CN111494650A - 基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法及其产品 - Google Patents
基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法及其产品 Download PDFInfo
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Abstract
本发明公开了基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法及其产品,制备方法包括:(1)制备还原响应的MABHD;(2)制备还原响应MABHD‑CPT;(3)制备亲水性的POEGMA;(4)两亲性的POEGMA‑PMABHD的制备;(5)中间体POEGMA‑PMABHD‑PNPCF的制备;(6)还原响应的两亲性聚合物前药递送系统PCC的制备;(7)PCC纳米颗粒的制备;聚合物前药通过对肿瘤细胞内高还原环境的响应性,聚合物前药中的二硫键被打开,实现荧光染料CyOH和化疗药物CPT的快速释放;具有高稳定性、可控的药物释放、灵敏的荧光成像及良好的生物相容性等特点。
Description
技术领域
本发明涉及药物载体领域,具体涉及基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法及其产品。
背景技术
近红外荧光染料(Near-Infrared Fluorescent Dyes、NIR)在生命科学、临床医学诊断、光学材料及生物检测和识别等领域得到了广泛的应用,并成为实现上述功能的一种主要手段,但传统的荧光染料也具有一些缺点,比如:易聚合、易发生光漂白、量子产率较低等。因此,合成化学和光学性质更加稳定的新型近红外荧光染料具有重大的理论意义和应用价值。目前NIR荧光染料正在被大量开发,种类众多,主要包括有机荧光染料,无机和生物纳米粒子等。NIR荧光染料能够通过化学和物理方法交联多种分子探针,可以实现肿瘤靶向的多功能成像,为肿瘤的检测提供了实时动态信息。NIR荧光染料在监测肿瘤生长和转移,评价抗肿瘤药物体内分布及化疗疗效方面具有一定优势。
CPT是典型的DNA毒素药物,通过影响细胞DNA的合成而抑制细胞的分裂分化。但其水溶性差,毒副作用大,血液清除速率快等问题限制了其在癌症治疗方面的应用。由于肿瘤细胞快速的新陈代谢,肿瘤细胞中的还原剂谷胱甘肽的含量是正常细胞的四倍。还原响应性聚合物前药到达病灶部位后,二硫键被破坏,药物能够被有效的释放并杀死癌细胞。因此,由必要通过利用肿瘤微环境特点设计合适的药物递送载体有利于提高抗癌药物的生物利用度。
发明内容
有鉴于此,本发明的目的之一在于提供一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法;本发明的目的之二在于提供由所述的制备方法制得的基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒。
为达到上述目的,本发明提供如下技术方案:
1、一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,包含以下步骤:
(1)MABHD的制备:以二硫代二乙二醇和甲基丙烯酰氯在含三乙胺的无水四氢呋喃溶液中进行反应,收集一取代产物,得到MABHD;
(2)MABHD-CPT的制备:在2-10Pa氩气和避光条件下,首先将喜树碱与4-二甲氨基吡啶溶于无水二氯甲烷,然后将三光气和无水二氯甲烷的混合液逐滴加入含喜树碱和4-二甲氨基吡啶的反应液中,搅拌混匀后将溶于四氢呋喃的MABHD溶液逐滴加入上述反应液,搅拌反应,加入乙酸乙酯稀释,最后依次用水、盐酸、饱和食盐水萃取,收集有机相并除去水,浓缩,最后用乙醚洗得到淡黄色固体MABHD-CPT;
(3)POEGMA的制备:在2-10Pa氩气条件下,称取4-氰基-4-(苯基羰基硫代硫基硫基)戊酸N-琥珀酰亚胺酯和乙二醇甲基丙烯酸甲酯溶解于二氧六环中;加入自由基引发剂偶氮异丁二腈后,冷冻解冻循环三次,避光反应后冷冻停止反应,加甲醇稀释,在二氯甲烷与甲醇的混合液中透析,浓缩得到POEGMA;
(4)POEGMA-PMABHD的制备:在2-10Pa氩气条件下,步骤(1)所制备的MABHD,步骤(2)所制备的MABHD-CPT以及步骤(3)所制备的POEGMA溶于二氧六环和N,N-二甲基甲酰胺中,加入自由基引发剂偶氮异丁二腈后,冷冻解冻循环三次,避光反应,反应到时间点后先冷冻停止反应,再加甲醇稀释,用二氯甲烷与甲醇形成的混合液中透析,浓缩后得到POEGMA-PMABHD;
(5)PCPT-PMABHD-PNPCF的制备:在2-10Pa氩气Ar条件下,将对硝基苯基氯甲酸酯PNPCF与步骤(4)所制备的PCPT-PMABHD溶于无水二氯甲烷中,冰浴,逐滴加入吡啶,剧烈搅拌下冰浴30分钟,然后25℃下反应24h;用二氯甲烷与甲醇的混合液中透析,浓缩后得到PCPT-PMABHD-PNPCF;
(6)PCC的制备:在2-10Pa氩气Ar条件下,近红外半菁染料CyOH与步骤(5)所制备的PCPT-PMABHD-PNPCF溶于无水二氯甲烷DCM溶液中,然后再加入三乙胺TEA,25℃下反应24h。用二氯甲烷与甲醇的混合液中透析,浓缩后得到PCC;
(7)PCC纳米颗粒的制备,包含以下步骤:将步骤(6)所制备的PCC溶于N,N-二甲基甲酰胺DMF中,逐滴加入水中搅拌20min后,用在水中透析,得到纳米颗粒水溶液。
优选的,步骤(1),中二硫代二乙二醇与甲基丙烯酰氯的摩尔浓度比为1:0.5;三乙胺与四氢呋喃的体积比为1:15。
优选的,所述收集一取代产物的方法是将反应液过滤,然后用旋转蒸发仪浓缩溶剂,进一步以乙酸乙酯和正己烷体积比为1:4的混合液为洗脱剂过硅胶柱除去二取代产物,旋转蒸发除去溶剂得到MABHD。
优选的,步骤(2)中,MABHD、喜树碱、三光气、4-二甲氨基吡啶的摩尔比为1:1:0.4:0.3;四氢呋喃、二氯甲烷、乙酸乙酯、水、盐酸、饱和食盐水的体积比为1:8:30:10:10:2。
优选的,步骤(3)中,4-氰基-4-(苯基羰基硫代硫基硫基)戊酸N-琥珀酰亚胺酯、乙二醇甲基丙烯酸甲酯、二氧六环、偶氮异丁二腈的摩尔浓度比为1:25.8:0.35:0.2;二氯甲烷与甲醇的体积比为1:1。
优选的,步骤(4)中,MABHD、MABHD-CPT、POEGMA和偶氮异丁二腈的摩尔浓度比为20:20:2:1;二氧六环和N,N-二甲基甲酰胺的体积比为1:1。
优选的,步骤(5)中,对硝基苯基氯甲酸酯PNPCF、PCPT-PMABHD和吡啶的摩尔浓度比为1.39:1.2:1.6;二氯甲烷与甲醇的体积比为6:1。
优选的,步骤(6)中,近红外半菁染料CyOH与PCPT-PMABHD-PNPCF的摩尔浓度比15:1;二氯甲烷与三乙胺的体积比为40:1。
优选的,步骤(7)中,N,N-二甲基甲酰胺和水的体积比为1:500;所述步骤(7)中透析后所得的纳米颗粒粒径范围为1~1000nm。
2、由所述的制备方法制得的基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒。
本发明的有益效果在于:本发明公开了一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,通过在肿瘤细胞内高还原环境的响应性,聚合物前药中的二硫键被打开,实现荧光染料CyOH和化疗药物CPT的快速释放;该系统具有高稳定性、可控的药物释放、灵敏的荧光成像及良好的生物相容性等优点,解决了抗癌药物水溶性差、毒副作用强、肿瘤部位药物富集效果差以及很多的NIR有机染料水溶性差、光不稳定和循环半衰期短等问题。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚,本发明提供如下附图进行说明:
图1为本发明实施例1中的近红外染料合成的聚合物载体的制备流程示意图。
图2为本发明实施例1中的中间产物PCC的核磁图。
图3为本发明实施例1中的近红外染料合成的聚合物载体的TEM和DLS图。
图4为本发明实施例1中的近红外染料合成的聚合物载体的毒性示意图。
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,以使本领域的技术人员可以更好的理解本发明并能予以实施,但所举实施例不作为对本发明的限定。
实施例1、基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备
基于近红外荧光成像和还原响应的两亲性聚合物前药递送系统的制备方法,合成步骤如图1所示,具体步骤如下:
(1)MABHD的制备:在冰浴和2-10Pa氩气条件下,将二硫代二乙二醇BHD溶于含三乙胺TEA的无水四氢呋喃THF溶液后,逐滴加入溶于THF的甲基丙烯酰氯MA的溶液,搅拌0.5h后,室温(18~25℃)反应过夜,过滤除杂,用旋转蒸发仪浓缩溶剂,进一步以乙酸乙酯、正己烷为洗脱剂过硅胶柱除去二取代产物,旋转蒸发除去溶剂得到MABHD;
(2)MABHD-CPT的制备:在2-10Pa氩气和避光条件下,首先将喜树碱CPT与4-二甲氨基吡啶DMAP溶于无水二氯甲烷DCM,然后将三光气和DCM的混合液逐滴加入含CPT、DMAP的反应液中,室温搅拌0.5h后,将溶于THF的MABHD溶液逐滴加入上述反应液,室温搅拌24h后,加适量乙酸乙酯稀释,依次用水、盐酸、饱和食盐水萃取,收集有机相并用无水硫酸镁除水,旋蒸浓缩,最后用乙醚洗三次得到淡黄色固体MABHD-CPT;
(3)POEGMA的制备:在2-10Pa氩气Ar条件下,称取4-氰基-4-(苯基羰基硫代硫基硫基)戊酸N-琥珀酰亚胺酯RAFT-NHS和乙二醇甲基丙烯酸甲酯OEGMA溶解于二氧六环Dio中。加入自由基引发剂偶氮异丁二腈AIBN后,冷冻-解冻循环三次,在70℃避光反应24h,反应到时间点后先冷冻停止反应,再加3~5mL甲醇稀释,用截留分子量MWCO为3500Da的透析袋在等体积二氯甲烷与甲醇形成的混合液中透析24h,旋蒸浓缩后得到POEGMA;
(4)POEGMA-PMABHD的制备:在2-10Pa氩气Ar条件下,步骤(1)所制备的MABHD,步骤(2)所制备的MABHD-CPT以及步骤(3)所制备的POEGMA一并溶于二氧六环Dio和N,N-二甲基甲酰胺DMF中,加入自由基引发剂偶氮异丁二腈AIBN后,冷冻-解冻循环三次,在70℃避光反应24h,反应到时间点后先冷冻停止反应,再加3~5mL甲醇稀释,用截留分子量MWCO为3500Da的透析袋在等体积二氯甲烷与甲醇形成的混合液中透析24h,浓缩后得到POEGMA-PMABHD;
(5)POEGMA-PMABHD-PNPCF的制备:在2-10Pa氩气Ar条件下,将对硝基苯基氯甲酸酯PNPCF与步骤(4)所制备的POEGMA-PMABHD溶于无水二氯甲烷DCM中,冰浴10分钟后,逐滴加入吡啶,剧烈搅拌下冰浴30分钟,然后25℃下反应24h。用截留分子量MWCO为3500Da的透析袋在等体积二氯甲烷与甲醇形成的混合液中透析24h,浓缩后得到POEGMA-PMABHD-PNPCF;
(6)PCC的制备:在2-10Pa氩气Ar条件下,近红外半菁染料CyOH与步骤(5)所制备的POEGMA-PMABHD-PNPCF溶于无水二氯甲烷DCM溶液中,然后再加入三乙胺TEA,25℃下反应24h;用截留分子量MWCO为3500Da的透析袋在等体积二氯甲烷与甲醇形成的混合液中透析24h,浓缩后得到PCC;
(7)PCC纳米颗粒的制备:将10mg步骤(6)所制备的PCC,溶于0.5mL N,N-二甲基甲酰胺DMF中,逐滴加入5mL二次水中搅拌20min后,用截流量为3500Da的透析袋在水中透析24h,得到纳米颗粒水溶液。
图2为PCC的核磁图,通过核磁我们分析了在氘代氯仿CDCl3中PCC的氢谱图中峰a(3.65ppm)和b(3.38ppm)代表OEGMA的亚甲基和甲氧基氢。来自MABHD的亚甲基的信号峰出现在4.34-3.98ppm(标记为i和e)和2.84ppm(标记为f和h),表明POEGMA-PMABHD合成成功;苯环中的氢信号(8.37-7.27ppm)出现,表明聚合物MABHD-CPT合成成功;来自CyOH的次甲基的信号峰c(5.26ppm)和峰d(6.58ppm)出现,表明PCC合成成功。
图3为近红外染料合成的聚合物载体的TEM和DLS图。由图可以知道PCC呈均匀的球形颗粒,粒径为63.17nm。
图4为近红外荧光成像和还原响应的两亲性聚合物前药的毒性示意图。PCC药物对HeLa和4T-1细胞毒性,用含有0.1μg/mL至10μg/mL CPT的不同药物处理HeLa和4T-1癌细胞。在药物作用了24h后,对于用10μg/mL CPT处理的贴壁细胞,HeLa细胞中PCC细胞死亡率达到21.36%,4T-1细胞中PCC细胞死亡率达到49.80%。说明了制备的共价自组装策略的电荷翻转型聚合物载体具有良好的抗肿瘤能力。
以上所述实施例仅是为充分说明本发明而所举的较佳的实施例,本发明的保护范围不限于此。本技术领域的技术人员在本发明基础上所作的等同替代或变换,均在本发明的保护范围之内。本发明的保护范围以权利要求书为准。
Claims (10)
1.一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于,包含以下步骤:
(1)MABHD的制备:以二硫代二乙二醇和甲基丙烯酰氯在含三乙胺的无水四氢呋喃溶液中进行反应,收集一取代产物,得到MABHD;
(2)MABHD-CPT的制备:在2-10Pa氩气和避光条件下,首先将喜树碱与4-二甲氨基吡啶溶于无水二氯甲烷,然后将三光气和无水二氯甲烷的混合液逐滴加入含喜树碱和4-二甲氨基吡啶的反应液中,搅拌混匀后将溶于四氢呋喃的MABHD溶液逐滴加入上述反应液,搅拌反应,加入乙酸乙酯稀释,最后依次用水、盐酸、饱和食盐水萃取,收集有机相并除去水,浓缩,最后用乙醚洗得到淡黄色固体MABHD-CPT;
(3)POEGMA的制备:在2-10Pa氩气条件下,称取4-氰基-4-(苯基羰基硫代硫基硫基)戊酸N-琥珀酰亚胺酯和乙二醇甲基丙烯酸甲酯溶解于二氧六环中;加入自由基引发剂偶氮异丁二腈后,冷冻解冻循环三次,避光反应后冷冻停止反应,加甲醇稀释,在二氯甲烷与甲醇的混合液中透析,浓缩得到POEGMA;
(4)POEGMA-PMABHD的制备:在2-10Pa氩气条件下,步骤(1)所制备的MABHD,步骤(2)所制备的MABHD-CPT以及步骤(3)所制备的POEGMA溶于二氧六环和N,N-二甲基甲酰胺中,加入自由基引发剂偶氮异丁二腈后,冷冻解冻循环三次,避光反应,反应到时间点后先冷冻停止反应,再加甲醇稀释,用二氯甲烷与甲醇形成的混合液中透析,浓缩后得到POEGMA-PMABHD;
(5)PCPT-PMABHD-PNPCF的制备:在2-10Pa氩气Ar条件下,将对硝基苯基氯甲酸酯PNPCF与步骤(4)所制备的PCPT-PMABHD溶于无水二氯甲烷中,冰浴,逐滴加入吡啶,剧烈搅拌下冰浴30分钟,然后25℃下反应24h;用二氯甲烷与甲醇的混合液中透析,浓缩后得到PCPT-PMABHD-PNPCF;
(6)PCC的制备:在2-10Pa氩气Ar条件下,近红外半菁染料CyOH与步骤(5)所制备的PCPT-PMABHD-PNPCF溶于无水二氯甲烷DCM溶液中,然后再加入三乙胺TEA,25℃下反应24h。用二氯甲烷与甲醇的混合液中透析,浓缩后得到PCC;
(7)PCC纳米颗粒的制备,包含以下步骤:将步骤(6)所制备的PCC溶于N,N-二甲基甲酰胺DMF中,逐滴加入水中搅拌20min后,用在水中透析,得到纳米颗粒水溶液。
2.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(1),中二硫代二乙二醇与甲基丙烯酰氯的摩尔浓度比为1:0.5;三乙胺与四氢呋喃的体积比为1:15。
3.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:所述收集一取代产物的方法是将反应液过滤,然后用旋转蒸发仪浓缩溶剂,进一步以乙酸乙酯和正己烷体积比为1:4的混合液为洗脱剂过硅胶柱除去二取代产物,旋转蒸发除去溶剂得到MABHD。
4.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(2)中,MABHD、喜树碱、三光气、4-二甲氨基吡啶的摩尔比为1:1:0.4:0.3;四氢呋喃、二氯甲烷、乙酸乙酯、水、盐酸、饱和食盐水的体积比为1:8:30:10:10:2。
5.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(3)中,4-氰基-4-(苯基羰基硫代硫基硫基)戊酸N-琥珀酰亚胺酯、乙二醇甲基丙烯酸甲酯、二氧六环、偶氮异丁二腈的摩尔浓度比为1:25.8:0.35:0.2;二氯甲烷与甲醇的体积比为1:1。
6.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(4)中,MABHD、MABHD-CPT、POEGMA和偶氮异丁二腈的摩尔浓度比为20:20:2:1;二氧六环和N,N-二甲基甲酰胺的体积比为1:1。
7.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(5)中,对硝基苯基氯甲酸酯PNPCF、PCPT-PMABHD和吡啶的摩尔浓度比为1.39:1.2:1.6;二氯甲烷与甲醇的体积比为6:1。
8.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(6)中,近红外半菁染料CyOH与PCPT-PMABHD-PNPCF的摩尔浓度比15:1;二氯甲烷与三乙胺的体积比为40:1。
9.根据权利要求1所述的一种基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒的制备方法,其特征在于:步骤(7)中,N,N-二甲基甲酰胺和水的体积比为1:500;所述步骤(7)中透析后所得的纳米颗粒粒径范围为1~1000nm。
10.由权利要求1~9任一项所述的制备方法制得的基于近红外荧光成像和还原响应的两亲性聚合物纳米颗粒。
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