CN105504293B - 一种荧光星形嵌段共聚物的制备及应用 - Google Patents
一种荧光星形嵌段共聚物的制备及应用 Download PDFInfo
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Abstract
本发明公开了一种荧光星形嵌段共聚物的制备方法及其作为药物载体的应用。本发明利用开环聚合制备了以双亲性聚乳酸‑聚磷酸酯为臂,以苝酰亚胺衍生物为核的荧光星形嵌段共聚物。该荧光星形嵌段共聚物在水溶液中自组装形成荧光超分子胶束并具有良好的荧光特性,可作为荧光探针用于细胞和活体成像。本发明制得的荧光超分子胶束可以有效装载疏水性药物并实现pH刺激释放。激光共聚焦显微镜和流式细胞仪分析表明,荧光超分子胶束易被癌细胞吞噬并实现细胞内在化。在体外和体内肿瘤增长抑制实验中,与游离药物相比,荧光超分子载药胶束对肿瘤生长的抑制作用更为明显,表明该载药胶束在生物成像和癌症治疗领域具有潜在的应用价值。
Description
技术领域
本发明属于药物载体制备技术领域,具体涉及一种荧光星形嵌段共聚物的制备及其作为药物载体在癌症治疗中的应用。
背景技术
癌症严重威胁人类生命,是导致发病率和死亡率高的主要原因。化疗作为一种传统的治疗手段,和手术、放疗一起,并称为癌症的3大治疗手段。然而,传统的抗癌药水溶性差、生物利用度低、治疗效率低,因此对药物载体的研究是近期国内外研究的重点。为了增加药物的溶解度和生物利用度,以及减少抗癌药物的副作用,近年来科研工作者制备出一系列纳米药物载体,如树枝状高分子、纳米胶束、高分子偶联药物、脂质体和无机纳米粒子,用于增加药物的溶解度和生物利用度,以及减少抗癌药物的副作用。其中纳米胶束,特别是由两亲性聚合物或树枝状分子形成的超分子胶束是使用最广泛的纳米载体之一。纳米胶束载药系统具有一些独特的特征,包括能有效封装疏水性抗癌药物,提高在水溶液中的溶解度,减少药物副作用,并通过增强渗透滞留(EPR)效应提高在肿瘤部位的富集。
荧光成像技术具有其高选择性和高敏感性,已广泛用于生物过程的可视化。为了实现生物成像,荧光探针应具有高的水溶性、光稳定性、生物相容性、吸收和发射波长在500nm以上,有效地减少细胞的自发荧光。苝酰亚胺(PDI)因其具有优异的化学和物理稳定性、高消光系数和高的荧光量子产率已经引起了科研工作者的极大兴趣。然而,由于固有的π-π堆积作用,苝酰亚胺在水溶液中容易聚集,表现出较差的溶解度和较弱的荧光性能,限制了其在生物医学领域上的应用。因此,许多科研工作者通过在苝酰亚胺的海岛位和酰亚胺位引入亲水性取代基来提高苝酰亚胺衍生物的水溶性。
近年来纳米胶束载药系统和荧光成像技术在生物医学领域得到广泛关注。将两者的优势结合,发明一种基于苝的荧光星形嵌段共聚物,研究这类荧光大分子作为药物载体在癌症治疗和生物成像领域的应用,将具有非常重要的意义。
发明内容
本发明提供了一种荧光星形嵌段共聚物的制备方法,并依据其在水溶液中自组装形成荧光超分子胶束的特点,将其作为一种新型的可被追踪的荧光药物载体,在生物医学领域及癌症治疗领域具有很好的应用价值。
本发明所述的荧光星形嵌段共聚物的结构式为:
其中,R为CH2CH3或CH2CH2NH2,m=5-50,n=5-50。
上述荧光星形嵌段共聚物是以苝环结构为核,其外围八个臂为双亲性嵌段共聚物,以聚乳酸为疏水链段,聚磷酸酯为亲水链段,具有大的π-π共轭电子结构;该共聚物的水溶液,在波长为300-650nm的紫外光照下可发出波长为550-750nm的荧光。
本发明所述的荧光星形嵌段共聚物的制备方法为:
1).制备外围含有8个羟基的化合物2;
2).以化合物2为引发剂,依次引发单体3和单体4开环聚合得到荧光星形嵌段共聚物;
所述的化合物2的结构如下:
所述的单体3为丙交酯,其结构式为
所述的单体4的结构式为:R1为乙基。
所述步骤1)的具体操作步骤为:将化合物5、4-二甲氨基吡啶和三乙胺以(1:4:4)-(1:10:10)的摩尔比溶解于四氢呋喃中,在氮气保护和冰浴条件下,逐滴加入化合物6的四氢呋喃溶液,化合物6与化合物5的摩尔比为(4:1)-(20:1);滴加完毕后,于室温下搅拌24-48小时后,用旋转蒸发仪除去四氢呋喃,所得混合物溶于二氯甲烷中,然后依次用饱和NaHSO4水溶液、饱和NaCl水溶液和去离子水洗涤,有机相用硅胶柱提纯,得到中间产物;将中间产物溶于甲醇中,使其浓度在3-7g/L范围内,然后逐滴加入体积浓度为2%-5%的硫酸溶液,硫酸与中间产物的摩尔比为(4:1)-(10:1),于室温下搅拌0.5-2小时后,用旋转蒸发仪除去甲醇,所得固体溶于二氯甲烷,再用去离子水洗至中性,有机相用旋转蒸发仪除去二氯甲烷,然后真空干燥至恒重,得到化合物2;
所述的化合物5的结构式为
所述的化合物6的结构式为
所述步骤2)的具体操作为:将化合物2和单体3以(1:50)-(1:450)摩尔比溶解于二氯甲烷中,再加入催化剂4-二甲氨基吡啶和4-二甲氨基吡啶磺酸盐,4-二甲氨基吡啶与化合物2的摩尔比为(8:1)-(20:1),4-二甲氨基吡啶磺酸盐与化合物2的摩尔比为(8:1)-(20:1);在氮气氛围下,在35-45℃下反应24-72小时后,在正戊烷中沉淀,所得固体真空干燥至恒重,得到均聚物;将均聚物和单体4以(1:50)-(1:450)的摩尔比溶于二氯甲烷中,经冷冻-抽排循环操作后,在氮气保护下,加入催化剂1,8-二氮杂双环[5.4.0]十一-7-烯,1,8-二氮杂双环[5.4.0]十一-7-烯与均聚物的摩尔比为(8:1)-(20:1),再次冷冻抽排后,在35-45℃下反应2-20小时;反应结束后,在乙醚中沉淀,所得固体真空干燥至恒重,得到荧光星形嵌段共聚物。
上述的荧光星形嵌段共聚物的制备方法中,所述的单体4的R1取代基为时,步骤2)的开环聚合产物通过R1取代基解保护反应后得到荧光星形嵌段共聚物。其具体操作为:将步骤2)的开环聚合产物溶于二氯甲烷中,使其浓度在3-7g/L范围内,在氮气保护和室温下,逐滴加入三氟乙酸,三氟乙酸和二氯甲烷的体积比为(0.5:1)-(2:1),继续搅拌1-10小时;反应结束后,用旋转蒸发仪除去三氟乙酸,在乙醚中沉淀,所得固体真空干燥至恒重,得到荧光星形嵌段共聚物。
将上述制备得到的荧光星形嵌段共聚物作为疏水药物载体的应用。所述的荧光星形嵌段共聚物在水溶液中自组装形成荧光超分子胶束并装载疏水药物。
将上述制备得到的荧光星形嵌段共聚物作为细胞内荧光成像染料的应用。
本发明的有益效果在于:
本发明通过分子设计合成了以有机荧光发色团为核,以聚乳酸和聚磷酸酯为臂的荧光星形嵌段共聚物。通过调整单体加料比例或反应时间可调控共聚物链长及疏水链段和亲水链段的比例。该类聚合物具有良好的光学性能、优异的生物相容性和生物可降解性等特性。本发明制备得到的荧光星形嵌段共聚物具有双亲性,在水溶液中自组装形成荧光超分子胶束并有效装载疏水性药物。该载药胶束与肿瘤细胞共孵育,可通过细胞内吞作用进入细胞内并实现细胞内在化。通过尾静脉注射,使载药胶束进入小鼠体内并在肿瘤部位富集。大幅提高肿瘤细胞杀伤及癌症治疗效率。
本发明合成的荧光星形嵌段共聚物以苝酰亚胺衍生物为核,利用开环聚合制备了以双亲性聚乳酸-聚磷酸酯为臂的荧光星形嵌段共聚物。该星形共聚物在水溶液中自组装形成荧光超分子胶束并具有良好的荧光特性,可作为荧光探针用于细胞和活体成像。本发明荧光超分子胶束可以有效装载疏水性药物并实现pH刺激释放。细胞毒性实验表明,荧光超分子胶束具有很好的生物相容性。激光共聚焦显微镜和流式细胞仪分析表明,荧光超分子胶束易被癌细胞吞噬并实现细胞内在化。在体外和体内肿瘤增长抑制实验中,与游离药物相比,荧光超分子载药胶束对肿瘤生长的抑制作用更为明显,表明该载药胶束在生物成像和癌症治疗领域具有潜在的应用价值。
附图说明
图1为实施例1合成化合物2的路线图;
图2为实施例1合成荧光星形嵌段共聚物的合成路线图;
图3为实施例1合成的荧光星形嵌段共聚物和药物喜树碱自组装成荧光超分子载药胶束的示意图;
图4为实施例1合成的荧光星形嵌段共聚物的(a)1H和(b)31P核磁谱图;
图5为实施例1合成的荧光星形嵌段共聚物水溶液的紫外吸收和荧光光谱图;
图6为实施例1合成的荧光星形嵌段共聚物自组装成的超分子胶束的透射电镜照片;
图7为实施例1合成的荧光星形嵌段共聚物形成的荧光载药胶束在不同pH的磷酸盐缓冲溶液中的药物累积释放曲线;
图8为实施例1中HeLa细胞与(a)胶束和(b)载药胶束共同培养一段时间后的细胞存活率;
图9为实施例1中荧光载药胶束进入活细胞后,(a):荧光载药胶束在细胞内的荧光成像图,(b):SYTO绿色荧光核酸染料的荧光成像图,(c):为喜树碱的荧光成像图,(d):三者合并的荧光成像图。
图10为实施例1中荧光载药胶束对人乳腺癌MDA-MB-231细胞移植瘤裸鼠的肿瘤治疗效果图,其中,(a):从尾静脉分别注射生理盐溶液、喜树碱、胶束和载药胶束的裸鼠,(b):注射生理盐溶液、喜树碱、胶束和载药胶束的裸鼠的肿瘤大小。
具体实施方式
实施例1:
(1)八臂引发剂化合物2的合成:如附图1所示,将化合物5(100mg,0.08mmol)、4-二甲氨基吡啶(42mg,0.32mmol)和三乙胺(0.23mL,1.6mmol)加入16mL四氢呋喃中,在氮气保护和0℃条件下,逐滴加入溶有化合物6(1.06g,3.2mmol)的10mL四氢呋喃溶液。滴加完毕后,于室温(25℃)下搅拌24小时。反应结束后,用旋转蒸发仪除去四氢呋喃,所得混合物溶于20mL二氯甲烷,之后依次用饱和NaHSO4水溶液(3×50mL)、饱和NaCl水溶液(3×50mL)和去离子水(3×50mL)洗涤。有机相用硅胶柱提纯,得到135mg中间产物记为PDI-ester,产率90%。将中间产物PDI-ester(100mg,0.053mmol)溶于20mL甲醇中,逐滴加入2mL体积浓度为2%硫酸溶液,于室温下(25℃)搅拌,用薄层色谱检测反应程度,0.5小时后反应结束。用旋转蒸发仪除去甲醇,所得固体溶于20二氯甲烷,再用去离子水(4×50mL)洗至水相呈中性。有机相用旋转蒸发仪除去二氯甲烷,然后真空干燥至恒重,得到87mg化合物2,产率95%。
(2)如附图2所示,将化合物2(34.4mg,0.02mmol)和单体3丙交酯(461.2mg,3.2mmol)溶解于2mL二氯甲烷中,再加入催化剂4-二甲氨基吡啶(19.55mg,0.16mmol)和4-二甲氨基吡啶磺酸盐(43.56mg,0.16mmol)。在氮气氛围下,在35℃下反应48小时。反应结束后,在正戊烷中沉淀(3×50mL),所得固体真空干燥至恒重,得到均聚物记为PDI-star-PLA8,产率75%。将PDI-star-PLA8(100mg,0.0053mmol)和单体4(R1为乙基)(300mg,1.97mmol)加入0.3mL二氯甲烷中使其溶解,进行3次冷冻-抽排循环。在氮气保护下,加入催化剂1,8-二氮杂双环[5.4.0]十一-7-烯(0.05mL),再次冷冻抽排后,在35℃下反应10小时。反应结束后,在乙醚中沉淀(3×50mL),所得固体真空干燥至恒重,得到荧光星形嵌段共聚物,记为PDI-star-(PLA15-b-PEEP20)8,产率53.7%。其核磁谱图见附图4,在水溶液中的紫外吸收和荧光光谱图见附图5。
上述制备的荧光星形嵌段共聚物的结构式为:
其中,R为CH2CH3,m=20,n=15。该共聚物是以苝环结构为核,含有8个聚合物链,为发散的星形结构,其外围八个臂为双亲性嵌段共聚物,以聚乳酸为疏水链段,聚乙氧基-2-氧-1,3,2-二氧磷杂环戊烷为亲水链段,具有大的π-π共轭电子结构;该共聚物的水溶液,在波长为300-650nm的紫外光照下可发出波长为550-750nm的荧光。其最大荧光发射波长在620nm。
上述制备得到的荧光星形嵌段共聚物作为疏水药物载体的应用,如附图3所示:
1、PDI-star-(PLA15-b-PEEP20)8(10mg)溶于2mL N,N-二甲基甲酰胺中,于室温(25℃)下搅拌0.5小时后,逐滴滴入2mL去离子水,再搅拌2小时。将所得溶液加入截留分子量为8000Da的透析袋中,在去离子水中透析24小时。将透析后的溶液冷冻干燥,得到胶束,其透射电镜图见附图6。
2、PDI-star-(PLA15-b-PEEP20)8(10mg)和喜树碱(2mg)溶于2mL N,N-二甲基甲酰胺中,与步骤1的操作相同,得到载药胶束。
通过荧光成像技术追踪荧光载药胶束在肿瘤细胞中的分布及肿瘤组织中的富集情况;通过激光扫描共聚焦显微镜观察载药胶束在细胞内的分布状况,并通过CCK-8比色法检测载药胶束对肿瘤细胞的杀伤性。
载药胶束体外累积释放:如附图7所示,将5mg载药胶束分别加入到3mL不同pH值的磷酸盐缓冲溶液中(PBS,pH=7.4或5.0)。然后,将这两种溶液转移到截留分子量为8000Da的透析袋中,并置于相应pH值的27mL PBS缓冲液中,在37℃的水浴中振荡。在预定时间取出2mL的透析袋外液,并加入新鲜的缓冲液。将所取出的外液冷冻干燥后,测定其中喜树碱的含量。
胶束及载药胶束进入活细胞:将胶束或载药胶束与活体HeLa细胞一起培养48小时,考察了HeLa细胞的存活率及载药胶束在细胞中的分布。如附图8所示,HeLa细胞的存活率在不同胶束浓度下存活率均能达到80%,具有很好的生物相容性;与喜树碱相比,载药胶束的具有更好的细胞杀伤能力。如附图9所示,载药胶束主要分布在细胞质和细胞核中。
载药胶束对肿瘤治疗:通过尾静脉注射方法,使生理盐溶液、喜树碱、胶束和载药胶束进入人乳腺癌MDA-MB-231细胞移植瘤裸鼠体内。24天后,将小鼠解剖,观察对肿瘤的治疗效果并通过荧光成像技术观察载药胶束在肿瘤组织中的富集情况,如附图10所示,注射载药胶束的小鼠肿瘤体积最小,肿瘤的治疗效果最好。
实施例2
(1)将实施例1步骤2)制备得到的PDI-star-PLA8(100mg,0.0053mmol)和单体4(R1为)(400mg,1.50mmol)加入0.4mL二氯甲烷中使其溶解,进行3次冷冻-抽排循环。在氮气保护下,加入催化剂1,8-二氮杂双环[5.4.0]十一-7-烯(0.05mL),再次冷冻抽排后,在35℃下反应10小时。反应结束后,在乙醚中沉淀(3×50mL),所得固体真空干燥至恒重,得到共聚物,记为PDI-star-(PLA13-b-PPEEABoc18)8,产率56.7%。将PDI-star-(PLA13-b-PEEABoc18)8(200mg)溶于0.6mL二氯甲烷中,在氮气保护和室温下,逐滴加入0.6mL三氟乙酸,继续搅拌3小时;反应结束后,用旋转蒸发仪除去三氟乙酸,在乙醚中沉淀(3×50mL),所得固体真空干燥至恒重,得到荧光星形嵌段共聚物,记为PDI-star-(PLA13-b-PPEEA18)8,产率90.2%。
上述制备的荧光星形嵌段共聚物的结构式为:
其中,R为CH2CH2NH2,m=18,n=13。该共聚物是以苝环结构为核,含有8个聚合物链,为发散的星形结构,其外围八个臂为双亲性嵌段共聚物,以聚乳酸为疏水链段,聚磷酸酯为亲水链段,具有大的π-π共轭电子结构;该共聚物的水溶液,在波长为300-650nm的紫外光照下可发出波长为550-750nm的荧光。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (7)
1.一种荧光星形嵌段共聚物的制备方法,其特征在于,所述的荧光星形嵌段共聚物的结构式为:
其中,R为CH2CH3或CH2CH2NH2,m=5-50,n=5-50;
所述的共聚物是以苝环结构为核,其外围八个臂为双亲性嵌段共聚物,以聚乳酸为疏水链段,聚磷酸酯为亲水链段,具有大的π-π共轭电子结构;该共聚物的水溶液,在波长为300-650nm的紫外光照下可发出波长为550-750nm的荧光;
所述的制备方法包括以下的步骤:
1).制备外围含有8个羟基的化合物2;
2).以化合物2为引发剂,依次引发单体3和单体4开环聚合得到荧光星形嵌段共聚物;
所述的化合物2的结构如下:
所述的单体3为丙交酯,其结构式为
所述的单体4的结构式为:R1为乙基;
所述步骤2)的具体操作为:将化合物2和单体3以(1:50)-(1:450)摩尔比溶解于二氯甲烷中,再加入催化剂4-二甲氨基吡啶和4-二甲氨基吡啶磺酸盐,4-二甲氨基吡啶与化合物2的摩尔比为(8:1)-(20:1),4-二甲氨基吡啶磺酸盐与化合物2的摩尔比为(8:1)-(20:1);在氮气氛围下,在35-45℃下反应24-72小时后,在正戊烷中沉淀,所得固体真空干燥至恒重,得到均聚物;将均聚物和单体4以(1:50)-(1:450)的摩尔比溶于二氯甲烷中,经冷冻-抽排循环操作后,在氮气保护下,加入催化剂1,8-二氮杂双环[5.4.0]十一-7-烯,1,8-二氮杂双环[5.4.0]十一-7-烯与均聚物的摩尔比为(8:1)-(20:1),再次冷冻抽排后,在35-45℃下反应2-20小时;反应结束后,在乙醚中沉淀,所得固体真空干燥至恒重。
2.根据权利要求1所述的荧光星形嵌段共聚物的制备方法,其特征在于,所述的单体4的R1取代基为时,步骤2)的开环聚合产物通过R1取代基解保护反应后得到荧光星形嵌段共聚物。
3.根据权利要求1所述的荧光星形嵌段共聚物的制备方法,其特征在于,所述步骤1)的具体操作步骤为:将化合物5、4-二甲氨基吡啶和三乙胺以(1:4:4)-(1:10:10)的摩尔比溶解于四氢呋喃中,在氮气保护和冰浴条件下,逐滴加入化合物6的四氢呋喃溶液,化合物6与化合物5的摩尔比为(4:1)-(20:1);滴加完毕后,于室温下搅拌24-48小时后,用旋转蒸发仪除去四氢呋喃,所得混合物溶于二氯甲烷中,然后依次用饱和NaHSO4水溶液、饱和NaCl水溶液和去离子水洗涤,有机相用硅胶柱提纯,得到中间产物;将中间产物溶于甲醇中,使其浓度在3-7g/L范围内,然后逐滴加入体积浓度为2%-5%的硫酸溶液,硫酸与中间产物的摩尔比为(4:1)-(10:1),于室温下搅拌0.5-2小时后,用旋转蒸发仪除去甲醇,所得固体溶于二氯甲烷,再用去离子水洗至中性,有机相用旋转蒸发仪除去二氯甲烷,然后真空干燥至恒重,得到化合物2;
所述的化合物5的结构式为
所述的化合物6的结构式为
4.根据权利要求2所述的荧光星形嵌段共聚物的制备方法,其特征在于,所述的步骤2)的开环聚合产物通过R1取代基解保护反应的具体操作为:将步骤2)的开环聚合产物溶于二氯甲烷中,使其浓度在3-7g/L范围内,在氮气保护和室温下,逐滴加入三氟乙酸,三氟乙酸和二氯甲烷的体积比为(0.5:1)-(2:1),继续搅拌1-10小时;反应结束后,用旋转蒸发仪除去三氟乙酸,在乙醚中沉淀,所得固体真空干燥至恒重,得到荧光星形嵌段共聚物。
5.根据权利要求1-4任一所述的方法制备得到的荧光星形嵌段共聚物作为疏水药物载体的应用。
6.根据权利要求1-4任一所述的方法制备得到的荧光星形嵌段共聚物作为细胞内荧光成像染料的应用。
7.根据权利要求5所述的应用,其特征在于,所述的荧光星形嵌段共聚物在水溶液中自组装形成荧光超分子胶束并装载疏水药物。
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