CN111358949A - 一种靶向抗肿瘤铁(iii)基纳米材料的制备和应用 - Google Patents
一种靶向抗肿瘤铁(iii)基纳米材料的制备和应用 Download PDFInfo
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Abstract
本发明公开了一种靶向抗肿瘤铁(III)基纳米材料的制备和应用。主要原料包括透明质酸、盐酸多巴胺、六水三氯化铁,制备方法操作简单,原料通过常温搅拌即可制成。本发明在透明质酸上通过酰胺反应接入盐酸多巴胺,通过盐酸多巴胺的酚羟基与三价铁离子在配位驱动下制备纳米材料。所制备的纳米材料不仅具有光声成像(PA)和磁共振成像(MR)功能,且在近红外区具有良好吸收,可用于光热治疗,而铁离子具有化学治疗效果,同时在光声成像和磁共振成像的精确引导下,可以实现癌症的精准靶向诊断与治疗,扩展了透明质酸在靶向材料方面的应用,在癌症诊断和治疗领域具有应用前景。
Description
技术领域
本发明纳米材料,具体是一种透明质酸-多巴胺-铁(III)基纳米材料及其制备方法和应用。
背景技术
近年来,基于光响应光热治疗(photothermal therapy, PTT)作为一种新型癌症治疗方式,由于具有非侵入性、毒副作用小等优点,吸引了广泛的研究兴趣。光热治疗(PTT)是利用具有较高光热转换效率的材料,在外部光源(一般是近红外光)的照射下将光能转化为热能来杀死癌细胞的一种治疗方法。众多的无机金属纳米材料具有良好的光热转换效率,比如Cu、Mn、Fe、Au、Ag等等。Fe是维持生物体生命的重要微量元素,在人体氧化代谢、细胞生长与增殖、氧的运输和储存中均有重要作用。近年来研究发现Fe代谢与一种新的细胞死亡形式—铁死亡(Ferroptosis)有关。铁死亡的实质是由于膜脂修复酶—谷胱甘肽过氧化物酶(GPX4)失效,从而阻断细胞的抗氧化防御,造成细胞内脂质氧化物代谢障碍,在Fe3+催化作用下,造成膜脂上活性氧自由基(ROS)堆积,使细胞内氧化还原失衡,诱导细胞死亡。谷胱甘肽(GSH)水平在肿瘤细胞中升高,由于其抗氧化和解毒能力,与癌症进展和耐药密切相关。GPX4与谷胱甘肽共同作用,可以防止铁死亡对细胞膜的损伤。因此,利用Fe3+抑制GPX4活性和消耗细胞内GSH的方法被视为潜在的抗癌策略。
癌症病人在化学治疗中通常需要使用高毒性的化疗药物。由于药物的非特异性,在杀死癌细胞的同时,同样杀死正常细胞,损害正常的组织和器官。事实上,70%以上接受化疗的癌症患者,最后死于药物毒性。因此使用对正常细胞和组织无毒的纳米材料或分子是非常重要的,靶向诊疗在癌症治疗方面是不可或缺的一种治疗方式。
透明质酸是人体内一种线性高分子生物多糖,可以主动靶向表面CD-44受体蛋白过表达的癌细胞(如人宫颈癌细胞HeLa,人乳腺癌细胞MCF-7等)而经常被用于纳米探针。因此,扩展透明质酸在癌症的诊断与治疗方面的应用具有重要意义。
发明内容
针对上述金属基纳米材料及抗肿瘤药物的现状分析,本发明提供一种具有光热治疗和化学治疗两种治疗功能的铁(III)基纳米材料及其制备方法。
本发明一种铁(III)基纳米材料的制备方法,以透明质酸HA、盐酸多巴胺DA、六水三氯化铁FeCl3·6H2O为原料,制备方法包括以下步骤:
1) 称取透明质酸0.2-0.3 g溶解于20-30 ml二次水;
2) 称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐0.1-0.2 g和N-羟基琥珀酰亚胺0.06-0.13 g溶解于20-30 ml二甲基亚砜DMSO;
3) 将步骤1)与步骤2)所得的溶液混合,搅拌活化;
4) 称取盐酸多巴胺0.1-0.2 g溶解于10-15 ml二甲基亚砜DMSO;
5) 在步骤3)所得的活化溶液中加入步骤4)所得的溶液,在氮气保护下搅拌,并用稀盐酸调节pH=5;
6) 将步骤5)所得的溶液用透析袋透析,冻干,得到透明质酸接枝盐酸多巴胺的产物HA-DA,取4-6 mg HA-DA溶于1-1.5 ml二次水中;
7) 将0.28-0.42 mg FeCl3·6H2O溶于1-1.5 ml二次水中;
8) 按1:1的体积比,取步骤6)所得溶液与步骤7)所得溶液,将二者混合搅拌,即得到铁(III)基纳米材料。
制备方法中,透明质酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺和盐酸多巴胺摩尔比为1:(1-2):(1-2):(1-2);
HA-DA与FeCl3·6H2O的摩尔比为1:(2-3)。
步骤3)中,活化时间为0.5-1 h;
步骤5)中,搅拌时间为23-25 h;
步骤6)透析袋的分子量为3000 Da,透析时间为72-84 h。
本发明的另一个目的是提供通过上述方法制备的具有多功能治疗效果的铁(III)基纳米材料。
盐酸多巴胺又称4-(2-氨基乙基)-1,2-苯二酚盐酸盐,具有伯胺和儿茶酚基团,临床上已被用于治疗各种休克。在2007年,Messersmith等人发现人体神经递质多巴胺可以在表面科学上发挥重要作用。由于多巴胺单体(商业上常用盐酸多巴胺)在碱性条件下容易氧化自聚合的特性,聚多巴胺的沉积及其功能化表面的构建受到广泛研究。因此,利用多巴胺单体(盐酸多巴胺)在癌症方面的研究非常具有挑战性。
为此,本发明利用盐酸多巴胺简单修饰透明质酸在混合溶液(H2O与DMSO)中发生酰胺反应,使得透明质酸与盐酸多巴胺的接枝率达到35-60%,突破了在H2O中接枝率底的局限性和防止多巴胺容易氧化自聚合的特性。透明质酸通过盐酸多巴胺的酚羟基与Fe3+配位驱动自组装,有效避免了直接使用透明质酸包裹药物而产生脱靶和泄露的问题。并且Fe3+与其他含铁材料如Fe3O4相比,具有制备简单,水溶性好,生物相容性好,催化性能高的特点。
因此,利用盐酸多巴胺修饰后的透明质酸与Fe3+配位制备具有光热治疗,化学治疗功能的靶向纳米材料,不仅具有探针分子光声成像(PA)和磁共振成像(MR)的诊断特性,而且具有抗癌药物治疗的功能,使得纳米药物诊断与治疗一体化。在光声成像(PA)和磁共振成像(MR)的精确引导下,可以实现癌症的精准靶向疗诊断与治疗。
研究发现,通过本发明方法制备的铁(III)基纳米材料除具有强的近红外吸收及良好的光热转换效率,还具有良好的化疗作用。这将进一步拓展其在癌症治疗方面的应用。
本发明的铁(III)基纳米材料可应用于光声成像介导的靶向抗肿瘤药物的制备。
本发明的优点是:
1)制备铁(III)基纳米材料的原料便宜、易得,且生物相容性好;
2)操作简单,方便,制备条件简易;
3)制备的铁(III)基纳米材料不仅具有良好的近红外吸收和光热转换性能,还具有化学治疗作用;
4)制备的铁(III)基纳米材料对癌症治疗具有选择性,靶向性;
5)制备的铁(III)基纳米材料可用于深层活体内组织成像。
附图说明
图1为铁(III)基纳米材料高分辨透射电镜下观测到的形貌分布图;
图2为铁(III)基纳米材料的紫外-可见-近红外吸收光谱图。
具体实施方式
下面结合实施例和附图对本发明内容作进一步的详细说明,但不 是以本发明的限定。
制备实施例
制备铁(III)基纳米材料,包括如下步骤:
1) 称取透明质酸0.201 g (0.5 mmol)溶解于20 ml二次水;
2) 称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐0.143 g (0.75 mmol)和N-羟基琥珀酰亚胺0.0863 g (0.75 mmol)溶解于20 ml DMSO;
3) 将步骤1)与步骤2)所得的溶液混合,搅拌活化0.5 h;
4) 称取盐酸多巴胺0.114 g (0.6 mmol)溶解于10 ml DMSO;
5) 将步骤3)所得的活化溶液中加入步骤4)所得的溶液中进行搅拌,搅拌时间为23-25h,并氮气保护,用稀盐酸调节pH=5;
6) 将步骤5)所得的溶液用透析袋透析(3000 Da,72-84 h),冻干,得到透明质酸接枝盐酸多巴胺的产物HA-DA,取4.2 mg HA-DA溶于1 ml二次水中;
7) 将0.28 mg FeCl3·6H2O溶于1 ml二次水中;
8) 按1:1的体积比,取步骤6)所得溶液与步骤7)所得溶液,将二者混合搅拌,即得到铁(III)基纳米材料。
应用实施例
将上述制备所得的铁(III)基纳米材料配置成水溶液后适当稀释。参照图1,在透射电镜观察下,所制备的透明质酸-多巴胺-铁(III)配合物具有纳米聚集体的形貌,说明纳米材料已经成功制备。
参照图2,可以发现所制备的铁(III)基纳米材料对波长范围为600-900 nm的光都有较好的吸收。用波长为808 nm 激光(0.3~1 W/cm2)照射,铁(III)基纳米材料的5~10 min可升高到42~49.5 ℃,具有良好的近红外光热转换能力。对荷瘤小鼠尾静脉注射铁(III)基纳米材料 (Fe3+的浓度为100~120 μg/ml)。3~24 h后,采用光声断层扫描仪,通过光声信号可观察小鼠肿瘤所在清晰部位;采用波长为808 nm 激光(0.3~1 W/cm2)照射,可在肿瘤部位产生显著的热消融,并通过化学治疗可抑制肿瘤生长。因此,本发明方法制备的铁(III)基纳米材料,可以用于在光声成像(PA)精确引导下,肿瘤的诊断与治疗。
Claims (5)
1.一种铁(III)基纳米材料的制备方法,其特征在于:以透明质酸HA、盐酸多巴胺DA、六水三氯化铁FeCl3·6H2O为原料,制备方法包括以下步骤:
1) 称取透明质酸0.2-0.3 g溶解于20-30 ml二次水;
2) 称取1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐0.1-0.2 g和N-羟基琥珀酰亚胺0.06-0.13 g溶解于20-30 ml二甲基亚砜DMSO;
3) 将步骤1)与步骤2)所得的溶液混合,搅拌活化;
4) 称取盐酸多巴胺0.1-0.2 g溶解于10-15 ml DMSO;
5) 在步骤3)所得的活化溶液中加入步骤4)所得的溶液,在氮气保护下搅拌,并用稀盐酸调节pH=5;
6) 将步骤5)所得的溶液用透析袋透析,冻干,得到透明质酸接枝盐酸多巴胺的产物HA-DA,取4-6 mg HA-DA溶于1-1.5 ml二次水中;
7) 将0.28-0.42 mg FeCl3·6H2O溶于1-1.5 ml二次水中;
8) 按1:1的体积比,取步骤6)所得溶液与步骤7)所得溶液,将二者混合搅拌,即得到铁(III)基纳米材料。
2.根据权利要求1所述的铁(III)基纳米材料的制备方法,其特征在于:
制备方法中,透明质酸、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、N-羟基琥珀酰亚胺和盐酸多巴胺摩尔比为1:(1-2):(1-2):(1-2);
HA-DA与FeCl3·6H2O的摩尔比为1:(2-3)。
3.根据权利要求1所述的铁(III)基纳米材料的制备方法,其特征在于:
步骤3)中,活化时间为0.5-1 h;
步骤5)中,搅拌时间为23-25 h;
步骤6)透析袋的分子量为3000 Da,透析时间为72-84 h。
4.根据权利要求1-3任一项所述的制备方法制得的铁(III)基纳米材料。
5.权利要求4所述铁(III)基纳米材料应用于光声成像介导的靶向抗肿瘤药物的制备。
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