CN108675280B - 吩噻嗪衍生物荧光碳点及其制备方法和应用 - Google Patents
吩噻嗪衍生物荧光碳点及其制备方法和应用 Download PDFInfo
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Abstract
吩噻嗪衍生物荧光碳点及其制备方法和应用,所述的制备方法包括水热合成反应的步骤,反应的原料包括吩噻嗪类衍生物和钝化剂;所述的吩噻嗪类衍生物具有通式I的结构。该方法合成过程简单、经济且绿色环保,所制备的吩噻嗪类衍生物荧光碳点粒径均匀,结构稳定,在可见光及近红外区域具有明显吸收及荧光发射。该碳点可用于细胞荧光成像,在可见光及近红外波长的光照射下可产生单线态氧并可用于肿瘤细胞的杀伤。是用于光动力治疗的理想光敏剂。
Description
技术领域
本发明涉及碳纳米材料及其制备方法、光动力治疗,特别涉及一种以吩噻嗪衍生物为原料制备荧光碳点的方法及其制备的荧光碳点。
技术背景
碳点是一种新型的碳纳米材料,尺寸10nm以下,能在紫外光照射下发出荧光,具有良好的水溶性、生物相容性、低毒性、抗光漂白性及光稳定性等优异性能,因此它在生物成像、荧光标记、生物传感、金属离子检测等领域具有广泛的应用前景。
光动力疗法(Photodynamic Therapy,PDT)是新兴的一种癌症治疗方法。当用特定的波长的光照射肿瘤部位时,聚集在肿瘤组织的光敏剂将被激发至激发态,随后会将能量传递给周围的氧气,生成活性很强的单线态氧。单线态氧能与附近的生物大分子发生氧化反应,产生细胞毒性进而杀伤肿瘤细胞。与肿瘤传统的疗法相比,光动力治疗的优势在于其可控和非侵入性,因而副作用较小。结合碳点与光动力治疗优点与长处,合成开发出一种可用于光动力治疗的碳点,对于光敏剂的研发与癌症治疗有着重要的意义。光敏剂是光动力治疗中的核心组成部,光敏剂的性能和特点决定了光动力治疗效果的大小,用于光动力治疗的理想光敏剂应具备以下特性:1)在光疗窗口 600-800nm有较强的吸收;2)高的单线态氧产率;3)光毒性强而暗度性低。
吩噻嗪类光敏剂是目前较为广泛应用于生物医学研究和临床治疗如精神病、抑郁症及帕金森氏症等疾病治疗的一种药物,是目前临床上应用广泛的光敏剂之一。然而吩噻嗪类染料可以侵染DNA,对人体有致癌危险,所以研发一种可以安全有效的吩噻嗪类荧光碳点是很有必要的。
发明内容
本发明的目的即在于提供一类具有良好的光动力特性,且安全有效的荧光碳点。
基于该目的,本发明首先提供一类吩噻嗪衍生物荧光碳点的制备方法,所述方法包括水热合成反应的步骤,反应的原料包括吩噻嗪类衍生物和钝化剂;所述的吩噻嗪类衍生物具有通式I的结构:
通式I中:
R1-R10各自独立地选自H、C1-8烷基、苯基或取代苯基;
所述取代苯基由以下一种或多种基团任意取代:CN、COOH、NH2、NO2、OH、 SH、C1-6烷氧基、C1-6烷基氨基、C1-6酰胺基、卤素或C1-6卤代烷基。
X是氧、硫、硒、碲、氮、磷、砷、锗或硅。
上述本发明所提供的吩噻嗪类衍生物荧光碳点的制备方法通过水热法制备的碳点,合成过程简单、经济且绿色环保。
本发明发明中吩噻嗪类衍生物荧光碳点具有以下显著的特征:①所述方法制备的荧光碳点粒径均匀,结构稳定,吸收与发射波长在近红外区域。②所述方法制备的碳点,在可见光及近红外区域(600-900纳米)具有明显吸收及荧光发射。③该碳点可用于细胞荧光成像。④可见光及近红外波长的光照射碳点时,可产生单线态氧并可用于肿瘤细胞的杀伤。是用于光动力治疗的理想光敏剂。基于此,本发明另一方面的目的在于提供上述本发明的所述的方法制备的吩噻嗪衍生物荧光碳点。并公开其在制备光动力治疗制剂中的应用。
附图说明
图1是亚甲基蓝碳点的透射电镜照片。
图2是亚甲基蓝碳点350-590nm的激发光条件下所获得的荧光光谱曲线图。
图3是是亚甲基蓝碳点在超纯水中的吸收光谱图。
图4是亚甲基蓝碳点的傅里叶变换红外光谱测试图。
图5是亚甲基蓝碳点的单线态氧产率测试图。
图6是亚甲基蓝碳点的DNA侵染性测试结果图。
图7是亚甲基蓝碳点对肿瘤细胞杀伤作用实验结果图。
以人乳腺癌细胞进行细胞毒性实验,以噻唑蓝(MTT)为检测物质,分别检测亚甲基蓝碳点在光照或无光照的情况下对肿瘤细胞的杀伤作用。
具体实施方式
本发明提供一类吩噻嗪衍生物荧光碳点及其制备方法和用途。该所述荧光碳点由所述方法直接获得。所述方法是反应原料的水热合成反应,反应的原料包括吩噻嗪类衍生物和钝化剂;所述的吩噻嗪类衍生物具有通式I的结构:
通式I中:
R1-R10各自独立地选自H、C1-8烷基、苯基或取代苯基;优选H或CH3;
所述取代苯基由以下一种或多种基团任意取代:CN、COOH、NH2、NO2、OH、 SH、C1-6烷氧基、C1-6烷基氨基、C1-6酰胺基、卤素或C1-6卤代烷基。
X是氧、硫、硒、碲、氮、磷、砷、锗或硅,优选氧或硫。
进一步具体的实施方式中,所述的通式I所代表的吩噻嗪类衍生物可举例但不限于已公开的染料化合物如亚甲基蓝、甲苯胺蓝和新亚甲基蓝。
进一步具体的实施方式中,本发明所述的制备方法,包括下述步骤:
(1)配制浓度为0.5-5mg/mL的吩噻嗪衍生物水溶液;
(2)向步骤(1)制备的溶液中加入钝化剂,水热反应后自然冷却至室温;
(3)步骤(2)所得产物离心,所得上清液经过后处理得到吩噻嗪衍生物荧光碳点。
其中,步骤(2)所述的钝化剂为1-30mg/mL的PEG200-2000或0.1-5mg/mL的尿素。该描述中,钝化剂的浓度代表钝化剂在反应体系中的浓度。
另一方面,步骤(2)中述及吩噻嗪衍生物在钝化剂存在条件下的水热反应,该反应可根据本领域现有技术限定条件。本发明中,优选于烘箱内反应釜中进行,烘箱温度 120-220℃,反应时间为8-24h。
再一方面,上述制备方法中,步骤(3)述及对产物的离心处理,可以是5000-12000r/min,离心5-30min。其后所述针对上清液的后处理可以采用包括微孔滤膜过滤、透析、旋转蒸发和冷冻干燥的步骤。作为举例的描述,所述的所述微孔滤膜过滤采用孔径为0.22μm的微孔滤膜;透析采用1000-3500Da的透析袋,透析时间为5-36h。
下述非限制性实施例用于进一步说明本发明的技术特征及效果,不应当理解为对本发明内容任意形式的限定。
实施例1
亚甲基蓝碳点的制备:称取15mg的亚甲基蓝置于25mL烧杯中,加入15mL去离子水后搅拌使其溶解,然后用移液枪量取150μLPEG800加入其中,搅拌均匀后。将所得溶液移入50ml反应釜内在180℃,反应12小时。反应结束后,在空气中冷却至室温,经过转速为8000r/min的离心机离心20分钟后得到亚甲基蓝碳点溶液,放置于4℃左右环境下保存,并用于下述性能测试实验1~5。
(1)性能测试实验1:对亚甲基蓝碳点进行形貌分析。
取亚甲基蓝碳量子点溶液,通过Zeta电位与粒径分析仪测得水合平均粒径为4.3nm,Zeta电位为-7.3V。通过300KV透射电镜(Tecnai F30)透射电镜获得亚甲基蓝碳点TEM图像(如图1)。图1中,大图比例尺为20nm,内图为高倍透射电镜图,比例尺为5nm,可见:碳点大小分布均匀,粒径在5nm左右,通过高倍TEM(图1内图)可知,该亚甲基蓝碳点具有明显的晶格结构。
(2)性能测试实验2:对亚甲基蓝碳点进行荧光与吸收光谱测试。
在比色皿中加入3ml超纯水,用紫外可见分光光度计测试空白样品,再加入100 ul亚甲基蓝碳点溶液,测试样品的吸收曲线。再将样品转移至荧光分光光度计中,测试荧光发射曲线。
在350-590nm的激发光条件下所获得的亚甲基蓝碳点荧光光谱曲线如图2所示。可见,随着激发波长逐渐增加,亚甲基蓝碳点的在540nm处的荧光发射逐渐减少,在 620nm处的荧光发射逐渐增强。
亚甲基蓝碳点在超纯水中的吸收光谱图如图3所示。可见,亚甲基蓝碳点在水溶液中的最大吸收波长在590nm处。
(3)性能测试实验3:对亚甲基蓝碳点进行红外光谱测试。
使用无水乙醇溶解亚甲基蓝碳点,傅里叶变换红外光谱仪测试亚甲基蓝红外光谱如图4所示,在1103和1077nm处的两个吸收峰代表着C-S键的伸缩振动峰。
(4)性能测试实验4:亚甲基蓝碳点单线态氧产率测试
以亚甲基蓝为对照组,以N-二甲基亚砜(DMSO)为溶剂,3-二苯基异苯并呋喃(DPBF)为单线态氧捕获剂,检测亚甲基蓝碳点单线态氧产率如图5,可见,亚甲基蓝碳点的单线态氧产率为0.17。
(5)性能测试实验5:亚甲基蓝碳点的DNA侵染性测试
据文献报道,亚甲基蓝分子本身会与DNA结合,导致亚甲基蓝本身的吸收减弱。因此分别向亚甲基蓝水溶液中与亚甲基蓝碳点溶液中加入不同浓度的小牛胸腺 DNA,用紫外可见分光光度计测试其吸光度。其结果如图6所示,亚甲基蓝分子在与微量的DNA(0.1/0.2/0.3μM)分子就可以看出明显的吸光度下降,而亚甲基蓝碳点溶液在加入十倍浓度的DNA(1/2/3μM)也没有吸光度下降,证明亚甲基蓝碳点不会与DNA结合,对DNA没有侵染性。
(6)性能测试实验7:亚甲基蓝碳点的MTT测试
采用人乳腺癌细胞(MCF-7)进行细胞毒性实验,使用MTT细胞增殖及细胞毒性检测试剂盒分别检测在无光和光照条件下,亚甲基蓝碳点对肿瘤细胞的细胞毒性。 MTT分析法以代谢还原噻唑蓝(MTT)为基础。活细胞的线粒体中存在与NADP相关的脱氢酶,可将黄色的MTT还原为不溶性的蓝紫色的甲臢,死细胞此酶消失,MTT 不被还原。用DMSO溶解甲臢后可用酶标仪在570与630nm波长处检测吸光度,并计算响应的细胞毒性计算,其结果如图7所示。可见,在无光的条件下,亚甲基蓝碳点并没有明显的细胞毒性,肿瘤细胞保持着良好的存活率。而在用波长为590nm光强为 30mw的光光照20min后,肿瘤细胞有着明显死亡情况,证明碳点在光动力治疗有着良好的作用。
实施例2
甲苯胺蓝(CAS登录号:92-31-9)碳点的制备:称取15mg的甲苯胺蓝置于25mL 烧杯中,加入15mL去离子水后搅拌使其溶解,然后用移液枪量取200μLPEG800加入其中,搅拌均匀后。将所得溶液移入50ml反应釜内在160℃,反应8小时。反应结束后,在空气中冷却至室温,经过转速为8000r/min的离心机离心20分钟后得到甲苯胺蓝碳点溶液,放置于4℃左右环境下保存待用。
实施例3
新亚甲基蓝(CAS登录号:6586-05-6)碳点的制备:称取15mg的新亚甲基蓝置于25mL烧杯中,加入15mL去离子水后搅拌使其溶解,然后用移液枪量取100
μLPEG800加入其中,搅拌均匀后。将所得溶液移入50ml反应釜内在120℃,反应12小时。反应结束后,在空气中冷却至室温,经过转速为10000r/min的离心机离心15分钟后得到新亚甲基蓝碳点溶液,放置于4℃左右环境下保存待用。
Claims (7)
1.吩噻嗪衍生物荧光碳点的制备方法,包括下述步骤:
(1)配制浓度为0.5-5mg/mL的吩噻嗪衍生物水溶液,
所述的吩噻嗪类衍生物具有通式I的结构:
通式I中:
R1-R10各自独立地选自H、C1-8烷基、苯基或取代苯基;
所述取代苯基由以下一种或多种基团任意取代:CN、COOH、NH2、NO2、OH、SH、C1-6烷氧基、C1-6烷基氨基、C1-6酰胺基、卤素或C1-6卤代烷基;
X是氧、硫、硒、碲、氮、磷、砷、锗或硅;
(2)向步骤(1)制备的溶液中加入钝化剂,水热反应后自然冷却至室温,
所述的钝化剂为1-30mg/mL的PEG200-2000或0.1-5mg/mL的尿素,
所述的水热反应于烘箱内反应釜中进行,烘箱温度120-220℃,反应时间为8-24h;
(3)步骤(2)所得产物离心,所得上清液经过后处理得到吩噻嗪衍生物荧光碳点。
2.根据权利要求1所述的方法,其特征在于,
所述的R1-R10优选H或CH3;
所述的X是氧或硫。
3.根据权利要求1所述的方法,其特征在于,步骤(3)所述产物离心是5000-12000r/min,离心5-30min。
4.根据权利要3所述的方法,其特征在于,步骤(3)所述的后处理包括微孔滤膜过滤、透析、旋转蒸发和冷冻干燥的步骤。
5.根据权利要求4所述的方法,其特征在于,所述微孔滤膜孔径为0.22μm;透析采用1000-3500Da的透析袋,透析时间为5-36h。
6.权利要求1~5中任一权利要求所述的方法制备的吩噻嗪衍生物荧光碳点。
7.权利要求6所述的吩噻嗪衍生物荧光碳点在制备光动力治疗制剂中的应用。
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