CN108653748A - 一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子及其制备方法 - Google Patents
一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种雷公藤甲素‑多臂聚乙二醇‑羟基喜树碱结合物纳米粒子及其制备方法,其特征在于,所述的雷公藤甲素‑多臂聚乙二醇‑羟基喜树碱结合物由雷公藤甲素、多臂聚乙二醇和羟基喜树碱通过酯键连接形成,多臂聚乙二醇作为亲水段、雷公藤甲素和羟基喜树碱作为疏水段,雷公藤甲素‑多臂聚乙二醇‑羟基喜树碱结合物在水溶液中自组装形成纳米粒子。
Description
技术领域
本发明涉一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子及其制备方法,属于医药和纳米医药技术领域。
背景技术
雷公藤甲素(Triptolide,TP)又称雷公藤内酯、雷公藤内酯醇,是从传统中药雷公藤中提取出来的环氧二萜内酯类化合物,是雷公藤的主要有效成分之一,具有免疫调节、抗氧化、抗炎、抗类风湿、抗老年性痴呆症、抗肿瘤等多种生物活性,可以抑制多种肿瘤的生长,及诱导凋亡的功效。近年来对雷公藤甲素的研究逐渐深入,在探索其强大的药理活性时,也发现了严重的不良反应,如对机体的消化系统、循环系统、泌尿系统、生殖系统及免疫系统等比较严重的毒副作用,限制了雷公藤甲素在临床上的广泛应用。如何降低雷公藤甲素的毒性,同时不影响其药理活性将会成为研究者关注的焦点。
羟基喜树碱(10-Hydroxy camptothecin,HCPT)是目前我国临床上使用较为广泛的喜树碱类抗癌药物,具有广谱的抗癌作用,但在临床应用中存在的主要问题是其半衰期短,内酯环对pH敏感,开环后抗癌活性降低且其极难溶于水,为了改善溶解性,HCPT多以开环形式的钠盐注射液、粉针应用,疗效低且毒副作用大。
传统大分子聚乙二醇(PEG)(食品级)广泛应用于药物修饰,合成步骤简单,具有良好的水溶性,但其载药能力低,故本研究以多臂聚乙二醇为载体,制备雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药,增加药物水溶性、药物循环半衰期的同时增加载药量,降低雷公藤甲素和羟基喜树碱的毒副作用,同时负载两种抗癌药物增加了药物的抗癌作用。在此基础上,本研究将所制雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药制成纳米粒,延长其在体内的循环时间并且可以将药物特异性释放于靶组织,起到增加疗效并降低毒副作用的效果。
随着载药纳米粒子体系的发展,该纳米药物载体将在癌症治疗中体现其巨大的优势和良好的临床应用前景。
发明内容
本发明的目的是建立一种水溶性雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药纳米粒子及其制备方法:首先雷公藤甲素和多臂聚乙二醇通过酯化反应形成多臂聚乙二醇-雷公藤甲素前药,再将多臂聚乙二醇-雷公藤甲素前药与羟基喜树碱通过化学键偶联形成雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物,最后将所得结合物于水中进行自组装形成水溶性纳米粒子。
所述雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物为以下结构:
本发明的技术方案:
(1)水溶性雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物的合成路线如下:
多臂聚乙二醇-雷公藤甲素前药制备,将多臂聚乙二醇分散于四氢呋喃(THF)溶剂中,磁力搅拌15-30分钟,使其充分溶解;然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)以活化聚乙二醇末端羧基,然后加入催化剂4-二甲氨基吡啶(DMAP);然后再称取一定量雷公藤甲素溶于上述溶液中,在35℃条件下磁力搅拌反应48h;反应完成后,向反应液中加入适量无水乙醚,出现白色絮状沉淀,以转速4000rpm离心沉淀15min,收集固体沉淀,继续用适量无水乙醚按上述方法洗涤该沉淀三次,收集白色固体A;
将上述白色固体A溶于一定量去离子水中,在磷酸缓冲液中透析8小时,透析完毕后,将透析溶液冷冻干燥48h,得到固体白色粉末B即为多臂聚乙二醇-雷公藤甲素前药;
雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物的制备,将聚乙二醇-雷公藤甲素前药B溶解于四氢呋喃(THF)溶剂中,加入适量活化剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS),磁力搅拌5-10min后,加入适量的羟基喜树碱,在35℃条件下,磁力搅拌反应48h;反应完成后,向反应液中加入无水乙醚出现絮状沉淀,以转速4000rpm离心沉淀15min,收集下层淡黄色固体,加入适量无水乙醚按上述方法充分清洗所得固体物三次;然后将所得淡黄色固体溶解于适量去离子水中,在磷酸缓冲液(PBS)中透析8小时,透析时可使用磁力搅拌加快透析速度;透析完毕后,将上述溶液在零下80℃下进行冷冻干燥,得到淡黄色粉末即为雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物C;
(2)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备:取适量雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物溶解于二甲基亚砜(DMSO)中,然后将所得溶液逐滴加入到高速搅拌的去离子水液中,自组装一段时间,将所得溶液置于磷酸盐缓冲液(PBS)中透析3h,滤膜过滤后冷冻干燥得到雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子。
本发明所述多臂聚乙二醇可为四臂聚乙二醇或八臂聚乙二醇且分子量介于10000-40000之间。所述的一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备方法,可通过改变雷公藤甲素、羟基喜树碱的摩尔比来改变多臂聚乙二醇的载药量。
本发明的优点:
(1)本发明将雷公藤甲素与羟基喜树碱同时化学连接在多臂PEG上,实现联合用药,增加了药物的抗癌作用提高了疗效,减少用药量;
(2)本发明采用医药级多臂聚乙二醇替代传统PEG载药,大幅提高载药量的同时,减少了药物的毒副作用且大幅增强了药物的水溶性;
(3)本发明的自组装过程是通过反应所得雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药上的疏水药物拒水作用形成空心内核,聚乙二醇的亲水基团作为外层,自组装形成粒径均一的纳米粒子;
(4)本发明工艺简单,易于操作且绿色环保,环境友好,可应用于工厂化生产。
附图说明
图1为雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子TEM示意图
具体实施方式
下面给出的实例对本发明进行具体描述,但不限制本发明,本发明的范围由权利要求限定。
实施例1:
(1)多臂聚乙二醇-雷公藤甲素前药的制备:
取100mg八臂聚乙二醇(MW40K)于50mL干燥三口烧瓶中,加入15mL四氢呋喃磁力搅拌20min使其充分溶解后,加入5.8mg EDC和6.1mg DMAP;之后加入5.4mg TP,在35℃条件下磁力搅拌48h;待反应完成后,反应结束后向反应液中加入15ml乙醚,出现大量白色絮状沉淀,随后以转速4000rpm离心沉淀15min,收集下层固体沉淀,然后继续用乙醚反复洗涤沉淀三次,离心得到白色固体,将所得白色固体溶于10mL去离子水中,将溶液转移至1000D的透析袋中于磷酸缓冲液中透析八小时,并伴有磁力搅拌以增加透析速度;透析完毕后,将上述溶液在零下80℃下进行冷冻干燥得到白色粉末即为八臂聚乙二醇-雷公藤甲素前药;
(2)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物的制备:
取50mg八臂聚乙二醇-雷公藤甲素前药于10mL四氢呋喃中,充分溶解后加入3.8mgEDC和5.7mg NHS,磁力搅拌10min,然后加入5.5mg羟基喜树碱,在35℃下反应48h;反应结束后向上述反应液中加入无水乙醚,出现大量黄色絮状沉淀,以转速4000rpm离心沉淀15min,收集下层淡黄色固体,反复用15mL乙醚洗涤沉淀三次,将所得沉淀溶解于10mL去离子水并转移至1000D的透析袋中,于磷酸盐缓冲液中透析8h,透析完毕后将透析液于零下80℃下冷冻干燥,得到淡黄色粉末即为雷公藤甲素-八臂聚乙二醇-羟基喜树碱前药;
(3)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备:
取10mg雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药溶解于1mL二甲基亚砜中,然后逐滴将溶液加入到高速搅拌的PBS溶液中,转速为800r/min,再用PBS溶液透析3h;过滤后,冷冻干燥得到载药纳米粒子。
实施例2:
(1)多臂聚乙二醇-雷公藤甲素前药的制备:
取100mg八臂聚乙二醇(MW20K)于50mL干燥三口烧瓶中,加入15mL四氢呋喃磁力搅拌20min使其充分溶解后,加入6.9mg EDC和7.3mg DMAP;之后加入11.4mg TP,在35℃条件下磁力搅拌48h;待反应完成后,反应结束后向反应液中加入15ml乙醚,出现大量白色絮状沉淀,随后以转速4000rpm离心沉淀15min,收集下层固体沉淀,然后继续用乙醚反复洗涤沉淀三次,离心得到白色固体,将所得白色固体溶于10mL去离子水中,将溶液转移至1000D的透析袋中于磷酸缓冲液中透析八小时,并伴有磁力搅拌以增加透析速度;透析完毕后,将上述溶液在零下80℃下进行冷冻干燥得到白色粉末即为八臂聚乙二醇-雷公藤甲素前药;
(2)雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药的制备:
取50mg八臂聚乙二醇-雷公藤甲素前药于10mL四氢呋喃中,充分溶解后加入4.6mgEDC和6.9mg NHS,磁力搅拌10min,然后加入10mg羟基喜树碱,在35℃下反应48h;反应结束后向上述反应液中加入无水乙醚,出现大量黄色絮状沉淀,以转速4000rpm离心沉淀15min,收集下层淡黄色固体,反复用15mL乙醚洗涤沉淀三次,将所得沉淀溶解于10mL去离子水并转移至1000D的透析袋中,于磷酸盐缓冲液中透析8h,透析完毕后将透析液于零下80℃下冷冻干燥,得到淡黄色粉末即为雷公藤甲素-八臂聚乙二醇-羟基喜树碱前药;
(3)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备:取10mg雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药溶解于1mL二甲基亚砜中,然后逐滴将溶液加入到高速搅拌的PBS溶液中,转速为800r/min,再用PBS溶液透析3h;过滤后,冷冻干燥得到载药纳米粒子。
实施例3:
(1)多臂聚乙二醇-雷公藤甲素前药的制备:
取100mg四臂聚乙二醇(MW20K)于50mL干燥三口烧瓶中,加入15mL四氢呋喃磁力搅拌20min使其充分溶解后,加入2.7mg EDC和1.3mg DMAP;之后加入3.0mg TP,在35℃条件下磁力搅拌48h;待反应完成后,反应结束后向反应液中加入15ml乙醚,出现大量白色絮状沉淀,随后以转速4000rpm离心沉淀15min,收集下层固体沉淀,然后继续用乙醚反复洗涤沉淀三次,离心得到白色固体,将所得白色固体溶于10mL去离子水中,将溶液转移至1000D的透析袋中于磷酸缓冲液中透析八小时,并伴有磁力搅拌以增加透析速度;透析完毕后,将上述溶液在零下80℃下进行冷冻干燥得到白色粉末即为四臂聚乙二醇-雷公藤甲素前药;
(2)雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药的制备:
取50mg四臂聚乙二醇-雷公藤甲素前药于10mL四氢呋喃中,充分溶解后加入2.3mgEDC和3.5mg NHS,磁力搅拌10min,然后加入10mg羟基喜树碱,在35℃下反应48h;反应结束后向上述反应液中加入无水乙醚,出现大量黄色絮状沉淀,以转速4000rpm离心沉淀15min,收集下层淡黄色固体,反复用15mL乙醚洗涤沉淀三次,将所得沉淀溶解于10mL去离子水并转移至1000D的透析袋中,于磷酸盐缓冲液中透析8h,透析完毕后将透析液于零下80℃下冷冻干燥,得到淡黄色粉末即为雷公藤甲素-四臂聚乙二醇-羟基喜树碱前药;
(3)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备:
取10mg雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药溶解于1mL二甲基亚砜中,然后逐滴将溶液加入到高速搅拌的PBS溶液中,转速为800r/min,再用PBS溶液透析3h;过滤后,冷冻干燥得到载药纳米粒子。
Claims (5)
1.一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子及其制备方法,其特征在于,所述的雷公藤甲素-多臂聚乙二醇-羟基喜树碱前药由雷公藤甲素、多臂聚乙二醇和羟基喜树碱通过酯键连接形成,多臂聚乙二醇作为亲水段、雷公藤甲素和羟基喜树碱作为疏水段,雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物在水溶液中自组装形成纳米粒子。
2.根据权利要求1所述的雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物,其特征在于,所述结合物包括式Ⅰ结构:
3.根据权利要求1和2所述的雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备方法,包括如下步骤:
(1)多臂聚乙二醇-雷公藤甲素前药制备,将多臂聚乙二醇分散于四氢呋喃(THF)溶剂中,磁力搅拌15-30分钟,使其充分溶解;然后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)以活化聚乙二醇末端羧基,然后加入催化剂4-二甲氨基吡啶(DMAP);然后再称取一定量雷公藤甲素溶于上述溶液中,在35℃条件下磁力搅拌反应48h;反应完成后,向反应液中加入适量无水乙醚,出现白色絮状沉淀,以转速4000rpm离心沉淀15min,收集固体沉淀,继续用适量无水乙醚按上述方法洗涤该沉淀三次,收集白色固体A;
(2)将上述白色固体A溶于一定量去离子水中,在磷酸缓冲液中透析8小时,透析完毕后,将透析溶液冷冻干燥48h,得到固体白色粉末B即为多臂聚乙二醇-雷公藤甲素前药;雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物的制备,将聚乙二醇-雷公藤甲素前药B溶解于四氢呋喃(THF)溶剂中,加入适量活化剂1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)和N-羟基琥珀酰亚胺(NHS),磁力搅拌5-10min后,加入适量的羟基喜树碱,在35℃条件下,磁力搅拌反应48h;反应完成后,向反应液中加入无水乙醚出现絮状沉淀,以转速4000rpm离心沉淀15min,收集下层淡黄色固体,加入适量无水乙醚按上述方法充分清洗所得固体物三次;然后将所得淡黄色固体溶解于适量去离子水中,在磷酸缓冲液(PBS)中透析8小时,透析时可使用磁力搅拌加快透析速度;透析完毕后,将上述溶液在零下80℃下进行冷冻干燥,得到淡黄色粉末即为雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物C;
(3)雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备,取适量雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物溶解于二甲基亚砜(DMSO)中,然后将所得溶液逐滴加入到高速搅拌的去离子水液中,自组装一段时间,将所得溶液置于磷酸盐缓冲液(PBS)中透析3h,滤膜过滤后冷冻干燥得到雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子。
4.根据权利要求1和3所述的一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备方法,其特征在于,所述多臂聚乙二醇可为四臂聚乙二醇或八臂聚乙二醇且分子量介于10000-40000之间。
5.根据权利要求1和3所述的一种雷公藤甲素-多臂聚乙二醇-羟基喜树碱结合物纳米粒子的制备方法,其特征在于,可通过改变雷公藤甲素、羟基喜树碱的摩尔比来改变多臂聚乙二醇的载药量。
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