CN111253565A - 一种小分子聚乙二醇修饰的磷脂类化合物及其制备方法和应用 - Google Patents
一种小分子聚乙二醇修饰的磷脂类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明提出了一种小分子聚乙二醇修饰的磷脂类化合物，该经过修饰的磷脂类化合物从分子结构水平改变了制剂材料的亲水性和疏水性分布，提高了药物对肿瘤的杀伤效率，降低了对正常细胞的毒性，减轻了患者的负担。
Description
技术领域
本发明涉及化学药物领域，具体涉及一种小分子聚乙二醇修饰的磷脂类化合物及其制 备方法和应用。
背景技术
脂质体的形成材料主要是磷脂类化合物，具体有两个碳链的细胞膜组成磷脂化合物， 碳链部分亲脂，磷脂部分亲水，所以可以自我聚集，形成有序排列，形成纳米微球，一般被称为脂质体纳米微球。其具有粒径可控且结构稳定，表面可修饰，载药量高，储存时间 长等特点。
市场现有的大分子聚乙二醇(聚合物，分子量2000以上)修饰的亲脂类脂质体纳米颗粒配方材料虽然会减小纳米颗粒的直径、增加其药物传输的组织穿透性，但纳米颗粒的直径仍然保持在500纳米左右，对肿瘤的杀伤效率不高；而且给患者注入了太多的大分子非降解性的物质，增大了对正常细胞的毒性；同时还需要添加聚乙二醇高分子抗免疫保护层修饰(Protective layer against immune destruction)，增加了药物传输过程中辅料的使用， 加重了患者的负担。上述问题是本领域亟需解决的问题。
发明内容
本发明要解决的技术问题是提供一种小分子聚乙二醇修饰的磷脂类化合物，其能有效 地提高药物对肿瘤的杀伤效率，降低对正常细胞的毒性，减轻患者的负担。同时本申请还 提供了该小分子聚乙二醇修饰的磷脂类化合物的制备方法和应用。
为了解决上述技术问题，本发明提供的方案是：一种小分子聚乙二醇修饰的磷脂类化 合物，所述化合物具有如式(A)所示的结构：
式(A)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或 者靶向分子的官能团。
同时，本发明提供了另一种方案是：一种小分子聚乙二醇修饰的磷脂类化合物，所述 化合物具有如式(B)所示的结构：
式(B)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或 者靶向分子的官能团。
同时，本发明提供了另一种方案是：一种小分子聚乙二醇修饰的磷脂类化合物，所述 化合物具有如式(C)所示的结构：
式(C)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或 者靶向分子的官能团。
本申请通过锲入短链的聚乙二醇，使形成的纳米颗粒堆积更加紧密，颗粒更小，实现 被动靶向，提高对肿瘤的杀伤效率，无需添加聚乙二醇高分子抗免疫保护层，大大减低药 物传输过程中辅料的使用，减轻患者的负担，由于无大分子非降解性物质注入，降低了对 正常细胞的毒性。
进一步地，所述R基团为羧基、马来酰亚胺、巯基或氨基。
进一步地，所述化合物具有如式(D)所示的结构：
羧基可以和有氨基的靶向分子，或者有氨基的单克隆抗体在偶联剂EDCI、DCC的催化下 有效结合。
进一步地，所述化合物具有如式(E)所示的结构：
马来酰亚胺可以和有巯基修饰的靶向分子或者单克隆抗体在水溶液中自然结合成共 价键，使载药纳米脂质体颗粒的表面具有了靶向分子或者抗原识别功能的抗体，使药物输 送实现精准靶向的功能。
本申请进一步的提供一种制备上述小分子聚乙二醇修饰的磷脂类化合物的方法，合成 路径如下：
同时，本申请进一步的提供一种制备上述小分子聚乙二醇修饰的磷脂类化合物的方 法，合成路径如下：
本申请进一步的提供了一种上述小分子聚乙二醇修饰的磷脂类化合物的应用：该化合 物用于链接或糅合基因治疗制剂、靶向分子、蛋白质抗体分或药物载体。
本申请进一步的提供了一种上述小分子聚乙二醇修饰的磷脂类化合物的应用：该化合 物用于治疗癌症。
本发明的有益效果：本申请制备了一种小分子聚乙二醇修饰的磷脂类化合物，该经过 修饰的磷脂类化合物从从分子结构水平改变了制剂材料的亲水性和疏水性分布，提高了药 物对肿瘤的杀伤效率，降低了对正常细胞的毒性，减轻了患者的负担。
附图说明
图1为本申请实施例十二的合成线路图；
图2为本申请实施例十三的合成线路图；
图3为本申请实施例十和十二产物的扫描电镜图。
图4为本申请对比产物的扫描电镜图。
具体实施方式
下面结合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地理解 本发明并能予以实施。下述公开了多种不同的实施所述的主题技术方案的实施方式或实施 例。为简化公开内容，下面描述了各特征存在的一个或多个排列的具体实施例，但所举实 施例不作为对本发明的限定。
本申请所出现的以下名词均为本领域的专属名字，本领域技术人员可以毫无疑义的确 认一下名词的含义：
Rt：室温：25±5℃；
TEA：三乙醇胺；
DCM：二氯甲烷；
Et2O：乙醚；
TFA：三氟乙酸；
HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；
DIPEA：N，N-二异丙基乙胺。
实施例一
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例二
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例三
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例四
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例五
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例六
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例七 一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例八
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例九
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例十
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例十一
一种小分子聚乙二醇修饰的磷脂类化合物，所述化合物具有下列结构：
实施例一至实施例十一所述的磷脂类化合物，从结构上改变了正离子亲脂类脂质体纳 米颗粒的组成，使之在亲水的正离子部分和亲脂的脂肪链之间，引进单一可以调节长短的 小分子聚乙二醇链(单一分子量500以下)这类亲水性物质，使用这种辅料将会使形成的 纳米颗粒堆积更加紧密，颗粒更小，实现被动靶向，提高对肿瘤的杀伤效率，减少对正常细胞的毒性。这一技术不再需要添加市场现有的聚乙二醇高分子抗免疫保护层修饰(Protective layer against immune destruction)，因而将大大减低药物传输过程中辅料的使 用，减轻患者的负担，并且可以很方便的挂载个各种靶向分子和药物，有望最终成为药物 定向传输领域的技术革新里程碑。
本申请引进单一可以调节长短的小分子聚乙二醇链(单一分子量500以下)，并且在 聚乙二醇链接剂的末端引进一个用于链接药物活性分子或者靶向分子的官能团，该官能团 可以为羧基、马来酰亚胺、巯基或氨基，也可以为溴乙酸或碘乙酸。制剂后存在于形成的 纳米颗粒表面。羧基可以和有氨基的靶向分子，或者有氨基的单克隆抗体在偶联剂EDCI， DCC的催化下有效结合；马来酰亚胺可以和有巯基修饰的靶向分子或者单克隆抗体在水溶 液中自然结合成共价键，使载药纳米脂质体颗粒的表面具有了靶向分子或者抗原识别功能 的抗体，使药物输送实现精准靶向的功能。从分子结构水平改变了制剂材料的亲水性和疏 水性分布，可以更好地自我聚集成稳定，并在特定条件下易降解的药物输送载体。
本申请利用脂质体纳米颗粒、小型集合物纳米颗粒等为载体，利用聚乙二醇类链接剂 修饰的纳米脂质体形成材料，可把药物(如Toxin)、基因治疗制剂(如siRNA,DNA)甚至靶向分子、蛋白质抗体分子等进行链接或糅合形成治疗配方，形成定向传输的抗癌类纳米新药生产，一些经典的抗癌药物如Doxorubinson、MMAFb、以及特定序列的小干扰核糖 核酸(siRNA)等，虽然具有抗癌活性，但如果不能定向传输，会导致药效降低或毒副作 用增加。PEG链接剂分子修饰的纳米脂质体形成材料通过制剂可把定向抗体与抗癌药物通 过可挂载靶向的纳米微球链接，也即改变了纳米脂质体的粒度，排列特性，同时增加了挂 载靶向分子的功能，从而形成定向传输的抗癌类新药。本专利保护的单一分子量功能团化 的聚乙二醇链接剂修饰的纳米脂质体形成材料可以促进纳米新药的研制开发，此类纳米药 物会极大程度地提高药物的分散度与稳定性，是新药开发的全新领域。
此外，本申请还提供了制备实施例十以及十一中小分子聚乙二醇修饰的磷脂类化合物 的方法，为了便于理解，以下提供了两种分别制备实施例十和实施例十一中小分子聚乙二 醇修饰的磷脂类化合物的具体实施例。
实施例十二：
参见图1，一种制备如实施例十所述的小分子聚乙二醇修饰的磷脂类化合物的方法，
包括以下步骤：
将
(1.1g,1.28mmol)溶于10mL的CH3Cl中，CH3Cl也可替 换为氯仿、THF、DMF或DMSO等溶剂；
搅拌下将
(0.83g,1.1mmol)加入上述溶液中，添加TEA 或DIPEA、NMM(氮甲基六氢吡啶)等非质子碱类，继续室温搅拌过夜，TLC检测反应 完毕，反应液加饱和食盐水淬灭，然后用食盐水洗两遍，收集有机相，加无水硫酸钠干燥， 过滤，除掉CH3Cl得到粗品；
得到的粗品，用反向柱纯化得到
(0.8g,收率：48％，白色固体)；对其进行核磁共振测试，其核磁图谱：1H NMR(400MHz,CDCl3):0.88(6H,t,J 8.0),1.25(46H,m),1.44(9H,s),1.79(18H,m),2.25-2.30(4H,dd,J8.0),2.71(2H,s), 3.09-3.11(2H,m),3.38(2H,s),3.61-3.72(50H,m),3.94(4H,m),4.15-4.88(6H,m),5.19(1H,s)；
将
(0.8g,0.536mmol)溶于8mL的二氯甲烷中，也可将二氯甲烷替换为氯仿、THF或二氧六环，然后缓慢滴加2mL的三 氟乙酸，室温搅拌过夜。TLC检测反应完毕，加饱和食盐水淬灭，有机相用食盐水洗涤两 遍，收集有机相，加无水硫酸钠干燥，过滤，除掉二氯甲烷，得到的固体用乙酸乙酯打浆， 过滤，重复两次，收集固体，烘干。得到最终产物(0.6g,收率：78％，白色固体)。该最 终产物结构式为：
对该最终产物进行核磁共振测试，其核磁图谱：1H NMR(400MHz,CDCl3):0.87(6H,t,J 8.0), 1.24(56H,m),2.24-2.30(6H,d,J 8.0),2.59(2H,m),3.36(2H,m),3.65-3.93(57H,m),4.10-4.37(4H,m), 5.19(1H,s),6.18(1H,s)。
实施例十三：
参见图1，一种制备如实施例十一所述的小分子聚乙二醇修饰的磷脂类化合物的方法， 包括以下步骤：
将
(10g,38.6mmol),溶于50mL的乙醚和50mL 的水中(分层，
在乙醚层)，搅拌下将PPh3(10.6g, 40.5mmol)加入上述反应液中，室温搅拌过夜，TLC检测反应完毕，将反应液中的乙醚蒸 掉，然后过滤，收集水相，用乙酸乙酯萃取3次，水相拉干，然后溶于二氯甲烷，加无水 硫酸镁干燥，过滤，脱溶得到
(8.5g,收率：94％，淡黄 色液体)；
将
(3g,12.8mmol),溶于30mL的二氯甲烷中，搅拌下将
(3.4g,12.8mmol)加入上述反应液中，室温搅拌过夜，TLC检测 反应完毕，旋掉二氯甲烷，得到4.7g的粗品，过柱纯化得到
(3g, 收率：60.7％，黄色液体)，其核磁图谱：1H NMR(400MHz,CDCl3):1.44(9H,s),2.49-2.55(4H,m), 3.41-3.43(2H,t,J 4.0),3.51-3.53(2H,t,J 4.0),3.57-3.66(4H,m),3.71-3.74(2H,t,J 4.0),3.83-3.86(2H,t,J 4.0),6.46(1H,s),6.69(2H,s)；
将
(3g,7.8mmol),溶于16mL的二氯甲烷中,搅拌下缓慢滴 加4mL的三氟乙酸，室温搅拌过夜，TLC检测反应完毕，加40mL的二氯甲烷稀释，用水萃取3次，收集二氯相，加无水硫酸钠干燥，过滤，脱溶，得到 
(2.3g,收率：89.8％，淡黄色液体)，其核磁图谱： 1H NMR(400MHz,CDCl3):2.55-2.65(4H,m),3.42-3.88(12H,m),6.63(1H,s),6.71(2H,s)；
将
(0.96g,2.93mmol),溶于30mL的 MeOH/CHCl3/H2O(VMeOH:V CHCl3:V H2O＝75:35:6)混合溶剂中,降温至0℃，搅拌下缓 慢加HATU(1.2g，3.16mmol)和DIEPA(1.1g,3.35mmol)。缓慢升至室温并搅拌1h后，将
(2g,2.67mmol)加入到反应液中，室温搅拌过夜，TLC检测 反应完毕，反应液中加100ml的二氯甲烷，加水萃取3次，收集有机相，加无水硫酸钠干 燥，过滤，脱溶，得到2.1g粗品，用PE:EA＝1:1的混合溶剂打浆，过滤得到最终产物(1.7g, 收率：59.6％，白色固体)。
该最终产物结构式为：
对该最终产物进行核磁共振测试，其核磁图谱：1H NMR(400MHz,CDCl3):0.86-0.89(6H,t,J 8.0), 1.21-1.28(46H,m),2.06(20H,s),2.28-2..36(4H,m),2.51-2.56(4H,m),4.01-4.11(4H,m),4.34-4.37(1H,m), 5.23(1H,s),6.71(2H,s).7.25(1H,s)。
将实施例十和实施例十二中所述的
选取50毫克，然后 选取二棕榈酰磷脂酰胆碱(DPPC)200毫克、胆固醇40毫克和紫杉醇20毫克作为原料，将四 种原料溶解在40毫升10/1体积比的二氯和甲醇中，在100毫升的圆底烧瓶里在旋转蒸发仪 上减压蒸干，然后加入4毫升水，40摄氏度超声两小时，形成白色悬浮乳液，在力度测试仪 上检测载药纳米颗粒的粒径，参见图3，平均粒径低于100纳米。
而将实施例十一和实施例十三中所述的
按上述方法同样测试 载药纳米颗粒的粒径，平均粒径低于100纳米。
为作为对比，选取二棕榈酰磷脂酰胆碱(DPPC)250毫克、胆固醇40毫克和紫杉醇20毫克作为原料，把三种原料溶解在40毫升10/1体积比的二氯和甲醇中，在100毫升的圆底烧瓶里在旋转蒸发仪上减压蒸干，然后加入4毫升水，40摄氏度超声两小时，形成白色悬浮乳液，在力度测试仪上检测载药纳米颗粒的粒径，参见图4，平均粒径均大于500纳米。由 此可见，本申请所述的小分子聚乙二醇链修饰的磷脂类化合物，可以降低产物的粒径。
纳米药物之所以有被动靶向作用，是因为肿瘤表面的毛孔比较大，大于100纳米，通 过测试，本申请将纳米药物粒径从大部分500纳米到200纳米的范围控制在大部分颗粒在 100纳米之下，实现了被动靶向，提高对肿瘤的杀伤效率，减少对正常细胞的毒性。
最后说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实 施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方 案进行修改或者等同替换，而不脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明 的权利要求范围当中。
Claims (10)
1.一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述化合物具有如式(A)所示的结构：
式(A)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或者靶向分子的官能团。
2.一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述化合物具有如式(B)所示的结构：
式(B)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或者靶向分子的官能团。
3.一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述化合物具有如式(C)所示的结构：
式(C)中，n＝2，3，4…36；x＝1，2，3…45；R基团选自用于链接药物活性分子或者靶向分子的官能团。
4.如权利要求1-3中任一所述的一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述R基团为羧基、马来酰亚胺、巯基或氨基。
5.如权利要求2所述的一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述化合物具有如式(D)所示的结构：
6.如权利要求2所述的一种小分子聚乙二醇修饰的磷脂类化合物，其特征在于：所述化合物具有如式(E)所示的结构：
7.一种制备如权利要求5所述的小分子聚乙二醇修饰的磷脂类化合物的方法，其特征在于：合成路径如下：
8.一种制备如权利要求6所述的小分子聚乙二醇修饰的磷脂类化合物的方法，其特征在于：合成路径如下：
9.如权利要求1-3任一所述的小分子聚乙二醇修饰的磷脂类化合物的应用，其特征在于：该化合物用于链接或糅合基因治疗制剂、靶向分子、蛋白质抗体分或药物载体。
10.如权利要求1-3任一所述的小分子聚乙二醇修饰的磷脂类化合物的应用，其特征在于：该化合物用于治疗癌症。
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