CN113384697A - 针对肿瘤诊疗一体化的多功能纳米粒子及制备、应用 - Google Patents
针对肿瘤诊疗一体化的多功能纳米粒子及制备、应用 Download PDFInfo
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Abstract
本发明公开了一种针对肿瘤诊疗一体化的多功能纳米粒子及其制备和应用;所述纳米粒子由药物运输载体和光活化药物组成;所述纳米粒子具有空腔介孔结构能够携带药物进入体内;纳米载体作为光转化器能够将外部施加的近红外光转化为可见光。该多功能纳米体系通过静脉注射,将药物携带运输至肿瘤部位并积聚,通过在肿瘤原位将近红外光转化为蓝光,从而刺激光活化药物与周围的水发生反应释放活性氧,最终导致肿瘤细胞凋亡。此外,掺杂钆离子的纳米粒子可作为磁共振成像剂,用于肿瘤成像和实时监测治疗过程,有助于实现肿瘤的高效治疗以及早期诊断,这为详细研究用于癌症诊疗的高效纳米剂提供了一种新方法。
Description
技术领域
本发明属于分子影像学技术领域,涉及一种肿瘤诊疗一体化的多功能纳米粒子及制备、应用。
背景技术
癌症是全球导致死亡的主要原因,由于预期寿命的延长,人口老龄化加剧,癌症新病例和死亡人数迅速增加,癌症负担在全球范围内持续增长,给个人、家庭、社区和卫生系统造成巨大的身体、情感和经济负担。其中,乳腺癌发病率位列女性恶性肿瘤之首,2020年,全球乳腺癌新发病例约为226.1万,占女性所有病例的24.5%;死亡病例68.5万,占女性所有病例的15.5%
传统的肿瘤治疗方法,如手术、化疗、放疗等,往往伴随致命的副作用、多药耐药、治疗效率低等缺点。纳米科学和纳米生物技术的发展丰富了抗肿瘤治疗策略。在各种新型治疗策略中,光动力疗法(Photodynamic therapy,PDT)作为一种局部治疗方法引起了广泛关注。PDT是传统的肿瘤治疗方法外新的肿瘤疗法,具有选择性强、创伤小、疗效好、不良反应少、可重复治疗等优点,已被中国和美国的食品及药物管理局批准用于临床上治疗恶性肿瘤的一种治疗手段。PDT通过适当波长的光激活光敏剂,引发特殊的光化学反应,产生可致肿瘤细胞坏死、凋亡和/或自噬的细胞毒性活性氧。但是,由于光动力疗法的氧依赖性和激发波长的组织穿透深度不足使其在低氧环境和深部肿瘤的应用受到了很大的限制。迫切需要开发不依赖氧的光活化化学疗法(Photoactivated chemotherapy,PACT),以通过近红外光激发产生具有细胞毒性的活性氧。
与PDT相比,PACT利用带有光可裂解保护基团的前药,通过光触发的去保护作用激活前药释放细胞毒性物质。在各种PACT试剂中,有机小分子因具有易于化学修饰的特点引起了广泛关注。(-)-Blebbistatin是一种高度选择性和可逆的非肌肉肌球蛋白II ATP酶抑制剂,可以在蓝光(λex:450-490nm)暴露条件下快速激活,并在细胞中产生光毒性。Blebbistatin不依赖氧气,但发生水依赖性质子化和激发态分子内质子转移,在蓝光照射下触发羟基自由基(·OH)的局部爆发,通过激活的与半胱氨酸蛋白酶相关的凋亡途径导致癌细胞死亡。然而,蓝光的组织穿透深度有限,并且具有皮肤光毒性,这对其在深层组织的临床应用提出了严峻的挑战。因此,在近红外光辐照下开发基于Blebbistatin的有效转运和按需生成·OH的多功能性纳米体系具有重要的临床需求和价值。
发明内容
本发明的目的在于针对现有自由基疗法的缺陷,设计了一种基于近红外光触发羟基自由基生成的不依赖氧的针对肿瘤诊疗一体化的多功能纳米粒子及其制备与应用。通过在掺钆的上转换纳米材料外包覆介孔二氧化硅,并在介孔中加载光活化药物Blebbistatin,携带药物进入体内,实现不依赖氧的·OH的定位释放和小鼠体内肿瘤的MR成像。本发明设计的装载光活化药物Blebbistatin的UCSNs纳米分子,能够对肿瘤进行有效治疗以及准确显示病灶。
本发明的目的是通过以下技术方案的内容来实现的:
第一方面,本发明提供一种针对肿瘤诊疗一体化的多功能纳米粒子,所述纳米粒子包括药物运输载体UCSNs和光活化药物Blebbistatin。所述纳米粒子能够携带药物进入体内;所述纳米载体作为光转化器能够将外部施加的近红外光转化为可见光。
作为本发明的一个实施方案,所述纳米粒子是在掺钆的上转换纳米颗粒外包覆介孔二氧化硅,并在介孔中加载光活化药物。
作为本发明的一个实施方案,所述纳米粒子中光活化药物的加载量为10-15%。
作为本发明的一个实施方案,所述上转换纳米颗粒为NaYF4:Yb/Tm@NaGdF4;所述光活化药物为Blebbistatin。
作为本发明的一个实施方案,所述纳米粒子含有稀土元素Yb和Tm。具有上转换发射蓝光的性能。所述纳米粒子中Y:Yb:Tm:Gd=1.5-1.7:0.35-0.4:0.01-0.03:1。作为一个具体示例,所述纳米粒子中Y:Yb:Tm:Gd=1.6:0.38:0.02:1。
作为本发明的一个实施方案,所述纳米粒子具有空腔介孔结构。可以作为药物的运输载体。
作为本发明的一个实施方案,所述纳米粒子包含顺磁性钆离子。具备T1磁共振成像性能。
作为本发明的一个实施方案,所述纳米粒子不依赖周围环境中的氧气生成活性氧。
作为本发明的一个实施方案,所述纳米粒子定点可控地产生羟基自由基。
第二方面,本发明提供一种针对肿瘤诊疗一体化的多功能纳米粒子的制备方法,所述方法包括如下步骤:
S1、利用高温热分解法制备NaYF4:Yb/Tm内核;
S2、利用外延生长法制备NaYF4:Yb/Tm@NaGdF4,即UCNPs;
S3、在UCNPs外包覆介孔二氧化硅,制备UCNPs@Mesoporous Silica(SiO2)Nanoparticles,即UCSNs;
S4、UCSNs@Blebbistatin的制备:将Blebbistatin溶于溶剂中,加入UCSNs,在黑暗环境中搅拌20-28小时;离心得到产物。
步骤S1中,内核形貌大致为球形,均一性良好,粒径分布均匀,约为15±2nm。
步骤S2中,UCNPs形貌大致为球形,均一性良好,粒径分布均匀,约为20±2nm。
步骤S4中,所述溶剂为二甲基亚砜。
作为本发明的一个实施方案,步骤S1具体为:将氯化钇、氯化镱和氯化铥加入油酸和十八碳烯中;得到的混合溶液缓慢加热到至150±5℃,并保持0.8-1.5小时以除去水分;随后停止加热并冷却至室温后,加入含氢氧化钠和氟化铵的甲醇溶液,在室温下搅拌30-40分钟;加热至100±5℃并持续搅拌0.8-1.5小时,无明显气泡产生后,冷凝抽真空以去除多余的甲醇;随后通氩气的同时加热至300±10℃并保持1-2小时;自然冷却至室温,加入无水乙醇,离心收集沉淀,将产物重新分散于环己烷中,用乙醇沉淀,离心收集;经多次乙醇洗涤后,将最终产物分散于环己烷中得到内核溶液。
其中,氯化钇、氯化镱、氯化铥、氢氧化钠和氟化铵的摩尔比为1.5-1.7:0.35-0.4:0.01-0.03:4.5-5.5:8。作为一个具体示例,氯化钇、氯化镱、氯化铥、氢氧化钠和氟化铵的摩尔比为1.6:0.38:0.02:5:8。
作为本发明的一个实施方案,步骤S2具体为:氯化钆加入油酸和十八碳烯中,搅拌均匀并加热到150±5℃,持续0.8-1.5小时;停止加热并冷却至室温,逐滴加入上一步制备好的内核溶液,混合均匀加热到80±2℃,维持15-25分钟以蒸发剩余的环己烷;冷却至室温后,缓慢加入含氢氧化钠和氟化铵的甲醇溶液;室温下搅拌30-40分钟后,加热至100±2℃并持续搅拌0.8-1.5小时,随后冷凝抽真空以去除多余的甲醇;向反应体系中通入氩气,缓慢升温到300±10℃并保持1-2小时;反应溶液逐渐冷却至室温,加入无水乙醇,离心收集沉淀,将产物重新分散于环己烷中,用乙醇沉淀,离心收集;重复三次无水乙醇洗涤后,将最终产物分散于环己烷中获得澄清溶液,即UCNPs的环己烷溶液。
其中,氯化钆、氢氧化钠和氟化铵的摩尔比为1:2-3:3.5-4.5;氯化钆和内核溶液的摩尔比为1:1.8-2.2;UCNPs的环己烷溶液中UCNPs的质量百分比浓度为2.0-0.8%。作为一个具体示例,氯化钆、氢氧化钠和氟化铵的摩尔比为1:2.5:4;氯化钆和内核溶液的摩尔比为1:2;UCNPs的环己烷溶液中UCNPs的质量百分比浓度为2.5%。
作为本发明的一个实施方案,步骤S3包括:
S3-1.将聚氧代乙烯(5)壬基苯基醚溶解在环己烷中,搅拌均匀后滴加UCNPs的环己烷溶液,混合反应2.5-3.5小时;然后逐滴加入氨水,密封搅拌;将正硅酸四乙酯的环己烷溶液以每小时100微升的速度注入反应体系后,密封搅拌22-26小时;加入甲醇终止反应,离心、洗涤、收集,最终分散于去离子水中得到溶液①;
S3-2.将十六烷基三甲基氯化铵和的三乙胺溶解在去离子水中,在室温下搅拌1.2-1.8小时;逐滴加入所述溶液①,并继续搅拌1.2-1.8小时;转移至70±2℃水浴锅中预热,滴加正硅酸四乙酯,继续搅拌0.8-1.2小时;自然冷却至室温,离心、洗涤、收集;离心产物溶于氯化钠的甲醇溶液中,搅拌4-7小时,离心、洗涤、收集,将产物重新分散到去离子水中得到溶液②;
S3-3.室温下混合聚乙烯吡咯烷酮、去离子水和溶液②,匀速搅拌0.4-1.6小时,加热至95±5℃并保持反应3-5小时;自然冷却至室温,离心、洗涤、收集,最终将产物分散到去离子水中,即得所述UCSNs。
步骤S3-1中,聚氧代乙烯(5)壬基苯基醚与UCNPs的环己烷溶液、正硅酸四乙酯的体积比为1:0.8-2.2:0.1-0.3。作为一个具体示例,聚氧代乙烯(5)壬基苯基醚与UCNP s的环己烷溶液、正硅酸四乙酯的体积比为1:2:0.2。
步骤S3-2中,十六烷基三甲基氯化铵、三乙胺、溶液①和正硅酸四乙酯的质量比为95-105:1:1.8-2.2:9-11。作为一个具体示例,十六烷基三甲基氯化铵、三乙胺、溶液①和正硅酸四乙酯的质量比为100:1:2:10。
步骤S3-3中,聚乙烯吡咯烷酮和溶液②的体积比为0.1-0.3:1;步骤S4中,Blebbistatin与UCSNs的质量比为1:3-5。作为一个具体示例,聚乙烯吡咯烷酮和溶液②的体积比为0.2:1;步骤S4中,Blebbistatin与UCSNs的质量比为1:4。
第三方面,本发明提供了前述的针对肿瘤诊疗一体化的多功能纳米粒子在制备肿瘤的诊疗一体化制剂中的应用。
本发明制备了均一性好、粒径分布均匀、稳定性高、具有空腔及介孔结构的多功能纳米体系UCSNs,实现了负载前体药物Blebbistatin,首次将上转换材料与光活化药物blebbistatin结合,实现肿瘤影像介导的高效的不依赖氧的释放自由基治疗肿瘤。首次结合是指将两者的性能结合,上转换材料作为一种光转换器,能够有效地将能量低但穿透性强的近红外光转化为能量高但穿透性弱的蓝光,继而激发Blebbistatin释放·OH。具体来说,UCNPs是包含具有将近红外光转化为蓝光性能的内核NaYF4:Yb/Tm以及具有T1成像性能的NaGdF4壳层;UCSNs则在UCNPs外包覆介孔二氧化硅,增加其水溶性并使其具备携带药物的性能。本发明主要是利用上转换颗粒发出的蓝光来激活光活化药物Blebbistatin释放ROS。掺杂的离子在上转换发光中具有重要作用,稀土Yb3+的激发光波长是980nm,可作为上转换敏化剂,提高上转换效率;稀土Tm2+则使其能够转换发出蓝紫光。
与现有技术相比,本发明具有如下有益效果:
1、本发明针对肿瘤诊疗一体化的多功能纳米粒子,是由运输载体UCSNs和光活化药物Blebbistatin组成;该运输载体核心部分为上转换材料UCNP,通过在UCNP中掺入NaGdF4,构建无机钆基纳米探针,实现肿瘤的T1-MR成像,进一步实现肿瘤的诊疗一体化。
2、本发明针对肿瘤诊疗一体化的多功能纳米粒子,载体含稀土离子可作为光转换器,将能量低但穿透性强的近红外光转化为能量高但穿透性弱的蓝光,从而有效光解药物Blebbistatin,可控地产生·OH,突破了传统PDT中可见光组织穿透深度的限制。
3、本发明针对肿瘤诊疗一体化的多功能纳米粒子,选择负载的前体药物Blebbistatin:是在蓝光激活的情况下、不依赖氧、与水发生光化学反应释放活性氧,实现了PDT与光激活化疗的有效结合,提高治疗效果的同时避免传统PDT对氧依赖的缺陷以及常规化疗的副作用。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1多功能纳米粒子UCSNs-B的合成示意图及作用原理示意图,其中,(A)为UCSNs-B的合成示意图;(B)为UCSNs-B反应生成羟基自由基的示意图;
图2为多功能纳米粒子的表征图,其中:(A)UCSNs的透射电镜图;(B)UCSN s-B分散在水、磷酸盐缓冲溶液和高糖培养基介质中的水动力直径;(C)980nm激光(1W/cm2)照射NaYF4:Tm/Yb、NaYF4:Tm/Yb@NaGdF4和UCSNs的发射光谱;(D)以5,5-二甲基-1-吡咯啉-N-氧化物(DMPO)为自由基捕获剂,980nm激光照射(1W/cm2,10min)UCSNs、Blebbistatin和UCSNs-B的ESR谱;
图3为UCSNs-B的磁敏感表征图,其中:(A)含不同钆离子浓度的UCSNs-B的T1加权MR图像;(B)T1弛豫率图;
图4为建立体外细胞模型,肿瘤细胞内吞荧光素异硫氰酸酯(FITC)标记的UCSN s-B(UCSNs-B-FITC)纳米粒子的激光共聚焦图像;
图5为建立体外细胞模型,分析肿瘤细胞经过不同处理后,细胞内产生ROS的结果示意图;
图6为建立体外细胞模型,分析UCSNs-B对肿瘤细胞的生存率影响的结果示意图,其中:(A)UCSNs孵育24/48小时后对肿瘤细胞的细胞毒性;(B)UCSNs-B孵育24/48小时后对肿瘤细胞的细胞毒性;(C)UCSNs-B孵育24小时后伴或者不伴980nm的激光激发(1W/cm2,10分钟)对肿瘤细胞的细胞毒性;(D)经过不同处理后对肿瘤细胞的毒性对比;
图7为建立体外细胞模型,分析肿瘤细胞经过不同处理后,细胞存活率的流式细胞术分析结果图;
图8为建立肿瘤动物模型,评估UCSNs-B的抗肿瘤能力,其中:(A)不同组肿瘤模型治疗后肿瘤体积增长曲线;(B)各组肿瘤模型的肿瘤生长抑制率;
图9为建立肿瘤动物模型,治疗后各组肿瘤组织的H&E、TUNEL和Ki-67染色图像;
图10为治疗后各组荷瘤小鼠体内各主要器官的毒性研究H&E染色示意图;
图11为建立肿瘤动物模型,尾静脉注射UCSNs-B前后小鼠T1加权MR图像。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干调整和改进。这些都属于本发明的保护范围。
实施例1多功能纳米粒子的制备与表征
多功能纳米粒子UCSNs-B的合成示意图及作用原理如图1所示,具体如下:
NaYF4:Yb(19%)/Tm(1%)内核的制备:将氯化钇(485.38毫克)、氯化镱(147.25毫克)和氯化铥(7.67毫克)加入油酸(12毫升)和十八碳烯(30毫升)中。得到的混合溶液缓慢加热到至150℃,并保持1小时以除去水分。随后停止加热并冷却至室温后,加入10毫升含氢氧化钠(200毫克)和氟化铵(296.3毫克)的甲醇溶液,在室温下搅拌35分钟。接下来,加热至100℃并持续搅拌1小时,无明显气泡产生后,接冷凝管抽真空20分钟以去除多余的甲醇。随后通氩气的同时加热至300℃并保持1.5小时。自然冷却至室温,加入20毫升无水乙醇,离心收集沉淀(11000r/min,10min),将产物重新分散于5毫升环己烷中,用20毫升乙醇沉淀,离心收集。经多次乙醇洗涤后,将最终产物分散于20毫升环己烷中进一步使用;
NaYF4:Yb(19%)/Tm(1%)@NaGdF4(简称为UCNPs)的制备:氯化钆(371.7毫克)加入12毫升的油酸和30毫升的十八碳烯中,搅拌均匀并加热到150℃,持续1小时。停止加热并冷却至室温,逐滴加入上一步制备好的内核溶液,混合均匀加热到80℃,维持20分钟以蒸发剩余的环己烷。冷却至室温后,缓慢加入10毫升含氢氧化钠(100毫克)和氟化铵(148.14毫克)的甲醇溶液。室温下搅拌35分钟后,加热至100℃并持续搅拌1小时,随后接冷凝管抽真空20分钟以去除多余的甲醇。向反应体系中通入氩气,缓慢升温到300℃并保持1.5小时。反应溶液逐渐冷却至室温,加入20毫升无水乙醇,离心收集沉淀(11000r/min,10min),将产物重新分散于5毫升环己烷中,用20毫升乙醇沉淀,离心收集。重复三次无水乙醇洗涤后,将最终产物分散于20毫升环己烷中获得澄清溶液;
UCNP@hmSiO2纳米粒子(UCSN)的制备:将1毫升聚氧代乙烯(5)壬基苯基醚溶解在20毫升环己烷中,搅拌1小时后缓慢加入2毫升UCNPs的环己烷溶液,混合反应3小时。然后缓慢逐滴加入0.14毫升的氨水(30%),密封搅拌2小时。将200微升的正硅酸四乙酯溶解在1.8毫升环己烷中,并以每小时100微升的速度注入反应体系后,密封搅拌24小时。然后加入甲醇终止反应,离心收集产物,用无水乙醇洗涤3次以去除多余的聚氧代乙烯(5)壬基苯基醚。最终得到的产物分散于10毫升去离子水中得到溶液1。将2克十六烷基三甲基氯化铵和0.02克的三乙胺溶解在去离子水中,在室温下搅拌1.5小时。逐滴加入上一步制备好的溶液1,并继续搅拌1.5小时。将反应体系转移至70℃水浴锅中预热2分钟,200微升的正硅酸四乙酯逐滴加入到上述溶液中,继续搅拌1小时。自然冷却至室温,离心收集反应产物(11000r/min,10min)。用无水乙醇洗涤三次。将离心产物溶于质量分数1wt%的氯化钠的甲醇溶液中,搅拌6小时,离心收集沉淀。重复洗涤三次后,将离心产物重新分散到10毫升去离子水中得到溶液2。圆底烧瓶中加入0.25克聚乙烯吡咯烷酮、10毫升去离子水和溶液2,室温下匀速搅拌0.5小时,然后加热至95℃并保持反应4小时。停止加热后,待溶液自然冷却至室温,离心收集产物。经多次乙醇清洗后,最终将产物分散到去离子水中;
UCSNs@Blebbistatin(UCSNs-B)的制备:将3毫克的Blebbistatin溶于二甲基亚砜中,加入UCSNs,在黑暗环境中搅拌24小时。离心得到产物,用乙醇洗涤三次。样品再次分散到去离子水中以备进一步使用。
多功能纳米粒子的表征:采用透射电子显微镜观察纳米粒子UCSNs的形态,采用粒径分析仪测定UCSNs-B在不同溶剂中的粒径,采用发射光谱仪分析不同纳米粒子转换发光情况,采用电子自旋磁共振光谱法测定不同材料产生羟基自由基的能力,结果如图2所示,UCSNs的粒径大约为42nm,呈规则的球状,内有中空结构,粒径分布均匀,水合粒径大约为122nm,在980nm激光激发下,能够实现上转换发光,并且发生反应释放羟基自由基。
实施例2多功能纳米粒子UCSNs-B的磁敏感表征图
取适量UCSNs-B溶液样品,用磷酸盐缓冲液配制成不同浓度的溶液,钆粒子浓度依次为0、31、62、125、250、500μmol/L,分别置于2ml离心管内。再将临床上常用的马根维显(钆喷酸葡胺)分别配置成相应钆浓度的溶液作为对照组。各管按顺序摆放在塑料试管架上。磷酸盐缓冲液作空白对照。利用临床3.0T MR system(DiscoveryMR750,GE Medical System,USA)及配套小动物线圈进行T1 Map序列扫描,评价成像效果。采用GE Function tool 4.6专用软件对T1 Map图像进行后处理。
磁敏感如图3A所示,与对照组一样,随着钆浓度的逐渐增加,T1加权的MR成像信号逐渐增强。经过测定与计算,T1弛豫时间与对比剂浓度呈良好的线性关系。以UCSNs-B溶液中不同Gd3+的浓度和相应的1/T1作散点图,如图3B所示,拟合的线性回归方程为:y=1.58x+0.53(R2=0.99,P<0.0001),其T1弛豫率1.58mM-1·s-1。
实施例3细胞吞噬纳米粒子UCSNs-B的定性分析
将MDA-MB-231细胞接种于35mm的共聚焦培养皿中(每皿105个细胞),孵育8小时。显微镜观察细胞贴壁后,按照设置的不同时间段依次加入1毫升用FITC探针标记过的UCSNs-B培养液孵育相应的时间。弃去孵育的含材料培养基,使用PBS清洗3次。加入DAPI染液(1mM)孵育5分钟。通过激光共聚焦显微镜观察不同时间组细胞吞噬UCSNs-B(绿色荧光)的情况并拍照记录。
MDA--MB-231细胞内吞UCSNs-B纳米粒子的情况如图4所示,从激光共聚焦图像中可以看出,随着孵育时间的延长,UCSNs-B-FITC产生的绿色荧光逐渐增强,说明UCSNs-B的细胞摄取与孵育时间有关,证明肿瘤细胞对UCSNs-B纳米粒子具有良好的吞噬性。
实施例4细胞内产生ROS的定性研究
将MDA-MB-231细胞接种于共聚焦培养皿中,孵育8小时。贴壁后,按照分组Control,UCSNs,Blebbistatin,UCSNs-B,Control+NIR,UCSNs+NIR,Blebbistatin+NIR,UCSNs-B+NIR和UCSNs-B+NIR(乏氧)分别加入相应的材料孵育24小时,对于有NIR的组在孵育24小时后用980nm激光(1W/cm2)照射10分钟。处理后用PBS轻轻清洗3次。加入DCFH-DA(10μM)探针后,在37℃的培养箱孵育30分钟。加入DAPI染液(1mM)孵育30分钟。倒掉染液后,用PBS清洗3次。通过激光共聚焦显微镜观察不同处理组细胞产生ROS(绿色荧光)的情况并拍照记录。
各种实验条件下细胞内·OH的产生情况如图5所示。MDA-MB-231细胞分别与UCSNs-B孵育后,再使用980nm的激光照射10分钟,不论正常条件还是乏氧条件下都可以在细胞内看到明显的绿色荧光,证明UCSNs-B在近红外光激发后能够不依赖肿瘤细胞内的氧气有效产生·OH。相比之下,Control、UCSNs、Blebbistatin、UCSNs-B、Control+NIR、Blebbistatin+NIR、和UCSNs+NIR组没有观察到明显的绿色荧光信号,说明只有UCSNs-B孵育并使用980nm激光照射后的细胞内·OH的水平显著提高。
实施例5UCSNs-B细胞毒性测定
1)酶标仪定量分析:
将MDA-MB-231细胞以每孔104个细胞的密度接种于96孔板中孵育8小时。显微镜观察细胞贴壁后,按照不同的分组分别加入相应的材料孵育相应时长,对于有NIR的组在材料孵育后用980nm激光(1W/cm2)照射10分钟。弃掉培养基,吸取少量PBS以洗去多余的培养基。每孔加入100μL提前配好并避光保存的CCK-8试剂。将96孔板放入培养箱继续孵育30分钟。使用酶标仪测定各处理组细胞在450nm的吸光度并记录数据进行计算、绘制柱状图。
2)流式细胞仪荧光定量分析:
将MDA-MB-231细胞以4×105的密度接种于6孔板后,孵育8小时。显微镜观察细胞贴壁后,按照分组Control,UCSNs,Blebbistatin,UCSNs-B,Control+NIR,UCSNs+NIR,Blebbistatin+NIR,UCSNs-B+NIR和UCSNs-B+NIR(乏氧)分别加入相应的材料孵育24小时,对于有NIR的组在孵育24小时后用980nm激光(1W/cm2)照射10分钟,继续孵育6小时。用PBS清洗三次,将贴壁的MDA-MB-231细胞用0.25%胰蛋白酶-EDTA(1X)消化液消化,离心收集。舍去上清液,用试剂盒中的缓冲液,清洗细胞,离心收集细胞。重新分散于缓冲液中,制成细胞密度为5×105/mL的细胞悬液。取200微升的细胞悬液,加入100微升的工作液,吹打均匀后置于37℃的培养箱中孵育15-30分钟。通过流式细胞仪检测细胞活死情况并记录数据以备后续处理。
MDA-MB-231细胞与不同浓度的UCSNs或UCSNs-B(0、20、50、100、200和500μg/mL)分别孵化24和48小时后,用CCK-8法检测细胞的存活率。结果如图6A所示,即使UCSNs的浓度升高到500μg/mL,MDA-MB-231细胞与之孵育48小时后仍有超过80%细胞存活,说明UCSNs具有可忽略不计的细胞毒性。然而将MDA-MB-231细胞分别与UCSNs-B(500μg/mL)孵育48小时后,细胞存活率为76.5%(图6B)。随后,评估近红外激光激活后的UCSNs-B对MDA-MB-231细胞的细胞毒性。如图6C所示,随着UCSNs-B剂量的逐渐升高,MDA-MB-231细胞在近红外激光照射10分钟后,存活率明显降低。在孵育剂量为500μg/mL的浓度时,MDA-MB-231细胞的细胞存活率约为27.3%。相比而言,Control、UCSNs、Blebbistatin、UCSNs-B、Control+NIR、UCSNs+NIR和Blebbistatin+NIR组的处理对MDA-MB-231细胞没有明显的细胞毒性(图6D)。
将MDA-MB-231细胞按照不同的分组处理后,进一步通过流式细胞仪检测凋亡情况,结果如图7所示。Control、UCSNs、UCSNs-B、Control+NIR、UCSNs+NIR组的细胞在处理后,存活率均大于80%。Blebbistatin和Blebbistatin+NIR组的细胞凋亡数量稍增加。只有UCSNs-B处理组的细胞在增加近红外激光照射后,不论正常还是乏氧条件下均出现了明显增加的细胞凋亡,仅有14.5%的细胞存活,这表明UCSNs-B在近红外激光照射后引起一系列的连锁反应实现不依赖氧气的·OH爆发,从而有效诱导肿瘤细胞凋亡,UCSNs-B和NIR的协同作用明显提高了体外治疗肿瘤细胞的效果。
实施例6多功能纳米粒子体外治疗效果的研究
将MDA-MB-231荷瘤裸鼠随机分成6组,每组5只小鼠。当肿瘤体积增长至50mm3时,每隔一天由小鼠尾静脉注入不同的制剂,持续7次,这些组分别是:①Contr ol,②Blebbistatin,③UCSNs,④NIR,⑤UCSNs-B,⑥UCSNs-B+NIR。UCSNs-B剂量为20mg/kg,Blebbistatin剂量为2mg/kg。对于每次治疗,仅NIR组的小鼠和UCSNs-B+NIR组的小鼠,在注射24小时后,腹腔注射事先配制好的5%水合氯醛溶液麻醉,随后用980nm的激光(1W/cm2)照射十分钟。每两天测量肿瘤大小和小鼠体重,记录并计算。
经过2周的治疗观察,各组的肿瘤生长曲线和如图8A所示。与注射PBS的对照组相比,UCSNs、UCSNs-B和NIR对肿瘤生长无明显的抑制作用,而近红外激光激发UCS Ns-B后在肿瘤微环境中产生大量·OH,从而明显抑制了肿瘤生长。进一步的肿瘤抑制率计算显示UCSNs-B+NIR对MDA-MB-231荷瘤小鼠的肿瘤抑瘤率最高约为96.5%,明显高于Blebbistatin(24.8%)(图8B)。证实了UCSNs-B在980nm激光诱导下对肿瘤有明显的抑制作用。
在各组治疗结束后,每组各取出一个肿瘤组织进行切片染色。采用H&E染色以评估不同的处理方式对肿瘤造成的损伤,如图9所示,UCSNs-B+NIR治疗组的肿瘤组织H&E染色图像可以看见更大的细胞间隙,说明进行UCSNs-B+NIR治疗对肿瘤组织造成了更大的细胞损伤。同时为了了解肿瘤组织内细胞凋亡的情况,使用脱氧核苷酸末端转移酶介导的dUTP缺口末端标记法(TUNEL)对各组取出的肿瘤进行荧光染色。可以看到类似的结果,与Control、UCSNs、Blebbistatin、UCSNs-B、NIR治疗组相比,UCS Ns-B+NIR处理的肿瘤细胞凋亡或坏死的区域明显更大。进一步进行Ki-67抗体染色分析,评价不同治疗组的肿瘤细胞增殖情况。与其他治疗组相比,UCSNs-B+NIR组对MDA-MB-231肿瘤细胞的增殖活性有明显抑制作用,以上结果均证明了所构建的纳米体系在980nm激光诱导下对肿瘤的杀伤作用。
实施例7多功能纳米粒子UCSNs-B的体内安全性实验
实施例6中的所有组别的裸鼠在治疗2周后,取出每组小鼠心、肝、脾、肺、肾五大主要器官进行组织学检查。如图10所示,各治疗组小鼠主要脏器没有发现明显的组织损伤或炎症表现,说明UCSNs-B+NIR对各主要器官无明显的毒副作用。这些结果进一步证实了UCSNs-B材料的生物安全性,仅在980nm激光照射后在特定部位产生·OH从而高效诱导肿瘤细胞凋亡。
实施例8多功能纳米粒子UCSNs-B体内MR成像的性能评估
随机挑选荷瘤小鼠。从尾静脉注射含UCSNs-B(20mg/kg)的生理盐水。腹腔注射事先配制好的5%水合氯醛溶液麻醉,采用SIEMENS MAGNETON Verio 3.0T MR扫描仪扫描仪,将小鼠俯卧位放置于专用的小动物线圈内。行冠状位和轴位T1WI成像扫描,如图11。
通过静脉注射UCSNs-B后对MDA-MB-231荷瘤小鼠进行体内MR成像,对比注射前和注射后的T1加权MR图像,可以观察到静脉注射UCSNs-B后肿瘤处的MR成像信号明显增强,说明UCSNs-B是小鼠体内MR成像的有效对比剂。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (10)
1.一种针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子由药物运输载体和光活化药物组成。
2.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子是在掺钆的上转换纳米颗粒外包覆介孔二氧化硅,并在介孔中加载光活化药物。
3.根据权利要求2所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述上转换纳米颗粒为NaYF4:Yb/Tm@NaGdF4;所述光活化药物为Blebbistatin。
4.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子含有稀土元素Yb和Tm。
5.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子具有空腔介孔结构。
6.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子包含顺磁性钆离子。
7.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子不依赖周围环境中的氧气生成活性氧。
8.根据权利要求1所述的针对肿瘤诊疗一体化的多功能纳米粒子,其特征在于,所述纳米粒子定点可控地产生羟基自由基。
9.一种根据权利要求1-8中任一项所述的针对肿瘤诊疗一体化的多功能纳米粒子的制备方法,其特征在于,所述方法包括如下步骤:
S1、利用高温热分解法制备NaYF4:Yb/Tm内核;
S2、利用外延生长法制备NaYF4:Yb/Tm@NaGdF4,即UCNPs;
S3、在UCNPs外包覆介孔二氧化硅,制备UCNPs@Mesoporous Silica(SiO2)Nanoparticles,即UCSNs;
S4、UCSNs@Blebbistatin的制备:将Blebbistatin溶于溶剂中,加入UCSNs,在黑暗环境中搅拌20-28小时;离心得到产物。
10.一种根据权利要求1-8中任一项所述的针对肿瘤诊疗一体化的多功能纳米粒子在制备肿瘤的诊疗一体化制剂中的应用。
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