CN107096028A - 一种超小粒径半金属纳米颗粒材料及其制备方法 - Google Patents
一种超小粒径半金属纳米颗粒材料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种超小粒径半金属纳米颗粒材料及其制备方法,该纳米颗粒材料为小分子多肽修饰的超小粒径半金属铋单质纳米颗粒材料,其中小分子多肽为N‑端修饰有半胱氨酸残基的LyP‑1,其序列为CGNKRTRGC,颗粒平均尺寸为3.2‑4nm,通过本发明技术方案得到的小分子多肽修饰的超小粒径半金属纳米颗粒在小鼠乳腺癌细胞和小鼠乳腺癌肿瘤中表现出更高的富集,具有高近红外二区光学吸收、高光热转换效率、高放疗增敏性、可用于计算机断层扫描成像和光声成像的双模式造影和乳腺癌小鼠模型的光热及放疗协同治疗,同时兼有良好的生物相容性、低长期毒性以及快速代谢的特点,在癌症诊断治疗一体化领域具有非常大的科研价值和应用前景。
Description
技术领域
本发明涉及一种纳米材料及其制备方法,尤其涉及一种超小粒径半金属纳米颗粒材料及其制备方法。
背景技术
癌症已成为目前为危害人类健康的一大主要疾病,对癌症,特别是对早期肿瘤的实时造影诊断和有效的干预对癌症的治愈具有非常重要的意义。目前来说,随着纳米技术和纳米医学的发展,多功能纳米材料逐渐成为肿瘤诊断治疗领域越来越重要的一种手段。肿瘤诊断治疗一体化是将多种诊断和治疗技术集合到单一的多功能纳米颗粒中,在纳米材料注射并富集到生物体内的肿瘤病灶后,通过外部诱导实现病灶造影,同步诊断和个性化的治疗。常见的多功能纳米材料策略分为两种,一种是将具有不同功能的纳米颗粒组装成纳米复合体,另一种是采用具有多重功能的某类纳米材料。受限于纳米材料在组织中富集可能引起的生物毒性和临床需求,可快速代谢的小尺寸纳米材料逐渐成为研究的热点,此外,这类能够兼顾多重造影和协同治疗的单一纳米材料体系对推动高效癌症诊断治疗的发展意义也十分重大。
放疗是目前临床癌症治疗的一大重要手段,其主要作用是通过X射线辐射带来的高能粒子及活性物种杀伤癌细胞达到治疗的目的。然而,由于X射线辐射对正常组织细胞也有损伤,以及肿瘤内部的乏氧状况引起活性物种不足使得单纯的放疗对肿瘤治疗的效率并不高。放疗增敏剂是一类提高放疗效率的物质,利用含有高原子序数元素的物质提高肿瘤组织中X射线的含量,达到提高治疗效率和降低对周围组织的射线损伤。另一种方法是将放疗与其他治疗手法相结合,通过协同作用达到治疗目的。热疗被报道可以通过热量提高肿瘤局部温度加快血液流通来改善乏氧状况,起到与放疗协同治疗的更高效率。作为热疗的一种,光热治疗是将可吸收的光电子转换成热量提高肿瘤微环境的温度进而杀死癌细胞,具有毒性小,治疗效率高的优点。虽然二区近红外光(1000-1350nm),特别是1000-1100nm的光具有生物组织吸收效率低和可最大激光照射功率高的优点,能够带来更高效率的治疗效果,但是目前报道的材料的光学吸收主要集中在近红外一区(700-950nm),具有二区光热吸收的纳米材料很少,因此这个领域研究结果不多,仍需要更深入的研究。半金属纳米材料含有更高的载流子浓度和高的近红外二区光学吸收,极有可能是一类潜在的二区光热纳米材料。
治疗效率的高低与纳米材料在肿瘤组织中的富集含量相关很大,但是未修饰的纳米颗粒经过血液循环在肿瘤中的富集含量并不高,因此提高治疗效率可以通过将纳米材料表面修饰具有肿瘤组织靶向性的小分子物质提高其富集含量来实现。除此之外,纳米材料在纳米医学中不可忽视的一个问题是材料的安全性,如果纳米材料在组织中滞留时间太久,可能会引起生物组织炎症和内脏损伤,严重的甚至是引起病变。然而该领域的研究依然较为薄弱,报道的成果中能够快速代谢的材料依然很少。
因此,本领域的技术人员一直致力于开发一种可快速生物代谢超小粒径半金属纳米颗粒材料,用于实现肿瘤诊断治疗一体化功能,并兼具高的近红外二区光学吸收,高的放疗增敏性、高的肿瘤富集含量、低的长期毒性、以及能够实现癌症诊断的同时发挥协同治疗功能等功效。
发明内容
有鉴于现有技术的上述缺陷,本发明所要解决的技术问题是开发一种可快速生物代谢超小粒径半金属纳米颗粒材料,用于实现肿瘤诊断治疗一体化功能,并兼具高的近红外二区光学吸收,高的放疗增敏性、高的肿瘤富集含量、低的长期毒性、以及能够实现癌症诊断的同时发挥协同治疗功能等功效。
为实现上述目的,本发明提供了一种超小粒径半金属纳米颗粒材料及其制备方法。具体技术方案如下:
本发明公开了一种超小粒径半金属纳米颗粒材料,该超小粒径半金属纳米颗粒为小分子多肽修饰的超小粒径半金属纳米颗粒,其中小分子多肽为N-端修饰有半胱氨酸残基的LyP-1,其序列为CGNKRTRGC。
优选地,半金属为铋单质。
优选地,超小粒径半金属纳米颗粒平均尺寸为3.2-4nm。
优选地,超小粒径半金属纳米颗粒平均尺寸为3.6nm。
本发明还公开了一种超小粒径半金属纳米颗粒材料制备方法,包括以下步骤:
步骤一:将乙酸铋与油酸的混合液加入油胺溶液中,搅拌条件下充分反应,然后离心纯化后得到超小粒径的半金属铋单质纳米颗粒;在该步骤中,通过利用油胺温和的还原性将铋粒子还原成铋单质纳米颗粒,并且在油胺的作用下得到稳定。与目前报道的方法对比,该制备方法原料常见易得,实验操作简单。
步骤二:将超小粒径的半金属铋单质纳米颗粒分散到氯仿中,制备得到超小粒径半金属铋单质纳米颗粒分散液;
步骤三:在超小粒径半金属铋单质纳米颗粒分散液中加入聚乙二醇衍生物,搅拌挥发得到聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒;
步骤四:将聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒溶于磷酸盐缓冲液中,加入小分子多肽LyP-1,搅拌一段时间,得到小分子多肽修饰的超小粒径半金属纳米颗粒。
优选地,步骤一中所述搅拌为磁力搅拌。搅拌方式也可选择其他方式如机械搅拌等。
优选地,步骤一中所述油胺溶液置于260℃、氮气保护条件下。也就是说,在步骤一中,首先是将乙酸铋与油酸的混合液,加入至260℃条件下氮气(N2)保护的油胺溶液中,再进行搅拌。
优选地,步骤三中所述聚乙二醇衍生物为二硬脂酰磷脂酰乙醇胺-聚乙二醇5000-马来酸甘交联物PEG5000-DSPE。
优选地,步骤四中所述磷酸盐缓冲液pH值为7.2-7.6。
优选地,步骤四中所述磷酸盐缓冲液pH值为7.4。
优选地,步骤四中所述搅拌为磁力搅拌。该搅拌也可选择机械搅拌,具有同样的效果。
优选地,步骤四中所述搅拌发生在室温条件下。
本发明公开的技术方案通过设计全新的合成路线制备了具有超小粒径的半金属铋单质纳米颗粒,然后通过将纳米颗粒表面修饰小分子多肽,制备出了一种具有高的近红外二区光学吸收,高的放疗增敏性、高的肿瘤富集含量、快速生物排泄及低的长期毒性、以及能够实现癌症诊断的同时发挥协同治疗功能的肿瘤诊断治疗一体化的纳米材料。
本发明公开的技术方案具有如下有益技术效果:
(1)本技术方案公开的超小粒径的半金属铋单质纳米颗粒材料,通过表面修饰小分子多肽,得到了在肿瘤组织中富集含量更高的纳米颗粒;
(2)本技术方案公开的超小粒径的半金属铋单质纳米颗粒材料具有高的近红外二区光学吸收,高的放疗增敏性、高的肿瘤富集含量、低的长期毒性、计算机断层扫面成像和光声成像双模式造影和二区光热与放疗协同治疗等功能;
(3)本技术方案公开的超小粒径的半金属铋单质纳米颗粒材料在肿瘤诊断治疗一体化领域具有非常广发的应用前景。
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明,以充分地了解本发明的目的、特征和效果。
附图说明
图1是本发明公开的超小粒径半金属纳米颗粒材料制备路线示意图;
图2是本发明一个较佳实施例的超小粒径半金属纳米颗粒材料的结构模型及其功能示意图;
图3是本发明一个较佳实施例的超小粒径半金属纳米颗粒材料的透射电镜照片;
图4是本发明一个较佳实施例的超小粒径半金属纳米颗粒材料的紫外可见吸收图谱;
图5是本发明一个较佳实施例的超小粒径半金属纳米颗粒材料相比未修饰材料在肿瘤细胞中的富集含量数据;
图6是医用造影剂碘海醇和本发明的超小粒径半金属纳米颗粒材料的计算机断层扫描成像;
图7是医用造影剂碘海醇和本发明的超小粒径半金属纳米颗粒材料的计算机断层扫描信号图谱。
具体实施方式
下面结合附图并参照数据进一步详细描述本发明。应理解,实施方式只是为了举例说明本发明,而非以任何形式限制发明的范围。
如图1所示,为本发明公开的超小粒径半金属纳米颗粒材料制备路线示意图,通过流程示意图的形式形象的表述了本发明公开的超小粒径半金属纳米颗粒材料的制备路线和步骤,首先通过将乙酸铋与油酸的混合液加入260℃、氮气保护条件下的油胺溶液中,搅拌反应,离心纯化后得到超小粒径的半金属铋单质纳米颗粒,然后通过将超小粒径的半金属铋单质纳米颗粒分散到氯仿中,制备得到超小粒径半金属铋单质纳米颗粒分散液,再加入聚乙二醇衍生物,搅拌挥发得到聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒,最后将聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒溶于磷酸盐缓冲液中,加入小分子多肽LyP-1,搅拌一段时间,得到小分子多肽修饰的超小粒径半金属纳米颗粒。
本发明的较佳实施例:
步骤一,将1mmol乙酸铋和2mL油酸混合后,滴入至260℃、氮气(N2)保护条件下的20mL油胺溶液中,进行磁力搅拌,反应15分钟后将混合溶液降至室温,通过离心纯化的方式得到超小粒径的半金属铋单质纳米颗粒,在该步骤中,通过利用油胺温和的还原性将铋粒子还原成铋单质纳米颗粒,并且在油胺的作用下得到稳定,与现有技术相比,该制备方法是使用的原料常见易得,操作简单。
步骤二,从步骤一制得的超小粒径的半金属铋单质纳米颗粒中称取2mg溶解到3mL的氯仿中,制备得到超小粒径半金属铋单质纳米颗粒分散液。
步骤三,在步骤二得到的超小粒径半金属铋单质纳米颗粒分散液中加入10mg聚乙二醇衍生物(二硬脂酰磷脂酰乙醇胺-聚乙二醇5000-马来酸甘交联物PEG5000-DSPE),进行磁力搅拌,挥发得到聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒。
步骤四,将步骤三制得的聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒溶解在6mL的磷酸盐缓冲液(pH7.4)中,加入100mM小分子多肽LyP-1,在室温条件下反应4小时得到小分子多肽修饰的超小粒径半金属纳米颗粒,其中小分子多肽为N-端修饰有半胱氨酸残基的LyP-1,其序列为CGNKRTRGC。
本发明的较佳实施例制得的小分子多肽修饰的超小粒径半金属纳米颗粒,其结构模型及功能示意如图2所示,可以用于计算机断层扫描成像和光声成像双模造影,可以用于肿瘤诊断治疗一体化,可以用于光热/放疗协同治疗。
本发明的较佳实施例制得的小分子多肽修饰的超小粒径半金属纳米颗粒,其透射电镜照片如图3所示,可以看到通过本发明制备的小分子多肽修饰的超小粒径半金属纳米颗粒为铋单质,具有较高的单分散性,平均粒径为3.6nm。
本发明的较佳实施例制得的小分子多肽修饰的超小粒径半金属纳米颗粒,其紫外可见吸收图谱如图4所示,其在近红外二区具有较高的光学吸收。
本发明的较佳实施例制得的小分子多肽修饰的超小粒径半金属纳米颗粒,其相比为未修饰的纳米材料在乳腺癌肿瘤细胞中的富集含量数据如图5所示,可以看出小分子多肽修饰后在癌细胞中富集含量更高。
如图6和图7所示,为医用造影剂碘海醇(iohxeol)和本发明的小分子多肽修饰的超小粒径半金属纳米颗粒材料的计算机断层扫描成像和信号图谱,证明了该小分子多肽修饰的超小粒径半金属纳米颗粒材料的造影能力与其浓度成正比,并且在相同浓度条件下,该纳米材料比医用造影剂碘海醇的造影能力更高。
以上详细描述了本发明的较佳具体实施例。应当理解,本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此,凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案,皆应在由权利要求书所确定的保护范围内。
Claims (10)
1.一种超小粒径半金属纳米颗粒材料,其特征在于,
所述超小粒径半金属纳米颗粒为小分子多肽修饰的超小粒径半金属纳米颗粒,所述小分子多肽为N-端修饰有半胱氨酸残基的LyP-1,其序列为CGNKRTRGC。
2.如权利要求1所述的一种超小粒径半金属纳米颗粒材料,其特征在于,所述超小粒径半金属纳米颗粒中半金属为铋单质。
3.如权利要求1所述的一种超小粒径半金属纳米颗粒材料,其特征在于,所述超小粒径半金属纳米颗粒平均尺寸为3.2-4nm。
4.如权利要求1-3中任一所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,所述方法包含如下步骤:
步骤一:将乙酸铋与油酸的混合液加入油胺溶液中,搅拌条件下充分反应,然后离心纯化后得到超小粒径的半金属铋单质纳米颗粒;
步骤二:将所述超小粒径的半金属铋单质纳米颗粒分散到氯仿中,制备得到超小粒径半金属铋单质纳米颗粒分散液;
步骤三:在所述超小粒径半金属铋单质纳米颗粒分散液中加入聚乙二醇衍生物,搅拌挥发得到聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒;
步骤四:将所述聚乙二醇衍生物修饰的超小粒径半金属铋单质纳米颗粒溶于磷酸盐缓冲液中,加入小分子多肽LyP-1,搅拌一段时间,得到小分子多肽修饰的超小粒径半金属纳米颗粒。
5.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤一中所述搅拌为磁力搅拌。
6.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤一中所述油胺溶液置于260℃、氮气保护条件下。
7.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤三中所述聚乙二醇衍生物为二硬脂酰磷脂酰乙醇胺-聚乙二醇5000-马来酸甘交联物PEG5000-DSPE。
8.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤四中所述磷酸盐缓冲液pH值为7.2-7.6。
9.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤四中所述搅拌为磁力搅拌。
10.如权利要求4所述的超小粒径半金属纳米颗粒材料制备方法,其特征在于,步骤四中所述搅拌发生在室温条件下。
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Cited By (6)
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CN108845013A (zh) * | 2018-04-27 | 2018-11-20 | 桂林理工大学 | 铋浆膜试条及其制备方法与应用 |
CN109530719A (zh) * | 2018-12-10 | 2019-03-29 | 江苏大学 | 一种双功能的金@多肽纳米复合材料及其制备方法和用途 |
CN109395106A (zh) * | 2018-12-12 | 2019-03-01 | 华中科技大学 | 一种结构稳定的纳米铋球簇及其制备方法与应用 |
CN109395106B (zh) * | 2018-12-12 | 2021-04-20 | 华中科技大学 | 一种结构稳定的纳米铋球簇及其制备方法与应用 |
CN115531532A (zh) * | 2021-06-29 | 2022-12-30 | 国家纳米科学中心 | 改性铋纳米颗粒、制备、应用及改善铋纳米颗粒性能方法 |
CN115531532B (zh) * | 2021-06-29 | 2024-02-13 | 国家纳米科学中心 | 改性铋纳米颗粒、制备、应用及改善铋纳米颗粒性能方法 |
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