CN113751079A - 一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用 - Google Patents
一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用 Download PDFInfo
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Abstract
本发明涉及生物医药材料技术领域,具体涉及一种生物材料负载的钙钛矿‑二氧化钛纳米复合光催化剂及其构建方法和应用,该纳米复合光催化剂包括钙钛矿纳米粒;包覆钙钛矿纳米粒的二氧化钛壳层。本发明以前沿新材料钙钛矿为基础,结合二氧化钛以提高结构稳定性并有效分离电子空穴对,构建用于长效Ⅰ型光动力治疗的纳米复合光催化系统。制备工艺简单,解决了临床常用光敏剂氧依赖性高以及无机光敏剂生物相容性低的问题。相较于其他光动力治疗系统,生物材料负载的钙钛矿‑二氧化钛纳米复合光催化系统经激光触发,在低剂量下即可发挥高效肿瘤治疗作用,且在合适的给药剂量下安全无毒,在光动力治疗中更具优势。
Description
技术领域
本发明属于生物医药材料技术领域,具体涉及一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用。
背景技术
光动力学疗法(Photodynamic therapy,PDT)作为一种新兴的无创治疗方式,近年来受到了广泛关注,其作为一种非侵入性温和的医学技术,通过光敏剂(Photosensitizer,PS)在特定波长的光源触发下产生具有细胞毒性的活性氧(Reactive oxygen species,ROS)发挥抗肿瘤作用。在过去的二十多年里,研究者们成功设计了多种PDT体系,体系内主要包含光敏剂和合适的光源。Ⅰ型PDT(TypeⅠreaction)反应底物主要为H2O、O2及H2O2等,可产生羟基自由基、超氧阴离子自由基等ROS。在II型PDT(TypeⅡreaction)过程中,光敏剂将能量释放给氧(Oxygen,O2),将O2转化为单线态氧(1O2)。由于需消耗大量氧气,II型PDT具有很强的氧依赖性。在实体肿瘤组织的乏氧环境下,这种氧依赖性极大地阻碍了II型PDT在临床上的实际应用。因此,Ⅰ型PDT的应用性更强,相关的研究更加迫切。
光催化材料具备高效稳定性,其在太阳能转换、环境净化和有机合成等领域得到了广泛的应用。在合适的光源,如近红外(NIR)、紫外可见(UV-Vis)和X射线波长光等触发下,可以吸收光子发生一系列光化学反应,产生具有细胞毒性的活性氧ROS发挥抗肿瘤作用。具体作用过程为,光催化剂吸收光子能量后,电子(e-)从价带(VB)跃迁到导带(CB),价带上的空穴(h+)可氧化H2O产生羟基自由基(.OH),同时电子将氧气还原为超氧自由基(˙O2-)。相比传统光敏剂,光催化材料的“催化”性质使其在底物和光照充足的条件下反复产生ROS,在低剂量下即可发挥高效治疗作用,且无氧依赖性,在光动力治疗中更具优势。
I型PDT中常用到的光催化材料有金属如金纳米粒;半导体类材料如二氧化钛(TiO2)、氧化锌(ZnO);量子点如碳量子点等一些无机纳米粒。为提高光催化材料抗肿瘤能力,需寻找光吸收范围与近红外光匹配的光催化材料来提高材料的光子吸收效率,进而提高ROS产率。现有技术中没有将钙钛矿(CH3NH3SnX3)作为I型PDT中的光催化材料的报道,原因是CH3NH3SnX3作为光催化剂存在的问题是光生电子空穴对在光催化过程中快速复合,同时CH3NH3SnX3自身稳定性较差,遇水易分解,Sn2+易被氧化,导致无法获得较好的光催化效果。
TiO2是应用最广泛的半导体,它具有稳定的化学结构、良好的生物相容性及光学、电学、催化等性质,可用于与光催化材料复合,从而有效地分离电子空穴对,提高光催化效率;另一方面,TiO2稳定的化学性质可防止钙钛矿被氧化及水解,提高整个体系的长期稳定性,使其源源不断发挥PDT效果。但TiO2难溶于水,且TiO2表面缺乏肿瘤特异性识别配体,导致其在体内循环时吸附血清蛋白具有毒性,在临床应用上选择性不足导致光动力学治疗效率低。
发明内容
为解决背景技术中存在的上述技术问题,本发明提供一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用。
本发明技术方案如下:
本发明的第一个目的是提供一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂制备方法,所述生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂包括钙钛矿纳米粒、二氧化钛壳层和生物递送材料;所述二氧化钛壳层包覆钙钛矿纳米粒,构成钙钛矿-二氧化钛纳米复合光催化剂;所述钙钛矿-二氧化钛纳米复合光催化剂由生物材料所负载;
所述钙钛矿纳米粒为卤化物钙钛矿纳米粒,分子结构式为CH3NH3SnX3,其中X为I、Br、Cl一价卤素阴离子中的一种或多种;
所述钙钛矿纳米粒粒径范围2~20nm;钙钛矿-二氧化钛纳米复合光催化剂粒径范围10~100nm;
优选的,所述生物材料选自表面具有双键(烯基)修饰的高分子聚合物,或表面双键修饰的高分子聚合物的衍生物,或表面双键修饰的高分子聚合物和/或其衍生物的组合;
如所述生物材料本身表面已有双键(烯基),则无需再修饰;如所述生物材料本身无双键(烯基),则先已常规方法进行表面官能团化,得到烯基,以便在后续制备过程中和巯基在存在光引发剂的情况下发生巯烯click反应。
进一步优选的,所述生物材料选自表面双键修饰的透明质酸、壳聚糖、聚乳酸、葡聚糖、明胶、瓜尔胶、泊洛沙姆、聚(N-异丙基丙烯酰胺)中的一种或多种的组合。
优选的,所述生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂在近红外区响应。光动力学疗法的最佳组织穿透深度的光是在700~850nm范围内,称为“光学窗口”或“近红外(NIR)窗口”。在某一个特殊的实施例中,所述生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂响应波长为808nm。
本发明的第二个目的是提供述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,包括以下步骤:
S1,合成钙钛矿纳米粒;
S2,制备钙钛矿-二氧化钛纳米复合光催化剂;
S3,构建生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂。
进一步的,S1的具体步骤为:
S1-1:分别配制SnX2的良溶剂母液和CH3NH3X的良溶剂母液,将SnX2的良溶剂母液和CH3NH3X的良溶剂母液混合均匀得到混合液,向混合液中加入油酸及油胺,配成前驱液;
优选的,所述混合液中SnX2与CH3NH3X摩尔比为(0.8~1.2):(0.8~1.2);
优选的,所述油胺在加入混合液前,预先加热为液态;
S1-2:将前驱液剧烈搅拌后冷却至室温,逐滴加入到混溶性抗溶剂中,得到分散的CH3NH3SnX3反应液;
S1-3:吸取CH3NH3SnX3反应液到非混溶性抗溶剂中,轻轻摇晃混匀后静置至溶液分层,收集下层的油状溶液,再次加入一定量非混溶性抗溶剂重复上述操作,得到纯化的CH3NH3SnX3纳米粒,即钙钛矿纳米粒。
进一步的,S1-1中所述良溶剂选自二甲基亚砜、二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、γ-丁内酯、二甲基丙烯脲中的一种或几种;
S1-1中所述前驱液中油酸的体积百分比为8%~14%;
所述前驱液中油胺的体积百分比为0.4%~1.0%。
进一步的,S1-2中所述混溶性抗溶剂选自甲苯、丙酮、乙腈、氯苯、乙醚、二氯甲烷、硝基甲烷、异丙醇、乙酸乙酯中的一种或几种;
S1-2中所述前驱液与混溶性抗溶剂的体积比为1:10~20。
进一步的,S1-3中所述非混溶性抗溶剂选自正己烷、二乙醚、仲丁醇、三氟甲苯、碘化苯、苯甲醚、乙酸甲酯、乙酸乙酯中的一种或几种;
S1-3中每次加入非混溶性抗溶剂的量为CH3NH3SnX3反应液与非混溶性抗溶剂的体积比为1:5~10。
进一步的,S2的具体步骤为:
S2-1:取S1制备得到的CH3NH3SnX3分散于混合溶剂中,超声后加入钛酸丁酯与浓盐酸常温下搅拌后,冷凝回流,得到反应液;所述混合溶剂由乙醇与正己烷组成;所述乙醇为无水乙醇;
S2-2:将S2-1得到的反应液加入正己烷纯化,离心收集析出的白色沉淀,真空干燥除去有机溶剂,得到CH3NH3SnX3-TiO2复合物,即钙钛矿-二氧化钛纳米复合光催化剂;
进一步的,S2-1中所述混合溶剂中乙醇与正己烷的体积比为2~4:1;所述超声的时间为10~30min;CH3NH3SnX3与钛酸丁酯的质量比为1:20~30;CH3NH3SnX3与浓盐酸的质量比为10:1~3;所述搅拌的时间为2~4h;冷凝回流时间为5~20h;冷凝回流温度为40~50℃;
S2-2中所述反应液与正己烷的体积比为1:3~5。
进一步的,S3的具体步骤为:
S3-1:将S2得到的钙钛矿-二氧化钛纳米复合光催化剂进行表面巯基化反应,得到表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂;
S3-2:将生物材料与S3-1得到的表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂在紫外光引发下发生Click反应,制备得到生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂;屏蔽复合光催化剂表面正电荷的同时提高其生物利用度,并赋予肿瘤选择性,具有亲水性强、生物相容性好、安全无毒的特点;
优选的,S3-1所述表面巯基化反应为将钙钛矿-二氧化钛纳米复合光催化剂分散在乙醇中,加入巯丙基三甲氧基硅烷,在氮气保护下进行表面巯基化反应,所述巯丙基三甲氧基硅烷与钙钛矿-二氧化钛纳米复合光催化剂的摩尔比为50:1;
进一步优选的,S3-1所述乙醇的体积百分比浓度为98%,所述钙钛矿-二氧化钛纳米复合光催化剂在乙醇中的浓度为0.4mg/mL,所述表面巯基化反应时间为5h;
优选的,所述表面巯基化反应结束后,分离反应产物,干燥,得到表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂;所述分离为16000rpm离心5min后乙醇洗两遍沉淀,所述干燥为真空干燥12h;
S3-2所述生物材料选自表面双键(烯基)修饰的高分子聚合物,或表面双键修饰的高分子聚合物的衍生物,或表面双键修饰的高分子聚合物和/或其衍生物的组合;,所述双键修饰的高分子聚合物或其衍生物或高分子聚合物及其衍生物的组合,可以直接购买,或按照常备方法自行制备;
如所述生物材料本身表面已有双键(烯基),则无需再修饰;如所述生物材料本身无双键(烯基),则先已常规方法进行表面官能团化,得到烯基,以便在后续制备过程中和巯基在存在光引发剂的情况下发生巯烯click反应。
进一步优选的,所述生物材料选自双键修饰的透明质酸、壳聚糖、聚乳酸、葡聚糖、明胶、瓜尔胶、泊洛沙姆、聚(N-异丙基丙烯酰胺)中的一种或多种的组合;
S3-2所述生物材料与S3-1得到的表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂的比例由生物材料的种类和给药形式常规确定;
S3-2所述Click反应为加入常规光引发剂后进行紫外光照,所述引发剂加入量和紫外光照时间根据生物材料的种类和给药形式常规确定。
本发明的第三个目的是提供前述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂在制备光动力治疗药物中的应用;优选的,所述光动力治疗药物为治疗肿瘤的光动力治疗药物;进一步优选的,为治疗肿瘤的长效I型光动力治疗药物。所述光动力治疗药物具备生物安全性的同时赋予肿瘤靶向性,可以静脉注射、局部注射等给药方式使其具有优秀的瘤内滞留性,用于肿瘤长效I型光动力治疗。
所述钙钛矿-二氧化钛纳米复合光催化剂在700~850nm光照激发下产生电子空穴对,在低剂量下即可产生大量活性氧:电子可以将氧分子还原为超氧自由基(.O2-),空穴能够将水分子氧化为羟基自由基(.OH)。在多轮NIR的触发下,持续产生ROS,破坏线粒体膜电位,促使线粒体释放Cyto-c,激活Caspase-3,诱导肿瘤细胞凋亡,发挥长效Ⅰ型光动力治疗作用。
所述钙钛矿-二氧化钛纳米复合光催化剂由生物材料所负载,在合适的给药剂量下有效抑制肿瘤生长的同时安全无毒,对肝、肾及甲状腺组织无损伤,无明显遗传毒性及基因毒性,具备生物安全性的同时赋予肿瘤靶向性,可应用于体内,以静脉注射、局部注射等给药方式使其具有优秀的瘤内滞留性。
本发明技术方案相对于现有技术具有以下有益效果:
1.钙钛矿类结构金属材料目前主要用于太阳能电池及光催化领域,本发明基于钙钛矿光催化及Ⅰ型PDT共性的原理出发,首次将钙钛矿材料作为光敏剂应用在体内进行抗肿瘤治疗。以卤化物钙钛矿纳米粒CH3NH3SnX3为基础材料,相比其他常见钙钛矿结构如铅基钙钛矿,锡卤杂化钙钛矿不含毒性重金属元素,其所含的锡、卤元素为人体内必需的微量元素,因此,锡卤钙钛矿具有生物应用的可能性,应用在肿瘤治疗领域安全性更高。
2.为提高光催化性能,在材料设计方面将钙钛矿半导体与二氧化钛半导体结合,有效的抑制电子空穴对的复合,且两者的不仅提高了稳定性,同时将光催化剂可响应的光波段延伸至近红外波段,使其具备应用在体内的基础。
3.借助生物递送材料的肿瘤靶向滞留性,使钙钛矿-二氧化钛纳米复合光催化剂如“能量站”般持续产生ROS,发挥长效PDT作用。
附图说明
图1为实施示例1制备的钙钛矿纳米粒和实施示例9制备的二氧化钛-钙钛矿纳米粒的电镜图;其中,图1A为钙钛矿纳米粒的透射电镜结果(比例尺为100nm),图1B为钙钛矿纳米粒的高分辨透射电镜结果(比例尺为2nm),图1C为二氧化钛-钙钛矿纳米粒的透射电镜结果(比例尺为50nm),图1D为二氧化钛-钙钛矿纳米粒的高分辨透射电镜结果(比例尺为2nm);
图2为实施示例1制备的钙钛矿纳米粒及实施示例9下构建的钙钛矿-二氧化钛纳米复合光催化剂的傅里叶变换红外光谱;
图3为实施示例9下构建的钙钛矿-二氧化钛纳米复合光催化剂的电子自旋共振图;
图4为实施示例1制备的钙钛矿纳米粒及实施示例9下构建的MT在4℃水溶液下存放的稳定性实验;其中图4A为一定时间后最大吸收波长吸光度的变化;图4B为光催化能力变化;
图5为实施示例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的细胞毒性考察;
图6为实施示例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂于荷瘤小鼠中的在体分布;
图7为实施示例9下制备的钙钛矿-二氧化钛纳米复合光催化剂及实施示例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂用于肿瘤治疗后的小鼠肿瘤组织病理切片;
图8实施示例9下制备的钙钛矿-二氧化钛纳米复合光催化剂及实施示例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂用于健康小鼠后的血样生化指标检测;其中,图8A为评价肝功能的碱性磷酸酶(ALP),图8B为评价肝功能的丙氨酸氨基转移酶(ALT),图8C为评价肾脏功能指标的肌酐(CREA),图8D为评价肾脏功能指标的尿素氮(BUN),图8E为评价甲状腺功能的游离三碘甲状原氨酸(FT3),图8F为评价甲状腺功能的游离甲状腺素(FT4);
图9为实施示例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂用于肿瘤治疗后小鼠的基因毒性考察;其中,图9A为彗星实验图片,图9B为对应统计数据。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合具体实施例和附图对本发明的技术方案做进一步说明。应当理解,此处所描述的具体实施方案仅仅用以解释本发明,并不用于限定本发明。
本发明所述“MA”是指:CH3NH3;
本发明所述“MASnX3”是指:CH3NH3SnX3,钙钛矿纳米粒;
本发明所述“MT”是指:CH3NH3SnX3-TiO2,钙钛矿-二氧化钛纳米复合光催化剂;
本发明所述的“HMT”是指:生物材料透明质酸负载的钙钛矿-二氧化钛纳米复合光催化剂;
本发明所述“OA”是指:油酸;
本发明所述“OAm”是指:油胺;
本发明所述“TBOT”是指:钛酸丁酯;
本发明所述“NIR”是指:近红外;
本发明所述“ROS”是指:活性氧;
本发明所述“Cyto-c”是指:细胞色素c。
一、钙钛矿-二氧化钛纳米复合光催化剂的制备工艺
1)钙钛矿纳米粒CH3NH3SnX3(MASnX3)的制备
S1-1:分别配制SnX2的良溶剂母液和CH3NH3X的良溶剂母液,将SnX2的良溶剂母液和CH3NH3X的良溶剂母液混合均匀得到混合液,向混合液中加入油酸及预热的油胺,配成前驱液;
所述良溶剂为二甲基亚砜(DMSO);
分别配制SnX2及CH3NH3X的DMSO母液,X的种类为表1所示卤素的一价阴离子,混合均匀得到混合液,向混合液中加入油酸(OA)及在55℃下预热为液态的油胺(OAm),配成前驱液。各实施例中所述混合液中SnX2与CH3NH3X摩尔比、前驱液中的油酸和油胺的体积百分比分别如表1所示;
S1-2:将前驱液剧烈搅拌后冷却至室温,逐滴加入到混溶性抗溶剂中,得到分散的CH3NH3SnX3反应液;
所述混溶性抗溶剂为甲苯;
前驱液与甲苯的体积比为1:15;
将S1-1得到的将前驱液在55℃下剧烈搅拌15min后冷却至室温,逐滴加入到甲苯中,得到分散的CH3NH3SnX3反应液;
S1-3:吸取S1-2得到的CH3NH3SnX3反应液到非混溶性抗溶剂中,轻轻摇晃混匀后静置至溶液分层,收集下层的油状溶液,再次加入一定量非混溶性抗溶剂重复上述操作,得到纯化的CH3NH3SnX3纳米粒,即钙钛矿纳米粒;
所述非混溶性抗溶剂为正己烷;
所述CH3NH3SnX3反应液与正己烷的体积比为1:10;
吸取S1-2得到的钙钛矿反应液到十倍量正己烷中,轻轻摇晃混匀后静置至溶液分层,收集下层的油状溶液,再次加入十倍量正己烷重复上述操作,得到纯化的CH3NH3SnX3纳米粒。
表1 MASnX3的合成处方
2)钙钛矿-二氧化钛纳米复合光催化剂MASnX3-TiO2(MT)的制备
S2-1:取S1制备得到的CH3NH3SnX3分散于乙醇与正己烷的混合溶剂中,超声后加入钛酸丁酯与浓盐酸常温下搅拌后,冷凝回流;
取1)制备得到的CH3NH3SnX3纳米粒分散于乙醇与正己烷的混合溶剂中,所述混合溶剂中乙醇与正己烷的体积比为3:1;超声15min后加入钛酸丁酯(TBOT),各实施例中CH3NH3SnX3与TBOT质量比为如表2所示;滴加浓盐酸,CH3NH3SnX3与浓盐酸的质量比为5:1;常温下搅拌3h后,在45℃下冷凝回流一定时间,回流反应时间如表2所示。
S2-2:将S2-1得到的反应液加入反应液3倍体积的正己烷纯化,离心收集析出的白色沉淀,真空干燥除去有机溶剂,得到CH3NH3SnX3-TiO2(MT)复合物粉末,即钙钛矿-二氧化钛纳米复合光催化剂。
表2 MASnX3-TiO2(MT)的合成处方
3)生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的构建
生物材料与2)制备的MASnX3-TiO2在紫外光引发下发生Click反应,所述生物材料为透明质酸(Hyaluronic acid,HA),所述反应的具体操作为:
步骤一:透明质酸表面无双键修饰,需先进行双键修饰透明质酸
称取0.1g HA溶于纯水中,再加入800μL甲基丙烯酸酐(MA),调节pH在8~9之间,在4℃搅拌条件下反应48h。反应结束后用冰乙醇纯化,将析出的白色沉淀复溶于纯水中,经透析、冻干得到双键修饰的透明质酸(m-HA);
步骤二:合成巯基化MT(MT-SH)
将2mg MT分散在5mL乙醇/水(49/1,v/v)混合溶剂中,加入30μL巯丙基三甲氧基硅烷(MPTMS)(MolMPTMS:MolMT=50:1)在氮气保护下反应5h。16000rpm离心5min后乙醇洗两遍沉淀,真空干燥12h,得到MT-SH;
步骤三:进行Click反应
分别配制0.2mg/mL的MT-SH水溶液、2mg/mL的光引发剂2,2-二甲氧基-2-苯基苯乙酮(DMPA)乙醇溶液及m-HA水溶液,所述m-HA水溶液的浓度为0.2~0.4mg/mL;吸取500μLMT-SH溶液、20μL DMPA溶液、500μL m-HA溶液混合均匀,所述生物材料与MASnX3-TiO2的质量比如表3所示;置于365nm紫外灯光照发生巯烯Click反应,所述光照时间如表3所示;反应结束后避光透析24h除去游离DMPO及有机溶剂,得到生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂(HA@MASnI3-TiO2,HMT)。
表3 HA@MASnX3-TiO2(HMT)的合成处方
二、生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的性质研究
利用实施示例1制备的钙钛矿纳米粒和实施示例9制备的钙钛矿-二氧化钛纳米复合光催化剂以及实施例13下构建的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂进行后续研究。
1.钙钛矿表征
采用透射电子显微镜(Transmission electron microscope,TEM)分析实施例1制备的MASnI3纳米粒和实施例9制备的MT的形态特征。结果如图1所示,在A图下可见钙钛矿呈圆球形均匀分布,尺寸约为5nm。这是由于晶体外层有长链油酸油胺配体的存在,很好的控制晶体尺寸并使纳米晶体形成“胶束”而呈现圆球形。包覆上二氧化钛后,亦呈圆球形均匀分布(C图),尺寸约为50nm。采用高分辨透射电子显微镜(High-resolution transmissionelectron microscope,HRTEM)分析实施例1制备的MASnI3纳米粒(B图)和实施例9制备的MT的晶体结构(D图),HRTEM图像呈现出清晰的晶格条纹,表明了MASnI3与MT皆具备高结晶度。
2.傅里叶变换红外光谱
对实施例1制备的MASnI3、TiO2、实施例9制备的MT的傅里叶变换红外测试,结果如图2所示,MASnI3谱图中的3424cm-1为N-H的伸缩振动峰,1407cm-1为C-N伸缩振动峰,1021cm-1为NH2面内摇摆振动峰,以上结果表明MASnI3中CH3NH3 +的存在;500~800cm-1为TiO2的特征峰;在MT峰谱图中出现的1120cm-1及838cm-1处吸收峰表示Ti-O-C键的存在,结合500~800cm-1处TiO2的特征峰可证明实施例9制备的MT中MASnI3与TiO2的成功结合。
3.MT产生自由基类型
用808nm光源触发实施例9制备的MT,以二甲基吡啶N-氧化物电子捕获剂DMPO作为电子自旋捕捉剂,进行电子自旋共振测试,验证钙钛矿光敏材料MT在光照下产生的自由基种类。结果如图3所示,没有经过光照的MT谱图中没有出现峰,说明没有自由基的产生;当MT经过激光照射后,谱图中出现了四个强度比为1:2:2:1的峰,此为羟基自由基的特征峰,表明MT在光照下可产生大量羟基自由基。
4.钙钛矿及MT的稳定性考察
配制相同MASnI3浓度的实施例1制备的MASnI3及实施例9制备的MT水溶液,静置贮存于4℃条件下,7天内在预设时间点下取样品测定在最大吸收波长下的吸光度。并考察存放一定时间后的MASnI3、及MT催化亚甲蓝降解能力。光催化材料经激光照射后产生的ROS可与亚甲蓝发生反应使其降解,因此在体外可通过光催化亚甲蓝降解实验评价光催化材料产生自由基的能力。配制2mg/mL的MT水分散液与亚甲蓝水溶液(0.02mg/mL)避光搅拌30min,达到吸附-解吸平衡后,暴露在808nm激光照射(2W/cm2)下,在预设时间点下吸取200μL反应液,离心后取上清用酶标仪测定其在664nm下吸光度,考察亚甲蓝降解情况。MASnI3、MT水溶液在4℃下存放一定时间后最大吸收波长吸光度的变化及光催化能力变化如图4所示。结果显示,存放一周内,MASnI3遇水分解,溶液变为无色吸光度接近0,不具有催化降解亚甲蓝的作用。而钙钛矿光敏材料MT仍然具有催化降解亚甲蓝的能力,且光催化能力无明显下降,表明MT结构稳定性良好。
5.HMT细胞毒性实验
向96孔板的每孔加入100μL小鼠乳腺癌4T1细胞(来源:中国科学院上海生物化学与细胞生物学研究所)悬液(约5000个/孔),孵育过夜后弃掉培养基用PBS清洗2次,将实施例13制备的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂HMT用无血清培养基稀释至0.1、1、5、10、50、100μg/mL(以MT浓度计算),各浓度下设置5个复孔,每孔加入100μL含药培养基。各孔孵育8h后,分别暴露在808nm激光(2W/cm2)下1、2、3、4、5、6、7、8次循环(t)。为避免培养基光照后过热,每光照5min后间隔5min,以此为一次光照循环。光照后继续孵育24h后在避光条件下向每孔加入20μL浓度为5mg/mL的MTT溶液,继续培养4h,除去培养基每孔加入100μL DMSO,振摇至甲臜结晶溶解,通过多功能酶标仪测定570nm波长下的吸光度,并按公式计算细胞活力。
Cell viability/%=(ODsample-ODblank)/(ODcontrol-ODblank)×100%
其中,ODsample是供试液处理的供试液孔的吸光度,ODcontrol是仅用空白培养液处理的对照孔的吸光度,ODblank以完全培养液为空白调零孔的吸光度。
结果如图5所示,随着制剂HMT浓度的提高及光照次数的增加,细胞存活率逐渐下降,细胞PDT效果显著。钙钛矿材料作为光催化材料,在一定范围内可以通过增加光照次数降低剂量并提高效果,体现了本发明的钙钛矿光催化材料应用在PDT中的优势。
6.体内分布
选用小鼠乳腺癌4T1细胞(来源:中国科学院上海生物化学与细胞生物学研究所)对BALB/c小鼠进行原位乳腺癌模型的建立。Cy5为荧光探针,构建Cy5HMT,以便于观察实施例13制备的HMT在小鼠体内的分布。瘤内注射Cy5HMT(以0.9%生理盐水为溶剂,以MT剂量为0.1mg/kg计算,给药剂量50μL)后的0h、2h、4h、8h、12h、24h、36h、48h、72h,通过小动物活体成像仪观察荷瘤小鼠体内荧光分布情况。结果如图6所示,瘤内注射Cy5HMT后肿瘤部位立即出现明显的荧光信号(图6虚线圈内),随着时间推移,体内的荧光信号逐渐减弱,说明HMT在HA纳米凝胶递送载体的作用下,可以高效的蓄积在肿瘤组织,在72h时认可明显观测到,现对于现有技术中的光动力治疗药物滞留性更强,有利于进行长期的光照。
7.小鼠肿瘤组织病理切片
以“6”中成功构建的小鼠原位乳腺癌模型,待肿瘤体积长至100mm3,对小鼠随机分成六组,各组分别为:(1)生理盐水组;(2)NIR照射组;(3)MT组;(4)MT与NIR照射组;(5)HMT组;(6)HMT与NIR照射组。
各组处理方式分别为:
(1)生理盐水组(Saline):每三天瘤内注射给予50μL生理盐水,共注射六次;
(2)NIR照射组(NIR):第一天瘤内注射给予50μL生理盐水,随后进行3个循环激光照射(每个循环为光照5min间隔5min),第二天继续给予3个循环NIR激光照射,第三天不做处理;共治疗六次;
(3)MT组(MT):每三天瘤内注射给予50μL实施例9下的MT药液,以0.9%生理盐水为溶剂,以MT 10mg/kg计算;共注射六次;
(4)MT与NIR照射组(MT+NIR):第一天瘤内注射给予50μL实施例9下的MT药液,以0.9%生理盐水为溶剂,以MT 10mg/kg计算;随后进行3个循环激光照射(每个循环为光照5min间隔5min),第二天继续给予3个循环NIR激光照射,第三天不做处理;共给药治疗六次;
(5)HMT组(HMT):每三天瘤内注射给予50μL实施例13下的HMT药液,以0.9%生理盐水为溶剂,以MT 10mg/kg计算;共注射六次;
(6)HMT与NIR照射组(HMT+NIR):第一天瘤内注射给予50μL实施例13下的MT药液,以0.9%生理盐水为溶剂,以MT 10mg/kg计算;随后进行3个循环激光照射(每个循环为光照5min间隔5min),第二天继续给予3个循环NIR激光照射,第三天不做处理;共给药治疗六次。
从首次给药开始计算,第18天取各组小鼠的肿瘤制备成H&E染色切片,考察肿瘤组织的细胞受损程度,结果如图7所示。细胞核被苏木精染色后呈紫色,细胞浆被伊红染色后呈粉色。生理盐水组的肿瘤细胞生长旺盛,排列紧密,细胞核着色较深且其形状不规则,胞浆较少,具有典型的肿瘤组织病理特征;NIR、MT、HMT治疗组表现出与生理盐水组相近的组织形态,没有明显的肿瘤细胞死亡;MT+NIR组瘤组织呈现出一定程度的肿瘤细胞坏死区域,细胞核数目减少,着色变浅,胞浆区域增多;相比之下,HMT+NIR组具有最强的肿瘤细胞杀伤效果,肿瘤细胞基本全部坏死,细胞核数目明显减少且着色不明显,视野内呈现一片粉色的胞浆。该结果再一次表明,HMT在NIR触发下发挥长效PDT的治疗作用,具有优秀的抗肿瘤活性。
8.HMT的血样生化指标检测
取健康BALB/c小鼠,随机分为三组进行安全性评价实验,分别为:(1)生理盐水组(Saline);(2)MT组(MT);(3)HMT组(HMT)。根据GLP法规,长期毒性试验用药周期为2周,每周给药2~3次。每3天对小鼠分别通过静脉注射给予50μL实施例9制备的MT(以0.9%生理盐水为溶剂,以MT 10mg/kg计算)、实施例13制备的HMT(以0.9%生理盐水为溶剂,以MT 10mg/kg计算)及0.9%生理盐水,持续两周。给药结束后取各组小鼠通过摘眼球取血,2000rpm离心5min后收集上层血清。将得到的各组小鼠血清样品进行生化指标检测,包括评价肝功能的碱性磷酸酶(ALP)、丙氨酸氨基转移酶(ALT),评价肾脏功能指标尿素氮(BUN)和肌酐(CREA)以及评价甲状腺功能的游离三碘甲状原氨酸(FT3)和游离甲状腺素(FT4),通过血样生化指标评价钙钛矿原位纳米凝胶系统HMT对健康小鼠组织器官的长期毒性。HMT所含的锡元素中毒主要引起肝脏损伤,碘元素吸收后作用于组织蛋白可能会引起各组织器官损害,尤以肾脏损害为甚,长期服用对甲状腺功能也有一定损伤。结果如图8所示。由结果可知,MT组、HMT组小鼠的各项血样生化指标与生理盐水组相比均在正常范围内变化,说明钙钛矿原位纳米凝胶系统HMT未引起小鼠的肝、肾及甲状腺器官损伤。
9.HMT的基因毒性考察
通过单细胞凝胶电泳实验及彗星电泳实验考察制剂对小鼠DNA损伤情况,评价制剂的基因毒性。采用生理盐水(静脉注射给予50μL)和实施例13制备的透明质酸负载的钙钛矿-二氧化钛纳米复合光催化剂HMT(以0.9%生理盐水为溶剂,以MT 10mg/kg计算,静脉注射给予50μL)对健康小鼠给药,用药周期为2周,每周给药2~3次。给药周期结束后分离各组小鼠外周血淋巴细胞进行凝胶电泳实验。小鼠外周血淋巴细胞被包埋在琼脂糖凝胶中后,经裂解与解旋,受损细胞的破碎DNA片段带负电荷,在电泳作用下向阳极迁移或延伸,形成拖尾,成彗星状。尽快在倒置荧光显微镜下观察细胞拖尾情况并拍照,用CASP图像分析软件对各组细胞的尾长、尾部DNA含量百分比、尾矩及Olive尾矩四个指标进行分析,评价钙钛矿原位纳米水凝胶系统HMT对小鼠DNA损伤情况,结果如图9所示。从A图的彗星实验图片可以看出,生理盐水组及HMT组细胞形态表现为椭圆形的光亮圆球,无明显的头部及尾部,结合B图的统计数据,HMT组细胞的尾长、尾部DNA含量、尾矩及Olive尾矩均在正常范围内变化,与生理盐水组相比无显著性差异。以上结果说明钙钛矿原位纳米水凝胶系统HMT对小鼠外周血淋巴细胞无明显DNA损伤,表明HMT无基因毒性。
Claims (10)
1.一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂,其特征在于:所述生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂包括钙钛矿纳米粒、二氧化钛壳层和生物递送材料;所述二氧化钛壳层包覆钙钛矿纳米粒,构成钙钛矿-二氧化钛纳米复合光催化剂;所述钙钛矿-二氧化钛纳米复合光催化剂由生物材料所负载;
所述钙钛矿纳米粒的分子结构式为CH3NH3SnX3,其中X为I、Br、Cl一价卤素阴离子中的一种或多种;
所述钙钛矿纳米粒粒径范围2~20nm;钙钛矿-二氧化钛纳米复合光催化剂粒径范围10~100nm;
优选的,所述生物材料选自表面双键修饰的高分子聚合物,或其衍生物,或高分子聚合物和/或其衍生物的组合;进一步优选的,所述生物材料选自表面双键修饰的透明质酸、壳聚糖、聚乳酸、葡聚糖、明胶、瓜尔胶、泊洛沙姆、聚(N-异丙基丙烯酰胺)中的一种或多种的组合;
优选的,所述生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂在近红外区响应。
2.权利要求1所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,包括以下步骤:
S1:合成钙钛矿纳米粒;
S2:制备钙钛矿-二氧化钛纳米复合光催化剂;
S3:构建生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂。
3.根据权利要求2所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,S1的具体步骤为:
S1-1:分别配制SnX2的良溶剂母液和CH3NH3X的良溶剂母液,将SnX2的良溶剂母液和CH3NH3X的良溶剂母液混合均匀得到混合液,向混合液中加入油酸及油胺,配成前驱液;
优选的,所述混合液中SnX2与CH3NH3X摩尔比为(0.8~1.2):(0.8~1.2);
S1-2:将前驱液剧烈搅拌后冷却至室温,逐滴加入到混溶性抗溶剂中,得到分散的CH3NH3SnX3反应液;
S1-3:吸取CH3NH3SnX3反应液到非混溶性抗溶剂中,轻轻摇晃混匀后静置至溶液分层,收集下层的油状溶液,再次加入非混溶性抗溶剂重复上述操作,得到纯化的CH3NH3SnX3纳米粒,即钙钛矿纳米粒。
4.根据权利要求3所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,
S1-1中所述良溶剂选自二甲基亚砜、二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、γ-丁内酯、二甲基丙烯脲中的一种或几种;
S1-1中所述前驱液中油酸的体积百分比为8%~14%;所述前驱液中油胺的体积百分比为0.4%~1.0%。
5.根据权利要求3所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,
S1-2中所述混溶性抗溶剂选自甲苯、丙酮、乙腈、氯苯、乙醚、二氯甲烷、硝基甲烷、异丙醇、乙酸乙酯中的一种或几种;
S1-2中所述前驱液与混溶性抗溶剂的体积比为1:10~20。
6.根据权利要求3所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,
S1-3中所述非混溶性抗溶剂选自正己烷、二乙醚、仲丁醇、三氟甲苯、碘化苯、苯甲醚、乙酸甲酯、乙酸乙酯中的一种或几种;
S1-3中每次加入非混溶性抗溶剂的量为CH3NH3SnX3反应液与非混溶性抗溶剂的体积比1:5~10。
7.权利要求2所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于,S2的具体步骤为:
S2-1:取S1制备得到的CH3NH3SnX3分散于混合溶剂中,超声后加入钛酸丁酯与浓盐酸常温下搅拌后,冷凝回流,得到反应液;所述混合溶剂由乙醇与正己烷组成;
S2-2:将S2-1得到的反应液加入正己烷纯化,离心收集析出的白色沉淀,真空干燥除去有机溶剂,得到CH3NH3SnX3-TiO2复合物,即钙钛矿-二氧化钛纳米复合光催化剂。
8.根据权利要求6所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于:
S2-1中所述混合溶剂中乙醇与正己烷的体积比为2~4:1;所述超声的时间为10~30min;CH3NH3SnX3与钛酸丁酯的质量比为1:20~30;CH3NH3SnX3与浓盐酸的质量比为10:1~3;
所述搅拌的时间为2~4h;冷凝回流时间为5~20h;冷凝回流温度为40~50℃;
S2-2中所述反应液与正己烷的体积比为1:3~5。
9.权利要求2所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂的制备方法,其特征在于:S3的具体步骤为:
S3-1:将S2得到的钙钛矿-二氧化钛纳米复合光催化剂进行表面巯基化反应,得到表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂;
优选的,S3-1所述表面巯基化反应为将钙钛矿-二氧化钛纳米复合光催化剂分散在乙醇中,加入巯丙基三甲氧基硅烷,在氮气保护下进行表面巯基化反应,所述巯丙基三甲氧基硅烷与钙钛矿-二氧化钛纳米复合光催化剂的摩尔比为50:1;
进一步优选的,所述乙醇的体积百分比浓度为98%,所述钙钛矿-二氧化钛纳米复合光催化剂在乙醇中的浓度为0.4mg/mL,所述表面巯基化反应时间为5h;
S3-2:将生物材料与S3-1得到的表面修饰巯基的钙钛矿-二氧化钛纳米复合光催化剂在紫外光引发下发生Click反应,制备得到生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂。
10.权利要求1所述的生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂在制备光动力治疗药物中的应用;优选的,所述光动力治疗药物为治疗肿瘤的光动力治疗药物;进一步优选的,为治疗肿瘤的长效I型光动力治疗药物。
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