CN116098999A - TiO2-x@GLNPs及其应用 - Google Patents
TiO2-x@GLNPs及其应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,具体公开了TiO2‑x@GL NPs及其应用,本发明利用铝还原法合成TiO2‑x NPs,然后利用谷氨酰胺对TiO2‑x NPs的表面进行修饰获得TiO2‑x@GL NPs。本发明制备得到的TiO2‑x@GL NPs能够抑制肿瘤细胞迁移,抑制肿瘤细胞的增殖,同时还能协同激光和超声抑制肿瘤增殖,为制备治疗癌症的药物提供了材料基础。
Description
技术领域
本发明涉及生物医药技术领域,具体涉及TiO2-x@GL NPs及其应用。
背景技术
二氧化钛纳米颗粒(TiO2 NPs)具有良好的生物相容性、高光活性、优良的稳定性和低毒性,TiO2 NPs已成为一种很有前途的抗癌材料,并被深入研究。众所周知,TiO2 NPs可以在紫外线照射后诱导多种类型的癌细胞中产生大量的活性氧(ROS),最终引起细胞死亡,因此被广泛应用于恶性肿瘤的光动力治疗(PDT)。TiO2 NPs及基于TiO2 NPs的合成材料作为PDT中光敏剂研究较多。大多数的研究都集中在通过掺杂各种金属或非金属掺杂剂来提高其生成ROS的能力和扩展光谱响应上。TiO2 NPs同样通过结合各种分子或抗体来提高传递效率。
肿瘤转移是恶性肿瘤的主要的有害特征,也是导致术后患者死亡的主要原因。因此,防止肿瘤细胞迁移是一种潜在的抗癌方法。虽然TiO2 NPs具有潜在的抗癌能力,但它也会引起不良反应,且其到达肿瘤组织发挥作用的浓度仍不理想。
既往研究表明,荷瘤机体存在缺乏谷氨酰胺(GL)的现象,且外源性补充的谷氨酰胺会被优先运送到肿瘤组织。但是,体外添加谷氨酰胺会促进肿瘤细胞增殖,反而促进肿瘤生长,因此,如何在抑制肿瘤细胞增殖和生长的同时将谷氨酰胺运送到肿瘤组织是一个难题,目前也没有发现能在抑制肿瘤增殖的前提下将谷氨酰胺运送到肿瘤组织的产品。
发明内容
为解决上述技术问题,本发明提供了TiO2-x@GL NPs及其应用,本发明制备得到的TiO2-x@GL NPs能够抑制肿瘤细胞迁移,抑制肿瘤细胞的增殖,同时还能协同激光和超声抑制肿瘤增殖,为制备治疗癌症的药物提供了材料基础。
本发明第一个目的是提供了TiO2-x@GL NPs,由如下步骤制备获得:
S1,TiO2-x NPs的制备:以二氧化钛和铝为原料,利用铝还原法合成TiO2-xNPs;
S2,TiO2-x@GL NPs制备:利用谷氨酰胺对TiO2-x NPs的表面进行修饰获得TiO2-x@GLNPs。
进一步地,S1中,铝还原法具体过程为:铝在700-800℃下加热融化,与TiO2样品混合后在300-500℃下加热还原6-10h,获得500℃-Al-TiO2-x,然后在800-900℃的氩气中对500℃-Al-TiO2-x退火10-12h,获得了TiO2-x NPs。
进一步地,S2中,谷氨酰胺对TiO2-x NPs的表面修饰具体为:将40-50mg谷氨酰胺加入8-10mL质量浓度为1-1.5mg/mL的TiO2-x NPs溶液中,然后在冰浴中120W超声处理3-5小时,10000r/min,10min离心三次,去离子水洗涤得到TiO2-x@GL NPs。
进一步地,S2中,谷氨酰胺对TiO2-x NPs的表面修饰具体为:将50mg谷氨酰胺加入10mL质量浓度为1mg/mL的TiO2-x NPs溶液中,然后在冰浴中120W超声处理4小时,10000r/min,10min离心三次,去离子水洗涤得到TiO2-x@GL NPs。
进一步地,所述TiO2-x@GL NPs的水合粒径为164.2nm。
本发明的第二个目的是提供所述TiO2-x@GL NPs在制备治疗肿瘤药物中的应用。
进一步地,所述TiO2-x@GL NPs能够用于制备肿瘤细胞迁移的抑制剂。
进一步地,所述TiO2-x@GL NPs能够用于制备肿瘤细胞增殖的抑制剂。
进一步地,所述TiO2-x@GL NPs能够用于制备激光和超声抑制肿瘤的协同剂。
进一步地,所述TiO2-x@GL NPs在300ppm浓度下的光热性能能够杀死癌细胞。
与现有技术相比,本发明的有益效果在于:
1、本发明通过谷氨酰胺对TiO2-x NPs的表面进行修饰获得TiO2-x@GL NPs,发现TiO2-x NPs的结构在GL的表面包封后保存良好,GL对NIR吸波能力和光热性能没有影响,GL使得TiO2-x@GL的含量比TiO2-x积累量增加了近3倍。
2、本发明制备的TiO2-x@GL NPs不仅能将GL运送到肿瘤组织,还能够抑制肿瘤细胞迁移,抑制肿瘤细胞的增殖,同时还能协同激光和超声抑制肿瘤增殖,为制备治疗癌症的药物提供了材料基础。
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简单地介绍,显而易见地,下面描述中的附图仅仅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。
需要说明的是,图1-图6中TiO2-x@GL和TiO2-x@GL NPs表示为同一物质,TiO2-x@GL为TiO2-x@GL NPs的简写。
图1为本发明制备得到的TiO2-x@GL NPs和TiO2-xNPs的TEM图像、SAED模式图像;
其中,图a为TiO2-x NPs的低倍率TEM图像;
图b为TiO2-x@GL NPs的低倍率TEM图像;
图c为TiO2-x NPs的高分辨率TEM图像;
图d为TiO2-x@GL NPs的高分辨率TEM图像;
图e为TiO2-x NPs的SAED模式图像;
图f为TiO2-x@GL NPs的SAED模式图像;
图g为TiO2-x NPs的DLS曲线;
图h为TiO2-x@GL NPs的DLS曲线;
图2为本发明制备得到的TiO2-x@GL NPs和TiO2-xNPs的SEM、EDS、Zeta电位、XRD和紫外与近红外光的吸收光谱;
其中,图a为TiO2-x NPs的SEM图像;
图b为TiO2-x@GL NPs的SEM图像;
图c为基于紫色矩形区域测得的TiO2-x NPs的EDS;
图d为TiO2-x@GL NPs的EDS;
图e为TiO2-x NPs和TiO2-x@GL NPs的Zeta电位;
图f为TiO2-x NPs和TiO2-x@GL NPs的XRD;
图g为TiO2-x NPs和TiO2-x@GL NPs的紫外与近红外光的吸收光谱;
图h为TiO2-x NPs和TiO2-x@GL NPs的光热加热曲线。
图3为TiO2-x@GL NPs体外声动力和光热效应;
其中,图a为不同超声强度下TiO2-x@GL NPs体外产生活性氧的结果;
图b为连续超声辐照(1.5W/cm2)下TiO2-x@GL NPs的累积活性氧浓度曲线;
图c为不同粒子浓度对活性氧产生影响的比较;
图d为不同浓度TiO2-x@GL NPs对正常上皮细胞的毒性;
图e为不同浓度TiO2-x@GL NPs(0,6.25,12.5,25,50,100和300ppm),在功率强度为1.5W/cm2的近红外线(1064nm)辐照下的光热加热曲线;
图f为50ppm TiO2-x@GL NPs在不同功率密度(0,0.5,1.0和1.5W/cm2)下的光热加热曲线。
图4为基于体外SDT/PTT的肿瘤协同治疗效果,
其中,图a为TiO2-x@GL NPs(50ppm)水分散体在超声后,功率强度为1.5W/cm2的近红外光照射下的光热性能,当光源熄灭后,水分散体的温度趋于稳定;
图b为TiO2-x@GL NPs水分散体在功率强度为1.5W/cm2的条件下,水分散体在水中的三个循环加热曲线;
图c为不同处理后4T1细胞的相对细胞活力,包括对照(未处理),仅TiO2-x@GL NPs处理,仅超声处理,TiO2-x@GL NPs与光照组合,TiO2-x@GL NPs与超声组合照射,以及TiO2-x@GL NPs与光照和超声联合照射。
图d为不同处理后4T1细胞的CLSM图像,用PI(红色荧光)和钙黄绿素-AM(绿色荧光)染色;
图e为TiO2-x@GL NPs,超声和光照的方差贡献率;
图f为对照,TiO2-x和TiO2-x@GL NPs的平板计数实验。
图5为SDT/PTT体内协同抑制肿瘤的研究结果;
其中图a为TiO2-x@GL NPs在SDT和PTT协同下用于根除肿瘤的示意图;
图b为静脉注射TiO2-x或TiO2-x@GL NPs 4h后肿瘤组织中钛的蓄积情况;
图c为对照组,TiO2-x@GL NPs组,TiO2-x@GL NPs联合超声组,TiO2-x@GL NPs联合激光组,TiO2-x@GL NPs联合激光+超声组中4T1荷瘤小鼠的时间依赖性体重曲线;
图d为第15天不同组的肿瘤重量;
图e为15天内的时间依赖性肿瘤体积曲线;
图f为4T1荷瘤小鼠经不同处理后的存活曲线;
图g为治疗后各组肿瘤区域的HE染色、Tunel染色和免疫组织化学Ki67抗原染色。
图6为TiO2-x@GL NPs的安全性评价;
其中,图a为第1,7和28天,TiO2-x@GL NPs+激光+超声组的主要器官组织的H&E染色图像。
图b为第0天至第28天血常规:白细胞、血小板、血红蛋白;
图c为第0天至第28天生化指标:尿素氮、c反应蛋白、球蛋白。
具体实施方式
下面对本发明的具体实施方式进行详细描述,但应当理解本发明的保护范围并不受具体实施方式的限制。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的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。本发明各实施例中所述实验方法,如无特殊说明,均为常规方法,下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1
本实施例提供了TiO2-x@GL NPs及其制备方法和应用。
一、TiO2-x@GL NPs的制备方法
TiO2-x NPs是通过以往文献报道的铝(Al)还原法进行合成的。具体过程如下:
将二氧化钛样品和铝分别置于双区管式炉中,然后抽空至基压低于0.5Pa。随后,铝在800℃下加热融化后,与TiO2样品混合在300℃下加热6小时,生成500℃-Al-TiO2-x。在800℃的氩气中对500℃-Al-TiO2-x样品进行12h的退火处理,获得TiO2-x NPs。
为了提高TiO2-x NPs的肿瘤靶向能力,我们利用谷氨酰胺(Glu,简写为GL)对TiO2-xNPs的表面进行了修饰。将50mg GL加入TiO2-x NPs溶液(1mg/mL,10mL)中,然后在冰浴中进行4小时的超声处理(120W)。通过三次离心(10000r/min,10min)和去离子水洗涤得到TiO2-x@GL NPs(也可简写为TiO2-x@GL)。
二、TiO2-x@GL NPs的表征测定
1、透射电子显微镜(TEM)观察TEM图像
在Rigaku D/MAX-2200PX XRD系统上获得x射线衍射(XRD)图样,参数设置为Cu,Kα、40mA和40kV。
2、采用分段能量色散谱(EDS)技术对钛、氧、氮元素进行了测定,并进行了相应的色谱分析
3、粒径分布和ζ电位是在Zetasizer系统(Nano ZS90,马尔文仪器有限公司)上进行的测量。
4、采用Shimadzu UV-3600光谱仪记录紫外与近红外光的吸收光谱。
5、采用1064nm多模泵浦激光器(上海连接光纤有限公司)作为光热热疗的辐照源,采用智能传输超声系统(Chattanooga Group,美国)作为超声治疗的声源。
6、采用安捷伦725电感耦合等离子体光学发射光谱仪(安捷伦技术公司)对纳米颗粒的含量进行定量分析。
7、共聚焦激光扫描显微镜图像由FV1000(奥林巴斯公司,日本)记录。
8、通过流式细胞术(美国Becton,Dickinson公司)观察细胞对纳米材料的摄取和细胞凋亡情况。
三、TiO2-x@GL NPs在制备肿瘤治疗药物中的应用
1、细胞培养
4T1细胞购自ATCC:全球生物资源中心(#CRL-2539)。细胞在RPMI-1640培养基中培养,并添加10%的胎牛血清(FBS),在5%的CO2中培养,温度为37℃,每天更换细胞培养基,当细胞浓度达到60%时接受处理。
2、体外声动力学和光热处理
商业化CCK-8检测试剂盒用于评估超声和光热治疗杀死癌细胞的效率。2×104/ml4T1接种于96孔板中,用含有10%胎牛血清的RPMI-1640培养基培养12小时,然后加入TiO2-x@GL(Ti浓度50ppm)共孵育。通过与对照组的比较,测定各组的细胞活力。激光功率强度设置为1.5W/cm2,超声强度参数设为40kHz,功率持续时间为180s。
3、活性氧(ROS)检测
取培养的4T1细胞,在37℃下与TiO2-x@GL共孵育4小时,或超声处理5min。完成孵育后,移除培养基,用PBS洗涤细胞三次,随后加入DCFHDA,再孵育1小时。通过流式细胞术检测ROS的产生,收集细胞,检测DCF的细胞内荧光强度。
4、TiO2-x@GL NPs的体外光热效应的评价
采用红外热成像记录仪(FLIR TM A325SC相机)对TiO2-x@GL的光热效应进行了评价,通过记录在NIR-II生物通道(1064nm)中的激光照射过程中的温度变化。Ti2-x@GL分散在去离子水中,调整Ti浓度分别为0、6.25、12.5、25、50、100和300ppm,暴露在1064nm的激光辐射下,激光强度为1.5W/cm2。此外,TiO2-x@GL的温度升高在Ti浓度为400ppm时,用1064nm激光在不同功率强度(0、0.5、1.0和1.5W/cm2)进行测试。
5、细胞迁移能力评估
用无血清培养基重悬4T1细胞,然后将100mL细胞悬液以2×104/ml密度接种于跨孔板上室,然后将小室放入装有含血清培养基的孔中。继续培养12h后,弃去培养基,用4%多聚甲醛固定细胞,然后在室温下用0.1%结晶紫染色15min。擦除小室上侧面的细胞后,并在光镜下进行观察计数迁移的细胞。细胞计数取自上下左右四个不同的视野。
6、活细胞和死亡细胞的区分
活细胞和死亡细胞通过商业化的Ca-AM/PI检测试剂盒(#04511,Sigma-Aldich)进行区分。染成绿色的为活细胞,死亡的细胞被PI染成红色。染色后,用共聚焦激光扫描显微镜(CLSM)观察细胞。
7、荷瘤模型的建立与体内SDT/PTT协同肿瘤治疗
为建立荷瘤模型,4T1细胞(1×106细胞)悬浮于100μL PBS中,注射到小鼠右背部,最后在实验动物中心成功建立40只雌性4T1荷瘤小鼠。在肿瘤长到近50mm3后,将小鼠分为5组(n=8):(a)对照组(生理盐水处理),(b)TiO2-x@GL组,(c)TiO2-x@GL+激光组(注射TiO2-x@GL,然后用1064nm光源照射),(d)TiO2-x@GL+超声(用TiO2-x@GL处理+超声照射),和(e)TiO2-x@GL+激光+超声组(注射TiO2-x@GL,然后是激光和超声照射)。TiO2-x@GL的注射剂量为15mg/mL,注射4T1细胞成瘤的时间记录为-7天,0天接受治疗处理。静脉注射TiO2-x@GL后为4小时,1064nm激光器(1.5W/cm2,10min)和超声(1MHz,50%占空比,1.0W/cm2)用于后续治疗。进行协同治疗时,第0天给予激光+超声治疗,第3、第5天给予以下超声治疗。每2天分别用数字秤和卡尺测量肿瘤的体重和长度和宽度。肿瘤体积的计算方法如下:肿瘤体积(mm3)=ab2/2,a=最大长度(mm),b=最小宽度(mm)。
8、TiO2-x@GL在肿瘤组织中的分布
为验证TiO2-x@GL可以穿透屏障并在肿瘤组织中积累,我们测量了5只荷瘤小鼠肿瘤组织中TiO2-x和TiO2-x@GL的分布情况。4T1雌性荷瘤小鼠随机分为三组,静脉注射溶于生理盐水,TiO2-x和TiO2-x@GL,剂量为50ppm。注射4h后处死小鼠,解剖收集肿瘤组织。肿瘤组织称重后,匀浆,并溶解在王水中。然后采用电感耦合等离子体光学发射光谱仪(ICP-OES)测定肿瘤组织中Ti元素的含量,并根据每克组织的原始重量计算其分布。
9、不同处理后的病理变化、细胞凋亡和细胞增殖
采用苏木精-伊红(HE)染色、tunel实验和Ki67抗体分别检测细胞的病理变化、细胞凋亡和细胞增殖情况。HE染色根据之前的研究报道进行,根据制造商的说明,使用商业化检测试剂盒进行tunel染色。用Ki67抗体联合山羊抗兔二抗进行免疫组化染色,显示细胞增殖。
10、统计分析
数据以均数±标准差(SD)表示,两组间的差异采用双侧t检验进行检验(*,p<0.05;**,p<0.01;***,p<0.001)。
四、实验结果
1、TiO2-x NPs、TiO2-x@GL NPs的表征
采用透射电镜观察TiO2-xNPs和TiO2-x@GL NPs的形态,结果如图1的图a所示,TiO2-xNPs为均匀的球形结构,平均尺寸为50纳米。在加入GL后,所制备的TiO2-x@GL NPs的形貌与TiO2-x NPs比较没有明显的变化(图1的图b。从TiO2-x NPs和TiO2-x@GL NPs的高分辨率TEM成像结果(图1的图c和图d)和相应的SAED图像(图1的图e和图g)来看,GL的包被并没有改变TiO2-x NPs的晶体结构。DLS结果表明,GL包被使得TiO2-x NPs的水合粒径从122.4nm增加到164.2nm(图1的图g和图h)。
SEM图像(图2的图a和图b)和EDS结果(图2的图c、图2的图d和图S1)显示,与TiO2-xNPs组相比,TiO2-x@GL NPs组的氮(N)含量显著升高,表明GL成功装载到TiO2-x NPs表面。尽管GL封装前后ζ电位发生了变化(从-36.1变为-9.1mV)(图2的图e),但XRD测量中TiO2-x NPs和TiO2-x@GL NPs的晶体峰与TiO2-x NPs的标准晶体结构非常匹配(JCPDS No.21-1272),表明TiO2-x NPs的结构在GL的表面包封后保存良好(图2的图f)。此外,从TiO2-xNPs和TiO2-x@GLNPs的UV-Vis-NIR光学吸收曲线(图2的图g)以及光热加热曲线(图2的图g)来看,我们可以看到NIR吸波能力和光热性能没有受到影响,这些结果均显示TiO2-x NPs和TiO2-x@GL NPs可以通过PTT治疗肿瘤。
2、TiO2-x@GL NPs的体外声动力学和光热效应
ROS的产生可能受到许多因素的影响,如超声的功率、持续时间和声敏剂的浓度。首先,ROS的产生随着超声强度的增加而增加,因此,超声持续时间设置为180s,TiO2-x@GLNPs浓度为50ppm(图3a)。为了确定40khz超声对ROS生成的影响,我们测定了50ppm TiO2-x@GL NPs浓度下ROS的生成(图3b)。利用1.0W/cm2的超声照射实现TiO2-x@GL NPs中持续释放INS.如图3C所示,在1.0W/cm2超声处理180s条件下,随着纳米颗粒浓度的增加,ROS生成略有增加。相反,TiO2-x@GL NPs在高浓度(>100ppm)下抑制细胞生长(<75%)。根据之前和以上的结果,一个优化的程序(1.0W/cm2超声强度,180s,和50ppm的TiO2-x@GL NPs)来实现高水平的ROS生成。此外,对TiO2-x@GL NPs的光热性能在不同浓度(0、6.25、12.5、25、50、100和300ppm)和1.5W/cm2下进行进一步评价。研究发现,在300ppm的浓度时,温度可高达59.2℃,足以通过热量杀死癌细胞。与激光功率相关的光热效应(0、0.5、1.0和1.5W/cm2)也同样得到了证实(图3f)。
3、基于SDT/PTT的体外协同癌症治疗
在本研究方案中,4T1细胞分别用SDT和PTT处理(序贯处理)。具体而言,4T1癌细胞与TiO2-x@GL NPs一起孵育,并在超声和NIR-II激光照射下处理4小时。超声的参数设置为1MHz、50%空占比,1.0W/cm2,240s.NIR-II激光器的功率设置为1.5W/cm2。研究发现,TiO2-x@GL NPs浓度为300ppm时,温度迅速上升,最高达66℃,足以通过热疗杀死癌细胞(图4a),当激光关闭时,温度迅速下降。值得注意的是,在NIR-激光照射下,极高的温度产生了明显的消融和吸烟现象。在三次激光开/关周期中,TiO2-x@GL NPs的光热性能没有明显的退化,显示了TiO2-x用于光热热疗的高光热稳定性(图4b)。CCK-8实验是为了研究TiO2-x@GL NPs在1064nm激光、超声、以及激光+超声联合处理下体外杀伤4T1细胞效果。在SDT和PTT处理组中,TiO2-x@GL NPs与癌细胞孵育4h后,细胞存活率下降至19.2%(图4c)。此外,经过各种处理后,通过CLSM直接观察到细胞的杀伤作用,活细胞和死细胞分别用钙黄绿素-am(绿色)和PI(红色)染色。在TiO2-x@GL NPs联合超声和激光处理组中观察到大量的死亡细胞,表明SDT和PTT协同作用广泛发生细胞凋亡和死亡(图4d)。从区域间差异的平均贡献率来看,TiO2-x@GL NPs的贡献率很巨大,平均为44.95%。US和NIR的方差贡献率分别为23.33%和31.72%(图4e)。与以往研究的结果相同,TiO2能抑制肿瘤细胞的迁移。细胞迁移实验表明,TiO2-x@GL NPs和TiO2-x各组的活细胞数均明显低于对照组。这意味着TiO2-x@GL NPs同TiO2一样也可以抑制肿瘤细胞的迁移(图4f)。
4、体内验证SDT/PTT协同治疗癌症
协同治疗方案如图5a所示,成功建立荷瘤模型记录为-7天,注射TiO2-x@GL NPs(简写为TiO2-x@GL)4h后采用激光照射和超声治疗并记为第0天,随后在第3天和第5天继续给予超声照射,肿瘤组织中Ti元素浓度在注射TiO2-x或TiO2-x@GL组明显升高,且GL使得TiO2-x@GL的含量比TiO2-x积累量增加了近3倍(图5b)。在治疗期间,各组小鼠的体重均无明显变化(图5c)。TiO2-x@GL+激光+超声组中的肿瘤重量显著低于(P<0.01)TiO2-x@GL组,且在第15天时,同样显著低于(P<0.05)TiO2-x@GL+激光组或TiO2-x@GL+超声组(图5d),同时,TiO2-x@GL+laser+超声组中肿瘤体积没有增长(图5e),协同治疗有助于延长无死亡生存期(图5f)。HE染色显示TiO2-x@GL+激光+超声组有明显的病理改变,主要表现为肿瘤细胞肿胀,Tunel检测显示TiO2-x@GL+激光+超声组肿瘤细胞凋亡增加。Ki67抗体的定位显示肿瘤细胞增殖下调,所有证据显示,TiO2-x@GL+激光+超声能够在体内情况下抑制肿瘤。
5、TiO2-x@GL NPs的安全性评价
TiO2-x@GL NPs的安全性评价是通过重要器官的病理变化和关键的血液及生化参数来显示。HE染色显示心脏、肝、肾、肺均无明显变化,第1天,第7天和第28天的白细胞(WBC)、血小板(PLT)和血红蛋白(HGB)在不同组间也无明显变化。同时,尿素氮(BUN)、c反应蛋白(Cr)和球蛋白(GLB)等生化指标与对照组相比也没有变化。
尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例作出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
1.TiO2-x@GL NPs,其特征在于,由如下步骤制备获得:
S1,TiO2-x NPs的制备:以二氧化钛和铝为原料,利用铝还原法合成TiO2-xNPs;
S2,TiO2-x@GL NPs制备:利用谷氨酰胺对TiO2-x NPs的表面进行修饰获得TiO2-x@GLNPs。
2.根据权利要求1所述的TiO2-x@GL NPs,其特征在于,S1中,铝还原法具体过程为:铝在700-800℃下加热融化,与TiO2样品混合后在300-500℃下加热还原6-10h,获得500℃-Al-TiO2-x,然后在800-900℃的氩气中对500℃-Al-TiO2-x退火10-12h,获得了TiO2-x NPs。
3.根据权利要求2所述的TiO2-x@GL NPs,其特征在于,S2中,谷氨酰胺对TiO2-x NPs的表面修饰具体为:将40-50mg谷氨酰胺加入8-10mL质量浓度为1-1.5mg/mL的TiO2-x NPs溶液中,然后在冰浴中120W超声处理3-5小时,10000r/min,10min离心三次,去离子水洗涤得到TiO2-x@GL NPs。
4.根据权利要求3所述的TiO2-x@GL NPs,其特征在于,S2中,谷氨酰胺对TiO2-x NPs的表面修饰具体为:将50mg谷氨酰胺加入10mL质量浓度为1mg/mL的TiO2-x NPs溶液中,然后在冰浴中120W超声处理4小时,10000r/min,10min离心三次,去离子水洗涤得到TiO2-x@GLNPs。
5.根据权利要求4所述的TiO2-x@GL NPs,其特征在于,所述TiO2-x@GL NPs的水合粒径为164.2nm。
6.权利要求1-5任一项所述的TiO2-x@GL NPs在制备治疗肿瘤药物中的应用。
7.根据权利要求5所述应用,其特征在于,所述TiO2-x@GL NPs能够用于制备肿瘤细胞迁移的抑制剂。
8.根据权利要求5所述应用,其特征在于,所述TiO2-x@GL NPs能够用于制备肿瘤细胞增殖的抑制剂。
9.根据权利要求5所述应用,其特征在于,所述TiO2-x@GL NPs能够用于制备激光和超声抑制肿瘤的协同剂。
10.根据权利要求5所述应用,其特征在于,所述TiO2-x@GL NPs在300ppm浓度下的光热性能能够杀死癌细胞。
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