CN108743948B - 超声一锅法制备碳点-羟基磷灰石纳米复合物及其修饰方法和应用 - Google Patents
超声一锅法制备碳点-羟基磷灰石纳米复合物及其修饰方法和应用 Download PDFInfo
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Abstract
本发明公开了超声一锅法制备碳点‑羟基磷灰石纳米复合物及其修饰方法和应用。碳点‑羟基磷灰石纳米复合物是以钙盐、磷盐、叶酸作为反应初始原料在碱性和超声条件下一锅制备,加以超支化聚合物修饰,其合成反法简便、快速、反应过程可观测,生物相容性好,可大量生产等优点,还具有良好亲水分散性能,同时含有荧光性能,肿瘤靶向性能。可作为癌细胞靶向成像探针,药物靶向传递载体,在癌症诊断和治疗等领域发挥重要作用。
Description
技术领域
本发明涉及超声一锅法制备碳点-羟基磷灰石纳米复合物及其修饰方法和应用,属于生物医用材料科学领域。
背景技术
生物纳米荧光材料在诊断和治疗应用中起着重要作用,是因为它们尺寸小,表面积大并且颜色可调。通常,荧光纳米材料包括荧光纳米颗粒,半导体量子点和光致发光的碳点等。与半导体量子点和荧光纳米颗粒相比,碳点在生物应用中具有明显的优势,如良好的水溶性,优异的生物相容性,独特的光学性质和无毒性。有趣的是,使用某些特殊碳源和合成方法制备的碳点会显示出对特定细胞的靶向性能。如:以D-葡萄糖和l-天冬氨酸为起始原料,通过简单的水热方法成功地制备了一种新型的对脑胶质瘤具有靶向功能的碳点;以叶酸为碳源所制备的碳点也对叶酸受体过表达的细胞具有靶向性能。
羟基磷灰石是人体和动物骨骼的主要无机成分。由于其优秀的生物相容性、生物活性和无毒性被广泛应用于生物医药领域,可作为骨组织修复材料,药物载体等。然而羟基磷灰石本身不具有靶向功能和荧光性质,因而无法实现在细胞内和生物体内成像“跟踪”,也无法靶向特定的肿瘤组织。因此,简单快速地制备一种带有荧光及肿瘤靶向的多功能碳点-羟基磷灰石纳米复合物在当前的医药生物领域具有重大意义。
发明内容
本发明的目的在于提供一种碳点-羟基磷灰石纳米复合物的制备及其修饰方法。
本发明的另一目的在于提供一种加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物的应用。
本发明所采取的技术方案是:
一种制备碳点-羟基磷灰石纳米复合物的超声一锅法,其特征在于,包括以下步骤:
1)将叶酸溶解在磷酸盐溶液中,用pH调节试剂调节pH至9~12;搅拌,逐滴滴加到钙盐溶液中,混匀,将所得混合液用pH调节试剂调节pH至9~12,并搅拌,在搅拌中超声,静置;所述的钙盐与磷酸盐的摩尔质量比为(1.66~1.68):1;
2)静置后分离得沉淀和上清液,将沉淀离心洗涤后,干燥,得碳点-羟基磷灰石纳米复合物。
进一步的,步骤1)所述叶酸溶解在磷酸盐溶液中后,叶酸的浓度为0.3~2.6mg/mL,磷酸盐的浓度为0.3~1mol/L。
进一步的,步骤1)中所述的磷酸盐溶液选自磷酸氢铵、磷酸氢二铵、磷酸氢二钠、磷酸氢二钾的中的至少一种。
进一步的,步骤1)中所述的pH调节试剂选自氨水、乙二胺中的至少一种。
进一步的,步骤1)中所述的钙盐溶液选自硝酸钙、四水硝酸钙、氯化钙、碳酸钙中的至少一种。
进一步的,步骤1)中所述的钙盐与磷酸盐的摩尔质量比为(1.66~1.68):1。
进一步的,步骤1)所述的超声温度为25~60℃,时间为3~5小时,功率为100W~500W。
进一步的,步骤2)中所述洗涤使用水和/或无水乙醇进行交替洗涤。
一种药载的超支化聚合物-碳点-羟基磷灰石纳米复合物的制备方法,其特征在于,包括以下步骤:
1)将上述制备的碳点-羟基磷灰石纳米复合物加入到缩水甘油中混匀,加热搅拌反应后,加水超声溶解得超支化聚合物修饰的碳点-羟基磷灰石纳米复合物;
2)将抗肿瘤药加入超支化聚合物修饰的碳点-羟基磷灰石纳米复合物中,搅拌反应完全,离心洗涤所得沉淀即药载的超支化聚合物-碳点-羟基磷灰石纳米复合物。
进一步的,步骤1)所述碳点-羟基磷灰石纳米复合物与缩水甘油的用量比为(3mg~10mg):1mL。
进一步的,步骤1)中所述的搅拌条件为室温和避光条件下磁力搅拌36~48小时。
进一步的,步骤2)中所述抗肿瘤药与超支化聚合物修饰的碳点-羟基磷灰石纳米复合物的用量比为(1mg~2.5mg):1mL。
进一步的,所述的超支化聚合物为超支化聚缩水甘油。
上述任一项方法制备的药载的超支化聚合物-碳点-羟基磷灰石纳米复合物。
上述药载的超支化聚合物-碳点-羟基磷灰石纳米复合物在制备靶向识别或/和抑制癌细胞的试剂的应用。
进一步的,所述的癌细胞为叶酸过表达的癌细胞。
本发明的有益效果是:
本发明中采用超声辅助在机械搅拌下一锅制备碳点-羟基磷灰石纳米复合物。该合成方法简便,快速,而且合成原料便宜,所得产物荧光性能与生物相容性好。采用超支化聚缩水甘油对所制备的碳点-羟基磷灰石进行水溶性修饰,所得产物不仅具有良好的亲水分散性能、稳定性能、无毒性能、靶向性能;而且仍具有较好的荧光性能。制得的药载的超支化聚合物-碳点-羟基磷灰石纳米复合物还可作为靶向癌细胞成像探针,靶向药物传递载体;为集合诊断、治疗于一体的多功能的荧光靶向复合生物材料的开发开辟一条新的道路。
附图说明
图1为碳点-羟基磷灰石纳米复合物的透射电子显微镜图像,其中羟基磷灰石的长度为20~150nm,直径为4~8nm;碳点的直径为1~3nm。
图2为碳点-羟基磷灰石纳米复合物与羟基磷灰石标准卡片对比的XRD图谱,JCDPSNO.009-0432为羟基磷灰石标准卡片。
图3为碳点-羟基磷灰石纳米复合物在360nm激发下的荧光发射光谱。
图4为超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物在360nm激发下的荧光发射光谱。
图5为激光共聚焦显微镜荧光成像图;其中HeLa代表叶酸过表达的HeLa细胞,MCF-7代表叶酸低表达的人MCF-7细胞;具体的每个图分别为HeLa细胞的明场图(A),HeLa细胞的细胞核DAPI染色荧光图(B)、HAp-CDs-PG在HeLa细胞的绿色荧光图(C)、阿霉素在HeLa细胞的红色荧光图(D)以及HeLa细胞的明场图、DAPI染色的细胞核、HAp-CDs-PG、阿霉素四者合并重叠图(E);图5第二排从左到右的图分别代表MCF-7细胞的明场图(F),MCF-7细胞细胞核DAPI染色荧光图(G)、HAp-CDs-PG在MCF-7细胞的荧光图(H)、阿霉素在MCF-7细胞的荧光图(I)以及MCF-7细胞的明场图、DAPI染色的细胞核、HAp-CDs-PG、阿霉素四者合并重叠图(J)。
图6为HAp-CDs-PG-Dox(HAp-CDs-PG-Dox为药载的超支化聚合物-碳点-羟基磷灰石纳米复合物,其中HAp代表羟基磷灰石;CDs代表碳点;PG代表超支化聚缩水甘油;Dox代表抗肿瘤药物阿霉素)以不同的Dox浓度与HeLa细胞共培养24小时后的细胞活力。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1碳点-羟基磷灰石纳米复合物的超声一锅法
(1)将叶酸20mg超声溶解于30ml、0.3mol/l的磷酸氢二铵水溶液中,用氨水调节pH至10;
(2)往步骤(1)所得溶液中,在搅拌下(转速为400转/分)逐滴加入到30ml的四水硝酸钙中,其中钙磷摩尔质量比为1.67:1,并用氨水调节pH至10。搅拌30min后,混合液在40℃下进行超声(300W)处理,并一直搅拌,超声时间为3小时,之后静置过夜;
(3)将静置过夜后的沉淀物与上清分离,将黄色沉淀物在转速为4000转/分的条件下离心,并用水与无水乙醇交替洗涤,洗涤6次后,将黄色沉淀物在60℃下干燥12小时,即得碳点-羟基磷灰石纳米复合物。
实施例2 HAp-CDs-PG-Dox的合成
(1)称取实施例1所得的50mg碳点-羟基磷灰石纳米复合物,将它超声分散于10ml的缩水甘油中,在140℃下加热并磁力搅拌,反应24小时后冷却至室温,再加入5ml去离子水超声溶解得分散液。在100KD的超滤管中用去离子水将分散液离心洗涤6次,以去除游离的超支化聚缩水甘油。最后加入去离子水稀释至5ml,得到超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物,放在4℃冰箱中保存,以下一步使用。
(2)称取2mg阿霉素超声分散到2ml的步骤(1)所制备的超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物中。在室温和避光的环境下,磁力搅拌48小时。然后倒入到10KD的超滤管中,使用去离子水离心洗涤4次,以移除未载上的阿霉素,得到加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox,其中HAp代表羟基磷灰石;CDs代表碳点;PG代表超支化聚缩水甘油;Dox代表抗肿瘤药物阿霉素)。在扣除载体吸光度的前提下,使用紫外分光光度计计算阿霉素的浓度。
实施例3碳点-羟基磷灰石纳米复合物的超声一锅法
(1)将叶酸80mg超声溶解于30ml、1mol/l的磷酸氢二钠水溶液中,用乙二胺调节pH至12;
(2)往步骤(1)所得溶液中,在搅拌下(转速为500转/分)逐滴加入30ml的氯化钙,其中钙磷摩尔质量比为1.66:1,并用乙二胺调节pH至12。搅拌10min后,混合液在60℃下进行超声(400W)处理,并维持搅拌,超声时间为5小时。反应完后,静置过夜;
(3)将静置过夜后的黄色沉淀物与上清分离,将黄色沉淀物在转速为8000转/分的离心机下离心洗涤,使用水与无水乙醇交替洗涤。洗涤8次后,浅黄色沉淀物在80℃下干燥12小时。即得碳点-羟基磷灰石纳米复合物;
实施例4 HAp-CDs-PG-Dox的合成
(1)称取实施例3所得的100mg碳点-羟基磷灰石纳米复合物,超声分散于10ml的缩水甘油中。在120℃下加热并磁力搅拌。反应24小时后,冷却至室温,加10ml去离子水超声溶解。在100KD的超滤管中用去离子水离心洗涤7次以去除游离的超支化聚缩水甘油。最后所剩分散液加去离子水稀释至5ml,得到超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物,放4℃冰箱中保存为下一步使用。
(2)称取5mg阿霉素超声分散于2ml的步骤(1)所制备的超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合中。在室温下和避光环境下,磁力搅拌36小时。然后倒入到10KD的超滤管中,使用去离子水离心洗涤7次,移除未载上的阿霉素,得到加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox)。在扣除载体吸光度的前提下,使用紫外分光光度计计算阿霉素的浓度。
实施例5碳点-羟基磷灰石纳米复合物的超声一锅法
(1)将叶酸10mg超声溶解于30ml、0.05mol/l含磷酸氢二钾水溶液中,用氨水调节pH至9;
(2)往步骤(1)所得溶液中,在搅拌下(转速为100转/分)逐滴加入30ml的碳酸钙中,其中钙磷摩尔质量比为1.68:1,并用氨水调节pH至9。搅拌30min后,混合液在25℃下进行超声(100W)处理,并维持搅拌,超声时间5小时。反应完后,静置过夜。
(3)将静置过夜后的黄色沉淀物与上清分离,将黄色沉淀物在转速为4000转/分的离心机下离心洗涤,使用水与无水乙醇交替洗涤。洗涤8次后,浅黄色沉淀物在50℃下干燥12小时,即得碳点-羟基磷灰石纳米复合物。
实施例6 HAp-CDs-PG-Dox的合成
(1)称取实施例5的30mg碳点-羟基磷灰石纳米复合物,超声分散于10ml的缩水甘油中,在90℃下加热并磁力搅拌。反应24小时后,冷却至室温,加5ml去离子水超声溶解得分散液。在100KD的超滤管中用去离子水离心洗涤8次以去除游离的超支化聚缩水甘油。最后加去离子水稀释至5ml,得到超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物,4℃冰箱中保存为下一步使用。
(2)称取5mg阿霉素超声分散于2ml的步骤(1)所制备的超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物中。在室温下和避光环境下,磁力搅拌46小时。然后倒入10KD的超滤管中,使用去离子水离心洗涤5次,移除未载上的阿霉素,得到加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox)。在扣除载体吸光度的前提下,使用紫外分光光度计计算阿霉素的浓度。
实施例7碳点-羟基磷灰石纳米复合物的超声一锅法
(1)将叶酸10mg超声溶解于30ml、0.05mol/l含磷酸氢铵水溶液中,用氨水调节pH至9;
(2)往步骤(1)所得溶液中,在搅拌下(转速为100转/分)逐滴加入30ml的硝酸钙中,其中钙磷摩尔质量比为1.68:1,并用氨水调节pH至9。搅拌30min后,混合液在25℃下进行超声(500W)处理,并维持搅拌,超声时间5小时。反应完后,静置过夜。
(3)将静置过夜后的黄色沉淀物与上清分离,将黄色沉淀物在转速为4000转/分的离心机下离心洗涤,使用水与无水乙醇交替洗涤。洗涤8次后,浅黄色沉淀物在50℃下干燥12小时,即得碳点-羟基磷灰石纳米复合物。
实施例8 HAp-CDs-PG-Dox的合成
(1)称取实施例7的30mg碳点-羟基磷灰石纳米复合物,超声分散于10ml的缩水甘油中,在90℃下加热并磁力搅拌。反应24小时后,冷却至室温,加5ml去离子水超声溶解得分散液。在100KD的超滤管中用去离子水离心洗涤8次以去除游离的超支化聚缩水甘油。最后加去离子水稀释至5ml,得到超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物,4℃冰箱中保存为下一步使用。
(2)称取5mg阿霉素超声分散于2ml的步骤(1)所制备的超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物中。在室温下和避光环境下,磁力搅拌46小时。然后倒入10KD的超滤管中,使用去离子水离心洗涤5次,移除未载上的阿霉素,得到加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox)。在扣除载体吸光度的前提下,使用紫外分光光度计计算阿霉素的浓度。
下面对实施例制备的加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox)进行进一步验证。
实施例9 HAp-CDs纳米复合物的表征及荧光性能
一种碳点-羟基磷灰石纳米复合物,并对其进行超支化水溶性修饰和药物加载,其表达式为:HAp-CDs-PG-Dox。其中HAp代表羟基磷灰石;CDs代表碳点;PG代表超支化聚缩水甘油;Dox代表抗肿瘤药物阿霉素。HAp-CDs-PG-Dox对叶酸过表达的癌细胞还具有靶向识别功能及荧光成像功能。
取实验中间产物碳点-羟基磷灰石纳米复合物进行电镜显像,发现为棒状,长度大约在20-150nm,直径在4-8nm;其表面上的碳点为球形,直径大约在1~3nm。它是以四水硝酸钙为钙源,磷酸氢二铵为磷源,叶酸分子作为碳源。见图1,透射电镜图像中显示碳点成功地结合在羟基磷灰石表面。图2的XRD图谱中发现,所制备的碳点-羟基磷灰石纳米复合物与羟基磷灰石标准卡相吻合,并具有较好的结晶度,此外相较于羟基磷灰石强的结晶峰,碳点的吸收峰被掩盖。图3的碳点-羟基磷灰石纳米复合物具有良好的荧光性能,最大激发波长为360nm,最大发射波长为452nm。图4超支化聚缩水甘油修饰后的碳点-羟基磷灰石纳米复合物仍具有较好的荧光性能;最大激发波长为360nm,最大发射波长红移至460nm。
实施例10 HAp-CDs-PG-Dox的细胞摄取及成像检测
方法:将叶酸过表达的HeLa细胞和叶酸低表达的MCF-7细胞接种于6孔板中,培养过夜后,将制备的加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox)以组成培养体系中最终阿霉素浓度为3mg/ml的量分别加入孔板中;与细胞共培养3小时后,用PBS清洗细胞3次,然后使用4%多聚甲醛的PBS溶液液固定细胞10min。最后,再用PBS清洗细胞两次,并使用DAPI标记细胞核,在共聚焦荧光显微镜下观察细胞。其中蓝色荧光属于DAPI染色的细胞核,绿色荧光属于HAp-CDs-PG,红色荧光属于Dox。
结果显示:HAp-CDs-PG-Dox在HeLa细胞中发出强烈的属于HAp-CDs-PG的绿色荧光(图5的(C)),与强烈的属于Dox的红色荧光(图5的(D))。然而在MCF-7细胞中绿色和红色荧光都非常弱(图5的(H)(I))。因此,HAp-CDs-PG-Dox在叶酸过表达的HeLa细胞中表现出更强的细胞摄取能力。图5的(A)(F)为明场,(B)(G)为DAPI染色的细胞核,(E)(J)为合并图。结果表明,HAp-CDs-PG可以选择性的对叶酸过表达的HeLa细胞进行成像,可以进行靶向传递抗癌药物用以***。
实施例11 HAp-CDs-PG-Dox与HeLa细胞共培养后的细胞活力检测
方法:将接种量为7000个/孔的叶酸过表达的HeLa细胞接种于96孔板中,培养过夜后,加入不同量的加载阿霉素的超支化聚缩水甘油-碳点-羟基磷灰石纳米复合物(HAp-CDs-PG-Dox),其以培养体系中阿霉素的浓度为0.25μg/ml、0.5μg/ml、1μg/ml、2.5μg/ml、5μg/ml为计算;对照组为只含细胞和培养基;细胞培养24小时后,检测其活力。
结果显示:图6中随着阿霉素浓度增加,HeLa细胞细胞的活力下降,表明HAp-CDs-PG-Dox对叶酸过表达的HeLa细胞具有较好的杀伤效果;在较低浓度的阿霉素(5μg/ml)下,HeLa的细胞活力下降至46%,这说明HAp-CDs-PG成功地被用于加载及传递抗肿瘤药物,并实现靶向治疗。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,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。
Claims (10)
1.一种制备碳点-羟基磷灰石纳米复合物的超声一锅法,其特征在于,包括以下步骤:
1)将叶酸溶解在磷酸盐溶液中,用pH调节试剂调节pH至9~12;搅拌,逐滴滴加到钙盐溶液中,混匀,将所得混合液用pH调节试剂调节pH至9~12,并搅拌,在搅拌中超声,静置;所述的钙盐与磷酸盐的摩尔质量比为(1.66~1.68):1;
2)静置后分离得沉淀和上清液,将沉淀离心洗涤后,干燥,得碳点-羟基磷灰石纳米复合物。
2.根据权利要求1所述的方法,其特征在于,步骤1)所述叶酸溶解在磷酸盐溶液中后,叶酸的浓度为0.3~2.6mg/mL,磷酸盐的浓度为0.3~1mol/L。
3.根据权利要求1所述的方法,其特征在于,步骤1)中所述的磷酸盐溶液选自磷酸氢铵、磷酸氢二铵、磷酸氢二钠、磷酸氢二钾的中的至少一种。
4.根据权利要求1所述的方法,其特征在于,步骤1)中所述的钙盐溶液为硝酸钙、四水硝酸钙、氯化钙、碳酸钙中的至少一种。
5.根据权利要求1所述的方法,其特征在于,步骤1)所述的超声温度为25~60℃,时间为3~5小时,功率为100W~500W。
6.一种药载的超支化聚合物-碳点-羟基磷灰石纳米复合物的制备方法,其特征在于,包括以下步骤:
1)将权利要求1制备的碳点-羟基磷灰石纳米复合物加入到缩水甘油中混匀,加热搅拌反应后,加水超声溶解得超支化聚合物修饰的碳点-羟基磷灰石纳米复合物;
2)将抗肿瘤药加入超支化聚合物修饰的碳点-羟基磷灰石纳米复合物中,搅拌反应完全,离心洗涤所得沉淀即药载的超支化聚合物-碳点-羟基磷灰石纳米复合物。
7.根据权利要求6所述的方法,其特征在于,步骤1)所述碳点-羟基磷灰石纳米复合物与缩水甘油的用量比为(3mg~10mg):1mL。
8.根据权利要求6或7所述的方法制备的药载的超支化聚合物-碳点-羟基磷灰石纳米复合物。
9.权利要求8所述的药载的超支化聚合物-碳点-羟基磷灰石纳米复合物在制备靶向识别或/和抑制癌细胞的试剂的应用。
10.根据权利要求9所述的应用,其特征在于,所述的癌细胞为叶酸过表达的癌细胞。
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