CN115006525A - 一种光热化学动力纳米复合物及其制备方法与应用 - Google Patents
一种光热化学动力纳米复合物及其制备方法与应用 Download PDFInfo
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- CN115006525A CN115006525A CN202210515929.2A CN202210515929A CN115006525A CN 115006525 A CN115006525 A CN 115006525A CN 202210515929 A CN202210515929 A CN 202210515929A CN 115006525 A CN115006525 A CN 115006525A
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Abstract
本发明提供一种光热化学动力纳米复合物及其制备方法与应用。所述纳米复合物包括硒化亚铜纳米颗粒、透明质酸化的过氧化钙纳米颗粒、有机变相材料制备而成;所述硒化亚铜纳米颗粒具有中空结构,所述硒化亚铜纳米颗粒表面负载所述透明质酸化的过氧化钙纳米颗粒并在外层包裹有所述有机变相材料。本申请纳米复合物制备方法简单,易于大规模生产,本申请纳米复合物可用于制备抗肿瘤药物,实现高效、高稳定性、安全的光热化学动力联合作用。
Description
技术领域
本发明属于纳米材料领域,尤其涉及一种光热化学动力纳米复合物及其制备方法与应用。
背景技术
目前,肿瘤患者的治疗主要以根治性切除联合术后辅助化疗为主的综合治疗。但是,传统的化疗药物(如奥沙利铂,紫杉醇等)容易引起脱发、恶心呕吐、骨髓抑制等全身多系统毒副作用,还易导致药物化疗耐药,在一定程度上降低了化疗药物的抗肿瘤作用。除了传统化疗外,越来越多的新型肿瘤防治手段被应用于肿瘤治疗。其中,化学动力疗法(Chemodynamic Therapy,CDT)就是其中一种比较有效的新兴癌症治疗策略。所谓的化学动力治疗(CDT),是指在肿瘤酸性微环境下,细胞中内源性过氧化氢(H2O2)在金属催化剂存在的前提下,发生芬顿或类芬顿反应并产生大量的羟基自由基(·OH),继而·OH可以氧化损伤脂质、蛋白质和DNA等引起癌细胞死亡的一种新型治疗模式。至今,以铁元素为基础的纳米材料,如FeS2、Fe2P、Fe5C2@MnO2,是作为主要的应用CDT杀伤肿瘤的药物。然而,基于铁元素材料的芬顿效应仅在较强的酸性条件下有效(pH=3~5),而肿瘤细胞内的弱酸性(pH=6.8)条件发生芬顿反应效率不高。此外,即使在合适的pH值,以铁元素为基础的纳米材料的芬顿反应效率相对较低,导致·OH生成缓慢。因此,如何提高肿瘤部位芬顿反应的效率将是CDT疗效进一步改进的关键。
近年来,光热治疗(photothermal therapy,PTT)受到了越来越多人的关注,它是一种通过光敏剂将近红外光能转化为热能破坏癌细胞的新兴肿瘤治疗手段,具有适用范围广、非侵入、选择性强、过程简单、正常组织损伤小等优点,在肿瘤治疗领域展现出巨大的应用价值。有趣的是,研究发现光热疗法(PTT)能提高肿瘤部位的局部温度,而温度的轻微上调能显著增强芬顿或类芬顿效应。例如,FePS3纳米片是具有芬顿催化活性的高效光热剂,在光热作用下芬顿催化效果能够被显著增强,但仍是基于铁元素的材料,所以芬顿效应增强有限。目前,较常应用于光热治疗的纳米材料,如碳纳米棒,氧化石墨烯(GO),金纳米棒(Au),硫化铜(CuS)等,主要是受到近红外一区(NIR I)激光激发在交变磁场的作用下产生热量而治疗肿瘤。相比于近红外一区纳米材料,近红外二区纳米材料具有两方面明显的优势:一方面是更强的组织穿透深度;另一方面,允许更高的照射剂量(根据美国激光安全使用的国家标准,皮肤可安全暴露于1064nm波长激光的功率密度为1W/cm2,而对于808nm激光,这个值仅为0.33W/cm2)。为提高肿瘤细胞内过氧化氢浓度,增强化学动力疗效,有相关专利成功构建了超小过氧化钙(CaO2),其一方面能与水反应生成过氧化氢;另一方面能在酸性环境下生成钙离子,细胞内钙离子的富集会引起肿瘤细胞钙超载继发细胞凋亡,然而,CaO2的稳定性差,遇水易分解。
发明内容
本发明旨在至少解决上述现有技术中存在的技术问题之一。为此,本发明第一个方面提出一种光热化学动力纳米复合物,能够在体内发挥高效、高稳定性、安全的光热化学动力联合作用。
本发明的第二个方面提出了一种光热化学动力纳米复合物的制备方法。
本发明的第三个方面提出了一种光热剂。
本发明的第四个方面提出了一种光热化学动力纳米复合物在制备抗肿瘤药物中的应用。
根据本发明的第一个方面,提出了一种光热化学动力纳米复合物,包括内核和外壳;所述内核为负载透明质酸化的过氧化钙纳米颗粒的中空硒化亚铜纳米粒子;所述外壳为有机变相材料层。
在本发明中,所述纳米复合物一方面具有良好的化学动力性能,能催化肿瘤细胞内的过氧化氢生成具有细胞毒性的羟自由基;另一方面还具有良好的光热性能及易于修饰等特性,可在近红外光二区(NIR II)激发下发光产热,进而增强其在细胞内的类芬顿效应。为提高肿瘤细胞内过氧化氢浓度,增强硒化亚铜的化学动力疗效。过氧化钙一方面能与水反应生成过氧化氢;另一方面能在酸性环境下生成钙离子,而细胞内钙离子的富集会引起肿瘤细胞钙超载继发细胞凋亡。然而,过氧化钙的稳定性差,遇水易分解。因此,本发明改进既往合成方法使硒化亚铜具有中空载体结构,继而负载过氧化钙,并在此纳米材料表面包裹有机相变材料以稳定过氧化钙,形成自供给过氧化氢的纳米系统。在有机变相材料的包覆下,该纳米复合物能携载过氧化钙进入肿瘤细胞内,在近红外照射后的光热效应下发生有机变相材料的降解,进而释放硒化亚铜和过氧化钙,实现高效、高稳定性、安全的光热化学动力联合化疗抗肿瘤作用,优化肿瘤综合冶疗策略。
在本发明的一些实施方式中,所述纳米复合物为球状或类球状,平均粒径为70nm~80nm。
在本发明的一些实施方式中,所述透明质酸化的过氧化钙纳米颗粒为球状或类球状,平均粒径为7nm~10nm。
在本发明的一些实施方式中,所述中空硒化亚铜纳米粒子、所述透明质酸化的过氧化钙纳米颗粒、所述有机变相材料的质量比为1~2:1~2:50~100。
在本发明的一些优选的实施方式中,所述中空硒化亚铜纳米粒子、所述透明质酸化的过氧化钙纳米颗粒、所述有机变相材料的质量比为1~1.5:1~1.5:50~100。
在本发明的一些更优选的实施方式中,所述中空硒化亚铜纳米粒子、所述透明质酸化的过氧化钙纳米颗粒、所述有机变相材料的质量比为1~1.5:1~1.5:70~90。
在本发明的一些更优选的实施方式中,所述有机变相材料选自月桂酸、癸酸、肉豆蔻酸、棕榈酸中的至少一种。
在本发明的一些更优选的实施方式中,所述中空硒化亚铜纳米粒子为修饰和/或未修饰的中空硒化亚铜纳米粒子;所述修饰为PEG类修饰。
根据本发明的第二个方面,提出了一种光热化学动力纳米复合物的制备方法,包括以下步骤:
S1:在惰性气体环境中,将硒粉与还原剂混合液体搅拌,加入氧化亚铜,反应,得到硒化亚铜纳米粒子;
S2:将钙盐与透明质酸溶液混合搅拌,再加入氨水、过氧化氢和碱溶液,反应,得到透明质酸化的过氧化钙纳米颗粒;
S3:将S1所述硒化亚铜纳米粒子和S2所述透明质酸化的过氧化钙纳米颗粒混合在有机溶剂中搅拌,加入有机变相材料,搅拌反应,将沉淀物洗涤,得到所述纳米复合物。
在本发明的一些实施方式中,若S1所述中空硒化亚铜纳米粒子为修饰的中空硒化亚铜纳米粒子,还包括如下步骤:将所述中空硒化亚铜纳米粒子与PEG修饰剂混合成溶液,搅拌反应,纯化,干燥得到修饰后的中空硒化亚铜纳米粒子。
在本发明的一些实施方式中,S1所述还原剂选自硼氢化钠、硼氢化锂、硼氢化镍、硼氢化钠锌中的至少一种。
在本发明的一些实施方式中,S1所述硒粉、还原剂、氧化亚铜的用量比为(1~5):(1~5):1。
在本发明的一些实施方式中,S1所述搅拌的时间为1h~3h。
在本发明的一些实施方式中,S1所述反应的时间为1h~4h。
在本发明的一些实施方式中,S2所述碱溶液选自氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠中的至少一种。
在本发明的一些实施方式中,S2所述搅拌的时间为24h~48h。
在本发明的一些优选的实施方式中,S3所述有机溶剂选自乙醇、甲醇、丙醇中的至少一种。
在本发明的一些优选的实施方式中,S3所述洗涤为用有机溶剂洗涤,次数为2~5次。
在本发明的一些更优选的实施方式中,所述PEG修饰剂选自SH-PEG、NH2-PEG、mPEG中的至少一种。
根据本发明的第三个方面,提出乐一种光热剂,包括上述纳米复合物。
根据本发明的第四个方面,提出了一种光热化学动力纳米复合物在制备抗肿瘤药物中的应用。
本发明的有益效果为:
1.具有良好的光热性能:在近红外二区(NIR II)1064nm的近红外光(NIR,1W/cm2)照射10min后,含有本发明的纳米复合物的体系温度从30℃提高到55℃,而对照PBS体系的温度只是略微升高,这提示该纳米体系具备良好的光热效应;
2.具有良好的化学动力性能:含有本发明的纳米复合物的体系在较低过氧化氢浓度和pH为近中性的条件下(pH=6.5)即可拥有良好的化学动力学效果。在亚甲基蓝(MB)验证实验中,相比于对照组(PBS),实验组具有良好的化学动力作用,且具有良好的浓度依赖性和温度协同作用;
3.具有自供给过氧化氢特性:在含有本发明的纳米复合物的体系中,由于负载超小过氧化钙纳米粒子(CaO2),CaO2可以在肿瘤微酸性环境中自供给产生过氧化氢从而增强此纳米系统的化学动力作用;
4.具有热敏感效应:由于熔点为42℃~45℃有机相变材料的包裹,使得此纳米系统具有热敏感效应,在光热作用下温度升高上述温度范围时使得纳米粒子的有机相变材料外膜破裂,在肿瘤部位定点释放纳米粒子;
5.肿瘤部位的定点释放:由于包裹有机相变材料,本申请纳米复合物在光热作用下温度达到熔点,使得有机相变材料破裂释放出其内的纳米粒子,从而达到定点肿瘤部位释放靶向杀伤肿瘤细胞,保护正常细胞;
6.通过光热效应和化学动力学效应协同作用在癌细胞内产生活性氧(ROS):在近红外二区(NIR II)1064nm的近红外光的照射下,本发明的纳米复合物能与化学动力效果产生协同作用,产生大量的ROS,损伤线粒体。
附图说明
下面结合附图和实施例对本发明做进一步的说明,其中:
图1为本发明实施例1制备的硒化亚铜的理化表征,其中A图从左至右为硒化亚铜透射电镜图,硒化亚铜透射电镜灰度图,硒化亚铜电镜mapping中铜元素分析,硒化亚铜电镜mapping中硒元素分析;B图为硒化亚铜与过氧化钙XPS分析图;C图为硒化亚铜与过氧化钙XRD分析图;D图为硒化亚铜与过氧化钙傅里叶红外分析图。
图2为A为Cu2Se在不同浓度下MB降解曲线;B为Cu2Se-CaO2不同浓度下MB降解曲线,C为A与B图在664nm波长下的定量分析,***代表P<0.001。
图3为A为高锰酸钾与不同浓度过氧化氢反应紫外吸收图;B为不同条件下,CaO2产生过氧化氢能力。
图4为本发明实施例1制备的Cu2Se、Cu2Se-CaO2、Cu2Se-CaO2@LA纳米复合物抗肿瘤作用,***代表P<0.001。
图5中A为ROS的生成水平检测;B为细胞内mPTP的开放程度检测;C为细胞内线粒体膜电势(MTP)检测图,***代表P<0.001。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
实施例1
本实施例制备了一种装载过氧化钙的硒化亚铜光热化学动力纳米复合物,具体过程为:
(1)氧化亚铜的制备:将85mg二水氯化铜(CuCl2-2H2O)与300mg聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP,MW=6000)放在20mL去离子水中搅拌1h,随后加入320mgNaOH搅拌溶解。将上述溶液置入氮气环境,逐渐加入抗坏血酸继续搅拌1h。经过离心,纯化,干燥后,得到氧化亚铜(Cu2O)
(2)硒化亚铜的制备:在氮气环境中,将50mg硒粉与50mg硼氢化钠,加入20mL去离子水中搅拌24h,加入步骤(1)中得到的氧化亚铜(Cu2O),随后继续搅拌,经过离心,纯化,干燥后,得到硒化亚铜(Cu2Se)。
(3)硒化亚铜的修饰:将10mg的硒化亚铜和10mg的SH-PEG,置入20mL去离子水体系中,搅拌24h,经过离心,纯化,干燥后,得到硒化亚铜(SH-PEG-Cu2Se)。
(4)透明质酸化的过氧化钙的制备:在搅拌下,将CaCl2(2mL,0.1g/mL)加入到透明质酸(Hyaluronic acid,HA)溶液(10mL,15mg/mL)中,搅拌24h。然后依次加入1mL的NH3·H2O(1M)和1.5mL 30wt%H2O2反应3h,然后超声下加入0.5mL NaOH(1M),得到含有HA-CaO2NPs的白色乳化液,将相应HA-CaO2 NPs用NaOH(0.1M)、水、乙醇洗涤,最后在4℃的乙醇中保存备用,采用水解-沉淀法合成了氧化钙纳米粒子。
(5)装载过氧化钙的硒化亚铜光热化学动力纳米平台的制备:将步骤(3)中制备的SH-PEG-Cu2Se(1mg)和步骤(4)中制备的HA-CaO2(1mg)混合在乙醇(5mL)中搅拌24h,然后将月桂酸(0.1g)溶解在乙醇(1mL)中。然后加入混合物,再搅拌5h,沉淀物用乙醇洗涤三次,所制备的复合材料为装载过氧化钙的硒化亚铜光热化学动力纳米复合物Cu2Se-CaO2@LA。
实施例2
本实施例制备了一种装载过氧化钙的硒化亚铜光热化学动力纳米复合物,具体过程为:
(1)氧化亚铜的制备:将85mg二水氯化铜(CuCl2-2H2O)与300mg聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP,MW=6000)放在20mL去离子水中搅拌1h,随后加入320mgNaOH搅拌溶解。将上述溶液置入氮气环境,逐渐加入抗坏血酸继续搅拌1h。经过离心,纯化,干燥后,得到氧化亚铜(Cu2O)
(2)硒化亚铜的制备:在氮气环境中,将50mg硒粉与50mg硼氢化钠,加入20mL去离子水中搅拌24h,加入步骤(1)中得到的氧化亚铜(Cu2O),随后继续搅拌,经过离心,纯化,干燥后,得到硒化亚铜(Cu2Se)。
(3)硒化亚铜的修饰:将10mg的硒化亚铜和10mg的NH2-PEG,置入20mL去离子水体系中,搅拌24h,经过离心,纯化,干燥后,得到硒化亚铜(NH2-PEG-Cu2Se)。
(4)透明质酸化的过氧化钙的制备:在搅拌下,将CaCl2(2mL,0.1g/mL)加入到透明质酸(Hyaluronic acid,HA)溶液(10mL,15mg/mL)中,搅拌24h。然后依次加入1mL的NH3·H2O(1M)和1.5mL 30wt%H2O2反应3h,然后超声下加入0.5mL NaOH(1M),得到含有HA-CaO2NPs的白色乳化液,将相应HA-CaO2 NPs用NaOH(0.1M)、水、乙醇洗涤,最后在4℃的乙醇中保存备用,采用水解-沉淀法合成了氧化钙纳米粒子。
(5)装载过氧化钙的硒化亚铜光热化学动力纳米平台的制备:将步骤(3)中制备的NH2-PEG-Cu2Se(1mg)和步骤(4)中制备的HA-CaO2(1mg)混合在乙醇(5mL)中搅拌24h,然后将月桂酸(0.1g)溶解在乙醇(1mL)中。然后加入混合物,再搅拌5h,沉淀物用乙醇洗涤三次,所制备的复合材料为装载过氧化钙的硒化亚铜光热化学动力纳米复合物Cu2Se-CaO2@LA。
实施例3
本实施例制备了一种装载过氧化钙的硒化亚铜光热化学动力纳米复合物,具体过程为:
(1)氧化亚铜的制备:将85mg二水氯化铜(CuCl2-2H2O)与300mg聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP,MW=6000)放在20mL去离子水中搅拌1h,随后加入320mgNaOH搅拌溶解。将上述溶液置入氮气环境,逐渐加入抗坏血酸继续搅拌1h。经过离心,纯化,干燥后,得到氧化亚铜(Cu2O)
(2)硒化亚铜的制备:在氮气环境中,将50mg硒粉与50mg硼氢化钠,加入20mL去离子水中搅拌24h,加入步骤(1)中得到的氧化亚铜(Cu2O),随后继续搅拌,经过离心,纯化,干燥后,得到硒化亚铜(Cu2Se)。
(3)硒化亚铜的修饰:将10mg的硒化亚铜和10mg的mPEG,置入20mL去离子水体系中,搅拌24h,经过离心,纯化,干燥后,得到硒化亚铜(mPEG-Cu2Se)。
(4)透明质酸化的过氧化钙的制备:在搅拌下,将CaCl2(2mL,0.1g/mL)加入到透明质酸(Hyaluronic acid,HA)溶液(10mL,15mg/mL)中,搅拌24h。然后依次加入1mL的NH3·H2O(1M)和1.5mL 30wt%H2O2反应3h,然后超声下加入0.5mL NaOH(1M),得到含有HA-CaO2NPs的白色乳化液,将相应HA-CaO2 NPs用NaOH(0.1M)、水、乙醇洗涤,最后在4℃的乙醇中保存备用,采用水解-沉淀法合成了氧化钙纳米粒子。
(5)装载过氧化钙的硒化亚铜光热化学动力纳米平台的制备:将步骤(3)中制备的mPEG-Cu2Se(1mg)和步骤(4)中制备的HA-CaO2(1mg)混合在乙醇(5mL)中搅拌24h,然后将月桂酸(0.1g)溶解在乙醇(1mL)中。然后加入混合物,再搅拌5h,沉淀物用乙醇洗涤三次,所制备的复合材料为装载过氧化钙的硒化亚铜光热化学动力纳米复合物Cu2Se-CaO2@LA。
对比例1
本对比例制备了一种Cu2Se-CaO2,与实施例1的区别在于不包裹有机相变材料,具体过程为:
(1)氧化亚铜的制备:将85mg二水氯化铜(CuCl2-2H2O)与300mg聚乙烯吡咯烷酮(polyvinyl pyrrolidone,PVP,MW=6000)放在20mL去离子水中搅拌1h,随后加入320mgNaOH搅拌溶解。将上述溶液置入氮气环境,逐渐加入抗坏血酸继续搅拌1h。经过离心,纯化,干燥后,得到氧化亚铜(Cu2O)
(2)硒化亚铜的制备:在氮气环境中,将50mg硒粉与50mg硼氢化钠,加入20mL去离子水中搅拌24h,加入步骤(1)中得到的氧化亚铜(Cu2O),随后继续搅拌,经过离心,纯化,干燥后,得到硒化亚铜(Cu2Se)。
(3)硒化亚铜的修饰:将10mg的硒化亚铜和10mg的SH-PEG,置入20mL去离子水体系中,搅拌24h,经过离心,纯化,干燥后,得到硒化亚铜(SH-PEG-Cu2Se)。
(4)透明质酸化的过氧化钙的制备:在搅拌下,将CaCl2(2mL,0.1g/mL)加入到透明质酸(Hyaluronic acid,HA)溶液(10mL,15mg/mL)中,搅拌24h。然后依次加入1mL的NH3·H2O(1M)和1.5mL 30wt%H2O2反应3h,然后超声下加入0.5mL NaOH(1M),得到含有HA-CaO2NPs的白色乳化液,将相应HA-CaO2 NPs用NaOH(0.1M)、水、乙醇洗涤,最后在4℃的乙醇中保存备用,采用水解-沉淀法合成了氧化钙纳米粒子。
(5)装载过氧化钙的硒化亚铜光热化学动力纳米平台的制备:将步骤(3)中制备的SH-PEG-Cu2Se(1mg)和步骤(4)中制备的HA-CaO2(1mg)混合在乙醇(5mL)中搅拌24h,所制备的复合材料为装载过氧化钙的硒化亚铜光热化学动力纳米复合物Cu2Se-CaO2。
相比于没有包裹LA的纳米材料Cu2Se-CaO2,实施例中的Cu2Se-CaO2@LA更加稳定,并且具有温控特性,在特定温度下才释放。
试验例1理化表征
1.通过透射电镜(TEM)扫描实验来观察实施例1制备的Cu2Se和CaO2的外部形貌特征。首先,收集并适当稀释样品溶液后,用移液枪吸取10uL样品滴加在镍网上。室温放置至溶液蒸发后,用离子溅射仪镀上导电金膜,在200kV的加速电压下,采用TEM观察纳米复合物的形貌特征。
2.将制备好的实施例1的纳米复合物样品经冷冻干燥,然后研磨成粉末,与溴化钾(KBr)混匀后并压制成颗粒状混合物,最后用Nicolet 7000-C FTIR分析仪对进行分析,获得纳米复合物的红外光谱图。
3.将制备好的实施例1的纳米复合物样品经冷冻干燥,然后研磨成粉末,然后在PANalytical X’Pert PRO X射线衍射仪记录并观察X射线衍射图谱;同时,利用PHI5000VersaProbe能谱仪观察记录纳米样品的X射线光电子能谱图。
上述各项测试结果见图1,其中,A图从左至右为硒化亚铜透射电镜图;硒化亚铜透射电镜灰度图,硒化亚铜电镜mapping中铜元素分析;硒化亚铜电镜mapping中硒元素分析;B图为硒化亚铜与过氧化钙XPS分析图;C图为硒化亚铜与过氧化钙XRD分析图;D图为硒化亚铜与过氧化钙傅里叶红外分析图。
结果分析:从红外吸收光谱、扫描电镜、X射线荧光衍射(XRD)、X射线光电子能谱分析(XPS)等理化性质均提示Cu2Se与CaO2纳米材料被成功合成。
试验例2增强型芬顿效应的检测
基于选择性·OH捕获后亚甲基蓝(MB)降解的经典比色法分析·OH生成量。
1:PBS(pH=6.5);4mM H2O2;MB溶液(10μg/mL),在25℃下,分别加入不同浓度的Cu2Se(0μg/mL;20μg/mL;40μg/mL;60μg/mL;80μg/mL;100μg/mL);
2.PBS(pH=6.5);4mM H2O2;MB溶液(10μg/mL),在25℃下,分别加入不同浓度的Cu2Se@CaO2(0μg/mL;20μg/mL;40μg/mL;60μg/mL;80μg/mL;100μg/mL);检测其λ=664nm的吸光度。然后将温度提高到45℃,模拟光热治疗过程中的热量,评价温度对·OH生成的影响,结果见图2,其中A为Cu2Se在不同浓度下MB降解曲线,从上到下曲线依次对应0μg/mL;20μg/mL;40μg/mL;60μg/mL;80μg/mL;100μg/mL的Cu2Se;B为Cu2Se@CaO2不同浓度下MB降解曲线,从上到下曲线依次对应0μg/mL;20μg/mL;40μg/mL;60μg/mL;80μg/mL;100μg/mL的Cu2Se@CaO2;C为A与B图在664nm波长下的定量分析,同个浓度条件中,左边蓝色柱状图对应Cu2Se,右边红色柱状图对应Cu2Se@CaO2(即Cu2Se-CaO2),***代表P<0.001。
结果分析:从图2中A可看出Cu2Se可以降解MB,证明Cu2Se产生芬顿效应;同时,B可看出Cu2Se@CaO2产生更强的芬顿效应;C可看出,经过定量分析,Cu2Se@CaO2与Cu2Se相比,Cu2Se@CaO2产生芬顿效应能力更强。
试验例3过氧化氢生成检测
依靠高锰酸钾测定过氧化氢从而得到标准曲线,标准曲线可用于定量分析溶液中过氧化氢的浓度。首先,用不同浓度的过氧化氢(0mM;20mM;40mM;60mM;80mM;100mM;200mM)滴定高锰酸钾(1mg/mL),得出标准曲线,根据标准曲线,算出相对应过氧化氢含量。CaO2被分为3个组(n=3):(i)在37℃或50℃下分散于去离子水(pH=7.0,100μg/mL)中。(ii)37℃或50℃条件下分散于PBS缓冲液(pH=6.5,100μg/mL)中的CaO2 NPs。(iii)CaO2 NPs分散于PBS缓冲液(pH=6.0,100μg/mL)中,温度为37℃或50℃。各组分别加入KI(0.1M)水溶液20μL。测定溶液的紫外-可见吸收光谱,5min后计算生成H2O2的浓度,结果见图3,图3中A为高锰酸钾与不同浓度过氧化氢反应紫外吸收图,其中,在不同浓度的过氧化氢与高锰酸钾反应后,因高猛酸钾的分解,紫外吸收会随之变化,因此测定其反应后的紫外吸收光谱,可以得出对应的过氧化氢浓度。曲线从上至下依次对应0mM、20mM、40mM、60mM、80mM、100mM、200mM的过氧化氢滴定高锰酸钾后的紫外吸收光谱;B为不同条件下,CaO2产生过氧化氢能力,同个pH条件下,左边蓝色柱状图对应50℃,右边红色柱状图对应37℃。
结果分析:从图3可看出CaO2具有良好的产过氧化氢能力,在不同pH和不同温度下,过氧化钙表现出良好的温度和pH响应特性。
试验例4 Cu2Se@CaO2@LA纳米复合物抗肿瘤作用测试
进行CCK-8细胞毒性实验,首先将处于对数生长期的HGC-27细胞经胰酶消化后获得单细胞悬液,并5000/孔的细胞量接种于96孔板上,置于恒温孵育箱中培养24h;随后,待细胞贴壁后,在每个微孔中加入不同浓度的Cu2Se和Cu2Se-CaO2@LA纳米复合物并进行光照或者非光照处理,继续放置在孵育箱中培养24h;然后,去除培养基、并在每个待测微孔中加入100μL预先配置好的10%的CCK-8试剂;最后,用酶标仪测定每个测量孔在450nm处吸光度,并记录结果进行对比分析,结果见图4。
结果分析:从图4可看出在单独的Cu2Se的作用下,可以产生一定的抗肿瘤作用,而在NIR II(1064nm)光照射后抗肿瘤作用进一步增加;在负载超小CaO2纳米粒子后,抗肿瘤作用明显增强。而在有机相变材料月桂酸LA的保护作用下,不产生细胞毒性作用。
试验例5 Cu2Se@CaO2@LA纳米复合物诱导线粒体功能障碍测试
将肿瘤细胞接种于6孔板中,分别用Cu2Se@CaO2@LA纳米复合物和Cu2Se纳米对细胞进行处理后,收集细胞分别加入JC-1检测试剂盒、ROS检测试剂盒、mPTP检测试剂盒对细胞内线粒体膜电势(MTP)、ROS的生成水平以及mPTP的开放程度,结果见图5,A为A为ROS的生成水平检测;B为细胞内mPTP的开放程度检测;C为细胞内线粒体膜电势(MTP)检测;***代表P<0.001。
结果分析:在Cu2Se作用下,可以使细胞产生活性氧(ROS)及线粒体功能障碍,如mPTP孔通道开放及膜电位下降;而在NIR II(1064nm)光照射后,活性氧产生量进一步增加;在负载超小CaO2纳米粒子后,ROS产生量明显增加。而在非光照和有机相变材料月桂酸LA限制作用下,细胞产生ROS的作用较弱。
上面对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (10)
1.一种光热化学动力纳米复合物,其特征在于,包括内核和外壳;所述内核为负载透明质酸化的过氧化钙纳米颗粒的中空硒化亚铜纳米粒子;所述外壳为有机变相材料层。
2.根据权利要求1所述的纳米复合物,其特征在于,所述纳米复合物为球状或类球状,平均粒径为70nm~80nm。
3.根据权利要求1所述的纳米复合物,其特征在于,所述透明质酸化的过氧化钙纳米颗粒为球状或类球状,平均粒径为7nm~10nm。
4.根据权利要求1所述的纳米复合物的制备方法,其特征在于,所述中空硒化亚铜纳米粒子、所述透明质酸化的过氧化钙纳米颗粒、所述有机变相材料的质量比为1~2:1~2:50~100。
5.根据权利要求1所述的纳米复合物,其特征在于,所述有机变相材料选自月桂酸、癸酸、肉豆蔻酸、棕榈酸中的至少一种。
6.根据权利要求1所述的纳米复合物,其特征在于,所述中空硒化亚铜纳米粒子为修饰和/或未修饰的中空硒化亚铜纳米粒子;所述修饰为PEG类修饰。
7.一种如权利要求1~6任一项所述的纳米复合物的制备方法,其特征在于,包括以下步骤:
S1:在惰性气体环境中,将硒粉与还原剂混合液体搅拌,加入氧化亚铜,反应,得到中空硒化亚铜纳米粒子;
S2:将钙盐与透明质酸溶液混合搅拌,再加入氨水、过氧化氢和碱溶液,反应,得到透明质酸化的过氧化钙纳米颗粒;
S3:将S1所述中空硒化亚铜纳米粒子和S2所述透明质酸化的过氧化钙纳米颗粒混合在有机溶剂中搅拌,加入有机变相材料,搅拌反应,将沉淀物洗涤,得到所述纳米复合物。
8.根据权利要求7所述的纳米复合物的制备方法,其特征在于,若S1所述中空硒化亚铜纳米粒子为修饰的中空硒化亚铜纳米粒子,还包括如下步骤:将未修饰的中空硒化亚铜纳米粒子与PEG修饰剂混合成溶液,搅拌反应,纯化,干燥得到所述修饰的中空硒化亚铜纳米粒子。
9.一种光热剂,其特征在于,包括权利要求1~6任一项所述的纳米复合物或权利要求7~8任一项所述的制备方法制备的纳米复合物。
10.一种光热化学动力纳米复合物在制备抗肿瘤药物中的应用,其特征在于,所述纳米复合物为权利要求1~6任一项所述的纳米复合物或权利要求7~8所述的制备方法制备的纳米复合物。
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Non-Patent Citations (4)
Title |
---|
LI CHEN ET AL: "Near-infrared and tumor environment Co-activated nanoplatform for precise tumor therapy in multiple models", 《APPLIED MATERIALS TODAY》 * |
MENG ZHANG ET AL: "Calcium-Overload-Mediated Tumor Therapy by Calcium Peroxide Nanoparticles", 《CHEM》 * |
MI WANG ET AL: "Synergistic H2O2 self-supplying and NIR-responsive drug delivery nanoplatform for chemodynamic-photothermal-chemotherapy", 《COLLOIDS AND SURFACES B: BIOINTERFACES》 * |
XIANWEN WANG ET AL: "Hollow Cu2Se Nanozymes for Tumor Photothermal-Catalytic Therapy", 《CHEM. MATER.》 * |
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---|---|---|---|---|
CN117618388A (zh) * | 2024-01-25 | 2024-03-01 | 北京大学口腔医学院 | 一种用于肿瘤治疗的纳米颗粒及其制备方法和应用 |
CN117618388B (zh) * | 2024-01-25 | 2024-04-23 | 北京大学口腔医学院 | 一种用于肿瘤治疗的纳米颗粒及其制备方法和应用 |
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