CN108516964B - 一种具有聚集诱导发光效应的纳米材料及其应用 - Google Patents
一种具有聚集诱导发光效应的纳米材料及其应用 Download PDFInfo
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Abstract
本发明公开一种具有聚集诱导发光效应的纳米材料,及其在制备治疗癌症药物的应用、在药物载体的应用、在细胞成像的应用、在活体成像的应用。本发明基于纳米材料的聚集诱导发光性质,有效地对肿瘤细胞和组织成像,对化合物的抗肿瘤作用进行探究,发现其具有良好的抗肿瘤活性,可以在有效杀伤癌细胞的同时观察药物去向,从而实现诊断治疗的一体化。本发明原料价廉易得,制备方法简单易行,且制备的产物重复性和稳定性良好,具有广阔的应用前景。
Description
技术领域
本发明属于纳米材料领域,具体涉及了一种具有聚集诱导发光效应的纳米材料及其应用。
背景技术
纳米材料技术是近来新兴的一门技术,纳米粒子容易制造,能装载各种药物,易于修饰。此外,纳米粒子还可以通过设计,增加各种具有生物响应性的功能。但是,纳米载药体系也有缺点,例如大部分纳米粒子不能分散在水溶液中,纳米粒子本身不带荧光,难以检测粒子在生物体内的去向。为了解决复上述问题在,人们合成了三类荧光纳米材料:半导体碳量子点,复合荧光纳米粒子和有机小分子聚合或聚集形成的荧光纳米粒子。
半导体碳量子点纳米材料因为结构的缘故,只适合于充当探针,或者作为被包埋的对象负载于复合纳米材料中。复合纳米材料。复合荧光材料骨架和荧光物质可以通过物理方式,如静电力作用、空间位阻、或氢键等结合;也可以通过化学方式,即共价键结合。两者都有自身的缺陷,如通过物理结合的纳米体系容易出现染料泄露,共价键作用力更强,使染料不易泄露性但是共价键连接时,往往需要苛刻的条件才能使反应发生,很容易破坏染料分子的结构或荧光性质。
发明内容
本发明的首要目的在于提供一种具有聚集诱导发光效应的纳米材料;另一目的在于提供上述纳米材料的应用。本发明的目的通过以下技术方案实现:
一种具有聚集诱导发光效应的纳米材料,所述纳米材料由单一的化合物自组装而成,导向基团4-(二苯基氨基)苯基之间产生π-π堆积,所述化合物的化学结构式为:
所述的纳米材料作为治疗癌症药物的应用。
所述的纳米材料在载药体系的应用,所述纳米材料,经功能化修饰,作为药物载体的组分或骨架,通过吸附或包裹的方式运载药物。
所述的纳米材料在细胞成像的应用,所述纳米材料作为荧光探针应用于细胞成像。
所述的纳米材料在活体成像的应用,所述纳米材料作为荧光探针应用于活体成像。
与现有技术相比,本发明具有以下优点及有益效果:
(1)本发明合成了一种全新的聚集诱导发光(AIE)效应的纳米材料。材料在血浆,DMEM等可以稳定存在,而在细胞内则可以迅速降解。材料自带荧光,不用修饰其他荧光基团或负载其他荧光分子,组分相对单一,可以有效地减少增加组分对纳米材料结构的影响。
(2)本发明合成的纳米材料与其他纳米材料相比,可以通过相对简便、贴合实际应用的方法制备。
(3)合成的纳米材料在生物体内具有明亮的绿色荧光性质,作为细胞成像的工具时,在较低的浓度下即可观察到明显的发光。AIE独特的性质,可以使其有效地避免荧光猝灭现象,使荧光的强度大大提高。
(4)合成的纳米材料具有可增敏化疗、光动力治疗、免疫治疗等其他药物或方法的抗肿瘤作用。
(5)本发明所得产物的原料廉价易得,合成和纯化步骤可操作性强,可通过优化工艺,适当扩大合成规模,实现药物的商业化和应用。
附图说明
图1为实施例1中纳米材料的聚集诱导发光效应性质光谱图。
图2为实施例1中纳米材料透射电子显微镜(TEM)图。
图3为实施例1中纳米材料粒度折线图。
图4为检测例1纳米材料抗肿瘤活性检测细胞存活率柱状图。
图5a-5d为检测例2纳米材料在体外细胞模型的成像检测图。
图6为检测例3纳米材料用流式细胞仪检测的U87细胞周期分布图。
图7为检测例4纳米材料对U87细胞内ROS的折线图。
图8为检测例5纳米材料在胞吞抑制剂处理后的U87细胞与正常细胞的细胞形貌对比图。
图9为检测例5纳米材料在胞吞抑制剂处理后的U87细胞与正常细胞的存活率柱状图。
图10为检测例7的纳米材料为骨架形成的纳米材料载药前后的A375 细胞存活率柱状图。
具体实施方式
本发明用下列实施例来进一步说明本发明,但本发明的实施方式并不限于以下实施例。
实施例1
化合物1A的合成
将4-甲酰基苯基硼酸(150mg,1.0mmol)的THF(10mL)溶液加至4-溴-7-[4-(二苯基氨基)苯基]-2,1,3-苯并噻二唑(458mg, 1.0mmol)在甲苯(10mL)和2M碳酸钠水溶液(2mL)的混合溶液中。在常温下将四(三苯基膦)钯(1.73mg,0.0015mmol)加入到反应中,温度升高到100℃回流过夜。反应液冷却至室温,低压旋蒸大部分的甲苯和四氢呋喃溶剂,并用20ml的二氯甲烷萃取三次反应液,合并萃取液并用无水硫酸镁干燥,过滤,旋干。通过层析色谱过柱得到纯净的产物(层析液正己烷:二氯甲烷=4:1Rf=0.5)为黄色固体(334mg,产率69%)。
1H NMR(CDCl3-d,δppm):10.12(s,1H),8.17(d,2H),8.06(d,2H), 7.90(d,2H),7.86(d,1H),7.79(d,1H),7.34-7.27(m,4H),7.25-7.178 (m,6H),7.09(t,2H).13C NMR(CDCl3-d,δppm):192.5,154.3,153.6, 148.4,147.4,143.8,137.9,136.2,133.8,132.2,131.6,131.2,130.4, 130.2,129.7,129.4,127.3,126.8,125.2,123.5,122.8.
合成纳米材料:取2.5mg上述化合物溶解于1mL DMSO中。超声5分钟使其完全溶解,制备成化合物的储备液。储备液的制备不需要无菌条件。在无菌的条件下,用移液枪移取616μL储备液加入含牛胎儿血清的DMEM中,超声5min使其分散均匀,用去离子水透析(Mw=5000kDa)48小时,除去未成球的粒子,便得到较纯净的纳米材料。样品需无菌储存。
纳米材料的表征:通过,荧光光谱仪测量AIE性质(图1),通过透射电子显微镜(TEM)用于表征样品的形貌(图2),纳米粒度仪检测样品的稳定性,即尺寸大小。
实施例2
化合物1B的合成
将对苯甲酸甲酯基苯硼酸(180mg,1.0mmol)的THF(10mL) 溶液加至4-溴-7-[4-(二苯基氨基)苯基]-2,1,3-苯并噻二唑(458mg, 1.0mmol)在甲苯(10mL)和2M碳酸钠水溶液(2mL)的混合溶液中。在常温下将四(三苯基膦)钯(1.73mg,0.0015mmol)加入到反应中,温度升高到100℃回流过夜。反应液冷却至室温,低压旋蒸大部分的甲苯和四氢呋喃溶剂,并用20ml的二氯甲烷萃取三次反应液,合并萃取液并用无水硫酸镁干燥,过滤,旋干。通过层析色谱过柱得到纯净的产物(层析液正己烷:二氯甲烷=5:1Rf=0.6)为淡黄色固体(363mg,产率71%)。
1H NMR(CDCl3-d,δppm):8.21(d,2H),8.06(d,2H),7.88(d,2H), 7.84(d,1H),7.78(d,1H),7.74-7.70(m,1H),7.54-7.50(m,1H), 7.34-7.26(m,3H),7.25-7.20(m,5H),7.08(t,2H),4.43(q,2H),1.43(t, 3H).13C NMR(CDCl3-d,δppm):168.1,154.6,151.3,148.4,147.4, 143.8,137.9,136.2,133.8,132.2,131.6,131.2,130.4,130.2,129.7, 129.4,127.3,126.8,125.2,123.5,120.7,60.9,14.1.
合成纳米材料:取2.5mg上述化合物溶解于1mL DMSO中。超声5分钟使其完全溶解,制备成化合物的储备液。储备液的制备不需要无菌条件。在无菌的条件下,用移液枪移取616μL储备液加入含牛胎儿血清的DMEM中,超声5min使其分散均匀,用去离子水透析(Mw=5000kDa)48小时,除去未成球的粒子,便得到较纯净的纳米材料。样品需无菌储存。
纳米材料的表征:通过透射电子显微镜(TEM)用于表征样品的形貌,纳米粒度仪检测样品的稳定性,即尺寸大小。
实施例3
化合物1C的合成
将(4-苯甲酸甲酯基-7-[4-(二苯基氨基)苯基]-2,1,3-苯并噻二唑513mg,1.0mmol)的THF(10mL)溶液加至过饱和的氢氧化钠的甲醇溶液,室温反应搅拌过夜,低压旋蒸四氢呋喃和甲醇溶剂,用1 N盐酸调节PH至1,加入10ml的蒸馏水,并用10ml的二氯甲烷萃取三次反应液,合并萃取液并用无水硫酸镁干燥,过滤,旋干。通过层析色谱过柱得到纯净的产物(层析液正己烷:二氯甲烷=1:2Rf=0.5)为黄色固体(454mg,产率91%)。
1H NMR(CDCl3-d,δppm):13.1(s,1H),8.16(d,2H),8.10(d,2H), 8.07-7.93(m,4H),7.41-7.33(m,4H),7.15-7.09(m,8H).13C NMR (CDCl3-d,δppm):167.6,153.8,153.7,148.1,147.3,141.5,133.1, 130.9,130.7,130.69,130.6,130.2,130.0,129.64,129.60,127.8,125.1, 124.1,122.6.
合成纳米材料:取2.5mg上述化合物溶解于1mL DMSO中。超声5分钟使其完全溶解,制备成化合物的储备液。储备液的制备不需要无菌条件。在无菌的条件下,用移液枪移取616μL储备液加入含牛胎儿血清的DMEM中,超声5min使其分散均匀,用去离子水透析(Mw=5000kDa)48小时,除去未成球的粒子,便得到较纯净的纳米材料。样品需无菌储存。
纳米材料的表征:通过透射电子显微镜(TEM)用于表征样品的形貌,纳米粒度仪检测样品的稳定性,即尺寸大小。
实施例4
化合物1D的合成
将4-甲酰基苯基硼酸(150mg,1.0mmol)的THF(10mL)溶液加至4-溴-7-[4-(二苯基氨基)苯基]-2,1,3-苯并硒二唑(505mg, 1.0mmol)在甲苯(10mL)和2M碳酸钠水溶液(2mL)的混合溶液中。在常温下将四(三苯基膦)钯(1.73mg,0.0015mmol)加入到反应中,温度升高到100℃回流过夜。反应液冷却至室温,低压旋蒸大部分的甲苯和四氢呋喃溶剂,并用20ml的二氯甲烷萃取三次反应液,合并萃取液并用无水硫酸镁干燥,过滤,旋干。通过层析色谱过柱得到纯净的产物(层析液正己烷:二氯甲烷=4:1Rf=0.5)为棕黄色个体(344mg,产率65%)。
1H NMR(CDCl3-d,δppm):10.10(s,1H),8.05(m,4H),7.80(d,2H), 7.71(d,1H),7.63(d,1H),7.34-7.25(m,5H),7.23-7.16(m,5H),7.07 (t,2H).13C NMR(CDCl3-d,δppm):192.1,153.9,153.2,147.6,147.1, 141.8,136.9,135.7,132.8,131.6,130.3,129.2,129.0,128.8,127.6, 127.3,126.1,125.4,124.1,123.1,120.9.
合成纳米材料:取2.5mg上述化合物溶解于1mL DMSO中。超声5分钟使其完全溶解,制备成化合物的储备液。储备液的制备不需要无菌条件。在无菌的条件下,用移液枪移取616μL储备液加入含牛胎儿血清的DMEM中,超声5min使其分散均匀,用去离子水透析(Mw=5000kDa)48小时,除去未成球的粒子,便得到较纯净的纳米材料。样品需无菌储存。
纳米材料的表征:通过透射电子显微镜(TEM)用于表征样品的形貌,纳米粒度仪检测样品的稳定性,即尺寸大小。
检测例1
纳米材料的抗肿瘤活性
本实验建立了体外肿瘤模型,并通过MTT(噻唑蓝)法检测实施例1中纳米材料的抗肿瘤活性。
肿瘤模型建立:实验所使用的细胞为:脑星形胶质母细胞瘤细胞(U87)、人脑胶质细胞(CHEM-5)、人恶性黑色素瘤细胞(A375),在37℃细胞培养箱中培养细胞至对数生长期,经0.25%胰酶(含 0.02%EDTA)消化,计数后,以接种到96孔板中,每孔接种2000 个细胞,培养基体积为100μL。置于培养箱中24h,待细胞贴壁。
活性检测:每孔加入用培养基稀释的不同浓度的药物各100μl,每个药物浓度均分三组平行。对照组加入100μL DMEM培养基。每个处理至少铺3个复孔,细胞置于37℃,5%CO2培养24h。细胞经药物作用处理72h后,每孔加入30μl MTT孵育3.5h后抽去每个孔的上清,并再次向每个孔加入150μl DMSO,振荡摇匀10 min,最后,在多功能酶标仪上测定读取570nm处的吸光值,并作图4计算不同细胞不同药物处理组的存活率。
细胞的存活率按以下公式计算:存活率=处理组吸光值/对照组吸光值×100%。
结果表明,在药物作用于细胞72小时后,在高浓度下药物显著地抑制了U87和A375的生长,与其相比,正常细胞CHEM-5 的细胞存活率显著高于A375和U87,显示出药物具有一定选择性 (详见图4)。
检测例2
纳米材料影响肿瘤细胞周期的检测
本实验建立了体外肿瘤模型,通过流式细胞术来检测评价实施例1中纳米材料影响肿瘤细胞周期能力。
肿瘤模型建立:实验用到的细胞为脑星形胶质母细胞瘤细胞 (U87)、人脑胶质细胞(CHEM-5)、人恶性黑色素瘤细胞(A375),在37℃细胞培养箱中培养细胞至对数生长期,经0.25%胰酶(含 0.02%EDTA)消化,计数后,接种在6cm培养皿中。接种细胞密度为2×104/ml,培养24h待细胞呈对数生长。
细胞损伤检测检测:在药物处理组加入8、16、32μM纳米材料。24h后用0.25%胰酶(含0.02%(m/v)EDTA)将细胞消化,再用PBS洗涤培养皿3次,收集到全部细胞于15ml离心管。用离心机1500r/min离心5min收集细胞。每管用4ml冷冻的70%乙醇重悬,于4℃冰箱中放置固定过夜。第二天用离心机1500r/min离心5min,倒掉上清并用PBS洗涤一次,再次离心收集细胞,最后每管加入500μl 50ug/ml PI(碘化丙啶,购于Sigma公司)染液同时将细胞轻轻吹打分散,然后避光孵育1小时,随后细胞经400目网筛过滤,再Beckman流式细胞仪检测分析染色细胞。每个样品最少收集10000个细胞。最后用MultiCycle软件分析细胞周期各阶段的比例,以DNA含量来反映G0/G1、S、G2/M期细胞数量的比值,亚二倍体Sub-G1峰来表示凋亡细胞比例。
实验结果如图5a-5d所示,经低浓度(4μM)的药物处理24h后,细胞周期未发生显著变化。而高浓度的变化很明显,Sub-G1峰从对照组的2.6%上升到处理组的59.1%。Sub-G1峰是细胞凋亡的标志, Sub-G1峰的出现说明了细胞中的DNA发生了断裂,证明纳米材料能诱发细胞DNA损伤,进而杀伤细胞。
检测例3
纳米材料在肿瘤细胞中的成像能力的检测
本实验通过荧光显微镜检测实施例1中纳米材料在细胞中成像能力及成像的位置位置。
肿瘤细胞模型建立:U87细胞以5×104cells/mL的密度接种于2 cm培养皿中,加入尼罗红红色荧光探针(5μg/mL)以标记脂滴, DAPI(0.1μg/mL)标记细胞核。去掉培养基,用PBS清洗细胞3 次以去除游离于细胞外的染液。在荧光显微镜下采集荧光信号。脂滴被尼罗红标记而发红色荧光,细胞核被DAPI标记而发蓝色荧光。
成像能力检测:加入16μM的纳米材料孵育8小时。在荧光显微镜下采集荧光信号。每隔一定时间采集信号。
实验结果(图6)表明,纳米材料在1小时内高效进入肿瘤细胞内,然后逐渐定位在脂滴中,说明了纳米材料进入细胞后主要定位在脂滴中。在这个过程中,绿色荧光并没有与蓝色荧光重叠,证明其进入细胞的作用范围并不包括细胞核。另外,实验发现,在两小时后,细胞中出现了亮度很高的斑点。通过细胞外实验可以证明,浓度越大纳米材料的发光强度越强。此现象可以说明药物在脂滴中实现了富集。随着时间的增加,斑点的数量不断增加,斑点的亮度也不断加强,药物在细胞内累积的量越来越多,成像能力液越来越强。
检测例4
纳米材料对肿瘤细胞活性氧(ROS)的影响
本实验检测实施例1中纳米材料改变肿瘤细胞中ROS数量的能力。
模型建立:U87细胞2×104/ml密度接种于96孔板,每孔100μl。待细胞贴壁后,加入DHE探针与细胞共培养2小时。
活性氧(ROS)检测:将多余的DHE吸走,加入纳米材料,并于多功能酶标仪中以488nm波长激发,检测525nm波长的荧光强度。结果如图7所示,纳米材料后,细胞内ROS显著上升。ROS 过量产生导致细胞DNA损伤从而引起细胞凋亡。因此本例证明了纳米材料改变细胞内ROS的能力。
检测例5
纳米材料进入细胞的机制检测
本实验探究了实施例1中纳米材料进入细胞的机制,用不同的胞吞抑制剂NaN3/DOG(抑制依赖ATP的主动运输过程),Dynasore(抑制肌动蛋白介导的胞吞过程),Nystatin(抑制Cavelin-1 活性,影响小窝蛋白介导的胞吞过程)和Sucrose(抑制网格蛋白介导的胞吞过程),及4℃低温处理U87细胞,再比较抑制剂处理前后吸收效率比较,以及抑制处理前后的细胞存活率变化,结果如图8、图9所示,4℃低温以及NaN3预处理明显抑制细胞对纳米材料的吸收效率,说明纳米材料通过主动运输的方式进入细胞。对比发现, Dynasore与其他胞吞抑制剂相比,更能有效地抑制药物进细胞的吸收率。说明肌动蛋白介导的胞吞作用是纳米材料进入蛋白质的最主要方式。
在16μg/L药物浓度下,将细胞用胞吞抑制剂处理2小时后再加入药物。实验结果对比发现,经4种胞吞抑制剂处理的细胞状态明显好于未加药物的空白对照。未添加胞吞抑制的细胞已呈病态的球形,而经胞吞抑制处理的细胞大都呈现出正常的状态。无论在10X 镜头还是在100X镜头中,经NaN3/DOG和Dynasore处理的荧光强度明显弱于对照组。因此可以证明纳米材料是通过细胞胞吞药物产生的现象。
检测例6
纳米材料在DMEM及血浆中的稳定性
本实验检测对实施例1中纳米材料在人血清和DMEM中的粒径进行长时间监测。
检测方法:将纳米材料加入PBS、DMEM培养基、人血浆中,检测粒径的变化情况。
纳米粒子在人血浆和培养基的稳定性对纳米粒子是一个重要的指标,粒子的稳定性越高,在生物体环境内越稳定,纳米粒子内负载的药物越不会提前释放,从而降低非目标区域的药物浓度,降低药物的毒副作用。实验结果表明,在72小时的实验时间内,人血清和水中的粒径保持在130纳米以下,证明了本纳米体系能在血液环境中和 DMEM环境中保持良好的稳定性。具有良好的应用前景。
检测例7
纳米材料载药体系的制备及其性能评价
纳米载药体系的制备:
纳米载药体系是在纳米材料制备的方法上改进的。与纳米骨架对比,对溶剂的要求有所提高,将纳米材料与需要负载的药物溶解在DMSO中,然后将药物滴加到含有牛胎儿血清的培养基中共沉淀形成纳米球。牛胎儿血清中的蛋白及氨基酸组分能增加纳米体系的稳定性。
载药体系性能评价的模型建立方法与检测方法与之前例子一致。
实验结果(图10)表明,作用于细胞72小时后,负载了RUPOP 的纳米态药物效果显著高于单独的药物、单独的RuPOP、纳米态的药物与未包裹的RuPOP,证明了我们的药物可以很好地负载药物。
本发明的实施方式不限于此,按照本发明的上述内容,利用本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,本发明还可以做出其它多种形式的修改、替换或变更,均落在本发明权利保护范围之内。
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