CN112516333B - 红光碳点及其核酸复合物/纳米复合物、制备和应用 - Google Patents
红光碳点及其核酸复合物/纳米复合物、制备和应用 Download PDFInfo
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Abstract
本发明提供一种红光碳点,属于生物材料技术领域。所述制备方法为将金属酞菁加入到有机溶剂中,超声处理后加入双氧水常温搅拌,然后加入阳离子聚合物或阳离子脂质进行水热反应,反应完成后自然冷却至室温,经稀释,离心,过滤,透析,干燥得到水溶性红光碳点或脂溶性红光碳点。所述红光碳点根据加入原料不同,可得到水溶性或脂溶性两种碳点。水溶性碳点可直接与基因药物混合形成红光碳点核酸复合物,脂溶性红光碳点加入生物相容性良好的两亲性高分子,得到两亲性红光碳点纳米复合物。红光碳点核酸复合物和两亲性红光碳点纳米复合物均可用于医学成像和肿瘤治疗产品,是一种极具临床转化潜力的多功能诊疗一体化的材料。
Description
技术领域
本发明属于纳米材料及生物医学技术领域,具体为一种红光碳点及其核酸复合物/纳米复合物、制备和应用。
背景技术
2004年,美国南卡罗来纳大学的科学家在研究电弧放电获得的单壁碳纳米管粗产物时,首次发现了一种新型荧光碳纳米材料—碳点。碳点是一种新型的零维碳材料,其粒径通常小于10nm。因碳点具有优异的水分散性、低毒性、高光稳定性和良好的生物相容性等性质,被广泛用于生物医学成像、纳米医学、催化、发光器件等领域。特别是在纳米医学领域,由于大多数碳点在一定条件不具有内在产生热或热声波信号的固有能力,因此碳点在癌症的诊断和治疗领域的应用仍处于初级阶段。此外,之前的报道大部分碳点的吸收/发射光谱主要集中在短波长和可见光区,这也限制碳点在肿瘤诊断和治疗中的应用。
近年来,光能通过非辐射转化为热能(光热治疗、光热成像)或光声信号(光声成像),已经被广泛研究用于癌症的治疗和诊断。由于长波长的红光不易被皮肤和组织吸收,具有较强的组织穿透能力。因此利用长波长红光照射注射有光敏剂的肿瘤组织,并利用产生的热杀死癌细胞。到目前为止,光热转换材料主要分为无机材料和有机材料。无机光热材料主要包括贵金属材料(如:纳米金、金纳米棒)、金属硫系材料、碳基纳米材料(如:石墨烯和碳纳米管)、和其他二维材料(如:黑磷、纳米片、氮化硼和石墨碳氮化物)。有机光热材料主要包括近红外响应有机小分子(如:吲哚菁绿)、有机半导体聚合物等。然而,有一些光热转换试剂由于合成复杂、光漂白、光热转换效率低、生物相容性差等因素,限制了其在肿瘤光热治疗中的应用。
发明内容
本发明的目的在于提供一种红光碳点及其核酸复合物/纳米复合物、制备和应用,利用双氧水辅助溶剂热法制备具有多模态成像性能的含金属碳点纳米材料,根据加入原料不同,可得到水溶性或脂溶性两种碳点,并制备得到红光碳点核酸复合物及红光碳点纳米复合物。
本发明目的通过以下技术方案来实现:
一种红光碳点的制备方法,所述制备方法为将金属酞菁加入到有机溶剂中,超声处理后加入双氧水常温搅拌,然后加入阳离子聚合物或阳离子脂质进行水热反应,反应完成后自然冷却至室温,经稀释,离心,过滤,透析,干燥得到水溶性红光碳点或脂溶性红光碳点。
本发明红光碳点的制备方法为将原料金属酞菁加入到有机溶剂并辅以超声进行溶解,超声处理后加入双氧水促进金属氧化物的生成,加入阳离子聚合物或脂质增强碳点的水溶性并使其带正电用于基因载体制备。经常温搅拌后进行水热反应,反应完成后自然冷却至室温,经稀释,离心,过滤,透析,干燥得到红光碳点粉末。
其中,金属酞菁的芳香大环结构可提供产生大的sp2区域从而降低电子能级,使得碳点的吸收和发射波长红移。而其中掺杂的金属离子会改变碳点的电子分布,引入新的能带结构,使碳点具有固有的红光吸收区和催化化学动力学反应的活性位点,从而使其具有优异的光热、光声成像及化学动力学、光热治疗性能。且金属离子的掺杂还可使碳点具备磁共振(锰、铁)或者计算机断层扫描成像的性能。
进一步,所述金属酞菁为铁酞菁、锰酞菁、铜酞菁、镍酞菁、锌酞菁、钴酞菁中的一种或多种;所述有机溶剂为N,N-二甲基甲酰胺(DMF)、无水乙醇、丙酮,甲酰胺,丙三醇中的一种或多种。
进一步,所述阳离子聚合物为聚乙烯亚胺,聚酰胺基胺,聚赖氨酸,壳聚糖中的一种或多种;所述阳离子脂质为树状精氨酸多肽脂质,树状赖氨酸多肽脂质,树状组氨酸多肽脂质中的一种或多种。
进一步,所述水热反应采用内衬聚四氟乙烯的反应釜,温度为160~250℃,时间为12~36h。因为酞菁是大环结构,比较稳定,不易碳化,水热反应选择时间和温度较长的条件,有利于碳点产率提高。
进一步,所述金属酞菁的加入量为10~200mg;有机溶剂的加入量为10~80mL;超声处理时间为10~60min,双氧水的加入量为8~40mg,阳离子聚合物或阳离子脂质的加入量为1~100mg。
进一步,所述离心条件为5000~10000rpm/min,5~30min;所述过滤采用0.22~0.45μm滤头过滤,透析采用MWCO=1000Da的透析袋透析12~72h,除去未被包载的红光碳点。
一种红光碳点,采用上述所述的方法制备得到的水溶性红光碳点或脂溶性红光碳点。
一种红光碳点核酸复合物,采用所述的水溶性红光碳点制备得到:将水溶性红光碳点溶解在水溶液中,加入核酸,常温孵育得到。
其中,所述核酸为DNA,siRNA,microRNA,mRNA;所述水溶性红光碳点和核酸的质量比为1:2~1:50;所述水溶性红光碳点和核酸的孵育时间为5~30分钟。
一种红光碳点核酸复合物的应用,所述水溶性红光碳点核酸复合物在医学成像产品及肿瘤治疗产品中的应用。水溶性红光碳点可直接与基因药物混合形成红光碳点核酸复合物(水溶性红光碳点和核酸的质量比为1:2~1:50)。本发明红光碳点核酸复合物具备荧光、光热、光声、磁共振其中一种或者多种成像性能,可以用在医学成像产品中;还具有基因递送、光热及化学动力学其中一种或者多种协同治疗作用,可以用在肿瘤治疗产品中。
一种两亲性红光碳点纳米复合物,采用所述的脂溶性红光碳点制备得到,包括以下步骤:
1)将生物相容性良好的两亲性高分子先溶于水和有机溶液的混合溶液中,然后将溶于有机溶剂中的脂溶性红光碳点滴入到混合溶液中;
2)将步骤1)的混合溶液,倒入经过活化处理的透析袋中透析,将透析处理后的复合物冻干保存,得到两亲性红光碳点纳米复合物。
一种两亲性红光碳点纳米复合物,所述两亲性高分子和脂溶性红光碳点的质量比为1:0.2~1:5所述两亲性高分子为聚乳酸-聚乙二醇(PLA-PEG),二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000),聚己内酯-聚乙二醇(PCL-PEG),聚乳酸羟基乙酸共聚物-聚乙二醇(PLGA-PEG)中的一种或多种。
一种两亲性红光碳点纳米复合物的应用,所述两亲性红光碳点纳米复合物在医学成像产品及肿瘤治疗产品中的应用。脂溶性红光碳点需要溶解在有机溶剂中,加入生物相容性良好的两亲性高分子,常温搅拌,经透析,冷冻保存,得到两亲性红光碳点纳米复合物,此纳米复合物也具有生物相容性良好,具有荧光/光声/光热/磁共振多模态医学成像以及化学动力/光热/光动肿瘤治疗的特性,是一种极具临床转化潜力的多功能诊疗一体化纳米材料,可用于医学成像产品及肿瘤治疗产品中。
与现有技术相比,本发明具有以下有益效果:
本发明采用双氧水辅助溶剂热法制备了光稳定性好、成本低、易保存的多功能红光碳点,利用该碳点独特的光热、光声造影、纳米酶性质,创造性地将该碳点用于生物医学领域。
本发明采用加入阳离子聚合物或阳离子脂质的方法改善碳点的水溶性并增强其正电性,利用这一特点,可将碳点应用于基因递送。
本发明红光碳点易制备且简单可控,原料价格低廉易获得,为碳点的大规模制备提供了有利条件。该碳点在红光区域有较强的吸收和发射;所得亲水碳点可用于基因递送,实现肿瘤的多模态医学成像及光热/光动/化学动力学/基因治疗;所得脂溶性碳点包裹在两亲高分子中,改善其血液循环时间和提高在肿瘤部位累积,形成的碳点纳米复合物在0.5W/cm2低能量密度近红外照射下其光热转换效率较高,可实现肿瘤的多模态医学成像及光热/光动/化学动力学/基因治疗。
附图说明
图1为实施例1掺铁碳点的电镜图,其中A为低分辨率,B为高分辨率;
图2为实施例1掺铁碳点的紫外可见吸收光谱图和荧光发射光谱图,其中A为紫外可见吸收光谱图,B为650nm荧光发射光谱图;
图3为实施例1制备的铁离子参杂碳点与核酸复合后的细胞转染效果图;
图4为PEG-Fe@CDs小鼠乳腺癌模型肿瘤靶向成像结果,其中A为荧光成像,B为光声成像,C为光热成像,D为磁共振成像;
图5为实施例3制备的水溶性锰酞菁金属掺杂碳点的光动力学性能检测结果;
图6为实施例4制备的脂溶性锰酞菁金属掺杂碳点的化学动力学检测结果。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
本实施例制备的铁酞菁碳点可用于荧光成像及基因治疗,制备过程包括:
称取20mg铁酞菁加至烧杯中,加入40毫升DMF,超声30min,加入10mg双氧水常温搅拌5分钟;加入3代树状精氨酸多肽脂质10mg,常温搅拌10min;
将上述溶液倒入到100毫升内衬聚四氟乙烯的反应釜,温度为180℃,反应24小时,放置室温冷却;加入160ml DMF稀释5倍,然后在转速为5000rpm/min条件下离心10分钟,用0.22μm的滤头去除大颗粒的物质,然后用分子量MWCO=1000Da的透析袋在无水乙醇透析24小时,每六小时换一次新的无水乙醇;透析24小时以后,减压蒸馏旋干去除溶剂,最后在35℃下真空干燥24小时,最终得到在水溶液中分散良好且带正电荷的红光碳点;
将所得红光碳点1.25mg分散在500μL水溶液中,吸取20μL加入绿色荧光蛋白的DNA质粒200ng混匀,常温孵育15分钟后加入96孔细胞培养板中的1个孔。孵育4小时后,去上清,更换新鲜培养基培养24小时后倒置荧光显微镜观察转染效率。
本实施例制备得到的水溶性正电铁离子掺杂碳点,其透射电镜图如图1所示,可见掺铁碳点形貌为类似球形结构,尺寸大约为2.3nm(图1A),并呈现明显的晶格衍射条纹(图1B),说明掺铁碳点结晶性较好。
图2为本实施例制备的铁离子掺杂碳点在DMF中的紫外可见吸收光谱和荧光发射光谱图(激发波长为650nm),说明本实施例铁碳点具有深红的荧光成像能力。
图3为本实施例制备的铁离子参杂碳点与核酸复合后的细胞转染效果,说明本实施例铁碳点具有基因递送的能力。
实施例2
本实施例制备的两亲性铁酞菁碳点纳米复合物可用于肿瘤被动靶向的荧光/光声/光热/磁共振成像及化学动力学/光热治疗,制备过程包括:
称取20mg铁酞菁加至烧杯中,加入40毫升DMF,超声30min,加入10mg双氧水常温搅拌5分钟;加入2代树状精氨酸多肽脂质5mg,常温搅拌10min;将上述溶液倒入到100毫升内衬聚四氟乙烯的反应釜,温度为180℃,反应24小时,放置室温冷却;加入160ml DMF稀释5倍,然后在转速为5000rpm/min条件下离心10分钟,用0.22μm的滤头去除大颗粒的物质,然后用分子量MWCO=1000Da的透析袋在无水乙醇透析24小时,每六小时换一次新的无水乙醇;透析24小时以后,减压蒸馏旋干去除溶剂,最后在35℃下真空干燥24小时,最终得到脂溶性红光碳点;
称量20mg二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)加入至12.5mL的纯水和2.5mL的DMF混合溶液中溶解;向混合溶液中逐滴加入1mL上述得到的铁酞菁碳点溶液(10mg/mL),搅拌过夜;然后将溶液装入截留分子量为3500的透析袋,在超纯水中透析72h,之后冻干处理72h,最终得到两亲性红光碳点纳米复合物。
本实施例制得的两亲性红光碳点纳米复合物可进行肿瘤被动靶向的荧光/光声/光热/磁共振成像及肿瘤的光热治疗,具体过程如下:
建立小鼠皮下乳腺癌模型,待肿瘤大小长至100mm3后,静脉注射25mg/kg本实施例制备的复合物100μL,于注射后2,4,6,24,28,32小时进行荧光/光声/磁共振成像,如图4所示,注射后28小时,肿瘤部位的荧光、光声、磁共振信号均达到最高值。并在注射28小时之后,用660nm激光以0.5W/cm2的光能量密度照射肿瘤部位,并进行实时热成像,结果表明其优越的热成像能力。治疗后隔天测量肿瘤体积,肿瘤抑制率为80%。
以上为本实施例制备的红光碳点两亲性纳米复合物在肿瘤部位靶向累积并进行荧光/光声/光热/磁共振成像及肿瘤治疗的能力。
实施例3
本实施例水溶性锰酞菁金属掺杂碳点制备,可用于基因治疗;制备过程包括:
称取40mg锰酞菁化合物加至烧杯中,加入60mL丙三醇,超声30min,加入双氧水30mg,常温搅拌5分钟;加入分子量25kD聚乙烯亚胺10mg,常温搅拌10min;
上述溶液倒入到100毫升内衬聚四氟乙烯的反应釜,温度为200℃,反应24小时,放置室温冷却;加入60mL丙三醇稀释两倍后,6000rpm/min离心10分钟;用孔径为0.22μm的滤头去除大颗粒的物质,然后用分子量MWCO=1000Da的透析袋在无水乙醇透析24小时,每六小时换一次新的无水乙醇;透析24小时以后,减压蒸馏旋干去除溶剂,最后在45℃下真空干燥24小时,最终得到在水溶液中分散良好且带正电荷的红光碳点;
将所得红光碳点1.25mg分散在500μL水溶液中,吸取20μL加入绿色荧光蛋白的DNA质粒200ng混匀,常温孵育15分钟后加入96孔细胞培养板中的1个孔。孵育4小时后,去上清,更换新鲜培养基培养24小时后倒置荧光显微镜观察转染效率。
本实施例制备得到的水溶性正电锰离子掺杂碳点,可进行荧光/磁共振成像及化学动力学/光动力/基因联合治疗。其光动力学性能检测结果图如5所示,产生单线态氧。
实施例4
本实施例制备的两亲性锰酞菁碳点纳米复合物可用于肿瘤被动靶向的荧光/磁共振成像及化学动力学/光动力联合治疗,制备过程包括:
称取40mg锰酞菁化合物加至烧杯中,加入60mL丙三醇,超声30min,加入双氧水30mg,常温搅拌5分钟;加入分子量2k D聚乙烯亚胺5mg,常温搅拌10min;
上述溶液倒入到100毫升内衬聚四氟乙烯的反应釜,温度为200℃,反应24小时,放置室温冷却;加入60mL丙三醇稀释两倍后,6000rpm/min离心10分钟;用孔径为0.22μm的滤头去除大颗粒的物质,然后用分子量MWCO=1000Da的透析袋在无水乙醇透析24小时,每六小时换一次新的无水乙醇;透析24小时以后,减压蒸馏旋干去除溶剂,最后在45℃下真空干燥24小时,最终得到脂溶性红光碳点;
称量20mg聚乳酸-聚乙二醇(PLA-PEG)加入至12.5mL的纯水和2.5mL的DMF混合溶液中溶解;向混合溶液中逐滴加入0.5mLDMF上述红光碳点溶液(10mg/mL),搅拌过夜;然后将溶液装入截留分子量为3500的透析袋,在超纯水中透析72小时,之后冻干处理72小时,最终得到黄褐色的碳点纳米复合物。
本实施例制得的两亲性红光碳点纳米复合物可进行荧光/磁共振成像及化学动力学/光动力联合治疗。其化学动力学性能检测结果图如6所示,催化双氧水产生羟基自由基。
上述实施例中,铁酞菁、锰酞菁可以替换成铁酞菁、锰酞菁、铜酞菁、镍酞菁、锌酞菁、钴酞菁中的一种或多种;DMF,丙三醇可以替换成N,N-二甲基甲酰胺(DMF)、无水乙醇、丙酮,甲酰胺,丙三醇中的一种或多种;聚乙烯亚胺可以替换成聚乙烯亚胺,聚酰胺基胺,聚赖氨酸,壳聚糖中的一种或多种;树状精氨酸多肽脂质可以替换成树状精氨酸多肽脂质,树状赖氨酸多肽脂质,树状组氨酸多肽脂质中的一种或多种;聚乳酸-聚乙二醇(PLA-PEG),二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)可以替换成聚乳酸-聚乙二醇(PLA-PEG),二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000),聚己内酯-聚乙二醇(PCL-PEG),聚乳酸羟基乙酸共聚物-聚乙二醇(PLGA-PEG)中的一种或多种。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种红光碳点的制备方法,其特征在于,所述制备方法为将金属酞菁加入到有机溶剂中,超声处理后加入双氧水常温搅拌,然后加入聚乙烯亚胺或阳离子脂质进行水热反应,反应完成后自然冷却至室温,经稀释,离心,过滤,透析,干燥得到水溶性红光碳点或脂溶性红光碳点;所述金属酞菁为铁酞菁、锰酞菁、铜酞菁、镍酞菁、锌酞菁、钴酞菁中的一种或多种;所述有机溶剂为N,N-二甲基甲酰胺、无水乙醇、丙酮,甲酰胺,丙三醇中的一种或多种;
所述阳离子脂质为树状精氨酸多肽脂质,树状赖氨酸多肽脂质,树状组氨酸多肽脂质中的一种或多种。
2.一种红光碳点,其特征在于,采用上述权利要求1所述的方法制备得到的水溶性红光碳点或脂溶性红光碳点。
3.一种红光碳点核酸复合物,其特征在于,采用权利要求2所述的红光碳点制备得到:将水溶性红光碳点溶解在水溶液中,加入核酸,常温孵育得到。
4.如权利要求3所述一种红光碳点核酸复合物的应用,其特征在于,所述水溶性红光碳点核酸复合物在制备医学成像产品及肿瘤治疗产品中的应用。
5.一种两亲性红光碳点纳米复合物,其特征在于,采用权利要求2所述的红光碳点制备得到,包括以下步骤:
1)将生物相容性良好的两亲性高分子先溶于水和有机溶液的混合溶液中,然后将溶于有机溶剂中的脂溶性红光碳点滴入到混合溶液中;
2)将步骤1)得到的混合溶液,倒入经过活化处理的透析袋中透析,将透析处理后的复合物冻干保存,得到两亲性红光碳点纳米复合物;
所述两亲性高分子和脂溶性红光碳点的质量比为1:0.2~1:5;所述两亲性高分子为聚乳酸-聚乙二醇,二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000,聚己内酯-聚乙二醇,聚乳酸羟基乙酸共聚物-聚乙二醇中的一种或多种。
6.如权利要求5所述一种两亲性红光碳点纳米复合物的应用,其特征在于,所述两亲性红光碳点纳米复合物在制备医学成像产品及肿瘤治疗产品中的应用。
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