CN115607669A - 一种诊疗一体化稀土纳米颗粒及其制备方法 - Google Patents
一种诊疗一体化稀土纳米颗粒及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种诊疗一体化稀土纳米颗粒及其制备方法,制备的NaErF4@NaYF4@SiO2@mSiO2‑Ce6纳米颗粒,可以在单一波长980nm激光源激发下,同时实现下转换发射1550nm近红外二区光进行成像以及上转换红光激发光敏剂Ce6进行光动力治疗。
Description
技术领域
本发明涉及纳米生物材料技术领域,尤其涉及一种利用近红外二区光成像的诊疗一体化稀土纳米颗粒及其制备方法。
背景技术
光学治疗是一种目前热门的新型治疗方式,主要包括光动力治疗以及光热治疗,分别是通过光照激发光敏剂和光热剂产生治疗效果。诊疗一体化,是近几年在纳米医学领域逐渐发出声音的一个概念,指的是纳米颗粒具备成像能力进行疾病诊断,同时具备治疗效果。
现有技术中使用的光学诊疗一体化纳米颗粒,其成像诊断与治疗使用不同的介质,如超声与激光或不同波长的激光等,需要借助多种设备,使用不便,其原因是由于其使用的激光多为近红外一区光,穿透深度及成像能力不佳。
发明内容
本发明的目的是针对现有技术中的不足,提供一种诊疗一体化稀土纳米颗粒及其制备方法。
为实现上述目的,本发明采取的技术方案是:
本发明第一方面是提供一种诊疗一体化稀土纳米颗粒的制备方法,包括如下步骤:
步骤一,取ErCl3-6H2O溶解于油酸和十八烯的混合溶剂中,搅拌,升温至140-160℃,真空抽气脱水脱氧40-60min,降温后得到透明混合溶液,然后将溶有NaOH和NH4F的甲醇溶液快速滴加至所述透明混合溶液中,加热至100-120℃时停止抽气通入氩气,继续升温至290-300℃后反应90-120min,反应产物经洗涤后得到NaErF4,并保存于环己烷中待用;
步骤二,取步骤一所得的NaErF4环己烷溶液,加入溶有三氟乙酸钇和三氟乙酸钠的溶液,升温,同时负压抽气,至110-120℃时停止抽气通入氩气,继续升温至290-300℃反应60-100min,反应产物经洗涤后得到NaErF4@NaYF4,并保存于环己烷中待用;
步骤三,配制含正辛醇、曲拉通X-100和环己烷的反应体系,加入步骤二得到的NaErF4@NaYF4环己烷溶液,搅拌,加入20-25wt%氨水,搅拌形成反向微乳液,加入硅酸四乙酯,常温搅拌反应16-24h,反应产物经洗涤后得到NaErF4@NaYF4@SiO2,并保存于水中待用;
步骤四,配制含三乙醇胺、水、十六烷基三甲基溴化铵的溶液,并加入步骤三得到的NaErF4@NaYF4@SiO2水溶液,于30-35℃搅拌30-60min后,加入硅酸四乙酯,继续搅拌,反应产物经洗涤后得到NaErF4@NaYF4@SiO2@mSiO2,少量水溶解,冻干成粉末待用;
步骤五,将上步骤四得到的的冻干粉末称重,与光敏剂二氢卟吩e6混合,用乙醇溶解后,常温下避光搅拌反应12-24h,反应产物经离心收集、洗涤后得到NaErF4@NaYF4@SiO2@mSiO2负载光敏剂二氢卟吩e6,少量水溶解,冻干成粉末,避光保存。
进一步地,步骤一中,所述混合溶剂中油酸与十八烯的体积比为3:(7-10),ErCl3-6H2O的浓度为0.04-0.1mmol/mL。
进一步地,步骤一中,溶有NaOH和NH4F的甲醇溶液中NaOH浓度为0.3-0.5mmol/mL、NH4F浓度为0.5-1.0mmol/mL。
进一步地,步骤二中,所述溶有三氟乙酸钇和三氟乙酸钠的溶液所采用的溶剂为油酸和十八烯的混合溶剂,其中油酸与十八烯的体积比为1:(1-5);所述NaErF4环己烷溶液与溶有三氟乙酸钇和三氟乙酸钠的溶液体积比为1:(20-30)。
进一步地,步骤二中,溶有三氟乙酸钇和三氟乙酸钠的溶液中三氟乙酸钇浓度为0.005-0.01mmol/mL、三氟乙酸钠浓度为0.005-0.01mmol/mL。
进一步地,步骤三中,含正辛醇、曲拉通X-100和环己烷的反应体系中正辛醇、曲拉通X-100和环己烷的体积比为6.7:(12-20):(50-100)。
进一步地,步骤三中,含正辛醇、曲拉通X-100和环己烷的反应体系、NaErF4@NaYF4环己烷溶液、氨水和硅酸四乙酯的体积比为(68.7-100):1:(0.4-1):(0.06-0.1)。
进一步地,步骤四中,含三乙醇胺、水、十六烷基三甲基溴化铵的溶液中三乙醇胺与水的体积比为1:(200-250)、十六烷基三甲基溴化铵的浓度为10-15mg/mL;所述NaErF4@NaYF4@SiO2水溶液与硅酸四乙酯的体积比为1:(0.2-0.5)。
进一步地,步骤五中,冻干粉末与光敏剂二氢卟吩e6的质量比为(100-120):1。
本发明第二方面是提供上述制备方法制备而成的诊疗一体化稀土纳米颗粒。
本发明采用以上技术方案,与现有技术相比,具有如下技术效果:
本发明制备的NaErF4@NaYF4@SiO2@mSiO2-Ce6纳米颗粒,可以在单一波长980nm激光源激发下,同时实现下转换发射1550nm近红外二区光进行成像以及上转换红光激发光敏剂Ce6进行光动力治疗。
附图说明
图1为本发明NaErF4@NaYF4@SiO2@mSiO2的电镜图;
图2为本发明NaErF4@NaYF4@SiO2@mSiO2-Ce6的紫外吸收光谱图;
图3为本发明NaErF4@NaYF4@SiO2@mSiO2-Ce6的体外成像能力;
图4为本发明NaErF4@NaYF4@SiO2@mSiO2-Ce6的体外治疗效果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,但不作为本发明的限定。需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。
实施例1
1.NaErF4的制备
取2mmol的ErCl3-6H2O溶解于50mL的油酸和十八烯的混合溶剂中,其中OA(油酸)与OD(十八烯)的体积比为3:7,搅拌,升温至140℃,真空抽气脱水脱氧60min,降温后得到透明混合溶液;然后将15mL的溶有5mmol NaOH和8mmol NH4F的甲醇溶液快速滴加至上述透明混合溶液中,孵育0.5-1h,按10℃/min给反应体系加热,加热过程中负压抽气,反应体系达到100℃时停止抽气通入氩气,继续升温至290℃后反应90min,得到的产物经环己烷-乙醇混合溶液洗涤三遍后保存到10ml环己烷中。
2.NaErF4@NaYF4的合成
取2mL上述步骤所得的含有NaErF4的环己烷溶液,加入溶有0.2mmol三氟乙酸钇和0.2mmol三氟乙酸钠的溶液,其中采用的溶剂为20mL油酸和20mL十八烯,按10℃/min升温,同时负压抽气,至110℃时停止抽气通入氩气,继续升温至290℃反应60min,得到的产物4500转离心收集,经环己烷-乙醇混合溶液洗涤三遍后保存到4ml环己烷中。
3.NaErF4@NaYF4@SiO2的合成
配制含6.7mLotcanol(正辛醇)、12mLtrixtonX-100(曲拉通X-100)和50mL环己烷的反应体系,加入1mL上述步骤得到的含有NaErF4@NaYF4的环己烷溶液,搅拌15min后加入0.4mL(25wt%)氨水,搅拌30min形成反向微乳液(水包油),加入60μLTEOS(硅酸四乙酯),常温搅拌反应16h,所得产物15000转离心收集,经水和乙醇洗涤三遍后保存于3mL水中。
4.NaErF4@NaYF4@SiO2@mSiO2的合成
配制含三乙醇胺0.1mL、水20mL、CTAB(十六烷基三甲基溴化铵)300mg的溶液,并加入1mL上述步骤得到的含有NaErF4@NaYF4@SiO2的水溶液,于30℃搅拌30min后,加入TEOS200μL,继续搅拌12h,所得产物15000转离心收集,经水和乙醇洗涤三遍后,少量水溶解,冻干成粉末待用。
5.NaErF4@NaYF4@SiO2@mSiO2负载光敏剂二氢卟吩e6(Ce6)
将上述步骤得到的冻干粉末称重,与Ce6质量比为100:1,用乙醇溶解后,常温下避光搅拌过夜,所得产物15000转离心收集经水和乙醇洗涤三遍后,少量水溶解,冻干成粉末,避光保存。
实施例2
本实施例对上述实施例1制备的诊疗一体化稀土纳米颗粒在体外的成像能力进行了验证,是通过近红外二区相机CCD达成的。
取不同质量的稀土纳米颗粒粒置于离心管中,用pH=7.4的tris-Hcl溶液重悬,配置成相应浓度的溶液,12mg/ml,6mg/ml,3mg/ml,1.5mg/ml,0mg/ml。使用980nm激光器照射下,使用近红外二区相机CCD拍摄成像图片。
实验结果如图3所示,稀土纳米颗粒在980nm激发下,可以发出明显的光,同时光强度与稀土颗粒浓度正相关。
实施例3
本实施例对上述实施例1制备的诊疗一体化稀土纳米颗粒在细胞层面的治疗效果进行了研究。
疗效评级使用的细胞为HCT116人结肠癌细胞。具体实验步骤如下:
利用CCK-8法对NaErF4@NaYF4@SiO2@mSiO2-Ce6进行体外肿瘤活性检测。将培养状态良好的HCT116铺满培养皿底部的细胞,先用胰酶进行消化,离心机离心,吸出上清液,加1mL培养基(DMEM培养基,含青链霉素1%,胎牛血清10%,下同)吹匀细胞,将细胞悬浮液取适量进行稀释,使其每孔细胞数约为8000个,接种于96孔板中,培养24h。将NaErF4@NaYF4@SiO2@mSiO2-Ce6用培养基稀释为不同浓度,放在离心管中待用,每个浓度含有6个复孔,并设置不接种细胞的空白组和不加药物的对照组,作用24小时。设置激光对照组,激光组在给药4h后使用980nm激光照射(1W/cm2,5min),继续培养至24h;非激光组在给药后培养至24h。每孔加入10%浓度CCK-8溶液100μL作用2h,用多功能酶标仪测450nm处的吸光值A;通过公式:细胞活性×100%=(实验组平均OD值-空白组平均OD值)/(对照组平均OD值-空白组平均OD值),计算样品各浓度对细胞的抑制率。结果见图4。
因此,本发明研制的NaErF4@NaYF4@SiO2@mSiO2-Ce6具有很大的潜力,可作为一种性能优异的诊疗一体化纳米颗粒,具有优良的抗肿瘤效果和成像效果。
上所述仅为本发明较佳的实施例,并非因此限制本发明的实施方式及保护范围,对于本领域技术人员而言,应当能够意识到凡运用本发明说明书内容及图示所作出的等同替换和显而易见的变化所得到的方案,均应当包含在本发明的保护范围内。
Claims (10)
1.一种诊疗一体化稀土纳米颗粒的制备方法,其特征在于,包括如下步骤:
步骤一,取ErCl3-6H2O溶解于油酸和十八烯的混合溶剂中,搅拌,升温至140-160℃,真空抽气脱水脱氧40-60min,降温后得到透明混合溶液,然后将溶有NaOH和NH4F的甲醇溶液快速滴加至所述透明混合溶液中,加热至100-120℃时停止抽气通入氩气,继续升温至290-300℃后反应90-120min,反应产物经洗涤后得到NaErF4,并保存于环己烷中待用;
步骤二,取步骤一所得的NaErF4环己烷溶液,加入溶有三氟乙酸钇和三氟乙酸钠的溶液,升温,同时负压抽气,至110-120℃时停止抽气通入氩气,继续升温至290-300℃反应60-100min,反应产物经洗涤后得到NaErF4@NaYF4,并保存于环己烷中待用;
步骤三,配制含正辛醇、曲拉通X-100和环己烷的反应体系,加入步骤二得到的NaErF4@NaYF4环己烷溶液,搅拌,加入20-25wt%氨水,搅拌形成反向微乳液,加入硅酸四乙酯,常温搅拌反应16-24h,反应产物经洗涤后得到NaErF4@NaYF4@SiO2,并保存于水中待用;
步骤四,配制含三乙醇胺、水、十六烷基三甲基溴化铵的溶液,并加入步骤三得到的NaErF4@NaYF4@SiO2水溶液,于30-35℃搅拌30-60min后,加入硅酸四乙酯,继续搅拌,反应产物经洗涤后得到NaErF4@NaYF4@SiO2@mSiO2,少量水溶解,冻干成粉末待用;
步骤五,将上步骤四得到的的冻干粉末称重,与光敏剂二氢卟吩e6混合,用乙醇溶解后,常温下避光搅拌反应12-24h,反应产物经离心收集、洗涤后得到NaErF4@NaYF4@SiO2@mSiO2负载光敏剂二氢卟吩e6,少量水溶解,冻干成粉末,避光保存。
2.根据权利要求1所述的制备方法,其特征在于,步骤一中,所述混合溶剂中油酸与十八烯的体积比为3:(7-10),ErCl3-6H2O的浓度为0.04-0.1mmol/mL。
3.根据权利要求1所述的制备方法,其特征在于,步骤一中,溶有NaOH和NH4F的甲醇溶液中NaOH浓度为0.3-0.5mmol/mL、NH4F浓度为0.5-1.0mmol/mL。
4.根据权利要求1所述的制备方法,其特征在于,步骤二中,所述溶有三氟乙酸钇和三氟乙酸钠的溶液所采用的溶剂为油酸和十八烯的混合溶剂,其中油酸与十八烯的体积比为1:(1-5);所述NaErF4环己烷溶液与溶有三氟乙酸钇和三氟乙酸钠的溶液体积比为1:(20-30)。
5.根据权利要求4所述的制备方法,其特征在于,步骤二中,溶有三氟乙酸钇和三氟乙酸钠的溶液中三氟乙酸钇浓度为0.005-0.01mmol/mL、三氟乙酸钠浓度为0.005-0.01mmol/mL。
6.根据权利要求1所述的制备方法,其特征在于,步骤三中,含正辛醇、曲拉通X-100和环己烷的反应体系中正辛醇、曲拉通X-100和环己烷的体积比为6.7:(12-20):(50-100)。
7.根据权利要求1所述的制备方法,其特征在于,步骤三中,含正辛醇、曲拉通X-100和环己烷的反应体系、NaErF4@NaYF4环己烷溶液、氨水和硅酸四乙酯的体积比为(68.7-100):1:(0.4-1):(0.06-0.1)。
8.根据权利要求1所述的制备方法,其特征在于,步骤四中,含三乙醇胺、水、十六烷基三甲基溴化铵的溶液中三乙醇胺与水的体积比为1:(200-250)、十六烷基三甲基溴化铵的浓度为10-15mg/mL;所述NaErF4@NaYF4@SiO2水溶液与硅酸四乙酯的体积比为1:(0.2-0.5)。
9.根据权利要求1所述的制备方法,其特征在于,步骤五中,冻干粉末与光敏剂二氢卟吩e6的质量比为(100-120):1。
10.一种由权利要求1-9任一项所述制备方法制备而成的诊疗一体化稀土纳米颗粒。
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