CN110755614B - 一种层状双氢氧化物纳米片及其制备方法和应用 - Google Patents
一种层状双氢氧化物纳米片及其制备方法和应用 Download PDFInfo
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及一种层状双氢氧化物(LDH‑MoS2‑Mn@BSA)纳米片及其制备方法和应用，其结构特点为：BSA修饰掺杂Mn源、Mo源的氢氧化铝和氢氧化镁片层表面。其制备方法，将镁源、铝源、锰源分散于碱性溶液中，搅拌使之充分溶解、混合均匀，离心并洗涤沉淀。所得产物溶解至适量溶剂中，加入硫源、钼源搅拌并转移至对位聚苯内衬的不锈钢反应釜中密封反应一段时间，离心分离、洗涤，后将冷冻干燥所得的LDH‑MoS2‑Mn粉末与BSA均匀分散至溶液，即可得具有可造影的药物分子或光敏剂载体层状双氢氧化物LDH‑MoS2‑Mn@BSA纳米片，本发明LDH‑MoS2‑Mn@BSA纳米片具有较好的生物相容性、优良的光热转换性能，及独有的造影、载药等特性，可应用于安全高效的肿瘤监测、协同诊断和治疗领域。
Description
技术领域
本发明涉及生物纳米材料技术领域，尤其涉及一种层状双氢氧化物纳米片及其制备方法和应用。
背景技术
癌症的检测技术和治疗方法发展迅速，但日趋年轻化的癌症问题受到了广泛关注。常见的临床癌症治疗方法存在诸多弊端，例如：肿瘤切除造成伤口感染难以愈合等问题；X射线放射治疗对健康组织造成严重损伤的问题；化疗导致的严重耐药性问题。因此，迫切需要探索一种高效的治疗方法，以最大限度地提高治疗效率并减少对组织及身体器官的损害。
Duan等人研究发现：层状双氢氧化物是一类由正电荷层组成的二维层状纳米材料，通过调节内部金属阳离子的比例和夹层阴离子的种类可以改变理化性质。由于无机的层状氢氧化物难溶于水，故可在纳米片表面修饰具有两亲性的生物或有机大分子使纳米片在溶液中均匀分散。此外，锰元素作为生物系统和生理代谢的关键元素，在机体中起着重要作用。在酸性还原条件下，锰氧化物被分解、还原并释放二价锰。当二价锰被水分子包围时，顺磁中心随之被加强，从而可以在肿瘤内成像并获得较好地T1-MRI造影性能。锰源纳米材料作为肿瘤组织造影剂具有较好效果、用量低和毒性小等优点，已广泛应用于肿瘤的磁共振成像的研究。
光疗法包括光热疗法和光动力疗法，其无创伤、低毒性和低成本的特性使其备受关注。其中，光热治疗将具有高光热转换效率的材料集中于肿瘤部位，在一定功率密度的激光照射下将近红外激光转化为热量从而杀死癌细胞，由于其高选择性和较好的疗效，在近些年被广泛应用于恶性肿瘤治疗。而光动力学治疗是一种更具创新性的癌症疗法，通过激光照射光敏剂分子促使组织内氧气分解产生有毒活性氧，从而杀死癌细胞以达到治疗效果。Qu等人的研究表明：在高功率密度的激光照射光热材料使肿瘤表面温度缓慢上升，有利于加强光敏剂的细胞摄取，从而促进光动力学的治疗效果，因而两种疗法的协同治疗常被视为一种高效的诊疗方式。
在单平台内整合成像和治疗功能，已成为准确、特异、高效肿瘤治疗的方法之一。基于此背景，我们设想通过溶剂热法一步合成掺杂钼、锰氧化物及硫化物的层状双氢氧化物，利用物理键合的方式连接牛血清白蛋白及药物分子或光敏剂来实现肿瘤造影监测、光热、光动力协同治疗应用。截止目前，尚无利用溶剂热法一步制备掺杂钼、锰氧化物及硫化物的药物分子或光敏剂载体LDH-MoS2-Mn@BSA层状纳米片的合成、表面修饰及肿瘤监测、协同治疗应用的文献或专利报道。
发明内容
本发明的目的在于提出一种制备简单，具有良好的生物相容性、光热转换效率及磁共振造影效果的层状双氢氧化物纳米片及其制备方法和应用。
为达到上述目的，本发明提出一种层状双氢氧化物纳米片，钼、锰氧化物或硫化物镶嵌在氢氧化物层间，纳米片表面通过共价键形式修饰牛血清白蛋白，使其在溶液中胶体稳定。
优选的，所述氢氧化物为氢氧化镁和氢氧化铝。
本发明还提出一种层状双氢氧化物纳米片的制备方法，包括以下步骤：
步骤1：在搅拌的作用下，将水合硝酸盐溶解于溶剂，形成混合溶液；
步骤2：将硫源、锰源溶解于所述混合溶液中，搅拌至完全溶解；
步骤3：将所述混合溶液离心分离，取沉淀溶液得到沉淀分散液；
步骤4：将钼源溶解于所述沉淀分散液中；
步骤5：将步骤4中所述沉淀分散液转移至对位聚苯内衬的不锈钢反应釜中密封反应体系；
步骤6：反应完全后，对步骤5中所述沉淀分散液进行离心分离；
步骤7：对离心后的产物进行洗涤，得到所述层状双氢氧化物纳米片。
优选的，在步骤1中，所述水合硝酸盐包括六水合硝酸镁、九水合硝酸铝和四水合硝酸锰。
所述溶剂为碱性溶液，包括氢氧化物或氨水。
优选的，在步骤2中，所述硫源为单质硫、二硫化碳、硫化氢、硫脲或四硫代钨酸铵中的任意一种；
在步骤1和步骤2中，搅拌采用磁力搅拌，搅拌的速率为50-400r/mi n，搅拌时间为60-90分钟。
优选的，在步骤4中，所述钼源为钼酸铵、钼酸钠或四硫代钼酸铵中的任意一种；
所述钼源的浓度为0.1～1.0mg/mL。
优选的，在步骤5中，所述对位聚苯内衬的不锈钢反应釜为聚四氟乙烯高压釜；所述聚四氟乙烯高压釜中的反应温度为180-220℃，反应时间为12-24小时。
优选的，在步骤6中，离心分离的转速为8000-13000r/min。
优选的，在步骤7中，采用蒸馏水对所述产物进行洗涤，清洗次数为2-3次。
本发明提出一种层状双氢氧化物纳米片的应用，所述层状双氢氧化物纳米片作为光热转换材料、光敏剂载体和药物载体材料。
与现有技术相比，本发明的优势之处在于：本发明工艺简便，所得产物无毒，并在体内体外具有良好的生物相容性、光热转换效率及磁共振造影效果。
本发明通过水热溶剂热反应法处理氢氧化物、钼源、硫源和锰源材料的混合溶液特定时间，即可得具有较大比表面积的层状双氢氧化物(LDH-MoS2-Mn@BSA)纳米片产物。另外，通过物理键合的方法修饰两亲性大分子，可以帮助片层纳米材料拥有更好的胶体稳定性和生物相容性。
具体的，本发明的有益效果表现在以下几个部分：
(1)本发明工艺流程简便，产品易得；
(2)产品在体内外均具有较好的生物相容性、胶体稳定性及光热转换效应；
(3)产品在弱酸还原型环境下更有利于富集并产生较优的磁共振造影效果；
(4)产品作为药物分子或光敏剂载体，能较好的在搅拌作用下负载、缓释药物分子或光敏剂分子。从而使得LDH-MoS2-Mn@BSA层状纳米片有望应用于肿瘤的诊断、监测、治疗等领域。
附图说明
图1为LDH-MoS2-Mn纳米片的SEM图(a)、TEM图(b)；
图2为LDH-MoS2-Mn纳米片中(a)S、(b)O、(c)Mo和(d)Mn的X-射线光电子能谱图；(e)和(f)分别为LDH和LDH-MoS2-Mn纳米片的X射线衍射图谱；(g)(h)(i)分别为牛血清白蛋白、LDH-MoS2-Mn和LDH-MoS2-Mn@BSA纳米片的傅里叶红外光谱图；
图3为LDH-MoS2-Mn纳米片在(a)蒸馏水、(b)生理盐水、(c)1640细胞培养基中的丁达尔现象；(d)细胞与浓度为0、50、100、250、500μg/mL的LDH-MoS2-Mn@BSA纳米片分散溶液共孵育24小时后的存活率；
图4中，(a)为不同浓度的LDH-MoS2-Mn@BSA纳米片的紫外-可见-近红外吸收光谱；(b)LDH-MoS2-Mn@BSA纳米片光热性质检测实验装置图；(c)在功率为1W/cm2波长为808nm近红外激光辐射下，LDH-MoS2-Mn@BSA纳米片分散液温度随辐射时间的变化曲线；(d)为(c)对应的红外热成像照片；(e)LDH-MoS2-Mn@BSA纳米片浓度为500μg/mL时，不同功率的808nm激光辐射下分散液温度的变化情况；(f)为(e)对应的红外热成像照片；(g)LDH-MoS2-Mn@BSA线性拟合冷却时间对热驱动常熟的自然对数的负值得曲线；(h)LDH-MoS2-Mn@BSA纳米片光热转换效率；(i)LDH-MoS2-Mn@BSA纳米片的光热稳定性10次升温-降温循环；
图5中，(a)为LDH-MoS2-Mn@BSA纳米片在pH 5.0柠檬酸缓冲液、谷胱甘肽缓冲液和蒸馏水中的磁共振造影光亮强度；(b)为(a)对应的纳米材料成像图；
图6中(a)为LDH-MoS2-Mn@BSA纳米片及负载后Ce6后上清液在300-800nm波长下的吸光度；(b)为在403nm下Ce6吸光度与其浓度的关系；
图7中(a)为LDH-MoS2-Mn@BSA纳米片负载后DOX后上清液在300-800nm波长下的吸光度，右上图为在480nm下DOX吸光度与其浓度的关系；(b)负载DOX的LDH-MoS2-Mn@BSA纳米片在不同条件下(介质pH＝7.4和pH＝6.0)的DOX释放曲线；
图8中(a)-(i)为生理盐水作对照的昆明尾静脉注射后在1天、7天、28天的血常规测试结果；
图9为昆明尾静脉注射200μL浓度为3mg/mL的LDH-MoS2-Mn@BSA纳米材料1天、28天后的组织病理切片H&E染色结果(生理盐水作对照)。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将对本发明的技术方案作进一步地说明。
实施例1：
称取0.164g六水合硝酸镁、0.06g九水合硝酸铝和0.04g四水合硝酸锰溶解于10mL蒸馏水中得A溶液。称取0.12g氢氧化钠溶解于20mL蒸馏水中得B溶液，待充分溶解后A、B溶液混合，室温下搅拌60分钟，可观察到溶液迅速变橙黄色，随不断搅拌溶液颜色加深直至变黑。离心分离(8000r/min,5min)，沉淀分散至35mL蒸馏水中，加入0.005mg/mL四硫代钼酸铵，室温下搅拌90分钟，转移至100mL对位聚苯内衬的不锈钢反应釜中密封。将反应釜置入高温烘箱中180℃热处理12小时，待自然冷却至室温后，离心分离反应混合物(8000r/min，10min)，蒸馏水洗涤三次，得产物LDH-MoS2-Mn纳米材料。取10mg冻干后产物于试管中，加入0.25g牛血清白蛋白，通过细胞粉碎机超声，两者通过共价键形式键合，使无机纳米片能够在溶液中稳定存在，得终产物LDH-MoS2-Mn@BSA纳米材料。
实施例2：
取少许实施例1中制备的LDH-MoS2-Mn纳米材料，通过SEM和TEM观察材料的形貌和微观结构。将适量纳米片粉末均匀粘覆在导电胶上，通过SEM观察、拍照。当适量纳米片超声均匀分散于无水乙醇后，将镀有碳膜的铜网浸入上述无水乙醇中。待样品自然干燥后，通过TEM观察、拍照(TEM操作电压为200kV)。由图1(a)和(b)可以看出实施例1中所得材料结构为厚度约0.3微米的不规则纳米片。
实施例3：
分别取实施例1中制备的LDH-MoS2-Mn纳米材料，分析其组成及结构。用ThermalScientific公司的ESCAlab250型X射线光电子能谱仪(XPS)表征纳米片中S、O、Mo和Mn元素的化合价。激发源为单色器Al KαX射线(λ＝0.8339nm)，能量为1486eV，线宽为0.9eV，功率为150W。结合能用C的1s峰(284.8eV)校正。使用XRD(Rigaku D/max-2200PC，日本)研究纳米片的XRD衍射图谱的晶体结构。以Cu2Kα射线为光源，操作电压为40kV，电流为200mA，扫描角度(2θ)范围为3°-70°。使用FTIR(NicoletNexus 670红外光谱仪)表征牛血清白蛋白修饰LDH-MoS2-Mn纳米片前后的结构，取少许牛血清白蛋白、LDH-MoS2-Mn及负载牛血清白蛋白的LDH-MoS2-Mn纳米片粉末，与干燥的KBr粉末混合研磨均匀后压片。置于Nicolet Nexus 670红外光谱仪样品架上进行扫描(扫描范围400-4000cm-1)。
分析图2(a)-(d)可知，产物中的S和O的价态分别为S2-和O2-，其电子能谱图分别归因为2p 3/2和1s轨道。而产物中Mo和Mn均具有多种氧化价态，分别为Mo4+、Mo6+和Mn2+、Mn3+，可分别归属于MoSx和MoOx中Mo的3d 5/2、3d 3/2和MnSx和MnOx中Mn的2p 3/2、2p 1/2电子轨道。分析图2(e)和(f)可知，掺杂Mo和Mn元素的纳米片与无掺杂LDH的XRD图谱相比，主要衍射峰(110)、(113)和低角度处(00l)系列峰位置并不完全吻合(有小程度的右移)并且伴随峰强度的明显减弱和消失，其主要的原因是由于在原层状双氢氧化物中填充了金属元素，使得X射线反射角增大而造成峰位置向右移动。同时，掺杂的Mo和Mn原子不具有同周期性排列，故其散射的次生X射线相互干扰抵消，使得峰强度削弱。
(g)-(i)牛血清白蛋白、LDH-MoS2-Mn和LDH-MoS2-Mn@BSA纳米片的傅里叶红外光谱图。无修饰的LDH-MoS2-Mn纳米片在低于1000cm-1波长处有较多的羟基吸收峰。而牛血清白蛋白在1640cm-1,1540cm-1,and 1390cm-1波长处具有特征酰胺I、II和III带，同时在3320cm-1和2950cm-1波长处有氨基和甲基的不对称伸缩振动吸收峰。从图(i)中可以清晰的看出，羟基吸收峰在LDH-MoS2-Mn@BSA纳米片红外光谱图中几乎消失，但在1640cm-1、1540cm-1和1390cm-1波长处出现吸收峰，说明牛血清白蛋白通过物理键合的方式被成功地修饰在LDH-MoS2-Mn表面。
实施例4
LDH-MoS2-Mn@BSA纳米片的胶体稳定性及细胞相容性测定。将实施例1中制备的纳米材料分别分散于装有蒸馏水、生理盐水和1640细胞培养基的玻璃比色皿中，观察其丁达尔效应。由图3(a)-(c)可知，均匀分散于蒸馏水、生理盐水和1640细胞培养基中的LDH-MoS2-Mn@BSA纳米片具有明显的丁达尔效应，证明纳米片在不同的溶剂中均具有良好的胶体稳定性。
将L929细胞种植于含有100μL1640细胞培养基的96孔板中，培养24小时，用100μL浓度为0(对照组)、50、100、250和500μg/mL的LDH-MoS2-Mn@BSA(分散介质为1640培养基)替换各孔原培养基，并设定浓度为0μg/mL LDH-MoS2-Mn@BSA内细胞存活率为100％。在CO2恒温培养箱中孵育24h，根据CCK-8试剂盒说明书，向各孔加入10μL工作液，继续培养1小时，利用BioTek酶标仪读取405nm处吸光度。由图3(d)可知，即使是浓度为500μg/mL的LDH-MoS2-Mn@BSA纳米片溶液，在与细胞共培养24小时后，细胞的存活率仍然有92.67％，表明纳米材料对L929细胞的毒性不大且具有良好的细胞相容性。
实施例5
用UV-Vis-NIR(Lambda 25，Perkin Elmer公司，美国)分析LDH-MoS2-Mn@BSA纳米片光吸收性质(波长范围400-1100nm)。由图4(a)可知，在波长为808nm的NIR激光下，材料有一定近红外吸收，且吸收强度随纳米材料浓度的增加而不断增大。
根据图4(b)装置照片搭建实验仪器，通过FLIR E60红外热像仪记录LDH-MoS2-Mn@BSA纳米材料分散液温度随时间的变化情况及对应的红外热成像照片，分析材料体外光热效果、光热转换效率和热稳定性情况。具体步骤如下：取100μLLDH-MoS2-Mn@BSA纳米片(溶剂为蒸馏水)分散在96孔细胞培养板孔中，先后改变材料浓度(0、50、100、200μg/mL)和808nm激光功率密度(0.2、0.5、0.8、1.0W/cm2)，监测激光照射5分钟内材料温度变化情况。从图4(c)可知，不同浓度的LDH-MoS2-Mn@BSA纳米材料均可以吸收一定强度的NIR激光，且随着材料浓度的增大，体系对NIR激光的光热转换能力不断加强。由图4(e)可知，材料对不同密度的NIR激光均有吸收，且随激光密度和时间间隔的增加，材料吸收能量的程度不断增强，温差逐渐增大。图4(d)和(f)中红外热成像照片更鲜明地说明了LDH-MoS2-Mn@BSA纳米片的光热转化与浓度及激光密度的关系。总体来说，本发明制备的LDH-MoS2-Mn@BSA纳米片表现出了较好的体外光热性能。
同上述方法搭建实验装置，通过FLIR E60型红外热像仪记录纳米材料温度随时间的变化关系，用808nm NIR激光(功率密度1W/cm2)照射500μg/mLLDH-MoS2-Mn@BSA纳米片分散溶液5分钟，再停止照射5分钟，记激光器开关一次为一单位，重复循环十次。从图4(g)-(h)可见，根据Korgel公式计算一单位的光热转换效率为25.75％，进一步证明本发明制备的LDH-MoS2-Mn@BSA纳米片表现出较好的光热转换能力。从图4(i)可知，LDH-MoS2-Mn@BSA纳米片表现出优良的光热稳定性。
实施例6
取实施例1中制备的LDH-MoS2-Mn@BSA纳米材料分别分散于蒸馏睡、pH5.0柠檬酸缓冲液和谷胱甘肽缓冲液中，置于37℃培养箱中培养2h。测定溶液在磁共振造影设备下的T1值、T2值及影像光亮强度，仪器参数设置如下：TR＝600ms,，TE＝Min Full，bandwidth＝15.63kHz，slice thickness＝3mm。从图5(a)和(b)可以看出，随着材料浓度的增大，造影图像亮度逐渐增强，并且材料在酸性、还原性条件下造影效果逐渐增强，其原因在于：Mn2+具有造影效果，而纳米材料中含有锰氧化物，其在酸性环境中被分解为锰离子(Mn2+、Mn3+)，在还原氛围中均被谷胱甘肽还原为Mn2+，从而产生显著的造影效果。总之，在实验条件下，掺杂锰元素的LDH-MoS2-Mn@BSA纳米材料具有良好的造影效果，且在酸性、还原性氛围下造影效果更佳。
实施例7
用UV-Vis-NIR(Lambda 25，Perkin Elmer公司，美国)分析LDH-MoS2-Mn@BSA纳米片负载光敏剂分子Ce6的能力(波长范围300-800nm)。将1mL LDH-MoS2-Mn@BSA纳米片(5mg·mL-1，溶剂为蒸馏水)与0.04mL Ce6溶液(5mg·mL-1，溶剂为二甲基亚砜)均匀分散于2.6mL蒸馏水中，搅拌过夜，离心洗涤三次，收集上清液，用UV-Vis-NIR检测在403nm波长下的吸光度。从图6(a)和(b)可知，利用Ce6浓度-吸光度标准曲线计算可得LDH-MoS2-Mn@BSA纳米片负载Ce6效率为62.15％。
实施例8
用UV-Vis-NIR(Lambda 25，Perkin Elmer公司，美国)测定抗癌药物DOX能力。将分散于蒸馏水中浓度1mg/mL的LDH-MoS2-Mn@BSA纳米片与10mg/mL的DOX溶液均匀混合，置于15mL容积的透明玻璃瓶中，于常温下避光搅拌24小时，离心分离，洗涤三次，收集上清液用UV-Vis-NIR检测在480nm波长下的吸光度。由图7(a)可知，DOX药物分子负载效率为66.91％。
取上述离心沉淀溶解于蒸馏水中，分装12组(每组1mL负载DOX药物分子的LDH-MoS2-Mn@BSA纳米片)，置于装有5mL PBS(pH＝7.4)(6组)或柠檬酸缓冲液(pH＝6.0)(6组)的离心管中。将离心管置于37℃(6组)或54℃(6组)的摇床中震荡，在预先设计好的时间点，从离心管中各取出1mL溶液，并补充1mL相应新的缓冲液。用UV-Vis-NIR(Lambda 25，PerkinElmer公司，美国)检测上述取出的1mL缓释液在480nm处的吸光度，根据DOX浓度-吸光度标准曲线计算出释放出来的DOX浓度，绘制出LDH-MoS2-Mn@BSA纳米材料对DOX的释放动力学曲线。从图7(b)可知，LDH-MoS2-Mn@BSA纳米片可以很好地控制DOX的释放速度，降低缓冲液pH更可促进药物的释放。
实施例9
将12只昆明鼠随机分为4组：对照组尾静脉注射生理盐水200μL；实验组尾静脉注射200μL的LDH-MoS2-Mn@BSA纳米材料(溶剂为生理盐水，3mg/mL)。在分别喂养1天、7天、14天后，心脏穿刺取血，测定各项血液参数进行活体水平血液相容性评价。血常规评价指标包括白细胞、红细胞、血红蛋白、红细胞比容、红细胞平均体积、红细胞平均血红蛋白量、红细胞平均血红蛋白浓度、红细胞分布宽度、血小板含量。从图8(a)-(i)可知，不同组别各参数均在正常范围内波动，证明LDH-MoS2-Mn@BSA纳米片具有良好的血液相容性。
将12只昆明鼠随机分为4组：对照组尾静脉注射生理盐水200μL；实验组尾静脉注射200μL的LDH-MoS2-Mn@BSA纳米材料(溶剂为生理盐水，3mg/mL)。在分别喂养1天、7天、14天后，麻醉处死，取各组别昆明鼠的心、肝、脾、肺、肾等重要组织，用戊二醛固定，苏木精—伊红染色，观察组织切片情况。由图9可知，与对照组相比，实验组各主要器官均无明显的组织损伤和病变，表明材料具有良好的组织相容性
上述仅为本发明的优选实施例而已，并不对本发明起到任何限制作用。任何所属技术领域的技术人员，在不脱离本发明的技术方案的范围内，对本发明揭露的技术方案和技术内容做任何形式的等同替换或修改等变动，均属未脱离本发明的技术方案的内容，仍属于本发明的保护范围之内。
Claims (1)
1.一种层状双氢氧化物纳米片的制备方法，其特征在于，包括以下步骤：
称取0.164 g 六水合硝酸镁、0.06 g 九水合硝酸铝和0.04 g 四水合硝酸锰溶解于10mL 蒸馏水中得A溶液；称取0.12 g 氢氧化钠溶解于20 mL 蒸馏水中得B溶液，待充分溶解后A、B溶液混合，室温下搅拌60分钟，可观察到溶液迅速变橙黄色，随不断搅拌溶液颜色加深直至变黑；离心分离，8000 r/min, 5 min，沉淀分散至35 mL蒸馏水中，加入0.005 mg/mL四硫代钼酸铵，室温下搅拌90 分钟，转移至100 mL 对位聚苯内衬的不锈钢反应釜中密封；将反应釜置入高温烘箱中180 ℃热处理12小时，待自然冷却至室温后，离心分离反应混合物8000 r/min，10 min，蒸馏水洗涤三次，得产物LDH-MoS2-Mn纳米材料；取10 mg 冻干后产物于试管中，加入0.25 g 牛血清白蛋白，通过细胞粉碎机超声，两者通过共价键形式键合，使无机纳米片能够在溶液中稳定存在，得终产物LDH-MoS2-Mn@BSA纳米材料。
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