价偶联剂活化,再加入氨基-聚乙二醇和细菌靶向分子,搅拌反应以将聚丙烯酸分子的羧基与氨基-聚乙二醇和细菌靶向分子的氨基反应,再加入步骤(3)得到的硅纳米颗粒和共价偶联剂,以使聚丙烯酸与聚阳离子电解质发生交联,从而将聚乙二醇和细菌靶向分子交联到硅纳米颗粒表面的聚阳离子电解质上。
进一步的,本发明的诊疗一体化纳米探针对体内细菌感染进行近红外荧光成像诊断和光热治疗。
进一步的,诊疗一体化纳米探针在无细菌情况下发生荧光淬灭,在细菌存在时,硅纳米颗粒外的聚阳离子电解质脱落,从而使得其荧光恢复,最终实现对体内细菌感染的高灵敏度诊断。
进一步的,进行光热治疗时,使用近红外激光器对细菌感染部位照射以使感染部位局部温度快速升高,杀灭细菌。
本发明在带有负电的硅纳米颗粒表面包裹带正电的聚阳离子电解质层,二者之间具有静电相互作用,聚阳离子电解质层外部修饰有疏水性的有机荧光染料分子,由于疏水性有机荧光染料分子在硅纳米颗粒表面的聚集,此纳米探针的荧光在正常情况下是淬灭的。在细菌存在的情况下,由于有机荧光染料外层的细菌靶向分子与细菌发生相互作用,该相互作用力强于上述硅纳米颗粒和聚阳离子电解质之间的静电相互作用力,因此硅纳米颗粒表面的聚电解质层会发生脱落,有机荧光染料分子间的距离加大,从而使得其荧光恢复,最终可实现对体内细菌感染的高灵敏度诊断;此外,由于本发明使用的碳菁类染料除近红外荧光外还具有光热转换效应,因此通过使用近红外激光器对细菌感染部位照射,可以使感染部位局部温度快速升高,从而在荧光诊断的同时实现对细菌感染的高效光热治疗。
借由上述方案,本发明至少具有以下优点:
相比于已经报道过的针对细菌感染的近红外荧光探针,本发明所制备的纳米探针具有检测灵敏度高、生物相容性好、检测准确等优点;另外本发明所制备的纳米探针在对细菌感染诊断的同时,还可以实现对其的高效光热治疗,因此可以作为一种诊疗一体化探针实现对体内细菌感染的快速、非侵入、高灵敏度诊断和高效治疗。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是本发明细菌感染诊疗一体化纳米探针的透射电镜图;
图2是本发明细菌感染诊疗一体化纳米探针的紫外吸收图;
图3是本发明细菌感染诊疗一体化纳米探针的生物毒性实验结果;
图4是本发明细菌感染诊疗一体化纳米探针的光热升温实验结果;
图5是本发明本发明细菌感染诊疗一体化纳米探针对不同浓度MRSA细菌感染的小鼠的荧光成像图;
图6是本发明细菌感染诊疗一体化纳米探针在小鼠体内的脏器分布实验结果;
图7是本发明细菌感染诊疗一体化纳米探针对小鼠体内细菌感染进行光热治疗的结果图;
图8是本发明细菌感染诊疗一体化纳米探针对体内细菌感染进行荧光成像诊断和光热治疗的过程示意图。
具体实施方式
下面结合附图和实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1
(1)硅纳米颗粒的制备:取40mL无水乙醇,加入10mL水,混合均匀,然后加入900μL氨水(质量分数为28-30%),搅拌5min,然后在搅拌条件下加入600μL TEOS(正硅酸乙酯),剧烈搅拌1h后,再次加入600μL TEOS,继续剧烈搅拌24h。最后,将反应液9500r/min离心25min,并用水和乙醇洗三次,最后分散在水里,得到实心的硅纳米颗粒。
(2)聚电解质包裹的硅纳米颗粒的制备:取100mg的PAH(聚丙烯氯化铵,Mw=15000g/mol),将其溶于10mL 1mM的NaCl水溶液里,然后加入1mL步骤(1)中合成的硅纳米颗粒,搅拌反应3h。最后,将反应液9500r/min离心25min,并用水洗三次,最后分散在水里,得到PAH聚电解质包裹的硅纳米颗粒的。
(3)荧光染料修饰的硅纳米颗粒的制备:取1mg吲哚菁绿羧基衍生物(Cypate)溶于3mL DMF(N,N-二甲基甲酰胺),然后加入共价偶联剂0.5mg的EDC和0.6mg的NHS,活化30min,再加入1mL步骤(2)中合成的聚电解质包裹的硅纳米颗粒,继续搅拌16h。最后,将反应液9500r/min离心25min,并用水洗三次,最后分散在水里,得到荧光染料修饰的硅纳米颗粒。
(4)细菌感染诊疗一体化纳米探针的制备:取228.6μL PAA(聚丙烯酸,Mw=15000g/mol),溶解在1770μL水里,然后加入0.2045g EDC和0.2316g NHS,活化30min,再加入25mL的氨基-聚乙二醇(mPEG-NH2,20mg/mL,Mw=5000g/mol)和万古霉素(0.084mg/mL)的混合水溶液,继续搅拌反应24h。然后将反应液进行透析纯化,再加入0.3680g EDC和0.4168g NHS活化30min,再加入2mL步骤(3)中合成的荧光染料修饰的硅纳米颗粒,继续搅拌24h。最后,将反应液9500r/min离心25min,并用水洗三次,得到细菌感染诊疗一体化纳米探针。
图1是本发明制备的细菌感染诊疗一体化纳米探针的透射电镜图,从图中可以看出该纳米探针形貌规整,尺寸均一性比较好。
图2是本发明合成的细菌感染诊疗一体化纳米探针的紫外吸收图,如图所示,所制备的纳米探针具有明显的Cypate近红外特征吸收峰。
将上述纳米探针分散到水溶液(纯水或PBS缓冲液)中对其进行生物毒性实验测试,图3是合成的细菌感染诊疗一体化纳米探针的生物毒性实验结果,如图3所示,在0-20μg/mL浓度范围内,细胞活性接近100%,说明本发明的纳米探针具有良好的生物相容性。
将上述纳米探针分散到水溶液(纯水或PBS缓冲液)中对其进行光热升温实验,如图4所示,在近红外激光(808nm,1.5W/cm2)照射下,本发明制备的纳米探针的温度在300s内可以快速升高,具有极强的光热转换效应;且随着纳米探针浓度的增大,其升温速率变快。
(5)体内细菌感染的高灵敏度诊断:在小鼠右侧尾部靠近大腿处皮下分别注射50μL(105-107CFU)的耐甲氧西林金黄色葡萄球菌MRSA溶液,构建小鼠细菌感染模型,16h后,将步骤(4)中合成的纳米探针(以Cypate计算:7.5mg/kg)注入到小鼠尾静脉中,4h后利用IVISLumina成像系统对感染的小鼠进行全身荧光成像。
图5是不同浓度MRSA细菌(105-107CFU)感染的小鼠荧光成像图,如图所示,所制备的纳米探针可以在4小时内在MRSA感染部位(箭头处)快速聚集,并发出荧光,说明本发明制备的纳米探针,可以实现对小鼠低浓度MRSA细菌感染的快速、准确和高灵敏度检测。对上述感染细菌后的小鼠脏器进行荧光检测,如图6所示,第一行的器官从左到右依次为心、肝、脾,第二行从左到右依次为肺、肾、细菌感染部位,可以看到,图中只有肾和细菌感染部位(箭头所指)发出荧光,说明所制备的纳米探针除了在细菌感染部位大量聚集外,在肾里也有聚集,其代谢主要以肾为主。
(6)体内细菌感染的光热治疗:在小鼠右侧尾部靠近大腿处皮下注射50μL(107CFU)的耐甲氧西林金黄色葡萄球菌MRSA溶液,构建小鼠细菌感染模型,16h后,将步骤4中合成的纳米探针(以Cypate计算:7.5mg/kg)注入到小鼠尾静脉中,4h后用808nm,功率为1.5W/cm2的激光器对MRSA感染部位照射5min,然后每隔两天记录小鼠感染部位的溃烂情况。如图7所示,与不进行激光照射的对照组相比,经纳米探针光热治疗后,小鼠感染部位的溃烂得到了快速好转,12天后得到了完全治愈,说明本发明制备的纳米探针可以实现对体内细菌感染的高效光热治疗。
实施例2
(1)硅纳米颗粒的制备:取11.4mL无水乙醇,加入72mL水,混合均匀,然后加入2.9gCTAB(十六烷基三甲基溴化铵)和625μL氨水(质量分数为28-30%),60℃搅拌30min,然后在搅拌条件下加入7.3mL TEOS(正硅酸乙酯),60℃剧烈搅拌2h。最后,将反应液9500r/min离心25min,并用水和乙醇洗三次,最后分散在水里,得到介孔硅纳米颗粒,经高温煅烧除去CTAB后分散到水里备用。
(2)聚电解质包裹的硅纳米颗粒的制备:取100mg的PEI(聚乙烯亚铵,Mw=20000g/mol),将其溶于10mL 1mM的NaCl水溶液里,然后加入1mL步骤(1)中合成的硅纳米颗粒,剧烈搅拌反应3h。最后,将反应液9500r/min离心25min,并用水洗三次,最后分散在水里,得到PEI聚电解质包裹的硅纳米颗粒。
(3)荧光染料修饰的硅纳米颗粒的制备:取1mg吲哚菁绿羧基衍生物(Cypate)溶于3mL DMSO(二甲亚砜),然后加入共价偶联剂0.5mg的EDC和0.6mg的NHS,活化30min,再加入1mL步骤(2)中合成的聚电解质包裹的硅纳米颗粒,继续搅拌16h。最后,将反应液9500r/min离心25min,并用水洗三次,最后分散在水里,得到荧光染料修饰的硅纳米颗粒。
(4)细菌感染诊疗一体化纳米探针的制备:取228.6μL PAA(聚丙烯酸,Mw=15000g/mol),溶解在1770μL水里,然后加入0.2045g EDC和0.2316g NHS,活化30min,再加入25mL的氨基-聚乙二醇(mPEG-NH2,20mg/mL,Mw=5000g/mol)和MRSA抗体(8.4mg/mL)的混合水溶液,继续搅拌反应24h。然后将反应液进行透析纯化,再加入0.3680g EDC和0.4168gNHS活化30min,再加入2mL步骤(3)中合成的荧光染料修饰的硅纳米颗粒,继续搅拌24h。最后,将反应液9500r/min离心25min,并用水洗三次,得到细菌感染诊疗一体化纳米探针。
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (6)
1.一种用于体内细菌感染的诊疗一体化纳米探针,其特征在于:包括硅纳米颗粒,所述硅纳米颗粒外包裹有聚阳离子电解质层,所述聚阳离子电解质层外侧修饰有近红外有机荧光染料,且交联有聚丙烯酸、聚乙二醇和细菌靶向分子;所述聚阳离子电解质选自聚丙烯氯化铵;所述聚丙烯氯化铵的分子量为15000g/mol;所述近红外有机荧光染料选自吲哚菁绿或Cypate;所述细菌靶向分子为万古霉素。
2. 根据权利要求1所述的用于体内细菌感染的诊疗一体化纳米探针,其特征在于:所述硅纳米颗粒的粒径为60-80 nm。
3.根据权利要求1所述的用于体内细菌感染的诊疗一体化纳米探针,其特征在于:所述硅纳米颗粒为实心二氧化硅纳米颗粒或介孔二氧化硅纳米颗粒。
4.根据权利要求1所述的用于体内细菌感染的诊疗一体化纳米探针,其特征在于:所述聚乙二醇的分子量为3000-5000 g/mol。
5.一种权利要求1-4中任一项所述的用于体内细菌感染的诊疗一体化纳米探针的制备方法,其特征在于,包括以下步骤:
(1)制备粒径为60-80 nm的硅纳米颗粒;
(2)将步骤(1)得到的所述硅纳米颗粒加入到聚阳离子电解质的盐溶液中,搅拌反应后得到聚阳离子电解质包裹的硅纳米颗粒;
(3)将近红外有机荧光染料溶于有机溶剂中,加入共价偶联剂进行活化,再加入步骤(2)得到的所述聚阳离子电解质包裹的硅纳米颗粒,搅拌反应后得到表面修饰有近红外有机荧光染料的硅纳米颗粒;
(4)将聚丙烯酸用共价偶联剂活化后与氨基-聚乙二醇和细菌靶向分子反应,然后再与步骤(3)得到的硅纳米颗粒表面的聚阳离子电解质交联,得到所述用于体内细菌感染的诊疗一体化纳米探针。
6.根据权利要求5所述的用于体内细菌感染的诊疗一体化纳米探针的制备方法,其特征在于:在步骤(3)和(4)中,所述共价偶联剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐和N-羟基琥珀酰亚胺。
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