CN111202853B - 具有光声显影、光热治疗和载药多功能的纳米颗粒 - Google Patents
具有光声显影、光热治疗和载药多功能的纳米颗粒 Download PDFInfo
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Abstract
本发明公开一种用于光声成像和光热治疗的杂化纳米颗粒及其制备方法和应用,涉及材料及医学领域,该杂化纳米颗粒呈核壳结构,包括由疏水性多孔ZIF‑8壳和具有光声成像和光热效应作用的聚吡咯核构成的核壳结构内层以及由亲水性多糖复合而成的外层。本发明通过将锌离子与2‑甲基咪唑配位形成多孔ZIF‑8,并将吡咯包封于ZIF‑8的孔隙中,然后加入稳定剂多糖及引发剂原位引发吡咯在ZIF‑8的空隙和表面聚合,制得用于光热效应和光声成像且水溶性和生物相容性良好的杂化纳米颗粒。本发明制备方法简单、效率高、成本低,同时所制备的杂化纳米颗粒光热转化效率高,在肿瘤诊疗一体化领域具有广阔应用前景。
Description
技术领域
本发明涉及材料及医学领域,尤其涉及一种用于光声成像和光热治疗的杂化纳米颗粒及其制备方法和应用。
背景技术
癌症治疗是改善人类健康的主要方法之一,目前,临床上用于治疗肿瘤的手段主要有手术治疗和化疗,手术治疗并不能完全消除肿瘤细胞,复发的可能性很大;而化疗会有很多副作用,包括肾毒性,神经毒性等。光热治疗是一种无创、可控靶向、副作用小的定向治疗手段,光热剂富集在肿瘤部位后,在近红外光的照射下将光能转换成热能,利用热量将肿瘤细胞杀伤从而达到肿瘤消融的效果。光热疗法将近红外光能转化为热能进行癌细胞的热消融,具有侵袭性小、特异性高、有效的肿瘤消融、对正常组织副作用小等独特优点,在肿瘤治疗方法中脱颖而出。
近年来,有机金属框架(MOF)作为一种新型的多孔晶体结构,被广泛应用于气体分离,储能,催化和药物输送,其中,ZIF-8是由毒性较低的2-甲基咪唑和锌离子配合作用形成的一类结晶型咪唑骨架结构。其具有主客体相匹配的孔径和大表面积,使载药量大幅度增加;表面易修饰,且在酸性条件下可分解,使其成为了优良的药物载体。因此,一系列多功能核壳纳米结构,包括聚丙烯酸@ZIF-8、硫化铜@ZIF-8和石墨烯量子点@ZIF-8,作为光热治疗和化疗的先进功能纳米材料,受到广泛关注。而聚吡咯纳米粒子作为一种最有前途的共轭聚合物,具有很强的近红外吸收能力、很高的光热转换效率和良好的光稳定性,被认为是光热治疗的一种优良的光热剂,具有很高的治疗效果,并且,聚吡咯在光声成像中用作光学造影剂也有巨大的应用潜力。
在自然界中,多糖种类繁多、来源丰富。天然存在的典型多糖包括壳聚糖、透明质酸、右旋糖酐、纤维素、普鲁兰、硫酸软骨素和海藻酸钠等。多糖具有独特的性质,包括:(1)种类丰富,分子量范围广,结构和功能多样性;(2)多糖的骨架上有各种各样的反应官能团(如羟基、氨基和羧酸基等),因此较易进行功能化和化学修饰;(3)自然界储存丰富;(4)优异的生物相容性且无毒性;(5)生物可降解性。因此将ZIF-8,聚吡咯与多糖复合成一种具有光声成像和光热治疗能力的杂化纳米颗粒,具有广阔的应用前景,这在之前的报道中未曾出现过。
因此,本领域的技术人员致力于开发一种将ZIF-8,聚吡咯与多糖复合成一种具有光声成像、光热治疗能力和载药功能的杂化纳米颗粒。
发明内容
有鉴于现有技术的上述缺陷,本发明所要解决的技术问题是如何能够将ZIF-8、聚吡咯与多糖复合成纳米级别,并能应用于光声成像和光热治疗诊疗一体化,尤其用于肿瘤定向诊断和治疗的杂化纳米颗粒。
为实现上述目的,本发明提供了一种用于光声成像和光热治疗的杂化纳米颗粒,其特征在于,包括由疏水性多孔ZIF-8壳和具有光声成像和光热效应作用的聚吡咯核构成的核壳结构内层以及由亲水性多糖复合而成的外层。
进一步地,杂化纳米颗粒通过吡咯原位聚合而成。
进一步地,杂化纳米颗粒的粒径取决于原位聚合所用吡咯与引发剂的量以及多糖的量。
进一步地,多糖为羟丙基纤维素及其衍生物、葡聚糖及其衍生物和壳寡糖及其衍生物当中的一种。
进一步地,引发剂为过硫酸铵、无水氯化铁、高碘酸钠和高锰酸钾当中的一种。
进一步地,杂化纳米颗粒为粒径均一且形貌均匀的球形纳米颗粒。
本发明还提供一种用于光声成像和光热治疗的杂化纳米颗粒的制备方法,其特征在于,包括以下步骤:
步骤1、将吡咯加入六水合硝酸锌的甲醇溶液中,搅拌至完全溶解;
步骤2、向步骤1所得的溶液中加入2-甲基咪唑的甲醇溶液,继续搅拌30min;
步骤3、向步骤2所得的溶液中加入水溶性多糖,继续搅拌30min,然后加入引发剂,反应6h;
步骤4、将步骤3所得的溶液离心分离并提纯,最后通过冷冻干燥收集产物,得到杂化纳米颗粒。
进一步地,吡咯已经过减压蒸馏提纯处理。
进一步地,提纯中使用的溶剂为N,N-二甲基甲酰胺/甲醇混合溶剂。
本发明还提供杂化纳米颗粒在制备用于光声成像和光热效应诊疗制剂中的应用。
本发明还提供杂化纳米颗粒在制备用于药物载体制剂的应用。
技术效果
本发明的杂化纳米颗粒具有核壳结构,形貌为均匀的球形,粒径均一可控且粒径分布窄。本发明通过吡咯原位聚合,所形成的杂化纳米颗粒具有良好的溶解性和胶体稳定性,在水溶液中3个月以上不发生沉淀。
所制备的纳米颗粒还具有如下优点:优异的光声成像和光热效应,在近红外光照射下,其光声信号值和光热转换效率分别达2.1和35.5%;优异的生物相容性,将细胞与所制备的杂化纳米颗粒共同孵育24h后,细胞保持90%以上的细胞存活率;优异的肿瘤光热治疗效果,肿瘤抑制率达63.6%,通过光声成像对所述杂化纳米颗粒进行实时成像追踪,在到达肿瘤部位后在近红外光的刺激下产生光热效果,实现肿瘤的精准定位和治疗。
本发明的纳米颗粒还可以包封化疗药物为实现癌症的“化疗和光热治疗”双重治疗模式提供了可能。
本发明制备方法简单、效率高、成本低,同时所制备的杂化纳米颗粒光热转化效率高,在肿瘤诊疗一体化领域具有广阔应用前景。
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明,以充分地了解本发明的目的、特征和效果。
附图说明
图1为本发明的设计示意图。
图2为本发明较佳实施例中杂化纳米颗粒光声信号示意图,将不同浓度杂化纳米颗粒置于超声/光声成像系统中获得光声信号。
图3为本发明较佳实施例中杂化纳米颗粒的光热效应示意图,将不同浓度杂化纳米颗粒置于808纳米的近红外光下(2.0W)照射10min的溶液升温效果图。
图4为本发明较佳实施例中杂化纳米颗粒透射电镜图像。
图5为本发明较佳实施例中杂化纳米颗粒高角环形暗场(HAADF)图像。
具体实施方式
为了使上述目的、优点、特征更加易于理解并付诸实践,以下参考附图对本发明具体实施方式进行说明。需要注意的是,本发明可通过多种不同实施方式得以体现,其范围并非仅限于文中提到的实施方式。
本发明的原理在于:锌离子与2-甲基咪唑通过配位作用形成多孔ZIF-8,并将吡咯包封于ZIF-8的孔隙中,加入多糖作为稳定剂,加入引发剂原位引发吡咯在ZIF-8的空隙和表面聚合,形成光声成像和光热治疗一体化的杂化纳米颗粒。
实施例1:
一种用于光声成像和光热效应的杂化纳米颗粒,包括以下原料:
六水合硝酸锌,2-甲基咪唑(2-MIM),吡咯(Py),多糖,引发剂;
六水合硝酸锌和2-甲基咪唑采用各自甲醇溶液;
所述引发剂为无水三氯化铁(FeCl3);
所述多糖为羟丙基纤维素(HPC)的水溶液(分子量为80000);
该杂化纳米颗粒的制备方法包括以下步骤:
S1、取10.0ml六水合硝酸锌的甲醇溶液(14.7mg/ml)于圆底烧瓶中,加入171.1μl吡咯,25℃下磁力搅拌(1000rpm)10min。
S2、向步骤S1的溶液中加入10.0ml的2-甲基咪唑的甲醇溶液(8.1mg/ml),继续搅拌30min。
S3、将步骤S2的溶液中加入20.0ml羟丙基纤维素的水溶液(50.0mg/ml),继续搅拌30min后加入0.80g无水氯化铁,溶液慢慢变为黑色,继续反应6h。
S4、将所得产物通过高速离心分离,并用N,N-二甲基甲酰胺/甲醇混合溶剂洗三遍后溶于超纯水中,最终通过冷冻干燥收集产物。
从图1本发明设计示意图可知,将六水合硝酸锌中的锌离子(Zn2+)与2-甲基咪唑(2-MIM)通过配位作用形成多孔ZIF-8,并将吡咯(Py)包封于ZIF-8的孔隙中,加入多糖羟丙基纤维素(HPC)作为稳定剂,加入引发剂无水三氯化铁(FeCl3)原位引发吡咯在ZIF-8的空隙和表面聚合,得到杂化纳米颗粒(PPy@ZIF-8)(图中“Zn2+”表示锌离子;“Py”表示吡咯;“2-MIM”表示2-甲基咪唑;“FeCl3”表示无水三氯化铁;“HPC”表示羟丙基纤维素;“PPy”表示聚吡咯;“PPy@ZIF-8”表示聚吡咯@ZIF-8杂化纳米颗粒;“NIR”表示近红外光;“PAI”表示光声成像;“PTT”表示光热治疗)。由于杂化纳米颗粒中的聚吡咯具有优异的光学成像和光热效应性能,因此制备的杂化纳米颗粒可用于光声成像和光热治疗一体化诊疗制剂用途。将该杂化纳米颗粒给予肿瘤模型小鼠后,用近红外光(NIR)激光(Laser)照射小鼠肿瘤部位,采集光声成像(PAI)信号,同时实现光热治疗(PTT)。结果表明其肿瘤抑制率可达63.6%,所制备的杂化纳米颗粒对肿瘤具有优异的光热治疗效果。
如图2所示,将实施例1制得的杂化纳米颗粒配制成不同浓度杂化纳米颗粒溶液,将其置于超声/光声成像系统中采集光声信号,结果表明所制备的杂化纳米颗粒的光声信号可达2.1,该杂化纳米颗粒具有优异的光声成像能力。
如图3所示,将实施例1制得的杂化纳米颗粒配制成不同浓度杂化纳米颗粒溶液,置于808纳米的近红外光下(2.0W)照射10min,测定溶液的升温效果,结果表明溶液升温效果明显。计算得到光热转换效率可达35.5%。
如图4所示,实施例1制得的杂化纳米颗粒透射电镜图像表明该杂化纳米颗粒为粒径均一、粒径分布窄及形貌均匀的球形纳米颗粒,粒径为92纳米。
如图5所示,所制备的杂化纳米颗粒高角环形暗场(HAADF)图像结果表明,所制得的纳米颗粒具有明显的核壳结构。
其中,通过调节吡咯的量可实现ZIF-8粒径的精准调控,原位引发吡咯聚合后合成的杂化纳米颗粒溶解性和胶体稳定性良好,能溶于水溶液3个月以上不发生沉淀。
此外,由于多糖具有优异的亲水性和生物相容性,因此所制备的纳米颗粒具有优异的生物相容性,将细胞与所制备的杂化纳米颗粒共同孵育24h后,细胞保持90%以上的细胞存活率。
实施例2:
一种用于光声成像和光热效应的杂化纳米颗粒,包括以下原料:
六水合硝酸锌,2-甲基咪唑,吡咯,多糖,引发剂;
六水合硝酸锌和2-甲基咪唑采用各自甲醇溶液;
所述引发剂为过硫酸铵;
所述多糖为羟丙基纤维素的水溶液(分子量为80000)。
该杂化纳米颗粒的制备方法包括以下步骤:
步骤a、取10.0ml六水合硝酸锌的甲醇溶液(14.7mg/ml)于圆底烧瓶中,加入171.1μl吡咯,25℃下磁力搅拌(1000rpm)10min。
步骤b、向步骤a的溶液中加入10.0ml的2-甲基咪唑的甲醇溶液(8.1mg/ml),继续搅拌30min。
步骤c、将步骤b的溶液中加入20.0ml羟丙基纤维素的水溶液(50.0mg/ml),继续搅拌30min后加入0.56g过硫酸铵,溶液慢慢变为黑色,继续反应6h。
步骤d、将所得产物通过高速离心分离,并用N,N-二甲基甲酰胺/甲醇混合溶剂洗三遍后溶于超纯水中,最终通过冷冻干燥收集产物。所制得的纳米颗粒具有良好的水溶性和胶体稳定性,水合粒径为600纳米。
实施例3:
一种用于光声成像和光热效应的杂化纳米颗粒,包括以下原料:
六水合硝酸锌,2-甲基咪唑,吡咯,多糖,引发剂;
六水合硝酸锌和2-甲基咪唑采用各自甲醇溶液;
所述引发剂为无水三氯化铁;
所述多糖为葡聚糖的水溶液(分子量为100000);
该杂化纳米颗粒的制备方法包括以下步骤:
步骤i、取10.0ml六水合硝酸锌的甲醇溶液(14.7mg/ml)于圆底烧瓶中,加入171.1μl吡咯,25℃下磁力搅拌(1000rpm)10min。
步骤ii、向步骤i的溶液中加入10.0ml的2-甲基咪唑的甲醇溶液(8.1mg/ml),继续搅拌30min。
步骤iii、将步骤ii的溶液中加入20.0ml葡聚糖的水溶液(50.0mg/ml),继续搅拌30min后加入0.80g无水氯化铁,溶液慢慢变为黑色,继续反应6h。
步骤iv、将所得产物通过高速离心分离,并用N,N-二甲基甲酰胺/甲醇混合溶剂洗三遍后溶于超纯水中,最终通过冷冻干燥收集产物。所制得的杂化纳米颗粒形貌为均匀的球形,尺寸均一,水合粒径为250纳米。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (2)
1.一种用于光声成像和光热治疗的杂化纳米颗粒的制备方法,其特征在于,包括以下步骤:
步骤1、将吡咯加入六水合硝酸锌的甲醇溶液中,搅拌至完全溶解;
步骤2、向步骤1所得的溶液中加入2-甲基咪唑的甲醇溶液,继续搅拌30min;
步骤3、向步骤2所得的溶液中加入水溶性多糖,继续搅拌30min,然后加入引发剂,反应6h;
步骤4、将步骤3所得的溶液离心分离并提纯,最后通过冷冻干燥收集产物,得到所述杂化纳米颗粒。
2.如权利要求1所述的制备方法,其特征在于,步骤4的提纯中使用的溶剂为N,N-二甲基甲酰胺/甲醇混合溶剂。
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