CN106177978B - 一种具有靶向和示踪功能的抗肿瘤高分子键合药及其制备方法 - Google Patents
一种具有靶向和示踪功能的抗肿瘤高分子键合药及其制备方法 Download PDFInfo
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- CN106177978B CN106177978B CN201610564588.2A CN201610564588A CN106177978B CN 106177978 B CN106177978 B CN 106177978B CN 201610564588 A CN201610564588 A CN 201610564588A CN 106177978 B CN106177978 B CN 106177978B
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Abstract
本发明公开了一种具有靶向和示踪功能的抗肿瘤高分子键合药及其制备方法;通过将靶分子键合到两亲性可降解聚合物上的亲水端,抗肿瘤药键合到聚合物的疏水端以及将可修饰量子点的基团(巯基、咪唑基和吡啶基)引入到疏水端,再将得到的聚合物与量子点混合,搅拌,分散到水相中,形成纳米粒子;制得的纳米粒子可降解,而纳米粒子表面的靶分子使得其具有主动靶向功能,进而靶向给药。聚合物包裹的量子点可以用来实时荧光示踪,其荧光性质稳定,从而达到抗肿瘤药物的监控作用;且抗肿瘤高分子键合药的制备方法操作简便,产物纯净无毒。
Description
技术领域
本发明涉及抗肿瘤药物,特别涉及一种具有靶向和示踪功能的抗肿瘤高分子键合药及其制备方法,属生物医用高分子领域。
背景技术
脂肪族聚酯因其具有良好的生物相容性及可降解性而被广泛地应用在生物医用高分子领域,而高分子载体纳米药物因其尺寸小,同样的具有生物相容性和可降解性、在血液循环系统中能够保留较长的时间、载药量可控同时能够保护未达到作用部位而被提前降解以及容易进行表面修饰和化学改性等特点,被认为是最常用和最简单的纳米药物传输载体,特别是后两者已经达到了临床应用的标准。一般来说,根据药物搭载机制可将其分为三类:通过共价键合的高分子键合药、通过物理包裹的集合物囊泡和通过疏水作用制备的聚合物胶束,大部分的经开发的高分子载体已经被美国食品药品监督管理局批准作为靶向药物的载体。
靶向治疗是将靶分子与纳米药物通过共价键的接合使之能够特异性定向蓄积于肿瘤组织,细胞甚至是细胞结合器,能大大的提高纳米药物的特异性,减少对正常组织的副作用,常用的靶分子有叶酸、半乳糖、抗体、生物素、核酸适配体,或者可以识别肿瘤组织表达受体的蛋白质等。
为了弄清生物体内的各种反应机理,人们必须对生物体内的各种细胞的相互作用进行监控,过去常常以同位素和有机荧光染色体标记生物大分子和细胞来达到这一目的,但是众所周知,同位素标记和有机荧光染色体标记在应用方面存在一系列的缺陷从而限制了其在生物活体内的应用,而量子点的出现解决了这一问题,其荧光寿命长、光稳定性好和尺寸可控及稳定而被看好成为下一代生物荧光标记物。
发明内容
针对现有技术中的抗肿瘤聚合物前药存在的降解性差,生物利用度低以及无法监控等问题,本发明的第一个目的是在于提供一种可完全降解、载药量可控,且具有肿瘤组织靶向和可监控治疗的抗肿瘤高分子键合药。
本发明的另一个目的是提供了一种经济、高效和无毒的制备高纯度抗肿瘤高分子键合药的方法。
为了实现上述技术目的,本发明提供了一种具有靶向和示踪功能的抗肿瘤高分子键合药,该抗肿瘤高分子键合药具有式1结构:
其中,
A为羟基官能化的具有靶向作用的基团;
B为含羟基或/和氨基的抗肿瘤药物基团;
D为配体基团;
Q为量子点;
x为20~100,y为1~100,z为1~100,n为8~17;
R1、R2、R3为各自独立地选自C1~C4的亚烷基;
优选的方案,A为羟基官能化的生物素基团和/或羟基官能化的叶酸基团。
优选的方案,B为紫杉醇基团、多西紫杉醇基团、喜树碱基团、丝裂霉素C基团、阿霉素基团、表阿霉素基团中的至少一种。
优选的方案,D为咪唑基团、吡啶基团、巯基基团中的至少一种。
优选的方案,Q为CdSe/ZnS、CdSe/ZnSe、CdTe/SeCd、CdTe/CdSe、CdZnSe/ZnS、CdSe/CdS/ZnS中的至少一种。
本发明还提供了一种制备所述的具有靶向和示踪功能的抗肿瘤高分子键合药的方法,包括以下步骤:
1)将靶分子与二醇化合物进行酯化反应,得到羟基官能化靶分子;
2)采用所述羟基官能化靶分子引发含降冰片烯基团的丙交酯单体进行聚合反应,得到含靶分子和降冰片烯侧基的聚丙交酯;所述含靶分子和降冰片烯侧基的聚丙交酯与含叠氮取代基的聚乙二醇单甲醚进行叠氮-烯点击反应,得到含靶分子和聚乙二醇单甲醚支链的聚丙交酯;采用所述含靶分子和聚乙二醇单甲醚支链的聚丙交酯引发含降冰片烯基团的丙交酯单体进行聚合反应,聚合反应产物进一步引发α位溴代己内酯进行聚合产物,得到式2载体聚合物;
3)将含巯基的羧酸化合物(巯基乙酸、巯基丙酸)与式2载体聚合物进行巯基-溴点击反应,得到含羧侧基的载体聚合物;所述含羧侧基的载体聚合物通过N-羟基琥珀酰亚胺活化羧基后,与含氨基的量子点配体化合物进行酰胺化反应,得到式3含量子点配体侧基的载体聚合物;
4)将含巯基的羧酸化合物(巯基乙酸、巯基丙酸)与式3含量子点配体侧基的载体聚合物进行巯基-烯光点击反应,得到含羧基和量子点配体侧基的载体聚合物;所述含羧基和量子点配体侧基的载体聚合物与含羟基或/和氨基的抗肿瘤药物进行酯化或/和酰胺化反应,即得式4抗肿瘤高分子键合药;
5)将所述抗肿瘤高分子键合药与表面带配体的量子点进行配体交换,即得具有靶向和示踪功能的抗肿瘤高分子键合药;
其中,
A为羟基官能化的具有靶向作用的基团;
B为含羟基或/和氨基的抗肿瘤药物基团;
D为配体基团;
20≤x≤100,1≤y≤100、1≤z≤100,8≤n≤17;
R1、R2、R3为各自独立地选自C1~C4的亚烷基。
优选的方案,靶分子为生物素和/或叶酸。
优选的方案,抗肿瘤药物为紫杉醇、多西紫杉醇、喜树碱、丝裂霉素C、阿霉素、表阿霉素中的至少一种。
优选的方案,含氨基的量子点配体化合物中配体为咪唑基团、吡啶基团或巯基基团。
优选的方案,量子点为CdSe/ZnS、CdSe/ZnSe、CdTe/SeCd、CdTe/CdSe、CdZnSe/ZnS、CdSe/CdS/ZnS中的至少一种。较优选的量子点CdSe/ZnS(表面配体为三辛基磷和三辛基磷)具有很好的生物相容性和荧光稳定性;
本发明的方案中,配体交换产物分散在水相中,通过透析除去有机相,即得具有靶向和示踪功能的抗肿瘤高分子键合药纳米粒子。
优选的方案,酯化反应过程中均以N,N-二异丙基碳二亚胺(DIC)为缩合剂,其副产物易除去,避免了传统二环己基碳二亚胺(DCC)缩合后剧毒物质二环己基脲(DCU)的产生。
本发明的羟基官能化靶分子是以含羧基靶分子中的羧基与二醇化合物中的一个羟基进行缩合反应得到的,经分离、过柱和纯化得到的羟基官能化靶分子。
本发明的含靶分子和降冰片烯侧基聚丙交酯的制备方法:将L-丙交酯和N-溴代丁二酰亚胺(NBS),以四氯化碳或苯为溶液,以过氧化二苯甲酰(BPO)做催化剂,在60~90℃下发生取代反应,得到溴代丙交酯;得到的溴代丙交酯以二氯甲烷溶剂中,在三乙胺的作用下,0~5℃下发生消去反应得到双键丙交酯;得到的双键丙交酯和新蒸环戊二烯在四氯化碳或苯溶液中,氩气保护,60~90℃下,通过Diels-Alder反应后,得到含降冰片烯基团的丙交酯单体;以TBD或DBU为催化剂,羟基官能化靶分子为引发剂,二氯甲烷为溶剂-20~40℃下,引发含降冰片烯基团的丙交酯单体开环聚合后得到含靶分子和降冰片烯侧基的聚丙交酯。
本发明的含靶分子和聚乙二醇单甲醚支链的聚丙交酯通过含靶分子和降冰片烯侧基的聚丙交酯与含叠氮取代基的聚乙二醇单甲醚(mOEG-azide)发生叠氮-烯环加成化学反应,得到含靶分子和聚乙二醇单甲醚支链的聚丙交酯。
本发明的α位溴代己内酯是利用溴代剂与环己酮反应,生成α位溴代的环己酮,产物经过柱分离得到。所得溴代环己酮与间氯过氧苯甲酸(m-CPBA)通过Baeyer-Villiger反应,生成α位溴代己内酯,产物同样经过硅胶柱分离,得到浅黄色油状液体,经过低温重结晶得到白色固体。
本发明的载体聚合物(含靶分子、降冰片烯侧基和溴取代基的两亲性三嵌段聚合物)以含靶分子和聚乙二醇单甲醚支链的聚丙交酯为引发剂,依次开环含降冰片烯侧基的丙交酯和α位溴代己内酯进行聚合得到,其中,开环聚合过程中以TBD或DBU为催化剂,二氯甲烷为溶剂,反应温度为-20~40℃。
本发明的高分子键合药载体聚合物与表面带配体的量子点进行配体交换反应优选的溶剂为四氢呋喃,反应条件为40℃,反应时间为2小时。
本发明的具有靶向和示踪功能的抗肿瘤高分子键合药的具体合成路线如下:以靶分子D-生物素(biotin)和抗肿瘤前药紫杉醇(paclitaxel)为例,二醇化合物采用己二醇,含巯基的酸类化合物为3-巯基丙酸:
相对现有技术,本发明的技术方案带来的有益效果:
1)本发明的技术方案以可降解的聚合物(聚丙交酯和聚己内酯嵌段共聚物)作为纳米药物载体,包裹量子点和抗肿瘤药物构成纳米粒子,既可以延长药物在体内释放的时间,提高药效,又能对被标记的抗肿瘤药物进行实时动态示踪。而将纳米载体的粒径控制在适当的粒径范围内(如10~200nm)时,可实现肿瘤被动靶向作用,将纳米载体外层修饰含有主动肿瘤靶向的小分子时,纳米药物载体就同时具有主动靶向和被动靶向,从而提高了抗肿瘤药物的生物利用率;
2)本发明的高分子键合药将具有靶向作用的生物素引入到可降解的两亲性载体聚合物的亲水端从而使得到的纳米胶束具有靶向性;
3)本发明的高分子键合药的载体聚合物在丙交酯主链上引入低聚聚乙二醇,使其具有亲水性且低聚聚乙二醇易于从人体排出;
4)本发明的高分子键合药的载体聚合物采用的聚丙交酯和聚己内酯具有良好的生物可降解性和生物相容性;
5)本发明的高分子键合药的载体聚合物采用的含咪唑基团的组胺等与量子点作用后的稳定性好,且耐酸碱性高;
6)本发明技术方案通过点击反应与低聚聚乙二醇单甲醚(mOEG)反应,无副反应、产率高,后处理简单;
7)本发明的抗肿瘤前药的制备方法成本低,产率高,安全无毒,可以广泛应用。
附图说明
【图1】为羟基官能化的生物素的核磁氢谱图;
【图2】为含靶分子和降冰片烯侧基的聚丙交酯的核磁氢谱图;
【图3】为含靶分子和聚乙二醇单甲醚支链的聚丙交酯的核磁氢谱图;
【图4】A为含靶分子和聚乙二醇单甲醚支链的聚丙交酯核磁氢谱图,B为含靶分子、聚乙二醇单甲醚支链和降冰片烯侧基的聚丙交酯核磁氢谱图,C为载体聚合物(含靶分子、聚乙二醇单甲醚支链、降冰片烯侧基及溴取代基的两亲性聚丙交酯-聚己内酯共聚物)核磁氢谱图;
【图5】A为含靶分子和聚乙二醇单甲醚支链的聚丙交酯凝胶色谱图,B为含靶分子、聚乙二醇单甲醚支链和降冰片烯侧基的聚丙交酯凝胶色谱图,C为载体聚合物(含靶分子、聚乙二醇单甲醚支链、降冰片烯侧基及溴取代基的两亲性聚丙交酯-聚己内酯共聚物)凝胶色谱图;
【图6】D为含羧基侧基的载体聚合物核磁氢谱图,E为N-羟基琥珀酰亚胺活化的含羧基侧基的载体聚合物的核磁氢谱图,F为含咪唑基团的载体聚合物的核磁氢谱图;
【图7】为抗肿瘤高分子键合药核磁氢谱图;
【图8】F为含咪唑基团的载体聚合物凝胶色谱图,G为含羧基侧基和咪唑侧基的载体聚合物的凝胶色谱图,H为抗肿瘤高分子键合药的凝胶色谱图;
【图9】QDs为纯的量子点,histamine-QDs为具有靶向和示踪功能抗肿瘤高分子键合药纳米粒子的紫外吸收图谱;
【图10】QDs为纯的量子点,histamine-QDs为具有靶向和示踪功能抗肿瘤高分子键合药纳米粒子的荧光发光图谱。
具体实施方式
以下实施例旨在对本发明内容进一步说明,而不是限制本发明权利要求的保护范围。
实施例1
1、羟基官能化的D-生物素的制备:
称取1.0g(1eq)的D-生物素和0.906g(1.1eq)的二环己基碳二亚胺(DCC)溶于5mL的N,N-二甲基甲酰胺(DMF)和2ml的二甲基亚砜(DMSO)的混合溶剂,冰浴下滴加到0.944g(2eq)的1,6-己二醇和催化量4-二甲氨基吡啶(DMAP)(0.1eq)的乙酸乙酯溶剂中,在氮气保护下45℃反应36小时。反应结束后,旋掉乙酸乙酯,抽滤除去大部分的二环己基脲(DCU),二氯甲烷稀释滤液饱和的氯化钠洗涤2遍,无水硫酸镁干燥有机相,浓缩,过柱分离,乙酸乙酯∶石油醚=1∶3除去DCU,乙酸乙酯淋洗得到产物。其结构见核磁图谱图1。说明该物质已成功合成。
2、含靶分子和降冰片烯侧基的聚丙交酯的制备:
称取1.0g(30eq)的降冰片烯丙交酯和0.057g(1eq)的羟基D-生物素于烘烤三次的干燥无氧的聚合管中,在氮气的保护下加入催化量的1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)和2.5mL精制的二氯甲烷,室温下反应24小时,反应结束后无水甲醇反复沉降三次,抽滤,干燥即得含靶分子和降冰片烯侧基的聚丙交酯。其结构表征见核磁图谱图2。说明该聚合物己成功合成。通过调节降冰片烯丙交酯和羟基D-生物素的比例可以得到不同聚合度的含靶分子和降冰片烯侧基的聚丙交酯。
3、含靶分子和聚乙二醇单甲醚支链的聚丙交酯的制备:
称取0.70g(1eq)的含靶分子和降冰片烯侧基的聚丙交酯和4.0g(1.5eq)的含叠氮取代基的聚乙二醇单甲醚(Mn=775)加入到干燥无氧的聚合管中,氮气保护下加入5mL精制的乙酸乙酯,80℃反应72h。反应完成后,旋掉乙酸乙酯,二氯甲烷溶解,用无水乙醚反复沉降三次,真空干燥。即得含靶分子和聚乙二醇单甲醚支链的聚丙交酯。其结构表征见核磁图谱图3和图4(A),分子量分布见图5(A)。说明该聚合物已成功合成。
4、载体聚合物(含靶分子、聚乙二醇单甲醚支链、降冰片烯侧基及溴取代基的两亲性聚丙交酯-聚己内酯共聚物)的制备:
称取1.0g的含靶分子和聚乙二醇单甲醚支链的聚丙交酯于干燥无氧的聚合管中,氮气保护下加入0.24g的含降冰片烯基团的丙交酯和催化量的1,5,7-三氮杂二环[4.4.0]癸-5-烯(TBD)以及2.5mL精制二氯甲烷,室温下反应24小时,无水乙醚反复沉降三次,真空干燥,得到含靶分子、聚乙二醇单甲醚支链和降冰片烯侧基的聚丙交酯,产物表征见图4(B)及图5(B);将得到的含靶分子、聚乙二醇单甲醚支链和降冰片烯侧基的聚丙交酯产物在加入到干燥无氧的聚合管中,氮气保护下加入0.18g的α位溴代己内酯和催化量的催化剂TBD,注射器滴加3mL精制的二氯甲烷,室温反应24小时,反应结束后,无水乙醚反复沉降三次,真空干燥即得载体聚合物。其结构表征见核磁图谱图4(C),分子量分布见图5(C)。说明该聚合物已成功合成。
5、含咪唑基团的载体聚合物的制备:
称取0.8g载体聚合物于装有磁石的50mL单口圆底烧瓶内,加入0.07g的巯基丙酸和10mL精制的乙腈溶液氩气保护下滴加0.16g的三乙胺,滴加完成后,25℃下反应2小时,停止反应,过滤以除去大部分的季铵盐,滤液浓缩,无水乙醚沉降2次,产物再经水透析24小时,冷冻干燥,得到含羧基侧基的载体聚合物,产物表征见图6(D),将产物转移至装有磁石的50mL圆底烧瓶中,加入0.083g N,N-二异丙基碳二亚胺(DIC)和催化量的DMAP以及10mL精制乙酸乙酯,在氮气保护和不断搅拌下加入0.075g N-羟基琥珀酰亚胺(NHS),将反应转移至40℃下反应16小时,反应结束后,过滤,滤液浓缩,无水乙醚沉降三次,产物经丙酮透析24小时,得到N-羟基琥珀酰亚胺活化的含羧基侧基的载体聚合物,产物表征见图6(E),转移至25mL圆底烧瓶,加入0.073g的组胺和8ml的无水甲醇,室温下搅拌8小时,反应结束后,经无水甲醇透析24小时干燥得纯净含咪唑基团的载体聚合物产物。其结构表征见核磁图谱图6(F),分子量分布见图8(F)。说明该聚合物已成功合成。
6、抗肿瘤高分子键合药的制备
称取0.3g含咪唑基团的载体聚合物和0.07g 3-巯基丙酸于50mL圆底烧瓶,并加入催化量的安息香二甲醚(DMPA)和15mL四氢呋喃,在紫外照射下反应30min,反应结束后,无水乙醚反复沉降三次,得到的产物分子量分布见图8(G),将得到的产物转移至50mL圆底烧瓶,加入催化量的DMAP,在氮气保护下逐滴滴加0.03g的紫杉醇和0.004g N,N-二异丙基碳二亚胺(DIC)的乙酸乙酯混合溶液,45℃下搅拌24小时,停止反应,旋蒸浓缩,异丙醇反复沉降三次,即得抗肿瘤高分子键合药,其核磁图谱见图7,分子量分布见图8(H)。说明该聚合物已成功合成。
7、具有靶向和示踪功能的抗肿瘤高分子键合药纳米粒子的制备
量取10μL CdSe/ZnS量子点(表面配体为三辛基膦和三辛基氧化膦)的环己烷溶液于10mL圆底烧瓶中,旋干溶剂,加入1mL四氢呋喃将其溶解,另外称取50mg抗肿瘤高分子键合药溶于2mL四氢呋喃,在气体保护的条件下将两者混合,40℃下反应2小时,停止反应,旋蒸浓缩,环己烷反复沉降三次,产物干燥,用3mL丙酮溶解,逐滴加入高速搅拌下的20mL中,滴加完毕,将溶液至于透析袋中(Cut off Mn=3500),用二次水透析24小时以除去丙酮。即得具有靶向和示踪功能的抗肿瘤高分子键合药纳米粒子。其紫外吸收图谱见图9,荧光图谱见图10。
Claims (2)
1.一种具有靶向和示踪功能的抗肿瘤高分子键合药,其特征在于:具有式1结构:
其中,
A为羟基官能化的生物素基团和/或羟基官能化的叶酸基团;
B为紫杉醇基团、多西紫杉醇基团、喜树碱基团、丝裂霉素C基团、阿霉素基团、表阿霉素基团中的至少一种;
D为咪唑基团、吡啶基团、巯基基团中的至少一种;
Q为CdSe/ZnS、CdSe/ZnSe、CdTe/SeCd、CdTe/CdSe、CdZnSe/ZnS、CdSe/CdS/ZnS中的至少一种;
x为20~100,y为1~100,z为1~100,n为8~17;
R1、R2、R3为各自独立地选自C1~C4的亚烷基。
2.制备权利要求1所述的具有靶向和示踪功能的抗肿瘤高分子键合药的方法,其特征在于:包括以下步骤:
1)将靶分子与二醇化合物进行酯化反应,得到羟基官能化靶分子;
2)采用所述羟基官能化靶分子引发含降冰片烯基团的丙交酯单体进行聚合反应,得到含靶分子和降冰片烯侧基的聚丙交酯;所述含靶分子和降冰片烯侧基的聚丙交酯与含叠氮取代基的聚乙二醇单甲醚进行叠氮-烯点击反应,得到含靶分子和聚乙二醇单甲醚支链的聚丙交酯;采用所述含靶分子和聚乙二醇单甲醚支链的聚丙交酯引发含降冰片烯基团的丙交酯单体进行聚合反应,聚合反应产物进一步引发α位溴代己内酯进行聚合产物,得到式2载体聚合物;
3)将含巯基的羧酸化合物与式2载体聚合物进行巯基-溴点击反应,得到含羧侧基的载体聚合物;所述含羧侧基的载体聚合物通过N-羟基琥珀酰亚胺活化羧基后,与含氨基的量子点配体化合物进行酰胺化反应,得到式3含量子点配体侧基的载体聚合物;
4)将含巯基的羧酸化合物与式3含量子点配体侧基的载体聚合物进行巯基-烯光点击反应,得到含羧基和量子点配体侧基的载体聚合物;所述含羧基和量子点配体侧基的载体聚合物与含羟基或/和氨基的抗肿瘤药物进行酯化或/和酰胺化反应;即得式4抗肿瘤高分子键合药;
5)将所述抗肿瘤高分子键合药与表面带配体的量子点进行配体交换,即得具有靶向和示踪功能的抗肿瘤高分子键合药;
其中,
A为羟基官能化的生物素基团和/或羟基官能化的叶酸基团;
B为紫杉醇基团、多西紫杉醇基团、喜树碱基团、丝裂霉素C基团、阿霉素基团、表阿霉素基团中的至少一种;
D为咪唑基团、吡啶基团、巯基基团中的至少一种;
所述量子点为CdSe/ZnS、CdSe/ZnSe、CdTe/SeCd、CdTe/CdSe、CdZnSe/ZnS、CdSe/CdS/ZnS中的至少一种;
x为20~100,y为1~100,z为1~100,n为8~17;
R1、R2、R3为各自独立地选自C1~C4的亚烷基。
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