CN110665014A - 一种双模式成像功能的稀土mof纳米颗粒的制备方法 - Google Patents
一种双模式成像功能的稀土mof纳米颗粒的制备方法 Download PDFInfo
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- CN110665014A CN110665014A CN201910979464.4A CN201910979464A CN110665014A CN 110665014 A CN110665014 A CN 110665014A CN 201910979464 A CN201910979464 A CN 201910979464A CN 110665014 A CN110665014 A CN 110665014A
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Abstract
本发明涉及一种双模式成像功能的稀土MOF纳米颗粒的制备方法,通过RAFT反应合成带有靶向卵巢癌细胞多肽的聚合物,再与反向微乳液法合成的Tb,Gd(BTC)phen‑MOF配位,得到具有靶向卵巢癌细胞和体内荧光核磁共成像功能的纳米颗粒。本发明通过RAFT反应将靶向抗肿瘤药物接枝到聚合物上,再将聚合物以配体的方式构建到稀土MOF纳米颗粒中,使MOF纳米粒子既有荧光核磁共成像性能也有靶向功能,邻菲啰啉配位的存在还会提高MOF纳米粒子的荧光强度。该方法得到的荧光材料,具有生物相容性好,靶向性强,以及发光强度高的特点。
Description
技术领域
本发明涉及一种双模式成像功能的稀土MOF纳米颗粒的制备方法。本发明属于纳米生物医药材料领域。
背景技术
近年来,纳米金属有机框架(MOFs)材料的合成及其在生物医学应用,特别是在肿瘤诊断和治疗方面的应用研究引起了科学家们广泛的关注。金属有机框架(MOFs)以其多孔性著名,其中稀土金属有机框架是由稀土金属离子簇和有机配体通过配位键构筑起来的杂化多孔材料,由于稀土金属离子的种类多样,并且拥有较高的配位数,人们通过引入不同的有机配体可以合成出多种多样具有不同结构和功能的稀土MOF。稀土MOF与传统的小分子稀土化合物具有类似的光学以及磁学性质,可用于荧光成像和磁共振成像。此外,鉴于MOFs在生物医学方面仍然存在一定的局限性,如生物相容性较低、无法进行靶向释放、可控释放性能不理想等等。可通过稀土纳米MOF表面连接靶向聚合物的方式,达到靶向释放的目的。因此,对表面修饰技术提供有效地控制,在产生稳定的纳米MOF结构的前提下增强其靶向性和生物相容性具有较高的研究意义和应用价值。
在传统的MOF制备研究中,生物成像主要包括:纳米粒子(中国发明专利:一种纳米颗粒@小尺寸金属有机框架材料的制备方法,公开号:CN107349964A)、稀土氟氧化物纳米材料(中国发明专利:稀土氟氧化物纳米材料及其制备方法和应用,公开号:CN105505392A)。这些MOF虽然具有较好的生物相容性,但是靶向性差。聚合物表面改性荧光材料可以对材料的表面功能进行控制,减少荧光强度的降低,提高生物相容性,增强靶向性等。其已在控制荧光强度(中国发明专利:一种有机荧光染料分子标记生物组织的荧光控制方法,公开号:CN106568753A;中国发明专利:一种用高分子改性有机荧光染料防止荧光淬灭的方法,公开号:CN106753335A)、药物靶向传输(中国发明专利:一种简易低成本的磁性微粒表面活性基团引入方法,公开号:CN105524492A;中国发明专利:一种药物靶向输送载体、制备方法及其应用,公开号:CN107158396A)中得到应用,但是这些功能物质往往只具有单一靶向功能或者荧光功能。因此,研究一种具有靶向性的纳米MOF体内荧光材料具有很高的研究价值。
发明内容
针对现有技术的不足,本发明目的在于提供一种双模式成像功能的稀土MOF纳米颗粒的制备方法,一种多功能高分子与金属有机骨架(MOFs)纳米颗粒的构建方法。
本发明目的通过下述方案实现:一种双模式成像功能的稀土MOF纳米颗粒的制备方法,通过RAFT反应合成带有靶向卵巢癌细胞多肽的聚合物,再与反向微乳液法合成的Tb,Gd(BTC)phen-MOF配位,得到具有靶向卵巢癌细胞和体内荧光核磁共成像功能的纳米颗粒,包括如下步骤:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将一定量的均苯三甲酸(BTC)和铽盐、钆盐溶于N,N-二甲基甲酰胺(DMF)与水的混合溶液中,所述的BTC和铽盐的摩尔比为:1/6,铽盐和钆盐的摩尔比为:1/5~5/1,DMF与水的混合溶液的体积比为:1/4;加入微量的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热5~30 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后将邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,使所述的铽盐和邻菲啰啉的摩尔比为:1/1,于65℃下搅拌回流反应12~24 h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将N-异丙基丙烯酰胺(NIPAM),三硫代碳酸酯(DATC),偶氮二异丁腈(AIBN)按质量比NIPAM/DATC/AIBN的质量比为:300/3/1,在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热12~48 h,得到产物PNIPAM-DATC;
将得到的产物再与NAOS进行RAFT反应,所述的NAOS的加入量与PNIPAM-DATC的质量比为:3/10;AIBN作为引发剂,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热12~48 h,得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物与靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应12~48 h,反应结束后将产物透析,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix(PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将一定量的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应12~48 h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
本发明原理是:以均苯三甲酸(BTC)为配体,以绿光铽盐为发光基体,钆盐为磁共振基体,制备了稀土铽和钆共掺杂金属有机框架(Tb,Gd-MOF)纳米粒子;进一步地,将N-丙烯酰氧基琥珀酰亚胺(NAOS)与N-异丙基丙烯酰胺(NIPAM)通过RAFT反应聚合,然后将靶向卵巢癌A2780细胞的抗肿瘤药物(Cetrorelix)接枝于聚N-丙烯酰氧基琥珀酰亚胺(PNAOS)分子链上,最后进一步与稀土MOF配位,即可得到具备体内荧光成像能力和磁共振成像能力的MOF纳米颗粒。本发明方法得到的纳米材料,具有生物相容性好,靶向性强,以及发光强度高的特点。
在上述方案基础上,所述的铽盐为硝酸铽(Tb(NO3)3·6H2O)、氯化铽(TbCl3·6H2O)、硫酸铽(Tb2(SO4)3·8H2O)和乙酸铽(Tb(OOCCH3)3·xH2O)中的一种;钆盐为硝酸钆(Gd(NO3)3·6H2O)、氯化钆(GdCl3·6H2O)、硫酸钆(Gd2(SO4)3·8H2O)和乙酸钆(Gd(OOCCH3)3·xH2O)中的一种。
所述的AIBN与DATC的物质的量比为:1/3。
PNIPAM-PNAOS-Cetrorelix与Tb,Gd(BTC)phen-MOF纳米颗粒的质量比为:10/1。
本发明的优点在于:
(1)本发明通过RAFT反应将靶向抗肿瘤药物接枝到聚合物上,再将聚合物以配体的方式构建到稀土MOF纳米颗粒中,使MOF纳米粒子既有荧光性能也有靶向功能,邻菲啰啉配位的存在还会提高MOF纳米粒子的荧光强度。同时,由于钆离子的加入,使MOF纳米粒子还具有磁共振成像能力。
(2)本发明制备的荧光纳米粒子具有良好的物理化学稳定性、生物相容性和发光性能。
附图说明
图1为实施例1所制备的未修饰的Tb,Gd(BTC)phen-MOF纳米颗粒的TEM图;
图2为实施例1所制备的接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒的TEM图;
图3为实施例1所制备的Tb,Gd(BTC)phen-MOF和Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒的XRD图;
图4为实施例1所制备的接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF的激发(a)和发射(b)荧光光谱图;
图5为实施例1所制备的接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF的纵向弛豫时间和弛豫速率;
图6为实施例2所制备的接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)(PPC)-MOF的激发(a)和发射(b)荧光光谱图。
具体实施方式
以下通过具体的实施例对本发明的技术方案作进一步描述。以下的实施例是对本发明的进一步说明,而不限制本发明的范围。
实施例1
一种双模式成像功能的稀土MOF纳米颗粒,通过RAFT反应合成带有靶向卵巢癌细胞多肽的聚合物,再与反向微乳液法合成的Tb,Gd(BTC)phen-MOF配位,得到具有靶向卵巢癌细胞和体内荧光核磁共成像功能的纳米颗粒,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21 g的均苯三甲酸(BTC)和0.271 g铽盐 Tb(NO3)3·6H2O以及0.271 g 钆盐Gd(NO3)3·6H2O溶于6 mL N,N-二甲基甲酰胺(DMF)与24 mL水的混合溶液中,加入0.6 g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11 g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12~24 h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;图1 为未修饰的Tb,Gd(BTC)phen-MOF纳米颗粒的TEM图,由图可见,Tb,Gd(BTC)phen-MOF纳米颗粒呈均匀球体,其平均粒径为100 nm。
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥得到产物PNIPAM-DATC;
将得到的产物0.5 g PNIPAM-DATC再与0.15 g NAOS进行RAFT反应,加入0.006 g AIBN作为引发剂,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24h,反应结束后置于石油醚中,出现黄色沉淀,即得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
图2为接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒的TEM图。由图可见,经多功能性聚合物配位后得Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒依然保持均匀球体形貌,其平均粒径为120 nm,大于未修饰的Tb,Gd(BTC)phen-MOF纳米颗粒。
图3为未修饰的Tb,Gd(BTC)phen-MOF纳米颗粒和靶向抗肿瘤药物修饰后的Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒的XRD图。由图可见,两种MOF的XRD图均呈现较尖锐的衍射峰,证明其结晶度均比较高,Tb,Gd(BTC)phen(PPC)-MOF纳米颗粒的衍射峰强度较未修饰的Tb,Gd(BTC)phen-MOF纳米颗粒的低,说明长分子链共聚物的引入造成了MOF纳米颗粒的结晶度下降。
图4为接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF的激发(a)和发射(b)荧光光谱图。由图可见,材料展示了稀土铽离子的绿光特征发射峰,说明该纳米材料有绿光成像功能。
图5为接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)phen(PPC)-MOF的纵向弛豫时间和弛豫速率。由图可以看出,材料的R1为65 mM-1s-1,R2为374 mM-1s-1,R2/R1为5.7,弛豫效率高于市售造影剂。
实施例2
一种双模式成像功能的稀土MOF纳米颗粒,与实施例近似,按如下步骤的制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21 g的均苯三甲酸(BTC)和0.271 g Tb(NO3)3·6H2O、0.271 g Gd(NO3)3·6H2O溶于6 mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,得到产物PNIPAM-DATC;
将得到的产物取0.5gPNIPAM-DATC再与0.15g NAOS进行RAFT反应,加入0.006g AIBN作为引发剂,溶于4mL的无水二氧六环中,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24 h,反应结束后置于石油醚中,出现黄色沉淀,得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物取0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应12~48 h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC) (PPC)-MOF。
图6为接枝靶向抗肿瘤药物的聚合物修饰后的Tb,Gd(BTC)(PPC)-MOF的激发(a)和发射(b)荧光光谱图。由图可见,材料展示了稀土铽离子的绿光特征发射峰,但相比于图4,其荧光强度稍有减弱,说明phen的加入可以敏化稀土铽离子的绿光发射。
实施例3
一种双模式成像功能的稀土MOF纳米颗粒,与实施例1近似,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21g的均苯三甲酸(BTC)和0.224gTbCl3·6H2O以及0.224gGdCl3·6H2O溶于6mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥得到产物PNIPAM-DATC;
与靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5mL二甲基亚砜(DMSO)中,加入1mL三乙胺,室温下搅拌反应24h,反应结束后将产物透析,冷冻干燥后,即获得接枝靶向卵巢癌细胞的高分子聚合物PNIPAM-PNAOS-Cetrorelix。
将反应得到的聚合物PNIPAM-DATC-PNAOS取0.5g与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
实施例4
一种双模式成像功能的稀土MOF纳米颗粒,与实施例1近似,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21g的均苯三甲酸(BTC)和0.45gTb2(SO4)3·8H2O以及0.45gGd2(SO4)3·8H2O溶于6mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃C温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥,得到产物PNIPAM-DATC;
将得到的产物PNIPAM-DATC取0.5g再与0.15gNAOS进行RAFT反应,加入0.006g AIBN作为引发剂,溶于4mL的无水二氧六环中,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24h,反应结束后置于石油醚中,出现黄色沉淀,即得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物取0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix;
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
Claims (8)
1.一种双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,通过RAFT反应合成带有靶向卵巢癌细胞多肽的聚合物,再与反向微乳液法合成的Tb,Gd(BTC)phen-MOF配位,得到具有靶向卵巢癌细胞和体内荧光核磁共成像功能的纳米颗粒,包括如下步骤:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将均苯三甲酸(BTC)和铽盐、钆盐溶于N,N-二甲基甲酰胺(DMF)与水的混合溶液中,所述的BTC和铽盐的摩尔比为:1/6,铽盐和钆盐的摩尔比为:1/5~5/1,DMF与水的混合溶液的体积比为:1/4,加入微量的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热5~30 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,所述的铽盐和邻菲啰啉的摩尔比为:1/1,于65℃下搅拌回流反应12~24 h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将N-异丙基丙烯酰胺(NIPAM),三硫代碳酸酯(DATC),偶氮二异丁腈(AIBN)按质量比NIPAM/DATC/AIBN的质量比为:300/3/1,在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热12~48 h,得到产物PNIPAM-DATC;
将得到的产物再与NAOS进行RAFT反应,所述的NAOS的加入量与PNIPAM-DATC的质量比为:3/10;AIBN作为引发剂,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热12~48 h,得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物与靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应12~48 h,反应结束后将产物透析,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix(PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将一定量的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5 μL的己胺,室温下搅拌一小时,同时,将Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应12~48 h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
2.根据权利要求1所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于所述的铽盐为硝酸铽(Tb(NO3)3·6H2O)、氯化铽(TbCl3·6H2O)、硫酸铽(Tb2(SO4)3·8H2O)和乙酸铽(Tb(OOCCH3)3·xH2O)中的一种;钆盐为硝酸钆(Gd(NO3)3·6H2O)、氯化钆(GdCl3·6H2O)、硫酸钆(Gd2(SO4)3·8H2O)和乙酸钆(Gd(OOCCH3)3·xH2O)中的一种。
3.根据权利要求1所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于所述的AIBN与DATC的物质的量比为:1/3。
4.根据权利要求1所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,PNIPAM-PNAOS-Cetrorelix与Tb,Gd(BTC)phen-MOF纳米颗粒的质量比为:10/1。
5.根据权利要求1或2所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21 g的均苯三甲酸(BTC)和0.271 g铽盐 Tb(NO3)3·6H2O以及0.271 g 钆盐Gd(NO3)3·6H2O溶于6 mL N,N-二甲基甲酰胺(DMF)与24 mL水的混合溶液中,加入0.6 g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11 g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12~24 h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥得到产物PNIPAM-DATC;
将得到的产物0.5 g PNIPAM-DATC再与0.15 g NAOS进行RAFT反应,加入0.006 g AIBN作为引发剂,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24h,反应结束后置于石油醚中,出现黄色沉淀,即得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
6.根据权利要求1或2所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21 g的均苯三甲酸(BTC)和0.271 g Tb(NO3)3·6H2O、0.271 g Gd(NO3)3·6H2O溶于6 mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,得到产物PNIPAM-DATC;
将得到的产物取0.5gPNIPAM-DATC再与0.15g NAOS进行RAFT反应,加入0.006g AIBN作为引发剂,溶于4mL的无水二氧六环中,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24 h,反应结束后置于石油醚中,出现黄色沉淀,得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物取0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应12~48 h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC) (PPC)-MOF。
7.根据权利要求1或2所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,按如下步骤制备:
(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21g的均苯三甲酸(BTC)和0.224gTbCl3·6H2O以及0.224gGdCl3·6H2O溶于6mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥得到产物PNIPAM-DATC;
与靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5mL二甲基亚砜(DMSO)中,加入1mL三乙胺,室温下搅拌反应24h,反应结束后将产物透析,冷冻干燥后,即获得接枝靶向卵巢癌细胞的高分子聚合物PNIPAM-PNAOS-Cetrorelix。
将反应得到的聚合物PNIPAM-DATC-PNAOS取0.5g与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix (PPC);
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
8.根据权利要求1或2所述双模式成像功能的稀土MOF纳米颗粒的制备方法,其特征在于,按如下步骤制备:(1)稀土铽和钆共掺杂金属有机框架纳米粒子的制备
将0.21g的均苯三甲酸(BTC)和0.45gTb2(SO4)3·8H2O以及0.45gGd2(SO4)3·8H2O溶于6mL N,N-二甲基甲酰胺(DMF)与24mL水的混合溶液中,加入0.6g的聚乙烯吡咯烷酮(PVP,K30)作为表面活性剂,反应物在100℃温度下,油浴搅拌加热10 min,过滤后室温下真空干燥,得到产物Tb,Gd(BTC)-MOF纳米粒子;
之后,将0.11g邻菲啰啉(phen)与得到的Tb,Gd-MOF纳米粒子按一定比例溶于无水乙醇中,于65℃下搅拌回流反应12h,得到邻菲啰啉配位的有机框架纳米粒子Tb,Gd(BTC)phen-MOF纳米粒子;
(2)接枝靶向抗肿瘤药物的高分子聚合物的合成
将1.4 g N-异丙基丙烯酰胺(NIPAM),0.045 g三硫代碳酸酯(DATC),0.006 g偶氮二异丁腈(AIBN)在氮气氛围内溶于4 mL的无水二氧六环中,其中,DATC作为链转移剂,AIBN作为引发剂,反应物在65℃C温度下,油浴搅拌加热24h,产物置于过量石油醚中分离,真空干燥,得到产物PNIPAM-DATC;
将得到的产物PNIPAM-DATC取0.5g再与0.15gNAOS进行RAFT反应,加入0.006g AIBN作为引发剂,溶于4mL的无水二氧六环中,整个反应在氮气氛围内进行,反应物在65℃温度下,油浴搅拌加热24h,反应结束后置于石油醚中,出现黄色沉淀,即得到聚合物PNIPAM-DATC-PNAOS;
将反应得到的聚合物取0.5gPNIPAM-DATC-PNAOS与1mg靶向卵巢癌细胞的抗肿瘤药物(Cetrorelix)溶于5 mL二甲基亚砜(DMSO)中,加入1 mL的三乙胺,室温下搅拌反应24h,反应结束后将产物透析3-5天,冷冻干燥后,即获得接枝靶向抗肿瘤药物的高分子聚合物,记为PNIPAM-PNAOS-Cetrorelix;
(3)聚合物改性金属铽有机框架纳米粒子的制备
将0.05g的PNIPAM-PNAOS-Cetrorelix分散在4 mL去离子水中,在N2保护条件下加入4.5μL的己胺,室温下搅拌一小时,同时,将0.01g的Tb,Gd(BTC)phen-MOF纳米粒子分散在2 mL去离子水中,氮气保护,将聚合物在氮气保护的条件下转移到MOF溶液中,在室温下搅拌反应24h,反应结束后将产物离心,固体颗粒室温下真空干燥,即获得聚合物修饰的铽和钆共掺杂的金属有机框架组成的体内靶向卵巢癌细胞成像纳米粒子Tb,Gd(BTC)phen(PPC)-MOF。
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