CN116179183A - 一种包载姜黄素引起aie发光的纳米制剂的制备方法及应用 - Google Patents
一种包载姜黄素引起aie发光的纳米制剂的制备方法及应用 Download PDFInfo
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Abstract
本发明一种包载姜黄素引起AIE发光的纳米制剂的制备方法及应用,纳米制剂包括纳米载体与具有AIE特性的姜黄素,具有AIE特性的姜黄素为基于‑OH产生簇聚而使结构刚硬化的姜黄素分子。本发明通过将中药活性单体包载于聚合物中,使本不具有AIE特性的姜黄素分子展现出AIE特性,本发明既保留姜黄素的药效学应用价值,同时赋予其新的光学性质,本发明提供的一种包载姜黄素引起AIE发光的纳米制剂具有较高的荧光强度和量子产量,细胞摄取能力强,具有较高的量子产量和较强的细胞成像能力,在细胞成像领域有重要的应用价值。
Description
技术领域
本发明属于荧光染料领域,特别涉及一种包载姜黄素引起AIE发光的纳米制剂的制备方法及应用。西
背景技术
荧光纳米药物具有水溶性好,细胞毒性低和荧光强度稳定性高等特点,在细胞成像,疾病诊断以及生物传感器等领域有着重要的应用价值。传统的荧光染料通常在溶液中表现出较好的光学性能,然而当处于聚集态时,发光效率大大降低甚至荧光猝灭,称之为聚集诱导猝灭(ACQ)效应,该效应极大地限制了荧光染料的应用范围。2001年,唐本忠课题组发现了聚集诱导发光的(AIE)的现象,该现象与ACQ截然相反,即化合物在稀溶液中发光较弱或者不发光,但在聚集或者固态下,发射强烈的荧光,使人们对传统荧光染料的认识达到一个全新的高度。AIE发光机理的研究进一步表明,分子内运动受限(RIM)对AIE的产生极为关键,因此,基于RIM原理,针对性地设计和合成了一系列的AIE分子,以便应用于生物成像和疾病诊断等不同领域。
但是迄今为止,并没有相关报道利用纳米技术,将不具有AIE特征的活性分子,包载于聚合物中,形成荧光强度高且拥有AIE特征的聚合物纳米制剂。
目前为止,大部分的AIE分子都是通过有机合成获得。虽然合成的技术手段可以获得多样且丰富的荧光染料,但复杂的合成路线,高成本的投入以及难降解等问题极大地限制了此类荧光染料的应用。
姜黄素(Cur)与纳米制剂(Cur@PLGA-NPs)的光学性质对比:传统的发光材料,因结构中含有芳杂环等大π-π共轭结构作为发射中心,故在稀溶液中可以发光。然而,随着不良溶剂浓度的增加,分子会形成强π-π相互作用的复合物,从而导致发光猝灭,大大限制了发光材料的实际应用,这些发光材料所具有的发光行为被称作聚集引起猝灭(aggregationcaused quenching,ACQ)。为了克服发光分子ACQ的难题,中国香港科技大学唐本忠课题组首次提出了“聚集诱导发光”(aggregationinducedemission)的科学概念,在溶液中,分子可以自由发生转动,因此激发态的能量以非辐射跃迁的形式进行耗散,使得分子不发光。聚集时,借助分子间的相互作用,限制了分子内旋转,从而产生了强发射光。
发明内容
针对上述问题,本发明一种包载姜黄素引起AIE发光的纳米制剂,纳米制剂包括纳米载体与具有AIE特性的姜黄素,具有AIE特性的姜黄素为基于-OH产生簇聚而使结构刚硬化的姜黄素分子。
其进一步的优选技术方案为:纳米载体为聚乳酸-羟基乙酸共聚物。
其进一步的优选技术方案为:纳米制剂为PLGA纳米制剂。
其进一步的优选技术方案为:纳米载体与不具有AIE特性的姜黄素通过非共价作用结合,非共价作用包括π-π共轭作用、疏水作用和/或分子间氢键。
其进一步的优选技术方案为:制备方法包括:
将质量比为1-100:1的纳米载体与姜黄素混合,置于EP管中,得到混合物;
在混合物中加入1-10mL有机溶剂使其溶解,得到油相混合物,有机溶剂为氯代烷烃和醇类有机溶剂;
将乳化剂溶于去离子水,得到水相溶液;
将油相混合物与所述水相溶液混合,涡旋1-5min后送入细胞破碎仪中超声破碎1-10min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
其进一步的优选技术方案为:纳米载体为聚乳酸-羟基乙酸共聚物,有机溶剂二氯甲烷、三氯甲烷,醇类有机溶剂乙醇、甲醇,乳化剂包括聚乙烯醇、白蛋白、蓖麻油聚氧乙烯醚、吐温20、十二烷基硫酸钠中任意一种。
其进一步的优选技术方案为:水相溶液中乳化剂浓度为1-10%,油相混合物与所述水相溶液混合比例为1:2-20。
其进一步的优选技术方案为:水相溶液中乳化剂浓度为3%。
其进一步的优选技术方案为:油相混合物与所述水相溶液混合比例为1.5:4.5。
其进一步的优选技术方案为:一种包载姜黄素引起AIE发光的纳米制剂的应用,包载姜黄素引起AIE发光的纳米制剂在细胞成像领域中的应用。
本发明的有益效果:1.提出了一种纳米技术制备AIE聚合物纳米粒的新方法。将中药活性单体包载于聚合物后,实现对单体分子的荧光“从无到有”的突破。
2.姜黄素本身不具有AIE特征,将其被包载于聚合物中形成纳米制剂后,荧光活性显著提高且聚合物纳米制剂具有AIE特征。
3.AIE聚合物纳米离子具有较高的荧光强度和量子产量,细胞摄取能力强,在细胞成像领域有重要的潜在应用价值。
本发明的其它特征和优点将在随后的说明书中阐述,并且,部分地从说明书中变得显而易见,或者通过实施本发明而了解。本发明的目的和其他优点可通过在说明书、权利要求书以及附图中所指出的结构来实现和获得。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作一简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1示出了根据本发明所得姜黄素(Cur)与PLGA纳米制剂(NPs)的光学性质,其中,(A)游离姜黄素在不同比例DMSO/H2O溶剂中的发射光谱图;(B)游离姜黄素的I/I0图;(C)PLGA纳米制剂在不同比例DMSO/H2O溶剂中的发射光谱图;(D)PLGA纳米制剂的I/I0图。
图2示出了根据本发明实施例所得Cur@PLGA-NPs纳米制剂和游离姜黄素的荧光谱图(250nm)。
图3示出了根据本发明实施例所得AIE聚合物纳米制剂的形态表征,其中,(A)Cur@PLGA-NPs纳米制剂的粒径分布柱状图;(B)Cur@PLGA-NPs纳米制剂的Zeta电位图;(C)Cur@PLGA-NPs纳米制剂的透射电镜图。
图4示出了根据本发明实施例所得AIE聚合物发光示意图。
图5示出了根据本发明实施例所得AIE聚合物纳米制剂的发光原理,其中,(A)Cur@PLGA-NPs纳米制剂在不同溶剂中的荧光谱图;(B)Cur@PLGA-NPs纳米制剂在不同激发波长下的荧光谱图;(C)Cur@PLGA-NPs纳米制剂在NaCl(5mg/mL),5%SDS加入后和加入前的荧光谱图;(D)Cur@PLGA-NPs和游离Cur的紫外光谱图。
图6示出了根据本发明实施例所得AIE聚合物纳米制剂在液态与固态中的光物理性质,其中,(A)Cur@PLGA-NPs和游离Cur的溶液在365nm下的对比图;(B)Cur@PLGA-NPs和游离Cur的粉末在365nm下的对比图;(C)Cur@PLGA-NPs溶液的激发(483nm)和发射波长(552nm)光谱图;(D)Cur@PLGA-NPs粉末的激发(427nm)和发射波长(537nm)光谱图;(E)Cur@PLGA-NPs溶液的量子产率(23.78%)谱图;(F)Cur@PLGA-NPs粉末的量子产率(21.52%)谱图;(G)Cur@PLGA-NPs溶液的荧光寿命(1.142ns)谱图;(H)Cur@PLGA-NPs粉末的荧光寿命(0.776ns)谱图;
图7示出了根据本发明实施例所得AIE聚合物纳米制剂的细胞毒性与凋亡活性,其中,(A)空白,游离Cur和Cur@PLGA-NPs与肿瘤细胞孵育后的AnnexinV/PI双阳性流式定量分析图;(B)空白,游离Cur和Cur@PLGA-NPs的细胞凋亡率;(C)游离Cur和Cur@PLGA-NPs的肿瘤细胞毒性图。
图8示出了根据本发明实施例所得不同浓度的AIE纳米制剂和细胞核染料DAPI与肿瘤细胞孵育后的共聚焦成像图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地说明,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:
将质量比为1:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入1mL二氯甲烷使其溶解,得到油相混合物;
将聚乙烯醇(PVA)溶于去离子水中,得到水相溶液,其中乳化剂PVA的浓度为3%;
在所述油相混合物中加入4.5ml水相溶液,涡旋3min后送入细胞仪中超声破碎5min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例2:
将质量比为50:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入2mL二氯甲烷使其溶解,得到油相混合物;
将白蛋白(BSA)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为1%;
在所述油相混合物中加入10ml水相溶液,涡旋5min后送入细胞仪中超声破碎1min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例3:
将质量比为100:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入1mL三氯甲烷使其溶解,得到油相混合物;
将蓖麻油聚氧乙烯醚(EL-40)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为5%;
在所述油相混合物中加入10ml水相溶液,旋涡5min后送入细胞仪中超声破碎10min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例4:
将质量比为50:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入3mL三氯甲烷使其溶解,得到油相混合物;
吐温20(Tween20)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为10%;
在所述油相混合物中加入15ml水相溶液,旋涡5min后送入细胞仪中超声破碎1min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例5:
将质量比为80:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入1mL二氯甲烷使其溶解,得到油相混合物;
十二烷基硫酸钠(SDS)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为10%;
在所述油相混合物中加入20ml水相溶液,旋涡5min后送入细胞仪中超声破碎1min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例6:
将质量比为20:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入1mL乙醇使其溶解,得到油相混合物;
将聚乙烯醇(PVA)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为1%;
在所述油相混合物中加入15ml水相溶液,旋涡3min后送入细胞仪中超声破碎5min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
实施例7:
将质量比为10:1的聚乳酸-羟基乙酸共聚物(PLGA)与姜黄素(Cur)混合物,置于EP管中;
在EP管中,加入1mL甲醇使其溶解,得到油相混合物;
十二烷基硫酸钠(SDS)溶于去离子水中,得到水相溶液,其中乳化剂的浓度为5%;
在所述油相混合物中加入10ml水相溶液,旋涡5min后送入细胞仪中超声破碎10min;
得到Cur@PLGA-NPs纳米制剂,Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
如图1所示,所得姜黄素(Cur)与PLGA纳米制剂(NPs)的光学性质如下:
游离的姜黄素在稀溶液60%DMSO中有荧光,随着水不良溶剂的浓度增加,分子产生聚集,姜黄素的荧光表现出降低的趋势,如图1A,1B所示,姜黄素的这一发光行为符合ACQ性质。当利用PLGA载体包裹姜黄素形成纳米制剂后,制剂在稀溶液(50%DMSO)中表现出弱发射光,随着水的浓度增加,分子产生聚集,纳米制剂的荧光表现出显著增加的趋势,如图1C,1D所示,这一发光行为符合AIE性质。游离的状态下,姜黄素中的非典型生色团(-OH)彼此隔离,难以被365nm紫外光激发;PLGA聚合物产生了粘度较大的环境,随着浓度增加,分子出现聚集,-OH产生簇聚,使原子间的距离减小,易于产生电子相互作用和离域扩展,从而产生有效的电子相互作用,使分子构象刚硬化,抑制了姜黄素的构象旋转,最终能被激发产生有效光发射。
如图2所示,相同浓度下(以姜黄素计),PLGA纳米制剂的荧光强度显著强于游离的姜黄素。传统AIE材料通常来源于人工合成化合物,生物分子以及天然产物等,目前尚未见报道采用聚合物载药的方式将ACQ药物分子制备成AIE药物。本发明既保留姜黄素的药效学应用价值,同时赋予其新的光学性质。
此外,Cur@PLGA-NPsAIE聚合物纳米制剂的形态表征如图3所示,其中(A)为Cur@PLGA-NPs纳米制剂的粒径分布柱状图;(B)为Cur@PLGA-NPs纳米制剂的Zeta电位图;(C)为Cur@PLGA-NPs纳米制剂的透射电镜图;
而本发明提供方法所制得的Cur@PLGA-NPsAIE聚合物纳米制剂的聚合物发光原理如图4所示,游离的状态下,姜黄素中的非典型生色团(-OH)彼此隔离,难以被365nm紫外光激发;PLGA聚合物产生了粘度较大的环境,随着浓度增加,分子出现聚集,-OH产生簇聚,使原子间的距离减小,易于产生电子相互作用和离域扩展,从而产生有效的电子相互作用,使分子构象刚硬化,抑制了姜黄素的构象旋转,最终能被激发产生有效光发射。
如图5所示,通过对比NaCl(5mg/mL)和5%SDS加入纳米制剂前后的光谱图可知(图5B和5C),纳米结构体系受离子键作用和疏水作用的影响,同时存在π-π共轭作用(图5D),此外,纳米结构体系中含有大量的氢键,这不仅可以使姜黄素构象刚硬化,还能缩短氧原子的接触距离,减少非辐射跃迁,从而提高发光效率。
以本发明提供方法所制得的Cur@PLGA-NPsAIE聚合物纳米制剂在液态与固态中的光物理性质如图6所示结果展示了AIE纳米制剂在液态和固态中的最大激发波长和发射波长,以及其量子产率,有利于进一步的体内外生物成像研究。其中,(A)为Cur@PLGA-NPs和游离Cur的溶液UV对比图;(B)为Cur@PLGA-NPs和游离Cur的粉末UV对比图;(C)为Cur@PLGA-NPs溶液的激发(483nm)和发射波长(552nm)光谱图;(D)为Cur@PLGA-NPs粉末的激发(427nm)和发射波长(537nm)光谱图;(E)为Cur@PLGA-NPs溶液的量子产率(23.78%)谱图;(F)为Cur@PLGA-NPs粉末的量子产率(21.52%)谱图;(G)为Cur@PLGA-NPs溶液的荧光寿命(1.142ns)谱图;(H)为Cur@PLGA-NPs粉末的荧光寿命(0.776ns)谱图。
以本发明提供方法所制得的Cur@PLGA-NPsAIE聚合物纳米制剂的细胞毒性与凋亡活性如图7所示,随着AIE纳米制剂浓度的增加,细胞存活率明显下降,体现出AIE纳米制剂作为抗肿瘤药物的潜力,本发明既增强了姜黄素的药效学应用价值,同时赋予其新的光学性质。其中,(A)为空白,游离Cur和Cur@PLGA-NPs与肿瘤细胞孵育后的AnnexinV/PI双阳性流式定量分析图;(B)为空白,游离Cur和Cur@PLGA-NPs的细胞凋亡率;(C)为游离Cur和Cur@PLGA-NPs的肿瘤细胞毒性图。
以本发明提供方法所制得的不同浓度的Cur@PLGA-NPsAIE聚合物纳米制剂和细胞核染料DAPI与肿瘤细胞孵育后的共聚焦成像图如图8所示,可见,以本发明提供方法所制得的Cur@PLGA-NPs,具有较高的荧光强度和量子产量,细胞摄取能力强,具有较高的量子产量和较强的细胞成像能力,在细胞成像领域有重要的应用价值。
尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (10)
1.一种包载姜黄素引起AIE发光的纳米制剂,所述纳米制剂包括纳米载体与具有AIE特性的姜黄素,所述具有AIE特性的姜黄素为基于-OH产生簇聚而使结构刚硬化的姜黄素分子。
2.根据权利要求1所述的一种包载姜黄素引起AIE发光的纳米制剂,其特征在于,所述纳米载体为聚乳酸-羟基乙酸共聚物。
3.根据权利要求2所述的一种包载姜黄素引起AIE发光的纳米制剂,其特征在于,所述纳米制剂为PLGA纳米制剂。
4.根据权利要求3所述的一种包载姜黄素引起AIE发光的纳米制剂,其特征在于,所述纳米载体与姜黄素分子通过非共价作用结合,所述非共价作用包括π-π共轭作用、疏水作用和/或分子间氢键。
5.一种包载姜黄素引起AIE发光的纳米制剂的制备方法,其特征在于,包括:
将质量比为1-100:1的纳米载体与姜黄素混合,置于EP管中,得到混合物;
在所述混合物中加入1-10mL有机溶剂使其溶解,得到油相混合物,所述有机溶剂为氯代烷烃和醇类有机溶剂;
将乳化剂溶于去离子水,得到水相溶液;
将所述油相混合物与所述水相溶液混合,涡旋1-5min后送入细胞破碎仪中超声破碎1-10min;
得到Cur@PLGA-NPs纳米制剂,所述Cur@PLGA-NPs纳米制剂为PLGA纳米制剂。
6.根据权利要求5所述的一种包载姜黄素引起AIE发光的纳米制剂的制备方法,其特征在于,所述纳米载体为聚乳酸-羟基乙酸共聚物,所述有机溶剂二氯甲烷、三氯甲烷,所述醇类有机溶剂乙醇、甲醇,所述乳化剂包括聚乙烯醇、白蛋白、蓖麻油聚氧乙烯醚、吐温20、十二烷基硫酸钠中任意一种。
7.根据权利要求6所述的一种包载姜黄素引起AIE发光的纳米制剂的制备方法,其特征在于,所述水相溶液中乳化剂浓度为1-10%,所述油相混合物与所述水相溶液混合体积比为1:2-20。
8.根据权利要求7所述的一种包载姜黄素引起AIE发光的纳米制剂的制备方法,其特征在于,所述水相溶液中乳化剂浓度为3%。
9.根据权利要求8所述的一种包载姜黄素引起AIE发光的纳米制剂的制备方法,其特征在于,所述油相混合物与所述水相溶液混合体积比为1.5:4.5。
10.一种包载姜黄素引起AIE发光的纳米制剂的应用,其特征在于,所述包载姜黄素引起AIE发光的纳米制剂在细胞成像领域中的应用,其纳米制剂如权利要求1-4任一项所述。
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