CN115154603A - 一种锰基MXenes二维纳米材料及其制备方法与应用 - Google Patents
一种锰基MXenes二维纳米材料及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种锰基MXenes二维纳米材料及其制备方法与应用,本发明通过化学刻蚀法、超声剥离和表面修饰的方法制备Mn‑Ti3C2Tx‑PEG,并通过表征证实Ti3C2Tx表面负载了Mn2+、MnO2、Mn纳米粒子,并且该纳米材料呈现出典型的片状结构。本发明公开的锰基MXenes二维纳米材料经过溶液测试、细胞实验、动物实验结果表明,其具备良好的磁共振T1成像性能、光热性能、生物相容性及CDT效应,能实现MRI引导下肿瘤的光热及化学动力学协同治疗。
Description
技术领域
本发明属于纳米材料合成技术领域,具体涉及到一种锰基MXenes二维纳米材料及其制备方法与应用。
背景技术
诊断方面,纳米材料可以整合一种或多种成像模式,常见的模式包括:超声成像、计算机X线断层扫描成像、磁共振成像(magnetic resonance imaging,MRI)等。其中MRI具有良好的软组织成像对比度、高空间分辨率、多方位成像、无创性、无电离辐射以及无穿透深度限制等优势,越来越多地用于肿瘤的早期监测。目前MRI最常用的对比剂为钆螯合对比剂,该类对比剂主要通过缩短纵向弛豫时间实现T1WI增强效应。该类对比剂的主要缺点是钆可能在晚期肾病患者中造成肾源性系统纤维化,并且可以在多个部位沉积,特别是脑沉积。目前尚不明确钆沉积是否会对人体的健康造成影响。为了避免钆沉积对人体的潜在风险,研究者们已开始寻找钆的替代品。
锰基对比剂具有高顺磁性、低毒性及高生物安全性的特点,被认为是钆对比剂良好的替代品。锰是一种非镧系金属,是存在于人体内的微量元素,具有重要的生理及生化功能,锰也是最早报道的用于T1WI增强的MRI对比剂。目前,锰福地匹三钠(manganesedipyridoxyl diphosphate,Mn-DPDP)已应用于临床,该对比剂是肝细胞特异性的并且具备良好的MRI成像性能。Mn-DPDP是FDA唯一批准的锰基对比剂,锰基对比剂的种类及临床使用量远低于钆对比剂,亟待进一步开发。
制备新的锰基对比剂需要解决Mn2+的毒性问题。虽然锰本身存在于人体内,但过量游离Mn2+仍会沉积于大脑导致神经系统功能紊乱,称为锰中毒,表现为类似帕金森病的症状。制备稳定的锰基纳米MRI对比剂是降低锰毒性的有效方法之一,Mn2+通常以较为稳固的形式存在于纳米颗粒中,因此,可以减少游离Mn2+的生成,从而降低Mn2+的毒性。此外,锰基纳米对比剂还具备以下优势:较大的比表面积、良好的生物安全性、特殊的反应性表面等。这种可修饰的反应性表面允许其结合靶向生物分子(如抗体、叶酸、生长因子等)及其他成像或治疗的功能组件,从而实现多功能诊疗一体化。
目前,手术、放疗和化疗是癌症治疗的三大手段,在临床上有着不可替代的作用。上述治疗方式可以使癌症患者获益,但其对正常组织、器官结构造成的损伤亦较大,并且存在一定局限性,比如,外科手术后仍可能出现复发或术后转移,化疗可能因耐药性的出现使有效性降低。随着纳米医学技术的快速发展,出现了许多新型的癌症治疗方法,如光热疗法、化学动力学疗法等,这些癌症疗法具有副作用小、高效率、可调控的特点,在癌症治疗领域展现出良好的应用前景。
光热治疗(photothermal therapy,PTT)是一种新兴的基于光敏剂的癌症治疗策略,通过向体内引入光敏剂并在近红外光照射下将光能高效地转换成热能,从而实现特定区域的肿瘤光热消融。PTT的优势表现在高选择性、时空可控性、非侵入性和低副作用等方面。此外,PTT还具有刺激药物释放、改善药物递送、调节肿瘤微环境(tumormicroenvironment,TME)的作用,为与其他协同疗法的结合创造了良好的条件。目前,PTT的光敏剂开发主要集中在:2D纳米材料(如石墨烯及其衍生物、MXenes等)、金属材料(如金属纳米颗粒、过渡金属氧化物等)和有机材料(如聚苯胺、聚吡咯和聚噻吩等)。
化学动力学疗法(chemodynamic therapy,CDT)是一种新兴的基于金属催化作用的肿瘤治疗策略。它主要通过金属离子(如:Fe2+、Mn2+、Cu2+等)介导的TME内原位芬顿或类芬顿反应,将癌细胞内过表达的过氧化氢转换为氧化能力更强的羟基自由基(·OH),通过蛋白质、DNA和脂质损伤诱导肿瘤细胞死亡。CDT是内源性启动的,因此CDT具有高度选择性并且在反应活化中不需要添加外源刺激。此外,CDT还具有许多独特优势,例如肿瘤特异性高、全身毒性低以及不受组织穿透深度的限制。尽管其潜力巨大,但单独使用CDT仍受到一些问题的限制,如微酸性TME中芬顿和类芬顿反应的催化效率低、TME中谷胱甘肽过度表达降低CDT效率。众所周知,温度是影响化学反应速率的重要因素,升温可以加快芬顿或类芬顿反应的反应速率,因此提高肿瘤区域的温度是提高TME芬顿或类芬顿反应效率的有效策略,由于该策略具备实用性且较为简单,因此被广泛采用。值得一提的是,PTT不仅直接对肿瘤细胞造成损伤,还可以加速·OH等活性氧的形成,从而提高CDT的疗效,提供更有效的癌症治疗。因此,PTT与CDT的合理组合有利于克服单一治疗方式的不足,提高协同治疗的效率。
二维层状过渡金属碳化物和氮化物纳米片(MXenes)材料具有高比表面积、良好的导电性和亲水性,在储能、催化、压敏、柔性器件及功能增强复合材料等方面有广阔的应用前景。
如何制备一种新型的二维纳米材料,实现MRI引导的肿瘤光热及化学动力学协同治疗是研究人员需要解决的问题。
发明内容
本发明的目的是提供一种锰基MXenes二维纳米材料及其制备方法与应用,可以成功制备一种新的二维纳米材料,并将其应用于MRI引导的肿瘤光热及化学动力学协同治疗的技术中。
为达上述目的,本发明提供了一种锰基MXenes二维纳米材料的制备方法,包括以下步骤:
(1)多层Ti3C2Tx的合成
将LiF溶解于酸溶液中,然后加入Ti3AlC2,恒温反应后分离出沉淀并清洗至中性,再冷冻干燥,制得多层Ti3C2Tx;
(2)少层Ti3C2Tx的合成
将多层Ti3C2Tx按1g:180-220mL的料液比分散于水中,于惰性气体环境中超声粉碎后再离心,收集上清液,冷冻干燥后,制得少层Ti3C2Tx;
(3)Mn-Ti3C2Tx-PEG的合成
将少层Ti3C2Tx和MnCl2分别分散于水中,并在搅拌条件下将两种分散液混合,然后离心,取沉淀物洗涤干燥,制得Mn-Ti3C2Tx;
将Mn-Ti3C2Tx与聚乙二醇分散于去离子水中,经超声-搅拌-离心后,取沉淀物冷冻干燥后制得。
进一步地,酸溶液为浓度为8-10M的盐酸溶液,LiF溶解于酸溶液后的浓度为0.04-0.06g/mL。
进一步地,LiF与Ti3AlC2的质量比为1:1,Ti3AlC2分8-10批加入。
进一步地,步骤(1)中恒温反应的温度为12-18℃,恒温反应时间为20-30h。
进一步地,步骤(1)中离心包括:将反应液经3500-4500rpm离心8-12min后,除去上清液,继续添加反应液两倍体积量的去离子水,再次超声分散并离心;重复上述过程多次,直至上清液pH值为中性。
进一步地,步骤(3)中少层Ti3C2Tx的分散溶液与MnCl2的分散溶液的体积比为1:1,少层Ti3C2Tx的分散溶液的浓度为2.2-2.8mg/mL,MnCl2的分散溶液的浓度为1.8-2.2mg/mL,分散溶液混合搅拌的时间为3.5-4.5h,分散溶液离心的转速为7500-8500rpm,离心的时间为25-35min。
进一步地,步骤(3)中Mn-Ti3C2Tx与聚乙二醇的质量比为2.5-3.5:5,超声-搅拌-离心包括:超声8-12min后,于室温下搅拌2.5-3.5h,再以9900-11000rpm离心10-15min。
本发明还公开了一种采用上述锰基MXenes二维纳米材料的制备方法制备得到的锰基MXenes二维纳米材料。
采用上述方案的有益效果是:其中Ti3C2Tx具有光热转换及负载Mn的作用,Mn用于MRI-T1成像并且催化TME内类芬顿反应实现CDT,聚乙二醇(polyethylene glycol,PEG)用于提高该纳米材料的生物相容性及分散性。
本发明还提供了一种上述锰基MXenes二维纳米材料在制备MRI引导的肿瘤光热及化学动力学协同治疗药剂中的应用。
综上,本发明具有以下优点:
1、本发明通过化学刻蚀、超声剥离和表面修饰的方法,实现了锰基MXenes二维纳米材料的合成,通过XPS、SEM以及TEM等多个表征方法证实了Mn负载于Ti3C2Tx表面。体外MR成像表明Mn-Ti3C2Tx-PEG具有良好的MR成像能力,并且成像效果与浓度呈正相关。体外光热性能分析表明Mn-Ti3C2Tx-PEG具有较好的光热性能和光热循环稳定性,并且温度升高的程度与浓度呈正相关。
2、本发明制备的锰基MXenes二维纳米材料,对正常细胞无明显毒性,对4T1细胞具有选择性杀伤作用。4T1细胞与Mn-Ti3C2Tx-PEG共孵育后装载DCFH-DA荧光探针检测·OH的生成,结果表明Mn-Ti3C2Tx-PEG能诱导4T1细胞产生·OH,从而实现CDT。即本发明制备的锰基MXenes二维纳米材料对癌细胞具有选择性,能通过类芬顿反应诱导4T1细胞产生·OH,从而实现CDT效应。
3、本发明制备的锰基MXenes二维纳米材料在体内具有良好的MRI成像能力及肿瘤光热消融能力。
附图说明
图1为实施例1制备的锰基MXenes二维纳米材料的XPS图谱;
图2为实施例1制备的锰基MXenes二维纳米材料的形貌图;
图3为不同浓度的Mn-Ti3C2Tx-PEG的MRI-T1WI、T1map图像及对应的T1信号强度及r1弛豫率;
图4为不同浓度Mn-Ti3C2Tx-PEG的PBS溶液经激光照射不同时间点的红外热像图及加热曲线;
图5为浓度为0.125mg/mL的Mn-Ti3C2Tx-PEG溶液经过5次加热-冷却循环后的加热曲线;
图6为MCF-10A和4T1细胞与不同浓度Mn-Ti3C2Tx-PEG共孵育24h后的细胞存活率;
图7为DCFH-DA荧光探针检测不同浓度Mn-Ti3C2Tx-PEG与4T1细胞共孵育后产生·OH的倒置荧光显微镜图像,比例尺为50μm;
图8为4T1荷瘤裸鼠尾静脉注射Mn-Ti3C2Tx-PEG前后的T1WI图像及相应T1信号强度,红色箭头表示肿瘤所在部位;
图9为4T1荷瘤裸鼠尾静脉注射Mn-Ti3C2Tx-PEG前后肝脏区域的T1WI图像及相应T1信号强度,红色箭头表示肝左叶所在部位;
图10为4T1荷瘤裸鼠尾静脉注射Mn-Ti3C2Tx-PEG前后左肾区域的T1WI图像及相应T1信号强度,红色箭头表示左肾所在部位;
图11为不同处理组荷瘤裸鼠肿瘤区域的红外热像图,红色圆圈表示肿瘤所在部位;
图12为不同处理组荷瘤裸鼠肿瘤区域的加热曲线;
图13为不同处理组荷瘤裸鼠治疗后15天内肿瘤区域的数码图片;
图14为不同处理组荷瘤裸鼠治疗后15天内肿瘤相对体积;
图15为不同处理组荷瘤裸鼠治疗后15天内的体重变化。
具体实施方式
本发明使用HF进行刻蚀,HCl和LiF之间的反应原位生成HF,以Ti3AlC2为主要原料,通过直接化学刻蚀的方法将大块Ti3AlC2陶瓷中铝层刻蚀掉,同时将其转变为纳米级MXene,得到多层Ti3C2材料,MXenes的表面引入大量亲水和活性基团,如氟(F)、羟基(OH)和氧(O),这使MXenes具有亲水性和易被表面功能化的特点。然后,在高功率超声作用下,多层MXene被剥离成少层的Ti3C2。含有大量-O,-F使得Ti3C2呈负电性,也较容易通过表面修饰的方法将Mn负载到Ti3C2上。
以下结合实施例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1
本实施例提供了一种锰基MXenes二维纳米材料的制备方法,包括以下步骤:
(1)多层Ti3C2Tx的合成
将1g LiF(98.5%)溶解到20mL 9M HCl溶液中,搅拌0.5h后,将1g Ti3AlC2分10批次加入到上述溶液中,在15℃水浴中搅拌24h。反应结束,将反应液转移到50mL的离心管中,4000rpm离心10min,将上清液除去分离。然后向离心管中加入40mL去离子水,超声分散,再次离心,此操作进行多次,检测离心上清液pH接近7后,对离心沉淀进行冷冻干燥处理得到多层Ti3C2Tx。
(2)少层Ti3C2Tx的合成
将1g多层Ti3C2Tx加入到200mL去离子水中,在氩气流下用细胞粉碎机(400W)超声0.5h。然后,分散溶液在4000rpm下离心0.5h。收集墨绿色上清液,得到少层Ti3C2Tx悬浮液,悬浮液经冻干后得到黑色粉末,即为少层Ti3C2Tx。
(3)Mn-Ti3C2Tx的合成
缓慢混合MnCl2(50mL,2mg/mL)和负性少层Ti3C2Tx纳米片(50mL,2.5mg/mL)两种分散溶液,将混合溶液超声10min并用磁力搅拌器在室温下搅拌4h。接着,上述溶液在8000rpm下离心0.5h,得到Mn-Ti3C2Tx沉淀物,在去离子水和乙醇中洗涤3次。沉淀物在真空干燥箱中干燥,即为Mn-Ti3C2Tx。
(4)Mn-Ti3C2Tx-PEG的合成
将Mn-Ti3C2Tx(30mg)分散于60mL去离子水中,然后加入PEG(50mg)。混合溶液超声10min,室温下在磁力搅拌器上搅拌3h。溶液以10000rpm离心0.2h,得到Mn-Ti3C2Tx-PEG沉淀物,除去上清液,沉淀物冷冻干燥后制得。
实施例2
本实施例提供了一种锰基MXenes二维纳米材料的制备方法,包括以下步骤:
(1)多层Ti3C2Tx的合成
将1g LiF(98.5%)溶解到20mL 9M HCl溶液中,搅拌0.5h后,将1g Ti3AlC2分8批次加入到上述溶液中,在17℃水浴中搅拌24h。反应结束,将反应液转移到50mL的离心管中,4000rpm离心10min,将上清液除去分离。然后向离心管中加入40mL去离子水,超声分散,再次离心,此操作进行多次,检测离心上清液pH接近7后,对离心沉淀进行冷冻干燥处理得到多层Ti3C2Tx。
(2)少层Ti3C2Tx的合成
将1g多层Ti3C2Tx加入到200mL去离子水中,在氩气流下用细胞粉碎机(400W)超声0.5h。然后,分散溶液在4000rpm下离心0.5h。收集墨绿色上清液,得到少层Ti3C2Tx悬浮液,悬浮液经冻干后得到黑色粉末,即为少层Ti3C2Tx。
(3)Mn-Ti3C2Tx的合成
缓慢混合MnCl2(50mL,2mg/mL)和负性少层Ti3C2Tx纳米片(50mL,2.5mg/mL)两种分散溶液,将混合溶液超声10min并用磁力搅拌器在室温下搅拌4h。接着,上述溶液在8500rpm下离心0.4h,得到Mn-Ti3C2Tx沉淀物,在去离子水和乙醇中洗涤3次。沉淀物在真空干燥箱中干燥,即为Mn-Ti3C2Tx。
(4)Mn-Ti3C2Tx-PEG的合成
将Mn-Ti3C2Tx(35mg)分散于60mL去离子水中,然后加入PEG(50mg)。混合溶液超声10min,室温下在磁力搅拌器上搅拌3h。溶液以10000rpm离心0.2h,得到Mn-Ti3C2Tx-PEG沉淀物,除去上清液,沉淀物冷冻干燥后制得。
实施例3
本实施例提供了一种锰基MXenes二维纳米材料的制备方法,包括以下步骤:
(1)多层Ti3C2Tx的合成
将1g LiF(98.5%)溶解到20mL 10M HCl溶液中,搅拌0.5h后,将1g Ti3AlC2分10批次加入到上述溶液中,在15℃水浴中搅拌24h。反应结束,将反应液转移到50mL的离心管中,4000rpm离心10min,将上清液除去分离。然后向离心管中加入40mL去离子水,超声分散,再次离心,此操作进行多次,检测离心上清液pH接近7后,对离心沉淀进行冷冻干燥处理得到多层Ti3C2Tx。
(2)少层Ti3C2Tx的合成
将1g多层Ti3C2Tx加入到200mL去离子水中,在氩气流下用细胞粉碎机(400W)超声0.5h。然后,分散溶液在4000rpm下离心0.5h。收集墨绿色上清液,得到少层Ti3C2Tx悬浮液,悬浮液经冻干后得到黑色粉末,即为少层Ti3C2Tx。
(3)Mn-Ti3C2Tx的合成
缓慢混合MnCl2(50mL,2.1mg/mL)和负性少层Ti3C2Tx纳米片(50mL,2.5mg/mL)两种分散溶液,将混合溶液超声10min并用磁力搅拌器在室温下搅拌4h。接着,上述溶液在8000rpm下离心0.5h,得到Mn-Ti3C2Tx沉淀物,在去离子水和乙醇中洗涤3次。沉淀物在真空干燥箱中干燥,即为Mn-Ti3C2Tx。
(4)Mn-Ti3C2Tx-PEG的合成
将Mn-Ti3C2Tx(28mg)分散于60mL去离子水中,然后加入PEG(50mg)。混合溶液超声10min,室温下在磁力搅拌器上搅拌3h。溶液以10000rpm离心0.2h,得到Mn-Ti3C2Tx-PEG沉淀物,除去上清液,沉淀物冷冻干燥后制得。
试验例1---用XPS分析Ti3C2Tx和Mn-Ti3C2Tx复合材料的表面化学成分和元素化学价态
以实施例1中制备的Ti3C2Tx和Mn-Ti3C2Tx复合材料为例,如图1(A)所示,在XPS测量谱中,Ti3C2Tx存在着C、Ti、O、F元素,相较于Ti3C2Tx,Mn-Ti3C2Tx的XPS测量谱中不仅发现了C、Ti、O、F元素,而且Mn元素也包含其中。以Ti峰值强度为对比,在Mn与Ti3C2Tx结合之后,Mn-Ti3C2Tx中O峰值的强度降低,而F峰值的强度相对增加,但F类化合物数量大量减少,这是由于部分Mn被F或O氧化形成Mn4+,从而形成-O-Mn-O-,形成的部分MnO2纳米片层在Ti3C2Tx表面掩盖了Ti3C2Tx表面O的信号。
从图1(B)可以看出,Mn-Ti3C2Tx的C1s谱中的结合能表现为三个组成峰:C-Ti(281.7eV)、C-C(284.6eV)、C-O(286.4eV),属于Ti3C2Tx中碳原子中1s轨道电子被激发所测光电子能量。
在图1(C)中,Mn-Ti3C2Tx的Ti 2p峰可以被拟合为5个组成峰:455.4eV属于Ti-C、459.2eV属于Ti-O(2p 3/2)、461.7eV属于Ti-F和464.7eV属于Ti-O(2p1/2)。
O 1s的XPS光谱如图1(D)所示,在纯Ti3C2Tx和Mn-Ti3C2Tx中发现3条子带,其中一条531.1eV属于Mn-O,另两个峰529.7和532.4eV分别对应于Ti-O和O-H。
图1(E)显示Mn-Ti3C2Tx的XPS高分辨谱中的Mn 2p,将Mn接合到Ti3C2Tx上后,Mn没有Mn 3s峰,在Mn-Ti3C2Tx中检测到分峰分别为Mn 2p 3/2和Mn2p 1/2。在641.6eV和653.5eV处有两个峰分别属于Mn 2p 3/2和Mn 2p 1/2,两个峰的能级差为2.9ev,所以Mn在Ti3C2Tx表面可以被认为是以Mn2+和Mn4+存在。
综上,XPS测试结果表明,Mn成功结合到Ti3C2Tx中。
试验例2---利用SEM和TEM研究Mn-Ti3C2Tx纳米材料的形貌
如图2(A),通过SEM观察到Mn-Ti3C2Tx呈现出卷曲的片状结构。200nm(图2B)和50nm(图2C)的两种标尺TEM图片结果显示,Mn-Ti3C2Tx呈现出两种特征形貌,即大片状Ti3C2Tx和MnO2纳米颗粒聚集。这一结果表明,Mn在Ti3C2Tx纳米薄片上进行了紧密的重组。Mn-Ti3C2Tx复合纳米材料的形成也通过元素映射分析得到验证(图2D)。根据Mn在Ti3C2Tx纳米片表面上的位置可以看出Mn的信号分布良好。此外,透射电镜能谱结果验证了含Mn元素在复合纳米材料中的组成(图2E)。
试验例3---Mn-Ti3C2Tx-PEG的体外MRI成像性能
为了评估Mn-Ti3C2Tx-PEG作为MR-T1WI阳性对比剂的成像性能,配置不同浓度的Mn-Ti3C2Tx-PEG溶液,使用Prisma 3.0T MR来进行扫描。Mn与Gd类似,均为T1阳性对比剂,主要通过缩短纵向弛豫时间来增强T1WI信号。选择T1WI序列进行成像,可以更加直观地观察信号随浓度的增大而增强,选择T1map序列进行成像,主要为了更准确地量化Mn-Ti3C2Tx-PEG缩短T1的能力,即纵向弛豫率,一般用r1表示,受温度、MR场强的影响。
如图3(A),随着Mn-Ti3C2Tx-PEG溶液中Mn含量的增加,MR-T1成像效果明显增强,表现为T1WI图像由暗变明,T1信号强度逐渐增加,T1map图像由红变蓝,T1值逐渐缩小。
图3(B)为不同浓度Mn-Ti3C2Tx-PEG纳米材料在同一幅T1WI图像上测量的T1信号强度,可以发现随Mn-Ti3C2Tx-PEG浓度增加,T1信号强度值随之增加。
如图3(C),通过计算T1值的倒数及对应的材料浓度作线性拟合获得的拟合曲线的斜,得到纵向弛豫率r1=1.05mM-1S-1。
综上,Mn-Ti3C2Tx-PEG具备良好的MR-T1成像能力。
试验例4---Mn-Ti3C2Tx-PEG的体外光热性能
光热转换性能及光热循环稳定性是PTT试剂的两个重要参数,为了评估Mn-Ti3C2Tx-PEG的光热转换性能,使用功率为1.5W/cm2、波长为808nm的近红外激光对Mn-Ti3C2Tx-PEG进行照射并利用红外热像仪监测升温情况。升温情况主要通过观察不同时间点(0、0.5、1、2、3、4、5min)的不同Mn-Ti3C2Tx-PEG浓度(0.0075、0.015、0.031、0.062、0.125、0.25及0.5mg/mL)PBS溶液的温度变化。
如图4(A)所示,随着时间的延长及材料浓度的上升,红外热像图逐渐由暗变明,表明温度逐渐升高。其中,在808nm激光照射5min后,在最大浓度为0.5mg/mL的条件下,温度从25.4℃上升至最高的85.6℃,而单纯PBS对照组通过5min的激光照射后,未观察到明显的温度变化。
如4(B)所示,红外热像仪每间隔10s获得一次温度数据,通过整理后得到加热曲线,从中可以看出,Mn-Ti3C2Tx-PEG材料的升温呈现出较好的时间依赖性及浓度依赖性。
本试验例中0.5mg/mL的Mn-Ti3C2Tx-PEG溶液在1.5W/cm2的808nm激光下照射5分钟,温度升至85.6℃,经历5次加热-冷却循环后,其升温性能未见明显的变化。从光热循环稳定性的加热曲线可以发现,循环次数越多,温度上升越高,这可能是由于水分蒸发导致浓度相对增大所致。以上结果表明,Mn-Ti3C2Tx-PEG具备高效的光热转换能力。
试验例5---Mn-Ti3C2Tx-PEG的体外光热循环稳定性分析
为了评估Mn-Ti3C2Tx-PEG的光热循环稳定性,配置了浓度为0.125mg/mL的Mn-Ti3C2Tx-PEG溶液分别在激光功率为1W/cm2和1.5W/cm2的808nm近红外激光条件下进行照射,通过5次加热-冷却循环来进行评估。如图5所示,Mn-Ti3C2Tx-PEG在经历5次加热-冷却循环后,其升温性能未见明显的变化。结果表明,Mn-Ti3C2Tx-PEG具备高效的光热循环稳定性。
综合试验例1-5,XPS分析表明,Mn-Ti3C2Tx复合材料中存在Mn峰,并与Ti3C2Tx的XPS谱图形成差异性对比。同样地,SEM和TEM分析表明,Mn成功负载在Ti3C2Tx纳米片表面,Ti3C2Tx表面形成大量Mn及其氧化物聚集体。通过透射电镜中元素映射分析及透射电镜能谱等多项表征检测表明本研究成功制备了二维多功能纳米诊疗剂Mn-Ti3C2Tx。通常情况下,虽然MXenes表面基团赋予其亲水性,但分层超薄MXenes纳米颗粒在复杂的生理条件下仍然不稳定,并且缺乏多功能化。表面功能化不仅能提升生物相容性、靶向性、而且避免了纳米颗粒在生物介质中快速聚集和沉淀。聚乙烯吡咯烷酮、聚乙二醇、大豆磷脂等聚合物分子可以通过非共价相互作用或静电吸引吸附在MXenes表面,本研究使用mPEG对Mn-Ti3C2Tx表面进行修饰,进一步提高其生物相容性、分散性及稳定性。
即本发明通过化学刻蚀、超声剥离和表面修饰的方法,实现了锰基MXenes二维纳米材料的合成,通过XPS、SEM以及TEM等多个表征方法证实了Mn负载于Ti3C2Tx表面。体外MR成像表明Mn-Ti3C2Tx-PEG具有良好的MR成像能力,并且成像效果与浓度呈正相关。体外光热性能分析表明Mn-Ti3C2Tx-PEG具有较好的光热性能和光热循环稳定性,并且温度升高的程度与浓度呈正相关。
试验例6---锰基MXenes二维纳米材料的细胞实验
本试验中所用小鼠乳腺癌4T1细胞和人正常乳腺上皮MCF-10A细胞均来自于西南医科大学附属医院临床医学研究中心赠送。
1、配置培养基
4T1细胞完全培养基配置:45mL 1640单纯培养基+5mL胎牛血清+0.5mL青霉素-链霉素溶液;
MCF-10A细胞完全培养基配置:45mL DMEM单纯培养基+5mL胎牛血清+0.5mL青霉素-链霉素溶液。提前使用50mL离心管配置好上述完全培养基后放置于4℃冰箱备用,封口胶密封。
2、细胞毒性实验(CCK-8法)
从液氮罐中取出赠送的4T1细胞和MCF-10A细胞冻存管放入程序降温盒,将细胞冻存管快速转移至37℃恒温水浴锅中快速升温,待冻存液融化后离心,经过细胞复苏、细胞传代等常规工作后,备用。
2.1、药物浓度配置
称取足量的Mn-Ti3C2Tx-PEG粉末,加入1640或DMEM完全培养基配置成0.5mg/mL的母液,超声30min,使纳米材料分散均匀。再逐级稀释,配置成6个浓度梯度:0.5、0.25、0.125、0.062、0.031、0.015mg/mL。每次稀释前均用滴管吹打混匀。
2.2、药物处理细胞
①取出孵育24h的96孔板,吸去旧培养基,向每个实验孔中加入100μL不同浓度Mn-Ti3C2Tx-PEG溶液,对照孔及调零孔中只加入100μL1640或DMEM完全培养基,将96孔板放入孵箱继续孵育24h。
②孵育24h后再次取出96孔板,吸去含纳米材料的旧培养基,用PBS缓冲液洗涤3次,实验孔、对照孔以及调零孔均加入之前配置好的100μL CCK-8稀释液,放回孵箱继续孵育1h。操作过程注意避光。
③1h后取出96孔板,将96孔板放入酶标仪,测量每个孔450nm处的吸光度OD值。
2.3、细胞存活率计算
每组的5个复孔在去除最高和最低OD值后计算平均值,细胞存活率计算公式如公式1。
细胞存活率=(OD实验组-OD调零组)/(OD对照组-OD调零组) 公式1
2.4实验结果
为了评估Mn-Ti3C2Tx-PEG的细胞毒性,选取了2种细胞:小鼠乳腺癌细胞(4T1)及正常乳腺上皮细胞(MCF-10A),将上述细胞与Mn-Ti3C2Tx-PEG共孵育24h后,采用CCK-8进行毒性分析。如图6所示,在0-0.5mg/mL的浓度范围内Mn-Ti3C2Tx-PEG与MCF-10A细胞共孵育24h后,细胞存活率均大于80%。不同的是,使用0-0.5mg/mL浓度的Mn-Ti3C2Tx-PEG处理4T1细胞24h,细胞存活率随处理浓度增加逐渐降低,在0.5mg/mL浓度下,细胞存活率为61%,以上结果表明Mn-Ti3C2Tx-PEG对正常细胞无明显毒性,在较高浓度下,对4T1细胞具有杀伤作用。
3、癌细胞内·OH生成检测
3.1活性氧荧光探针DCFH-DA的配置
2′,7′-二氯二氢荧光素二乙酸酯探针为-20℃保存,将其解冻、分装后使用,避免多次冻融。配置适量的含DCFH-DA的1640单纯培养基(DCFH-DA:1640单纯培养基=1:1000),用锡箔纸避光保存备用,遵循现配现用原则。
3.2细胞点板
将对数期的4T1细胞经过清洗、消化、离心后加入1mL1640完全培养基重悬,混匀后取少许细胞悬液接种于24孔板中,共设置2个实验孔及1个对照孔,每孔补充1640完全培养基至0.5mL,摇晃震荡24孔板使细胞分布均匀,将24孔板放入细胞孵箱孵育24h,使细胞贴壁生长。
3.3药物浓度配置
称取足量的Mn-Ti3C2Tx-PEG粉末,加入1640完全培养基配置成0.5mg/mL的母液,超声30min,使纳米材料分散均匀。再逐级稀释,配置成2个浓度梯度:0.5mg/mL、0.25mg/mL。稀释前均用滴管吹打混匀。
3.4药物处理细胞
取出孵育24h的24孔板,吸去旧培养基,向每个实验孔中加入0.5mL不同浓度Mn-Ti3C2Tx-PEG溶液,对照孔中只加入0.5mL 1640完全培养基,将24孔板放入孵箱继续孵育4h。孵育4h后再次取出24孔板,吸去含纳米材料的旧培养基,用PBS缓冲液洗涤3次。
3.5DCFH-DA探针装载
①实验孔、对照孔均加入之前配置好的0.5mL含DCFH-DA的1640单纯培养基,放回孵箱继续孵育30min。操作过程注意避光。
②取出孵育30min的24孔板,吸出含DCFH-DA的1640单纯培养基,用PBS缓冲液反复冲洗、震荡3次以去除未进入细胞内的DCFH-DA,最后加入PBS缓冲液维持细胞状态。操作过程注意避光。
3.6倒置荧光显微镜成像
将装载好探针的24孔板放在倒置荧光显微镜下进行观察,用蓝色通道进行激发。显微镜放大倍数设置为200倍,曝光时间设置为100ms。操作过程注意避光。
3.7实验结果
为了评估Mn-Ti3C2Tx-PEG的CDT效应,配置了不同浓度的Mn-Ti3C2Tx-PEG处理4T1细胞,使用商业化的细胞内活性氧检测试剂DCFH-DA荧光探针检测4T1细胞内产生的·OH,绿色荧光强度与细胞内·OH的含量呈正比,荧光强度通过倒置荧光显微镜进行观察。如图7所示,在处理浓度为0.25mg/mL条件下,部分细胞产生了绿色荧光,在0.5mg/mL条件下,基本所有细胞均产生了较强的绿色荧光,而PBS对照组呈现出可以忽略的少量绿色荧光。以上结果充分说明,Mn-Ti3C2Tx-PEG可以诱导癌细胞产生·OH,从而对癌细胞自身产生杀伤作用。因此,Mn-Ti3C2Tx-PEG具备良好的CDT效应。
综上,本发明采用CCK-8法检测Mn-Ti3C2Tx-PEG对4T1细胞及MCF-10A细胞的毒性,使用不同浓度Mn-Ti3C2Tx-PEG处理2种细胞,24h后MCF-10A细胞的细胞存活率均>80%,而4T1细胞的细胞存活率随处理浓度增大而减少。根据实验设计,推测出现这种差异的原因可能是4T1细胞内的过氧化氢明显高于MCF-10A,Mn-Ti3C2Tx-PEG中的Mn介导原位类芬顿反应将癌细胞内的过氧化氢转化成活性更强的·OH,对4T1细胞起到杀伤作用。
为了进一步验证上述观点,本发明使用了细胞内活性氧检测试剂DCFH-DA荧光探针检测Mn-Ti3C2Tx-PEG处理4T1细胞后产生的·OH,在与0-0.5mg/mL Mn-Ti3C2Tx-PEG共孵育后,在最大浓度0.5mg/mL的条件下,观察到了最明显的绿色荧光。结果表明了本发明合成的Mn-Ti3C2Tx-PEG纳米材料具备类芬顿反应的活性,能选择性杀伤癌细胞。
试验例7---锰基MXenes二维纳米材料的动物实验
本发明中的实验动物为4-6周龄、15g左右的雌性裸鼠购自重庆腾鑫生物技术有限公司。动物实验相关操作均按照西南医科大学实验动物伦理要求进行。
1、实验方法
1.1动物模型建立
提前预计好接种所需的4T1细胞数目,待培养瓶内细胞密度达到70-80%时,进行清洗、消化、离心、PBS缓冲液重悬、细胞计数等步骤,使用PBS缓冲液稀释细胞悬液至2×106个/mL;于裸鼠右侧背部皮下注射混匀的细胞悬液,每只注射约0.2mL,注射前需进行常规酒精消毒,注射后使用棉签按压1min。以后每天观察裸鼠活动状态,并用游标卡尺测量肿瘤体积大小。当肿瘤体积长至50-100mm3时进行下一步处理。肿瘤体积计算公式如公式2.
裸鼠肿瘤体积=ab2×0.5, 公式2
其中,a表示肿瘤最长径,b表示肿瘤最短径。
1.2、Mn-Ti3C2Tx-PEG的体内MRI-T1成像
首先使用麻醉机对皮下移植瘤裸鼠进行气体麻醉,麻醉剂量控制在0.8左右,然后将裸鼠置于腕关节线圈中,摆好体位,在裸鼠旁放置水模,以便于MRI定位,利用3.0TPrisma MR仪对裸鼠进行横断面T1WI序列扫描。第一次扫描完成后,向裸鼠尾静脉内注射40mg/kg的Mn-Ti3C2Tx-PEG纳米材料溶液,注意控制注射速率,不易过快推注。注射完成后立即行相同序列第二次扫描,每次扫描尽量保证裸鼠位于同一部位、同一体位,然后于不同时间点重复相同T1WI序列扫描。整个扫描过程中需密切观察裸鼠呼吸频率并注意对裸鼠进行保温。扫描结束后在MR后处理工作站上进行测量。在T1WI横断面图像上,选取尾静脉注射前后肿瘤T1信号变化最明显的层面勾画ROI,尽量保证不同时间点所勾画层面为同一层面,ROI面积约10mm2。此外,测量不同时间点肝左叶、左侧肾脏相同部位的T1信号强度。
T1WI序列扫描参数设置如下:TR=2000ms,TE=3.1ms,层厚=0.8mm,矩阵256×256,FOV=64.3mm,矩阵=144×224,翻转角=8°。
1.3、Mn-Ti3C2Tx-PEG对体内肿瘤的光热消融
为了评估Mn-Ti3C2Tx-PEG对裸鼠皮下移植瘤光热消融的最佳治疗效果,设置了3个实验组及1个对照组。
瘤内注射组:皮下移植瘤裸鼠瘤内注射4mg/kg的Mn-Ti3C2Tx-PEG纳米材料溶液,然后立即使用波长为808nm的近红外激光照射肿瘤区域(功率及时间:1.5W/cm2×10min);尾静脉注射4h组:皮下移植瘤裸鼠尾静脉注射40mg/kg的Mn-Ti3C2Tx-PEG纳米材料溶液4h后,使用波长为808nm的近红外激光照射肿瘤区域(功率及时间:1.5W/cm2×10min);尾静脉注射6h组:皮下移植瘤裸鼠尾静脉注射40mg/kg的Mn-Ti3C2Tx-PEG纳米材料溶液6h后,使用波长为808nm的近红外激光照射肿瘤区域(功率及时间:1.5W/cm2×10min);仅激光组:皮下移植瘤裸鼠不经纳米材料处理,直接使用波长为808nm的近红外激光照射肿瘤区域(功率及时间:1.5W/cm2×10min)。照射过程中,使用麻醉机对皮下移植瘤裸鼠进行气体维持麻醉,麻醉剂量控制在0.8左右,并且使用红外热像仪监测肿瘤区域的升温变化,拍照间隔时间设置为10s。照射结束后对裸鼠进行为期15天的观察。每2天对裸鼠肿瘤区域进行数码拍照、用游标卡尺测量肿瘤体积大小以及用电子秤测量裸鼠体重的大小。
2、实验结果
2.1 Mn-Ti3C2Tx-PEG在荷瘤裸鼠皮下肿瘤区域的MRI-T1WI成像
为了评估Mn-Ti3C2Tx-PEG对肿瘤的T1增强效果,建立了裸鼠4T1皮下移植瘤模型,并通过尾静脉注射的方式注入Mn-Ti3C2Tx-PEG,然后在Prisma 3.0T磁共振上进行扫描成像。如图8所示,Mn-Ti3C2Tx-PEG注射后与注射前肿瘤区域T1信号强度比较,注射后10min T1信号强度明显增高;随着注射后时间的延迟,虽T1信号强度有所减低,但仍维持在较高水平。结果证明了Mn-Ti3C2Tx-PEG具备被动靶向肿瘤的能力以及对肿瘤具有T1增强效应。
2.2 Mn-Ti3C2Tx-PEG在荷瘤裸鼠肝、肾区域的MRI-T1WI成像
除了观察肿瘤区域的信号变化外,在荷瘤裸鼠尾静脉注射Mn-Ti3C2Tx-PEG后,还评估了裸鼠肝脏及肾脏区域的T1信号强度变化。如图9所示,Mn-Ti3C2Tx-PEG注射后与注射前肝左叶区域T1信号强度比较,注射后10min T1信号强度明显增高,注射后1h肝脏T1信号强度较10min时有所减低,但仍高于注射前的T1信号强度,在注射后24h,T1信号强度基本恢复正常;如图10所示,Mn-Ti3C2Tx-PEG注射后与注射前左肾区域T1信号强度比较,注射后10minT1信号强度增高,注射后1h左肾T1信号强度明显增高,在注射后24h T1信号强度基本恢复正常。以上结果说明,Mn-Ti3C2Tx-PEG纳米材料具备肝脏、肾脏MRI-T1增强的能力,并且Mn-Ti3C2Tx-PEG纳米材料进入体内后,在短时间内(约24h)可以通过肝、肾途径进行代谢、清除。
2.3 Mn-Ti3C2Tx-PEG对体内肿瘤的光热消融效果
为了评估Mn-Ti3C2Tx-PEG纳米材料对实体肿瘤的治疗效果,建立了裸鼠4T1皮下移植瘤模型,通过尾静脉或瘤内注射的方式给药,注射后对肿瘤区域进行808nm近红外激光照射,并用红外热像仪进行监测。如图11-12所示,Mn-Ti3C2Tx-PEG尾静脉注射后4及6h进行荷瘤裸鼠肿瘤区域808nm近红外激光照射。随着时间延长,肿瘤区域的温度逐渐升高,在照射10min后,6h组可升温至55.1℃。瘤内注射Mn-Ti3C2Tx-PEG组也观察到了温度的上升,照射10min后温度升至51.3℃,而仅激光对照组只观察到轻微的温度变化。治疗后对不同组的荷瘤裸鼠进行了15天的随访观察,图13显示了各组裸鼠在治疗后15天内肿瘤区域的数码照片,图14显示了各组裸鼠治疗后不同时间点测量的相对肿瘤体积。可以发现,Mn-Ti3C2Tx-PEG 6h+laser组抑制肿瘤生长的效果最好,其次是瘤内注射组、Mn-Ti3C2Tx-PEG 4h+laser组。以上结果说明,Mn-Ti3C2Tx-PEG纳米材料具备体内肿瘤光热消融的能力。在整个治疗过程中,各组荷瘤裸鼠体重未发生明显的变化(如图15),说明了Mn-Ti3C2Tx-PEG纳米材料具备良好的生物安全性。
综上,可以看出,本发明将Mn-Ti3C2Tx-PEG纳米材料通过尾静脉注射到荷瘤裸鼠体内进行MRI-T1WI序列扫描,结果表明在尾静脉注射后10min,肿瘤组织内的T1信号强度达到最高,这是由于肿瘤的高通透性和滞留效应(enhanced permeability and retentioneffect,EPR)使得纳米材料在肿瘤内聚集,在注射后20-60min,T1信号强度有所降低,但仍维持在较高水平,说明绝大部分进入肿瘤组织的纳米材料可以较长时间滞留在肿瘤组织内。药物排泄速率一定程度上反映了纳米材料的生物安全性,排泄越快,残留在体内的纳米材料可能越少,越不容易引起生物毒性。对同一只荷瘤裸鼠的肝左叶、左侧肾脏进行T1WI成像,在10min-1h之间,肝左叶以及左肾的T1信号强度达到最大,在24h时,肝左叶以及左肾的信号恢复正常。该结果可能从侧面反映了Mn-Ti3C2Tx-PEG纳米材料的生物安全性。
温度的变化是直接影响肿瘤光热消融效果的因素,当组织温度达到41℃时,热休克蛋白可以作为细胞抵抗热损伤的防御机制而上调。然而,当组织温度超过42℃时,由于血管栓塞诱导的缺血,细胞可能会被杀死。如果温度继续升高,细胞的蛋白质和细胞膜将迅速被破坏,导致不可逆转的坏死。激光照射后,3个实验组肿瘤区域温度均超过50℃,因此,Mn-Ti3C2Tx-PEG可能对上述肿瘤均起到了较好的光热消融作用。但3个实验组也略有区别,瘤内注射组的纳米材料注射量为尾静脉注射组的1/10。3个实验组之间升温顺序为:Mn-Ti3C2Tx-PEG6h+laser组>瘤内注射Mn-Ti3C2Tx-PEG组>Mn-Ti3C2Tx-PEG 4h+laser组。
激光照射后进行为期15天的观察,每2天测量一次荷瘤裸鼠肿瘤体积及体重并拍摄肿瘤区域数码照片。15天内,裸鼠体重无明显变化,说明该纳米材料较为安全;从3个实验组及1个对照组的肿瘤相对体积可以看出,抑瘤率顺序为:Mn-Ti3C2Tx-PEG 6h+laser组>瘤内注射Mn-Ti3C2Tx-PEG组>Mn-Ti3C2Tx-PEG 4h+laser组>对照组,同升温顺序保持一致,说明了温度越高,杀死的肿瘤细胞数越多,抑瘤率越明显。
虽然对本发明的具体实施方式进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (8)
1.一种锰基MXenes二维纳米材料的制备方法,其特征在于,包括以下步骤:
(1)多层Ti3C2Tx的合成
将LiF溶解于酸溶液中,然后加入Ti3AlC2,恒温反应后分离出沉淀并清洗至中性,再冷冻干燥,制得多层Ti3C2Tx;
(2)少层Ti3C2Tx的合成
将多层Ti3C2Tx按1g:180-220mL的料液比分散于水中,于惰性气体环境中超声粉碎后再离心,收集上清液,冷冻干燥后,制得少层Ti3C2Tx;
(3)Mn-Ti3C2Tx-PEG的合成
将少层Ti3C2Tx和MnCl2分别分散于水中,并在搅拌条件下将两种分散液混合,然后离心,取沉淀物洗涤干燥,制得Mn-Ti3C2Tx;
将Mn-Ti3C2Tx与聚乙二醇分散于去离子水中,经超声-搅拌-离心后,取沉淀物冷冻干燥后制得。
2.如权利要求1所述的锰基MXenes二维纳米材料的制备方法,其特征在于,所述酸溶液为浓度为8-10M的盐酸溶液,所述LiF溶解于酸溶液后的浓度为0.04-0.06g/mL。
3.如权利要求1所述的锰基MXenes二维纳米材料的制备方法,其特征在于,所述LiF与Ti3AlC2的质量比为1:1,所述Ti3AlC2分8-10批加入。
4.如权利要求1所述的锰基MXenes二维纳米材料的制备方法,其特征在于,所述步骤(1)中恒温反应的温度为12-18℃,恒温反应时间为20-30h。
5.如权利要求1所述的锰基MXenes二维纳米材料的制备方法,其特征在于,所述步骤(3)中少层Ti3C2Tx的分散溶液与MnCl2的分散溶液的体积比为1:1,所述少层Ti3C2Tx的分散溶液的浓度为2.2-2.8mg/mL,所述MnCl2的分散溶液的浓度为1.8-2.2mg/mL,分散溶液混合搅拌的时间为3.5-4.5h;离心的转速为7500-8500rpm,离心的时间为25-35min。
6.如权利要求1所述的锰基MXenes二维纳米材料的制备方法,其特征在于,所述步骤(3)中Mn-Ti3C2Tx与聚乙二醇的质量比为2.5-3.5:5,所述超声-搅拌-离心包括:超声8-12min后,于室温下搅拌2.5-3.5h,再以9900-11000rpm离心10-15min。
7.如权利要求1-6任一项所述的锰基MXenes二维纳米材料的制备方法制备得到的锰基MXenes二维纳米材料。
8.如权利要求7所述的锰基MXenes二维纳米材料在制备MRI引导的肿瘤光热及化学动力学协同治疗药剂中的应用。
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