CN110183578A - 一种两亲性嵌段线粒体靶向聚合物的制备方法及其应用 - Google Patents
一种两亲性嵌段线粒体靶向聚合物的制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种两亲性嵌段线粒体靶向聚合物的制备方法及其应用,其关键在于,葡聚糖具有很好的生物相容性,可以有效降低药物毒性,磷酸三苯酯(TPP)带正电,在细胞里可以和线粒体膜静电吸引,破坏膜电位,从而释放活性氧,同时化疗破坏DNA,从而具有靶向性。通过一系列的ATRP聚合反应,将葡聚糖、TPP、以及稳定性良好的聚乙二醇和抗癌效果优良的药物喜树碱结合成为两亲性嵌段线粒体靶向聚合物,采用了核磁,紫外光谱等表征手段对其化学结构进行了系统性的确定,也通过一系列的体内、外实验,对毒性、成像等进行了研究,共同确定了该两亲性嵌段线粒体靶向聚合物在肿瘤靶向治疗的优良特性。
Description
技术领域
本发明涉及靶向药物递送领域,具体涉及了线粒体靶向药物的递送,活性氧协同治疗肿瘤细胞的双亲性聚合物制备方法及其生物应用。
背景技术
长期以来,癌症是困扰人类的最大疾病之一,其居高不下的发病率和死亡率,对人类的生命健康造成了严重的威胁。对肿瘤进行靶向治疗是现在化疗的热门研究方向,同时也需要:1)提高药物上载量;2)减少化疗药物毒副作用;3)增加药物释放效率。将具有生物相容性的葡聚糖与亲水性单体(如聚乙二醇,PEG)共聚形成的两亲性聚合物,再与具有线粒体靶向的三苯基膦以及抗肿瘤药物喜树碱共聚,得到一种两亲性线粒体靶向聚合物,该聚合物的优势在于:1)水溶性良好;2)毒副作用小;3)具有靶向性;4)可以在肿瘤细胞中产生活性氧。通过这种方法可以协同药物高效杀死肿瘤细胞且生物毒性较小。
发明内容
本发明的目的之一是一种两亲性嵌段线粒体靶向聚合物的制备方法,该制备方法简单高效。目的之二是使用所述制备方法制备的两亲性嵌段线粒体靶向聚合物具有生物相容性、靶向性以及良好的水溶性等优点。为实现上述目的,采用以下技术方案:
两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:包含以下步骤:
(1)MABHD的制备,包含以下步骤:冰浴和2-10Pa氩气Ar条件下,用无水四氢呋喃溶液溶解二硫代二乙二醇BHD并加入三乙胺溶液,将甲基丙烯酰氯MA溶于无水四氢呋喃并放入滴液漏斗之后均匀的滴入上述溶液中,搅拌0.5h,撤除冰浴,室温搅拌过夜,过滤萃取除杂,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,用旋转蒸发仪浓缩所收集溶液得到2-((2-hydroxyethyl)disulfanyl)ethyl methacrylate,简记MABHD;其反应式如下所示;
(2)MABHD-CPT的制备,包含以下步骤:在2-10Pa氩气Ar和避光条件下,将喜树碱CPT与4-二甲氨基吡啶DMAP放入无水二氯甲烷DCM中搅拌溶解,再用二氯甲烷溶解三光气并装入注射器中再逐滴加入至反应液中,室温搅拌0.5h后,将MABHD用无水四氢呋喃THF溶解并装入注射器中再逐滴加入至反应液中,室温搅拌24h,反应结束后,加乙酸乙酯稀释,然后用二次水萃取2次,再用盐酸萃取2次,最后用饱和食盐水萃取2次,将有机相收集,用无水硫镁除水,浓缩,用乙醚洗三次即得淡黄色固体MABHD-CPT;其反应式如下所示;
(3)PEGTPP的制备,包含以下步骤:在冰浴和2-10Pa氩气Ar条件下,将TPP-COOH和二环己基碳二亚胺DCC溶解于无水二氯甲烷中,搅拌0.5h,再逐滴加入溶于无水二氯甲烷的OEGMA-OH和DMAP的溶液,接着搅拌0.5h,冷却至室温反应12h,反应结束后,用分子量MWCO为1000的透析袋在甲醇中透析6-8h后旋干,得到PEGTPP;其反应式如下所示;
(4)DEX-P(TPP-CPTss-OEGMA)的制备,包含以下步骤:在2-10Pa氩气Ar条件下,加冷肼,将25ml玻璃支管抽真空,换管子里的Ar两次,再换瓶子里的Ar,持续通Ar,将葡聚糖溴DEX-Br和PEGTPP、OEGMA、MABHD-CPT、Me6TREN溶于DMF和DMSO溶液中并转移至反应管中,在手套箱用玻璃吸管取CuBr再迅速加入反应管,冷冻-解冻循环三次;转移至25℃油浴反应24h,反应结束后,用MWCO为14000透析袋,THF溶液透析后得到DEX-P(TPP-CPTss-OEGMA),简称DCT;其反应式如下所示;
(5)两亲性嵌段线粒体靶向聚合物纳米颗粒的制备,包含以下步骤:取4ml步骤(4)得到的DEX-P(TPP-CPTss-OEGMA)的THF溶液,均匀地滴加到4ml二次水中,室温搅拌0.5h,装入MWCO为3500透析袋中,用二次水透析24小时,得到两亲性嵌段线粒体靶向聚合物纳米颗粒水溶液。
进一步,所述步骤(1)中二硫代二乙二醇与甲基丙烯酰氯的摩尔浓度范围比为1:(0.4~1.6);三乙胺与四氢呋喃的体积比范围为1:(6~24);乙酸乙酯与正己烷的体积比范围为1:(3.2~4.8)。
进一步,所述步骤(2)中MABHD、CPT、三光气、DMAP的摩尔比范围为1:(3~15) :(0.5~2.5) :(0.6~1.8);四氢呋喃、二氯甲烷、乙酸乙酯、水、盐酸、饱和食盐水的体积比范围为1:(68~79) :(280~330) :(80~140) :(23~76) :(23~76)。
进一步,所述步骤(3) 中TPP-COOH、DCC、OEGMA-OH、DMAP的摩尔浓度比范围为1:(1~2.4):(1.0~2.5) :(0.1~0.8);DCM与甲醇的体积比范围为1: (40~60)。
进一步,所述步骤(4)中DEX-Br、PEGTPP、OEGMA、MABHD-CPT、三(2-吡啶基甲基)胺、CuBr的摩尔浓度比范围为1: (4~12) : (1~4) : (0.5~3) : (0.5~2): (0.5~2);DMF、DMSO、THF的体积比范围为1:(0.5~2.5):(40~60)。
进一步,所述步骤(6)中DEX-P(TPP-CPTss-OEGMA)的THF溶液与二次水的体积比范围为1:(220~280);两亲性嵌段线粒体靶向聚合物纳米颗粒的粒径范围为1~1000nm。
主要优点:
针对药物毒性问题,本项目结合了生物相容性良好的葡聚糖,降低了药物的生物毒性,与亲水性良好的聚乙二醇结合,形成两亲性聚合物,有助于药物粒子延长体内循环时间,有助于药物快速进入细胞,增强细胞内化。同时该聚合物与三苯基膦(TPP)结合,使得该聚合物增加了线粒体靶向性,三苯基膦带正电,进入线粒体与膜静电吸引,破坏膜电位,从而释放活性氧,同时化疗破坏DNA ,发挥协同治疗和精准治疗的作用,是本项目最大的特色之一。
附图说明
为了更加清楚的展现本发明的目的及其技术方案,本发明提供如下附图:
图1为本发明实施例1中的两亲性嵌段线粒体靶向聚合物的制备流程示意图。
图2为本发明实施例1中的中间产物PEGTPP的核磁示意图。
图3为本发明实施例1中两亲性嵌段线粒体靶向聚合物的最终产物DCT的核磁示意图。
图4为本发明实施例1中的两亲性嵌段线粒体靶向聚合物DCT纳米颗粒的TEM示意图。
图5为本发明实施例1中的两亲性嵌段线粒体靶向聚合物DCT纳米颗粒的体外释药示意图以及对4T1、HeLa和 MCF-7细胞的毒性对比图示意图。
具体实施方式
下面将结合附图,对本发明的实施例进行详细的描述
实施例1 制备两亲性嵌段线粒体靶向聚合物纳米颗粒
如图1所示的制备流程图来制备两亲性嵌段线粒体靶向聚合物纳米颗粒,包括如下制备步骤:
1)MABHD的制备:冰浴(温度≤0℃)和氩气(Ar,2-10Pa)条件下,用30ml无水四氢呋喃溶液溶解6.25g二硫代二乙二醇(BHD)并加入3.3ml三乙胺溶液,将2.2ml甲基丙烯酰氯(MA)溶于20ml无水四氢呋喃放入滴液漏斗,均匀的滴入上述溶液中,搅拌0.5h,恢复至室温过夜,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,用旋转蒸发仪浓缩所收集溶液即得纯的MABHD 2.6g。
2)MABHD-CPT的制备:在氩气(Ar,2-10Pa)和避光条件下,将1.3g喜树碱(CPT)与1.56g 4-二甲氨基吡啶(DMAP)放入70ml无水二氯甲烷(DCM)中搅拌溶解,待溶解完全后,再用二氯甲烷溶解500mg三光气,将溶液转移到注射器再逐滴加入至反应液中,室温搅拌0.5h后,将1g MABHD用11ml无水四氢呋喃(THF)溶解转移至注射器中逐滴加入至反应液中,室温搅拌24h,反应结束后,加300ml乙酸乙酯稀释,然后用50ml二次水、盐酸、饱和食盐水各萃取2次,收集有机相,干燥浓缩后用乙醚沉淀即得1.55g淡黄色固体MABHD-CPT。
3)PEGTPP的制备:在冰浴(温度≤0℃)和氩气(Ar,2-10Pa)条件下,将834.67mgTPP-COOH和498.29mg DCC溶解于4ml无水二氯甲烷中,搅拌0.5h,再将1.5075g OEGMA-OH和109.95mg DMAP 溶于4ml无水二氯甲烷中,逐滴加入至反应液中。搅拌0.5h,冷却至室温反应12h,反应结束后,用分子量MWCO=1000的透析袋在甲醇溶液中透析(除去DCC副产物)6-8h后旋干即得纯的PEGTPP 1.3553g;如图2所示为PEGTPP的核磁图。
4)DEX-P(TPP-CPTss-OEGMA)(DCT)的制备,包含以下步骤:在氩气(Ar,2-10Pa)条件下,加冷肼,将25ml玻璃支管抽真空,换管子里的Ar两次,再换瓶子里的Ar,持续通Ar,将23mg DEX-Br和105mg PEGTPP、420mg OEGMA、126mg MABHD-CPT、Me6TREN溶于2ml DMF和2mlDMSO溶液中并转移至反应管中,在手套箱取CuBr,用玻璃吸管迅速加入反应管,冷冻-解冻循环三次。转移至25℃油浴反应24h.反应结束后,用MWCO=14000透析袋,THF溶液透析后保存,得到DEX-P(TPP-CPTss-OEGMA)(DCT)。如图3所示为DCT的核磁图。
5)两亲性嵌段线粒体靶向聚合物DCT纳米颗粒的制备:取4ml存于THF中的产物DEX-P(TPP-CPTss-OEGMA)(DCT),均匀地滴加到4ml二次水中,室温搅拌0.5h,装入MWCO=3500透析袋中,用二次水透析24小时,即得两亲性嵌段线粒体靶向聚合物纳米颗粒水溶液。如图4所示,可以看到两亲性嵌段线粒体靶向聚合物DCT纳米颗粒的TEM图,粒径在20-80nm。
图5为两亲性嵌段线粒体靶向聚合物DCT纳米颗粒的体外释药示意图以及对4T1、HeLa和 MCF-7细胞的毒性对比图,说明胶束DCT在2ml的浓度下释放效果更好以及在MCF-7细胞中,毒性效果最强。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (6)
1.一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:包含以下步骤:
(1)MABHD的制备,包含以下步骤:冰浴和2-10Pa氩气Ar条件下,用无水四氢呋喃THF溶液溶解二硫代二乙二醇BHD并加入三乙胺TEA溶液,将甲基丙烯酰氯MA溶于无水四氢呋喃并放入滴液漏斗之后均匀的滴入上述溶液中,搅拌0.5h,撤除冰浴,室温搅拌过夜,过滤萃取除杂, 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,用旋转蒸发仪浓缩所收集溶液得到2-((2-hydroxyethyl)disulfanyl)ethylmethacrylate,简记MABHD;其反应式如下所示;
(2)MABHD-CPT的制备,包含以下步骤:在2-10Pa氩气Ar和避光条件下,将喜树碱CPT与4-二甲氨基吡啶DMAP放入无水二氯甲烷DCM中搅拌溶解,再用二氯甲烷溶解三光气BTC并装入注射器中再逐滴加入至反应液中,室温搅拌0.5h后,将MABHD用无水四氢呋喃THF溶解并装入注射器中逐滴再加入至反应液中,室温搅拌24h,反应结束后,加乙酸乙酯稀释,然后用二次水萃取2次,再用盐酸萃取2次,最后用饱和食盐水萃取2次,将有机相收集,用无水硫镁除水,浓缩,用乙醚洗三次即得淡黄色固体MABHD-CPT;其反应式如下所示;
(3)PEGTPP的制备,包含以下步骤:在冰浴和2-10Pa氩气Ar条件下,将2-羧乙基三苯基溴化磷TPP-COOH和二环己基碳二亚胺 DCC溶解于无水二氯甲烷中,搅拌0.5h,再逐滴加入溶于无水二氯甲烷的聚乙二醇甲基丙烯酸酯 OEGMA-OH和DMAP的溶液,接着搅拌0.5h,冷却至室温反应12h,反应结束后,用分子量MWCO为1000的透析袋在甲醇中透析6-8h后旋干,得到PEGTPP;其反应式如下所示;
(4)DEX-P(TPP-CPTss-OEGMA)的制备,包含以下步骤:在2-10Pa氩气Ar条件下,加冷肼,将25ml玻璃支管抽真空,换管子里的Ar两次,再换瓶子里的Ar,持续通Ar,将葡聚糖溴DEX-Br和PEGTPP、聚乙二醇甲醚OEGMA、MABHD-CPT、三(2-二甲氨基乙基)胺Me6TREN溶于DMF和DMSO溶液中并转移至反应管中,在手套箱用玻璃吸管取CuBr再迅速加入反应管,冷冻-解冻循环三次;转移至25℃油浴反应24h,反应结束后,用MWCO为14000透析袋,THF溶液透析后得到DEX-P(TPP-CPTss-OEGMA),简称DCT;其反应式如下所示;
(5)两亲性嵌段线粒体靶向聚合物纳米颗粒的制备,包含以下步骤:取4ml步骤(4)得到的DEX-P(TPP-CPTss-OEGMA)的THF溶液,均匀地滴加到4ml二次水中,室温搅拌0.5h,装入MWCO为3500透析袋中,用二次水透析24小时,得到两亲性嵌段线粒体靶向聚合物纳米颗粒水溶液。
2.根据权利要求1所述的一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:所述步骤(1)中二硫代二乙二醇与甲基丙烯酰氯的摩尔浓度范围比为1:(0.4~1.6);TEA与THF的体积比范围为1:(6~24);乙酸乙酯与正己烷的体积比范围为1:(3.2~4.8)。
3.根据权利要求1所述的一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:所述步骤(2)中MABHD、CPT、三光气、DMAP的摩尔比范围为1:(3~15) :(0.5~2.5) :(0.6~1.8);四氢呋喃、二氯甲烷、乙酸乙酯、水、盐酸、饱和食盐水的体积比范围为1:(68~79) :(280~330) :(80~140) :(23~76) :(23~76)。
4.根据权利要求1所述的一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:所述步骤(3) 中TPP-COOH、DCC、OEGMA-OH、DMAP的摩尔浓度比范围为1:(1~2.4):(1.0~2.5) :(0.1~0.8);DCM与甲醇的体积比范围为1: (40~60)。
5.根据权利要求1所述的一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:所述步骤(4)中DEX-Br、PEGTPP、OEGMA、MABHD-CPT、Me6TREN、CuBr的摩尔浓度比范围为1:(4~12) : (1~4) : (0.5~3) : (0.5~2) : (0.5~2);DMF、DMSO、THF的体积比范围为1:(0.5~2.5):(40~60)。
6.根据权利要求1所述的一种两亲性嵌段线粒体靶向聚合物的制备方法,其特征在于:所述步骤(6)中DEX-P(TPP-CPTss-OEGMA)的THF溶液与二次水的体积比范围为1:(220~280);两亲性嵌段线粒体靶向聚合物纳米颗粒的粒径范围为1~1000nm。
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