CN114209676A - 一种纳米诊疗材料及其应用 - Google Patents
一种纳米诊疗材料及其应用 Download PDFInfo
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- CN114209676A CN114209676A CN202111466626.8A CN202111466626A CN114209676A CN 114209676 A CN114209676 A CN 114209676A CN 202111466626 A CN202111466626 A CN 202111466626A CN 114209676 A CN114209676 A CN 114209676A
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- hyaluronic acid
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Abstract
本发明公开了一种纳米诊疗材料及其应用,属于诊疗纳米材料领域。所述纳米诊疗材料由铁离子与多巴胺接枝透明质酸及多酚类化合物配位组装,并包裹产H2O2的药物形成,所述产H2O2的药物为β‑拉帕醌或维生素K3。本发明通过一种配位自组装的方法在室温下制备得到纳米材料,该纳米材料作为纳米级磁共振造影剂,具有T1加权磁共振成像、体内循环时间长、生物兼容性高和毒副作用小等优点。且该纳米材料可通过携载药物产生H2O2的性质级联放大铁离子的芬顿反应效果,提升了ROS水平,并进一步引起肿瘤细胞发生免疫原性死亡,实现增强化学动力学治疗的效果。
Description
技术领域
本发明涉及诊疗纳米材料领域,具体涉及一种基于多巴胺接枝透明质酸、多酚、铁盐和产H2O2药物配位组装的纳米诊疗材料,应用于磁共振成像及肿瘤增强化学动力学治疗。
背景技术
氧化还原稳态的调节对于维持正常的细胞功能和细胞存活至关重要,而肿瘤细胞则表现出高水平的氧化应激行为,这种氧化应激是由于活性氧(ROS)的产生和消除之间不平衡而积累造成的,因此氧化应激的调节是抗癌疗法中的重要部分。
基于此,化学动力疗法,即通过将具有芬顿反应性能(过渡金属,如铁)的纳米材料引入肿瘤细胞/组织中,将内源性H2O2转化为高毒性·OH用于癌症治疗,得到了广泛应用。肿瘤细胞中H2O2浓度相对较高(100μM-1mM),能够充当触发肿瘤细胞中芬顿反应的反应物。而且肿瘤微环境呈弱酸性,已有研究证明酸性能促进芬顿反应的有效发生。因此,一旦芬顿基纳米材料积累到肿瘤中,这种化学动力治疗方法对癌症的微环境是高度特异性的。但实际上,人体中的铁元素含量很低,大多数铁通常都结合在某些特定的蛋白质中,仅剩下很少的游离铁离子可用于芬顿反应。另外,肿瘤部位内源性H2O2含量有限导致化学动力疗法无法达到很好的抗癌效果,且不能引起有效的免疫应答。
目前,Fe2+作为一类重要的芬顿反应催化剂,在肿瘤化学动力学疗法中发挥了巨大的应用。申请号为202110036507.2的中国专利文献公开了一种含有Fe2+的硫铁矿纳米酶以诱导·OH产生的抗肿瘤应用。发表在《Nano Letters》的论文(2019,19,2,805-815)设计了一种包含Fe2+和丁硫氨酸的脂质体,通过提高肿瘤细胞内·OH水平增敏化疗和放疗的疗效。为了提高Fe2+通过芬顿反应产生的肿瘤抑制效率,申请号为202110028074.6的中国专利文献公开了一种通过CaO2增加H2O2自增强Fe2+化学动力学循环的肿瘤治疗材料。此外,发表在《Advanced Materials》的论文(2019,1808278)制备了一种含呼吸链酶II和Fe3O4纳米颗粒的工程化大肠杆菌,通过呼吸链酶II额外产生的H2O2可进一步增强Fe3O4中Fe2+产生·OH的能力。尽管以上方法能在一定程度上提高肿瘤部位H2O2的浓度,但是制备过程复杂,产生的H2O2总含量有限,且作用持续时间较短,不能显著增加化学动力学疗效。
已知某些药物,如β-拉帕醌或维生素K3等具有产生大量H2O2的性质,因此可作为增强铁-多酚配位纳米材料在肿瘤部位芬顿反应的发生及循环的催化剂,在一定程度上实现了肿瘤部位ROS水平的级联放大。但目前缺乏将β-拉帕醌或维生素K3等产H2O2药物与铁纳米材料结合,实现两者之间的协同以增强肿瘤化学动力学治疗效果的方法。
因此,开发一种装载β-拉帕醌或维生素K3等产H2O2药物的铁基纳米材料,实现两者之间的协同,级联放大肿瘤细胞内ROS水平,增强肿瘤化学动力学治疗的效果,是本领域技术人员需要解决的问题。
发明内容
本发明的目的在于提供一种新的增强肿瘤化学动力学治疗效果的纳米材料,实现递药纳米颗粒的高安全性、高载药效率、高肿瘤治疗效果。
为实现上述目的,本发明采用如下技术方案:
本发明提供了一种纳米诊疗材料,所述纳米诊疗材料由铁离子与多巴胺接枝透明质酸及多酚类化合物配位组装,并包裹产H2O2的药物形成,所述产H2O2的药物为β-拉帕醌或维生素K3。
进一步的,所述纳米诊疗材料的制备方法包括:在水介质中加入接枝率为10-60%的多巴胺接枝透明质酸、多酚类化合物和铁盐,再滴加产H2O2药物溶液,室温下反应自组装制备得到。
本发明提供的纳米诊疗材料,在制备过程中,铁离子能与多巴胺接枝的透明质酸及多酚类化合物中的酚羟基配位,并能包裹产H2O2的药物,自组装形成纳米材料。
研究表明,该自组装纳米材料由于含有大量顺磁性金属离子Fe3+,其能够与水分子中的氢核直接作用来缩短其纵向弛豫时间(T1),从而增强T1信号,可以作为T1磁共振造影剂,并且由于其纳米尺寸导致的高渗透长滞留(EPR)效应富集在肿瘤组织中,提高磁共振成像的灵敏度,提升早期癌症的诊断水平。
另外,该纳米材料酸性条件下能够释放产H2O2的药物β-拉帕醌或维生素K3,它们能在肿瘤内特异性环境下产生大量的H2O2,同时在酸性条件下释放Fe3+能被多酚化合物还原为Fe2+,与H2O2发生芬顿反应,产生大量的·OH,引起肿瘤细胞的高氧化应激,实现化学动力学治疗,并促进免疫原性死亡。
所述多巴胺接枝透明质酸为在EDC/NHS条件下,透明质酸与多巴胺反应制得。
作为优选,透明质酸采用分子量为3k-40k的透明质酸钠。透明质酸有助于提高纳米材料的生物相容性。
多巴胺采用盐酸多巴胺,分子式:C8H12ClO2N。
本发明研究发现,多巴胺接枝透明质酸中多巴胺的接枝率影响所述纳米诊疗材料的自组装。当多巴胺接枝率小于10%时,制备不成纳米颗粒;当多巴胺接枝率大于60%时,HADA更易氧化,制备的纳米颗粒配位作用不强,易引起沉淀。
作为优选,透明质酸钠与盐酸多巴胺的质量比为1:0.5-5,反应时间为12-48h。在上述条件下,可制得接枝率10-60%的多巴胺接枝透明质酸。
作为优选,多巴胺接枝透明质酸的接枝率为20-40%。
作为优选,所述多酚类化合物为鞣酸、表儿茶素、没食子酸、表没食子儿茶素、多巴胺、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯和儿茶酚中的任意一种或几种。
作为优选,所述铁盐为硫酸铁、氯化铁和硝酸铁中的任意一种或几种。三价铁离子与多酚类物质在酸性条件下发生反应,产生二价铁离子,催化H2O2生成高毒性·OH。
本发明研究表明,各原料的配比影响纳米材料的形成及尺寸,如铁盐浓度与配位多酚的比例太大时容易产生沉淀,成不了纳米颗粒;太小则导致纳米颗粒形成不致密,容易产生较大的粒径。如透明质酸量增多会导致尺寸变大。过大的颗粒无法经EPR效应有效富集在肿瘤组织中,而且容易被网状内皮系统截留。如药物浓度太高时容易使纳米颗粒沉淀,浓度太低,包裹的药物浓度不够不足以产生很好的治疗效果。
作为优选,多巴胺接枝透明质酸以透明质酸单体计、多酚类化合物以酚羟基计、铁盐以铁离子计、产H2O2药物的投料摩尔比为1:10-40:1-8:4-25。在该配比条件下,可制得350nm以下的纳米颗粒,适合体内应用。
作为优选,反应体系中,多巴胺接枝透明质酸质量浓度为14-100μg/mL,多酚类化合物质量浓度为40-500μg/mL,铁盐质量浓度为20-100μg/mL,产H2O2药物质量浓度为100-500μg/mL。
所述室温条件为20~26℃,反应时间为2~4h。
本发明提供的纳米诊疗材料,其制备方法还包括:多巴胺接枝透明质酸、多酚、铁盐和产H2O2药物,配位制备得到纳米材料之后,利用透析膜截留所述纳米材料,再进行冷冻干燥或利用超滤管离心浓缩得到相应浓度的纳米材料。
本发明提供的纳米诊疗材料中铁的质量百分比含量为1-2%。纳米材料的铁含量需达到一定量才能达到T1造影效果。
所述纳米诊疗材料在去离子水、生理盐水、PBS和RMPI-1640培养基等介质中均表现出稳定性。
本发明还提供了所述的纳米诊疗材料在制备磁共振成像T1造影剂和/或肿瘤化学动力学治疗剂中的应用。
所述肿瘤为实体瘤。进一步的,所述肿瘤包括但不限于乳腺癌。
本发明具备的有益效果:
(1)本发明提供了一种用于肿瘤治疗过程中实现高效药物递送的配位纳米体系,该纳米材料可通过携载药物产生H2O2的性质级联放大铁离子的芬顿反应效果,提升了ROS水平,进而引起肿瘤细胞发生免疫原性死亡,并进一步引发机体的抗肿瘤免疫反应,实现增强的化学动力学治疗的效果。
(2)本发明提供的纳米材料作为纳米级造影剂,具有T1加权磁共振成像、体内循环时间长、生物兼容性高和毒副作用小等优点。
(3)本发明提供的纳米材料通过一种配位自组装的方法室温下制备得到,制备方法简单高效、治疗效果好、实用性强。
附图说明
图1为实施例1中合成纳米材料在水中的动态光散射测得的粒径分布图。
图2为实施例1中合成的纳米材料透射电镜图。
图3为纳米材料各个浓度体外磁共振成像图,图中分别为水、0.05mM、0.10mM、0.15mM、0.2mM浓度下纳米材料水溶液的造影。
图4为纳米材料和马根维显(Magnevist)作为T1磁共振造影剂增强乳腺肿瘤磁共振成像图以及信号强度定量图,其中(a)纳米材料和马根维显(Magnevist)在4T1细胞接种的乳腺肿瘤成像图,图中圈出来的位置是肿瘤组织,其他地方为正常组织;(b)纳米材料和Magnevist注射后肿瘤(tumor)和正常组织(normal tissue)信号强度图。
图5为纳米材料对4T1细胞增殖效果图,其中NP是指透明质酸、多酚和铁离子形成的纳米材料;LP是指药物;LP+NP是指以上二者的混合物;LPNP是指实施例1合成的纳米材料。
图6为纳米材料对4T1细胞ROS提升效果图。
图7为纳米材料对4T1乳腺癌细胞荷瘤Balb/c小鼠肿瘤的抑制实验中肿瘤生长曲线图。
图8为纳米材料对4T1乳腺癌细胞荷瘤Balb/c小鼠肿瘤的抑制实验过程中,Balb/c小鼠体重变化曲线图。
图9为纳米材料对293T细胞增殖效果图。
具体实施方式
下面结合具体实施例对本发明做进一步说明,但本发明并不局限于此。
实施例中所使用的实验技术与方法如无特殊说明,均为常规方法。所用的材料、试剂等,如无特殊说明,均可从商业途径购得。
透明质酸钠,CAS号:9067-32-7,购自南京草本源生物科技有限公司。
盐酸多巴胺,分子式:C8H12ClO2N,分子量:189.64,CAS号:62-31-7,其结构式如下:
鞣酸,CAS号:1401-55-4;没食子酸,CAS号:149-91-7;表儿茶素,CAS号:490-46-0;表没食子儿茶素,CAS号:970-74-1;儿茶酚,CAS号:120-80-9。
氯化铁,CAS号:7705-08-0;硝酸铁,CAS号:10421-48-4;硫酸铁,CAS号:10028-22-5。
β-拉帕醌,CAS号:4707-33-9;维生素K3,CAS号:58-27-5。
实施例1
1、多巴胺接枝透明质酸的制备
将0.5g透明质酸钠(HA,3kDa)溶解在去离子水中,滴加1M HCl将溶液pH调节至5.5。然后,加入0.498g EDC,0.598g NHS和1.722g多巴胺盐酸盐(DA),并在避光条件下,氮气保护反应24小时。反应后的溶液经10kDa的透析袋透析48小时,通过冷冻干燥获得纯化的接枝率为38%的HA-DA。
2、纳米材料的制备
(1)在70mL去离子水中同时加入4mg的HADA(透明质酸分子量3k,多巴胺接枝率38%)、21mg的鞣酸、3mg的氯化铁和13mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应2-4小时。
(2)经过透析,然后冻干或者超滤离心浓缩,获得纳米材料LPNP。
3、纳米材料的性能分析
如图1所示,动态光散射(DLS)测得纳米材料的平均粒径是70nm。
如图2所示,透射电镜(TEM)观察到纳米材料的粒径为70nm左右,与DLS测得的粒径结果相符。其中铁的质量百分比为1.3%,纵向弛豫率为5.3mM-1s-1。
进一步的,通过调整步骤2反应体系中铁离子浓度制得不同铁含量的纳米材料,通过磁共振成像仪进行扫描得到图像。如图3所示,水的信号值非常弱,图像很暗淡,而纳米材料在一定浓度范围内随着铁离子浓度的增加,T1造影的图像更亮,因而能够展示出优越的T1成像效率。
如图4所示,(a)纳米材料和临床用马根维显(Magnevist)在4T1细胞接种的乳腺肿瘤成像图。实验表明,与Magnevist相比,纳米材料在肿瘤部位显示出明显的对比强度和持久的造影时间窗口。(b)纳米材料和临床用马根维显(Magnevist)在肿瘤(tumor)和正常组织(normal tissue)信号强度图。实验表明,与Magnevist相比,注射了纳米材料后,肿瘤的信号强度在1h内一直是增加的,并且在1h时,其信号强度到达峰值,能够为乳腺肿瘤提供更加清晰和准确的诊断窗口。
如图5所示,肿瘤细胞4T1孵育纳米材料后,细胞存活率随纳米材料浓度的增加而降低,说明该纳米材料对肿瘤细胞有很强的杀伤作用。
将肿瘤细胞4T1以5万/孔的密度铺于Confocal皿中,24小时后分别加入PBS和LPNP,继续孵育24小时,吸走培养基并用PBS清洗细胞3次后,孵育ROS染料DCFH-DA 15分钟,吸走染料,PBS洗3次,加入1mL新鲜培养基,置于激光共聚焦显微镜下观察DCFH-DA的荧光。如图6所示,肿瘤细胞4T1孵育纳米材料后ROS水平显著提高,说明纳米材料能放大肿瘤细胞中的ROS水平,有应用于化学动力治疗的潜力。
如图7所示,4T1细胞接种后的乳腺肿瘤模型小鼠经尾静脉注射纳米材料(药物浓度为5mg/kg)治疗五次后,纳米材料相比对照组(PBS组)的肿瘤生长程度显著降低,说明该纳米材料适合作为化学动力治疗试剂应用于肿瘤治疗中。
如图8所示,小鼠体重在治疗期间(2周)均没有显著性变化,说明纳米材料对小鼠并没有显著性毒性,生物安全性较高。
如图9所示,正常293T细胞经纳米材料孵育后存活率相比肿瘤细胞高,说明该纳米材料对正常细胞的增殖能力影响较小,证明了其对肿瘤细胞化学动力治疗的特异性。
实施例2
1、多巴胺接枝透明质酸的制备
将0.5g透明质酸钠(HA,40kDa)溶解在去离子水中,滴加1M HCl将溶液pH调节至5.5。然后,加入0.498g EDC,0.598g NHS和1.722g多巴胺盐酸盐(DA),并在避光条件下,氮气保护反应24小时。反应后的溶液经10kDa的透析袋透析48小时,通过冷冻干燥获得纯化的接枝率为38%的HA-DA。
2、纳米材料的制备
在70mL去离子水中同时加入4mg的HADA(透明质酸分子量40k,多巴胺接枝率38%)、18mg的鞣酸、3mg的氯化铁和18mg的维生素K3,室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是101nm,其中铁的质量百分比含量为1.2%。
实施例3
1、多巴胺接枝透明质酸的制备
将0.5g透明质酸钠(HA,15kDa)溶解在去离子水中,滴加1M HCl将溶液pH调节至5.5。然后,加入0.498g EDC,0.598g NHS和2.46g多巴胺盐酸盐(DA),并在避光条件下,氮气保护反应48小时。反应后的溶液经10kDa的透析袋透析48小时,通过冷冻干燥获得纯化的接枝率为60%的HA-DA。
2、纳米材料的制备
在70mL去离子水中同时加入2.8mg的HADA(透明质酸分子量15k,多巴胺接枝率60%)、7.1mg的没食子酸、4.2mg的硝酸铁和7mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是170nm,其中铁的质量百分比含量为1.1%。
实施例4
1、多巴胺接枝透明质酸的制备
将0.5g透明质酸钠(HA,25kDa)溶解在去离子水中,滴加1M HCl将溶液pH调节至5.5。然后,加入0.498g EDC,0.598g NHS和0.492g多巴胺盐酸盐(DA),并在避光条件下,氮气保护反应12小时。反应后的溶液经10kDa的透析袋透析48小时,通过冷冻干燥获得纯化的接枝率为20%的HA-DA。
2、纳米材料的制备
在70mL去离子水中同时加入1mg的HADA(透明质酸分子量25k,多巴胺接枝率20%)、3.55mg的多巴胺、7mg的硫酸铁和9mg的维生素K3,室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是400nm,其中铁的质量百分比含量为2.0%。
实施例5
1、多巴胺接枝透明质酸的制备
将0.5g透明质酸钠(HA,40kDa)溶解在去离子水中,滴加1M HCl将溶液pH调节至5.5。然后,加入0.498g EDC,0.598g NHS和1.722g多巴胺盐酸盐(DA),并在避光条件下,氮气保护反应24小时。反应后的溶液经10kDa的透析袋透析48小时,通过冷冻干燥获得纯化的接枝率为38%的HA-DA。
2、纳米材料的制备
在70mL去离子水中同时加入4mg的HADA(透明质酸分子量40k,多巴胺接枝率38%)、12mg的表儿茶素、5mg的氯化铁和23mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应3小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是230nm,其中铁的质量百分比含量为1.7%。
实施例6
在70mL去离子水中同时加入2mg的HADA(透明质酸分子量40k,多巴胺接枝率38%)、2.8mg的表没食子儿茶素、3mg的氯化铁和25mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应4小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是200nm,其中铁的质量百分比含量为1.4%。
实施例7
在70mL去离子水中同时加入4mg的HADA(透明质酸分子量40k,多巴胺接枝率38%)、15mg的表没食子儿茶素没食子酸酯、2mg的氯化铁和10mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是350nm,其中铁的质量百分比含量为1.1%。
实施例8
在70mL去离子水中同时加入3mg的HADA(透明质酸分子量40k,多巴胺接枝率38%)、15mg的表儿茶素没食子酸酯、4mg的氯化铁和15mg的β-拉帕醌(溶于1mL DMSO溶液),室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是300nm,其中铁的质量百分比含量为1.3%。
实施例9
在70mL去离子水中同时加入4mg的HADA(透明质酸分子量40k,多巴胺接枝率20%)、18mg的儿茶酚、3mg的氯化铁和18mg的维生素K3,室温反应2小时。经过透析,然后冻干或者超滤离心浓缩,获得纳米材料。该纳米材料的平均粒径是180nm,其中铁的质量百分比含量为1.2%。
上述实施例制得的纳米材料均适合作为本发明的磁共振成像造影剂及肿瘤的化学动力治疗试剂使用。
上述实施例仅用来解释说明本发明,而不是对本发明进行限制,在本发明的精神和权利要求的保护范围内,对本发明作出的任何修改和改变,都落入本发明的保护范围。
Claims (10)
1.一种纳米诊疗材料,其特征在于,所述纳米诊疗材料由铁离子与多巴胺接枝透明质酸及多酚类化合物配位组装,并包裹产H2O2的药物形成,所述产H2O2的药物为β-拉帕醌或维生素K3。
2.如权利要求1所述的纳米诊疗材料,其特征在于:所述纳米诊疗材料的制备方法包括:在水介质中加入接枝率为10-60%的多巴胺接枝透明质酸、多酚类化合物和铁盐,再滴加产H2O2药物溶液,室温下反应自组装制备得到。
3.如权利要求2所述的纳米诊疗材料,其特征在于,多巴胺接枝透明质酸以透明质酸单体计、多酚类化合物以酚羟基基团计、铁盐以铁离子计、产H2O2药物的投料摩尔比为1:10-40:1-8:4-25。
4.如权利要求2所述的纳米诊疗材料,其特征在于,反应体系中,多巴胺接枝的透明质酸质量浓度为14-100μg/mL,多酚类化合物质量浓度为40-500μg/mL,铁盐质量浓度为20-100μg/mL,产H2O2药物质量浓度为100-500μg/mL;反应时间为2~4h。
5.如权利要求2所述的纳米诊疗材料,其特征在于,所述铁盐为硫酸铁、氯化铁和硝酸铁中的任意一种或几种。
6.如权利要求1所述的纳米诊疗材料,其特征在于,所述多巴胺接枝透明质酸为在EDC/NHS条件下,透明质酸与多巴胺反应制得;所述透明质酸采用分子量为3-40kDa的透明质酸钠,所述多巴胺采用盐酸多巴胺。
7.如权利要求6所述的纳米诊疗材料,其特征在于,透明质酸钠与盐酸多巴胺的质量比为1:0.5-5,反应时间为12-48h。
8.如权利要求1所述的纳米诊疗材料,其特征在于,所述多酚类化合物为鞣酸、表儿茶素、没食子酸、表没食子儿茶素、多巴胺、表没食子儿茶素没食子酸酯、表儿茶素没食子酸酯和儿茶酚中的任意一种或几种。
9.如权利要求1-8任一项所述的纳米诊疗材料在制备磁共振成像T1造影剂和/或肿瘤化学动力学治疗剂中的应用。
10.如权利要求9所述的应用,其特征在于,所述肿瘤为实体瘤。
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