CN115520888A - 一种聚乙烯亚胺的二氧化碳加合物制备碳酸钙的应用 - Google Patents
一种聚乙烯亚胺的二氧化碳加合物制备碳酸钙的应用 Download PDFInfo
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Abstract
本发明公开了一种聚乙烯亚胺的二氧化碳加合物作为原料制备碳酸钙的用途。所述聚乙烯亚胺可以是单独的聚合物链,也可以作为接枝聚合物的主链,这些聚乙烯亚胺链段首先和二氧化碳反应形成加合物,然后作为二氧化碳来源和改性剂合成碳酸钙。本发明的碳酸钙颗粒具有粒径小、高度分散、粒径分布窄、晶型稳定性,具有可反应位点用于接枝功能侧链等特点。
Description
技术领域
本发明涉及一种由聚乙烯亚胺的二氧化碳加合物制备碳酸钙的应用,属于无机材料制备技术领域,尤其涉及一种纳米级的碳酸钙微球的制备技术。
背景技术
碳酸钙是地球上广泛存在的物质,也是碳循环的重要环节,存在方解石、球霰石、文石及无定型结构。其中,方解石晶型最为稳定,无定型结构最不稳定。球霰石是其中应用较为广泛的碳酸钙晶型,尤其是具有规整球状的多孔结构,有较高的比表面积,药物装载量高,低毒性,能够响应肿瘤微环境,在生物医学领域应用极为广泛。
碳酸钙通常的合成方法是采用可溶性钙盐和可溶性碳酸盐混合,从而得到碳酸钙沉淀(沉淀法);或者是采用氢氧化钙吸收CO2而得(碳化法)。如果不添加任何添加剂得到的是方解石晶型的碳酸钙,其粒径可达到几十微米甚至毫米级别。这种碳酸钙在水或者有机物中均不能有效分散,应用价值不大。方解石型碳酸钙常作为塑料添加剂使用,这时候要求碳酸钙的表面为疏水性的,以利于其在塑料中的分散。球霰石型碳酸钙通常为球形颗粒,由直径为几纳米到几十纳米的球形微晶粒聚集形成,球霰石微晶粒之间的空隙非常适合装载具有治疗作用的药物或生物分子,是优良的药物控制释放的载体。但通常单纯的球霰石在水溶液中不稳定,会在几个小时或几天内发生晶型转变,成为稳定密实的方解石结构。因此需要加入一些添加剂来稳定球霰石结构。
另外作为治疗肿瘤的药物载体,通常需要载体能够在血液中循环、在肿瘤部位聚集然后释放抗癌药物。为了达到这些目的,需要设计载体的粒径在几百纳米范围内、以及载体具有水相的胶体稳定性,同时也需要在载体颗粒表面接枝亲性的柔性链(如聚乙二醇链)和具有特异识别肿瘤细胞的分子(如叶酸)。这就要求载体颗粒表面有可反应的基团来接枝所需的目标分子。而碳酸钙颗粒表面缺乏可反应的基团,限制了其应用。
先前的技术通过添加不同类型的聚合物,来保持球霰石结构稳定。这样的聚合物有淀粉、羧甲基壳聚糖、含聚乙二醇和聚丙烯酸的嵌段聚合物等等。这些添加剂可以制备出具有胶体稳定、球霰石晶型稳定的碳酸钙纳米微球,但微球表面仍然缺乏足够的可反应基团用于进一步改性。另外,这些添加剂是通过和碳酸钙表面的钙离子螯合起到晶型和胶体稳定作用的。碳酸钙粒子在形成过程中,可能已经发生了部分团聚,然后改性剂才覆盖该团聚体,已经发生团聚的粒子就很难分散开了。因此先前的工艺很难控制碳酸钙的粒径,其粒径分布宽,粒径大小不一而均匀性差,这极大地影响了碳酸钙后期应用的稳定性。
发明内容
本发明人注意到,聚乙烯亚胺含有很高的胺基密度,可以和CO2反应生成加合物从而把CO2固定到聚乙烯亚胺分子链上;这种加合物是不稳定的,可以在加热的条件下重新释放CO2用于聚氨酯发泡。本发明人猜想,这种CO2加合物在适当条件下也可以释放CO2参与化学反应;为此本发明人采用聚乙烯亚胺的CO2加合物作为CO2来源尝试合成碳酸钙。聚乙烯亚胺的CO2加合物将CO2原料固定在聚乙烯亚胺的分子链中,因此碳酸钙的成核和最初的晶体生长都被限制在聚合物链中,使聚合物链贯穿于碳酸钙的晶粒之间,和碳酸钙晶粒之间有紧密的接触。因此聚乙烯亚胺分子链一方面提供CO2供碳酸钙晶体生长,另一方面将碳酸钙晶核的生长限制在聚合物链中,使聚合物链成为碳酸钙晶体生长的模板。虽然聚乙烯亚胺的CO2加合物是溶于水的,从物理化学的角度看其水溶液是均相的;但CO2(以氨基甲酸根的形式结合在聚乙烯亚胺主链上)在水溶液中的分布却是不均匀的,其被限制在了单个的聚合物分子链中,聚合物分子之间的水中是没有CO2分子的(水中CO2以碳酸根或碳酸氢根的形式存在)。水中的钙离子只能在聚合物链所分布的空间(聚合物在溶液中一般以无规线团形式存在)里才能和CO2结合形成碳酸钙。因此,在本发明的体系中,聚乙烯亚胺的CO2加合物就扮演了独立的“微反应器”,将碳酸钙的成核和最初的生长限制在该“微反应器”中,从而得到纳米级的碳酸钙微晶粒;而聚乙烯亚胺和碳酸钙粒子紧密结合,调节和稳定其晶型,提供碳酸钙粒子的胶体稳定性,同时聚乙烯亚胺的胺基还可以提供反应性,为碳酸钙粒子的进一步改性提供了可能性。
传统的碳酸钙的合成,碳酸根和钙离子是均匀溶于水中,然后二者相互反应生成沉淀;也会加入一些水溶性的聚合物作为晶型和胶体稳定剂,这些聚合物一般具有和钙离子螯合的能力,但并不能完全把钙离子限制在聚合物分子链上,不存在本发明中所说的“微反应器”。这是本发明和传统合成方法的本质区别。
在本发明中,聚乙烯亚胺可以是线性的,也可以是支链型的,其中支链型的更容易稳定碳酸钙颗粒。聚乙烯亚胺的分子量没有特别的限制,甚至乙烯亚胺(又称氮丙啶)的二聚体也可以和CO2形成加合物,用于碳酸钙的合成;但分子量越大,其作为“微反应器”的效果就越明显,所得的粒径就越小。
在本发明中,聚乙烯亚胺还可以先接枝特定功能的侧链,所得接枝聚合物的主链聚乙烯亚胺链段仍然可以和CO2形成加合物,从而合成碳酸钙;接枝聚合物中的非“聚乙烯亚胺”链段还可以对所得碳酸钙进行进一步修饰,赋予其特定的功能。所述的接枝聚合物的侧链包括但不限于以下结构:
(1)聚乙二醇、聚乙烯醇、聚甲基丙烯酸羟乙酯、聚丙烯酸羟乙酯、聚2-甲基丙烯酰氧基乙基磷酰胆碱等电中性的亲水性链段;
(2)叶酸、亲和体、RGD(精氨酸-甘氨酸-天冬氨酸)肽、肿瘤细胞表皮生长因子GE11肽(多肽序列结构为YHWYGYTPQNVI)、精氨酸八肽(R8肽)等具有肿瘤细胞靶向的小分子和多肽(亲和体是以葡萄球菌蛋白A为基础改造的小分子蛋白,可以认为是一种多肽);
(3)肿瘤细胞表皮生长因子、西妥昔单抗、利妥昔单抗、卡瑞珠单抗、阿特利珠单抗、帕博利珠单抗等具有肿瘤靶向的生长因子和抗体;
(4)核酸适配体(为核苷酸寡聚体);
(5)碳原子数1到22的烷基链;
(6)含有至少一个丙二醇重复单元的聚丙二醇链;
(7)碳原子数为4以上的硅烷;
(8)含有至少一个重复单元的聚二甲基硅氧烷;
(9)碳原子数为1到22的含氟烷基。
上述结构(1)中的亲水链段可以提高碳酸钙微球在血液中的循环时间和稳定性,有利于碳酸钙微球在肿瘤处的聚集;上述结构(2)~(4)为具有靶向肿瘤细胞的分子,有利于碳酸钙微球靶向富集于肿瘤处。在肿瘤治疗领域的人员可以根据需要选择和设计靶向分子,在此不一一叙述。
上述聚乙烯亚胺的接枝聚合物的侧链(1)~(4)一般都是水溶性的(可以在水相中合成碳酸钙),其主链聚乙烯亚胺的质量占比不小于50%,其侧链不含有CO2,因此在合成碳酸钙的过程中,碳酸钙的成核和晶体生长发生在主链聚乙烯亚胺区域,侧链则倾向于分布在碳酸钙粒子的表面,起到靶向肿瘤细胞的功能。上述聚乙烯亚胺的接枝聚合物的侧链(5)~(9)为疏水链,其主链聚乙烯亚胺的质量占比不小于50%,合成可以在有机溶剂和水的混合物中进行。在合成碳酸钙的过程中,碳酸钙的成核和晶体生长发生在主链聚乙烯亚胺区域,疏水侧链则倾向于分布在碳酸钙粒子的表面,有利于改进碳酸钙粒子在疏水聚合物中的分散。
不管聚乙烯亚胺接枝何种功能侧链,但起合成碳酸钙作用的仍然是聚乙烯亚胺的CO2加合物,其本质上仍然是利用聚乙烯亚胺的CO2加合物来合成碳酸钙,仍然属于本发明的保护范围。
在本发明中,合成碳酸钙的钙源来自于氢氧化钙。氢氧化钙和(接枝改性)聚乙烯亚胺的CO2加合物反应,生成碳酸钙,同时聚乙烯亚胺的CO2加合物转变成聚乙烯亚胺,并附着于碳酸钙颗粒表面和穿插于碳酸钙的微晶粒中,起到稳定碳酸钙晶型、提供可反应位点的作用。
本发明的目的在于提供聚乙烯亚胺及接枝改性聚乙烯亚胺的CO2加合物作为原料制备碳酸钙的用途。
本发明的目的可以通过以下技术方案实现:
(1)配置聚乙烯亚胺或者接枝改性聚乙烯亚胺的CO2加合物水溶液:将聚乙烯亚胺或接枝聚乙烯亚胺配置成一定浓度的水溶液,通入二氧化碳反应至饱和;可选的,还可以将具有治疗作用的物质溶于水中和所得CO2加合物水溶液混合;
(2)配置澄清饱和氢氧化钙水溶液,在搅拌条件下将氢氧化钙水溶液滴入聚乙烯亚胺的CO2加合物水溶液,搅拌反应6h,离心洗涤,冷冻干燥;或者在搅拌条件下将(接枝改性)聚乙烯亚胺的CO2加合物水溶液滴入氢氧化钙水溶液,搅拌反应6h,离心洗涤,冷冻干燥。
在上述步骤中,如果接枝改性聚乙烯亚胺的接枝链是疏水链,还可以在四氢呋喃/水的混合溶剂中合成碳酸钙,具体的,第(1)步改为:配置聚乙烯亚胺或者接枝改性聚乙烯亚胺的CO2加合物的四氢呋喃溶液或者悬浮液:将聚乙烯亚胺或接枝聚乙烯亚胺配置成一定浓度的四氢呋喃溶液,通入二氧化碳反应至饱和。其余步骤不变。
上述技术方案中的接枝改性聚乙烯亚胺的接枝链包括但不限于以下结构:
(1)聚乙二醇、聚乙烯醇、聚甲基丙烯酸羟乙酯、聚丙烯酸羟乙酯、聚2-甲基丙烯酰氧基乙基磷酰胆碱等电中性的亲水性链段;
(2)叶酸、亲和体、RGD(精氨酸-甘氨酸-天冬氨酸)肽、肿瘤细胞表皮生长因子GE11肽(多肽序列结构为YHWYGYTPQNVI)、精氨酸八肽(R8肽)等具有肿瘤细胞靶向的小分子和多肽(亲和体是以葡萄球菌蛋白A为基础改造的小分子蛋白,可以认为是一种多肽);
(3)肿瘤细胞表皮生长因子、西妥昔单抗、利妥昔单抗、卡瑞珠单抗、阿特利珠单抗、帕博利珠单抗等具有肿瘤靶向的生长因子和抗体;
(4)核酸适配体(为核苷酸寡聚体);
(5)碳原子数1到22的烷基链;
(6)含有至少一个丙二醇重复单元的聚丙二醇链;
(7)碳原子数为4以上的硅烷;
(8)含有至少一个重复单元的聚二甲基硅氧烷;
(9)碳原子数为1到22的含氟烷基。
上述技术方案中所述的“具有治疗作用的物质”包括但不限于:阿霉素、紫杉醇、5-氟尿嘧啶、长春新碱、白藜芦醇、苯达莫司汀、阿帕替尼、卡铂、辣椒素、贝伐单抗、阿柏西普、雷莫芦单抗、卵清蛋白、帕纳替尼、布立伐尼、多韦替尼、索拉非尼、舒尼替尼、帕唑帕尼、橄榄苦苷、尼罗替尼、核酸适配体等等。
本发明的技术方案将通过实施例进行进一步的说明。
区别于现有技术,本发明的优点如下:
本发明使用聚乙烯亚胺或接枝改性聚乙烯亚胺的CO2加合物作为CO2来源合成碳酸钙,同时聚乙烯亚胺或接枝改性聚乙烯亚胺对碳酸钙晶型进行调控。提供碳酸钙粒子的胶体稳定性,以及赋予碳酸钙粒子的表面可反应性,为碳酸钙的后续应用提供广阔的空间。本发明解决了现有工艺存在的晶型不稳定,颗粒分布宽,粒径尺寸不均一等问题,得到的球霰石型或方解石型碳酸钙晶型稳定。
附图说明
图1为实施例1~7的红外光谱图。
图2为实施例1~7的X-射线衍射图。
图3为实施例1~7的热失重图。
图4为实施例1~7的颗粒形貌图。
图5为实施例8~10的碳酸钙颗粒溶解于三氟醋酸钙和重水中所得的核磁谱图;
图6为实施例5和8~10的X-射线衍射图;
图7为实施例11~13的X-射线衍射图;
图8为实施例11~13的形貌图,上为扫描电镜图;下为透射电镜图;
图9实施例14~16制备的碳酸钙的X-射线衍射图;
图10为实施例10(未载药)和实施例16(载药)所制备的碳酸钙的形貌图。左为扫描电镜图;右为透射电镜图。
图11为实施例17~22所用的聚乙烯亚胺的侧链的化学结构图。
具体实施方式
下面结合实施例对本发明进行详细说明。需要说明的,所有这些实施例均是为了进一步说明本发明,不得理解为对本发明的限制。该领域的技术熟练人员根据上述本发明内容对本发明作出的一些非本质的改进和调整仍属于本发明的保护范围。需要说明的是,以下实施例中“wt%”表示质量百分含量。
实施例1-7
实施例1~7采用饱和氢氧化钙溶液向聚乙烯亚胺(PEI)的CO2加合物溶液滴加的方式制备碳酸钙,包括以下步骤:
(1)选分子量如表1所示的PEI(为支化结构)配置成浓度为0.1g/mL的PEI水溶液10mL,按1mL/min的速度通入CO2反应1天,制成PEI的CO2加合物(PEI-CO2)溶液,备用;
(2)约1000转/分搅拌条件下滴加50~400mL(如表1所示)的澄清饱和Ca(OH)2水溶液,搅拌反应6h,离心洗涤,冷冻干燥,即得到PEI-CO2改性的碳酸钙颗粒。
(3)将PEI-CO2改性的碳酸钙颗粒研磨并放进高压釜,在0.5MPa CO2气氛保压24h,得到最终的碳酸钙产物。
图1显示了所制备的碳酸钙的红外光谱,能够看到PEI主链2935cm–1和2832cm–1亚甲基的伸缩振动峰,以及3100~3300cm–1的胺基峰;碳酸钙的碳酸根的非对称振动峰出现在1400~1500cm–1,面外弯曲振动在875cm–1。碳酸根的面内弯曲振动与碳酸钙的晶型有关,其中712cm–1的峰为方解石晶型的特征峰(见^标记的峰),而745cm–1的峰为球霰石的特征峰(见#标记的峰)。图2为所制备碳酸钙的X-射线衍射图谱,其晶型和红外测试一致,实施例5是混合晶型(含78.4%的球霰石和21.6%的方解石),实施例1~3为球霰石晶型,实施例4、6和7为方解石晶型。
图3为所制备碳酸钙的热失重图。其中,30~150℃之间的质量损失是PEI的CO2加合物受热释放出CO2,200~500℃为材料中PEI分解的质量损失,600℃后的质量损失是材料中的CaCO3发生热分解所致。表2列出了各实施例的热重数据,由此可以分析各实施例所制备的碳酸钙的组成。由表2知,所得碳酸钙为PEI的CO2加合物和碳酸钙组成,PEI的质量和其加合物释放的CO2量基本符合理论量(饱和度较高);碳酸钙的残留物(CaO)和释放的CO2的摩尔比和理论值(1:1)非常接近。从表可知,碳酸钙的含量在66~99%之间变化。
表1
注:Mn表示分子量,25k表示分子量为25000,依次类推;PEI-CO2溶液中含CO2510.08mg;25℃时,氢氧化钙的溶解度为159mg每100mL水;实际碳酸钙的量来自于热失重数据。
表2
图4为实施例1~7的形貌图。由图可知,以球霰石结构为主的碳酸钙其形貌为由球形微晶组成的球形形貌,在320~420nm之间,而方解石结构则为不规则的块状形貌,粒径可以达到微米级别。
从实施例1~7的结果可知,可以通过PEI的分子量、以及氢氧化钙的添加量的变化来控制所得碳酸钙的晶型和粒径。本组实施例所得的球霰石纳米微球可以在水中稳定分散,其晶型在水中可以保持8个月以上;这种晶型稳定和胶体稳定均优异的球霰石纳米颗粒可以用于负载具有治疗作用的药物,球霰石颗粒表面的胺基(来自于PEI)还可以用于接枝具有靶向作用的分子。
实施例8-13
本组实施例制备接枝改性PEI的CO2加合物稳定的碳酸钙。聚乙二醇(PEG)是常用的用于提高载药颗粒在血液中循环时间的聚合物,为了将PEG接枝到PEI的CO2加合物稳定的碳酸钙上,先合成带醛基的PEG(PEG-CHO)。其合成方法如下:将20.0g的聚乙二醇单甲醚(PEG,分子量2000)溶解于50mL四氢呋喃(THF)中,将2.0g NaOH溶于20mL去离子水,滴加进溶解好的PEG溶液中,在冰浴条件下搅拌30min。将7.6g的对甲苯磺酰氯(PTSC)溶于30mLTHF,滴加进PEG和NaOH的混合溶液中,自然升至室温后继续反应4h。向反应好的产物中倒入100mL冰水,加二氯甲烷萃取三次(3×80mL),向萃取出的有机层中加入去离子水洗涤(2×50mL),再用饱和NaCl溶液洗涤一次(1×50mL)。将洗好的有机层旋蒸浓缩,随后倒入大量冰乙醚沉淀出白色固体物质,过滤后50℃真空干燥一天,得到白色PEG对甲苯磺酸酯(PEG-OTs)固体粉末,产率为85%。将15.0g PEG-OTs于200mL的三口烧瓶中,加入2.6g对羟基苯甲醛,再称取19.3g无水K2CO3加入烧瓶中,倒入100mL无水CH2CN,在85℃和氮气保护条件下回流反应48h。将反应后的样品进行减压蒸馏除溶剂,加200mL去离子水溶解粗产物,将溶解好的产物倒入分液漏斗,用CH2Cl2萃取三次(3×60mL),萃取好的样品进行浓缩,倒入大量冰乙醚沉淀,得到米白色固体物质沉淀PEG-CHO,过滤,50℃干燥一天,产率为76%。
实施例8到10,PEI主链分别接枝PEG,叶酸(FA)以及PEG和叶酸,先合成PEI-CO2稳定的碳酸钙,然后接枝侧链,如表3所。实施例8的制备工艺步骤如下:
(1)选分子量为10000的支化PEI配置成浓度为0.1g/mL的PEI水溶液10mL,按1mL/min的速度通入CO2反应1天,制成PEI的CO2加合物(PEI-CO2)溶液,备用;
(2)约1000转/分搅拌条件下滴加100mL的澄清饱和Ca(OH)2水溶液,搅拌反应6h,得到PEI@CaCO3白色乳液。
(3)称取4g PEG-CHO(合成方法见前述)溶解于40mL去离子水中,37℃搅拌条件下,匀速滴加进制备好的PEI@CaCO3白色乳液中,继续反应24h,得到接枝PEG的PEI@CaCO3纳米悬液,将溶液封装于透析袋(截留分子量10000)中放入1000mL蒸馏水中透析两天,每8h更换一次蒸馏水,以除去游离未反应的PEI以及PEG-CHO。将透析后的溶液50℃旋转蒸发2h,然后冷冻干燥得到接枝有PEG链的PEI-CO2改性的碳酸钙颗粒。
(4)将第(3)步所得碳酸钙颗粒研磨并放进高压釜,在0.5MPa CO2气氛保压24h,得到最终的碳酸钙产物。
表3
注:表中碳酸钙的含量来自于CO2(CaCO3)和残重之和。实施例11~13侧链的百分数表示该侧链的接枝度。
实施例9的制备工艺步骤和实施例8相同,除了第(3)步改为:称取0.4g叶酸(FA),均匀分散在10mL去离子水中,加入0.35g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),活化40min后,滴加进第(2)得到的PEI@CaCO3白色乳液中,37℃恒温搅拌避光反应24h,得到接枝FA的PEI@CaCO3纳米悬液。将溶液封装于透析袋(截留分子量10000)中放入1000mL蒸馏水中透析两天,每8h更换一次蒸馏水,以除去游离未反应的PEI以及FA。将透析后的溶液50℃旋转蒸发2h,然后冷冻干燥得到接枝有FA的PEI-CO2改性的碳酸钙颗粒。
实施例10的制备工艺步骤和实施例8相同,除了第(3)步改为:称取4g PEG-CHO(合成方法见前述)溶解于40mL去离子水中,37℃搅拌条件下,匀速滴加进制备好的PEI@CaCO3白色乳液中,继续反应24h,得到接枝PEG的PEI@CaCO3纳米悬液。然后称取0.4g叶酸(FA),均匀分散在10mL去离子水中,加入0.35g 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),活化40min后,滴加进接枝PEI的PEI@CaCO3白色乳液中,37℃恒温搅拌避光反应24h,得到接枝PEG和FA的PEI@CaCO3纳米悬液。将溶液封装于透析袋(截留分子量10000)中放入1000mL蒸馏水中透析两天,每8h更换一次蒸馏水,以除去游离未反应的PEI、PEG以及FA。将透析后的溶液50℃旋转蒸发2h,然后冷冻干燥得到接枝有PEG和FA的PEI-CO2改性的碳酸钙颗粒。
实施例11~13先合成接枝改性PEI,再合成其加合物,最后合成接枝PEI的CO2加合物稳定的碳酸钙。本组实施例所用的接枝侧链为二丙二醇单甲醚链(DPG)。首先合成二丙二醇单甲醚缩水甘油醚(DPG-EPO)接枝的PEI。按照设计接枝度3%,9%,16%(如表3所示,DPG前的百分数表示接枝度),分别称取14.21g,42.63g,75.78g DPG-EPO,分别加入含有100g支化PEI(10000Da)的单口瓶中,1000转/分搅拌混合均匀后,水浴70℃恒温反应8h,真空烘箱70℃干燥,制得淡黄色粘稠状不同接枝度的DPG-PEI。其次合成DPG-PEI的CO2加合物,DPG-PEI在CO2气氛下不停的来回吹扫,使PEI充分与CO2反应,反应完全得到白色固体物质,放置在研钵中在CO2气氛条件下研磨成粉末,将粉末放入高压釜中,在0.6MPa CO2保压继续使PEI与CO2反应24h,即制得DPG-PEI-CO2白色粉末。最后合成DPG-PEI-CO2稳定的碳酸钙,称取不同接枝度的DPG-PEI-CO2各10g溶解在50mL的去离子水中,溶解好的DPG-PEI-CO2快速倒入1000转/分搅拌下的3L饱和Ca(OH)2水溶液中,室温条件下反应过夜,得到DPG-PEI@CaCO3白色乳液,50℃旋转蒸发2h,8000转/分离心5min得到白色DPG-PEI@CaCO3,将沉淀进行冷冻干燥,研磨成粉末,置于高压釜中,在0.6MPa CO2气氛下保压24h,使CaCO3中的PEI与CO2中充分反应,即得到系列不同接枝度的DPG-PEI-CO2稳定的CaCO3颗粒。
图5为实施例8~10的碳酸钙溶于三氟醋酸和重水中所得的核磁谱图。席夫碱在酸性环境下水解,会重新形成醛基,因此可以看到实施例8在9.13ppm处出现了醛基氢的信号峰,以及6~7.5ppm之间出现了苯环的质子峰,PEG上亚乙基的信号峰和PEI上的亚甲基有部分重叠,在2.5~3.5ppm间。实施例9的碳酸钙结合了叶酸(FA),能看到8.23ppm处有叶酸结构中嘧啶环上CH=N质子信号峰,以及6~7.5ppm之间一些苯环的质子峰。实施例10接枝了PEG和FA,二者的峰均能看到。核磁谱图证明FA和PEG成功接枝在纳米颗粒上。
图6为实施例5和8~10的X-射线衍射图,其中实施例5没有接枝侧链,实施例8~10接枝有不同侧链,由图可知,四种碳酸钙的晶型主要为球霰石型,有少量方解石存在,接枝侧链并不改变碳酸钙的晶型。
图7实施例11~13的X-射线衍射图,由图可知,四种碳酸钙的晶型主要为方解石型。图8为实施例11~13的形貌图,有扫描电镜图可知,微晶粒组成了大小不等的团聚体,透色电镜显示晶粒为块状结构(为方解石的特征形貌)。
对本组实施例所制备的碳酸钙进行了热重分析,其图谱和图3类似,具体的热失重数据见表3。由表可知,本组实施例的碳酸钙含量在59~83%之间。
实施例14-16
本组实施例制备载药的PEI的CO2加合物稳定的碳酸钙。采用共沉淀法制备载药颗粒。其中实施例14的工艺步骤如下:
(1)选分子量为10000的支化PEI配置成浓度为0.1g/mL的PEI水溶液10mL,按1mL/min的速度通入CO2反应1天,制成PEI的CO2加合物(PEI-CO2)溶液,备用;
(2)称取50mg阿霉素(DOX)溶解于10mL去离子水中,室温条件下,与上述第(1)步制备的PEI-CO2溶液混合,搅拌30min,滴加100mL饱和Ca(OH)2澄清溶液,反应6h得到紫红色乳液。离心洗涤,冷冻干燥,即得到载药的PEI-CO2改性的碳酸钙颗粒。
(3)将载药的PEI-CO2改性的碳酸钙颗粒研磨并放进高压釜,在0.5MPa CO2气氛保压24h,得到最终的碳酸钙产物。
实施例15和实施例14制备工艺相同,只是在第(2)步合成载药的PEI-CO2改性的碳酸钙颗粒后,对颗粒接枝了叶酸(FA),所采取的接枝方法和实施例9的相应接枝叶酸的方法是一样的。
实施例16和实施例14制备工艺相同,只是在第(2)步合成载药的PEI-CO2改性的碳酸钙颗粒后,对颗粒接枝了PEG和叶酸(FA),所采取的接枝方法和实施例9的相应接枝PEG和叶酸的方法是一样的。
表4为所制备载药的PEI的CO2加合物稳定的碳酸钙的组成成份。对本组实施例所制备的碳酸钙进行了热重分析,其图谱和图3类似,具体的热失重数据见表4。抗癌药物阿霉素(DOX)的分析方法为分光光度法,首先将载药颗粒溶于稀盐酸,定容后测定480nm的吸光度,根据标准曲线得到DOX含量。由表4可知,DOX的质量百分含量在5.7~6.6%之间。
表4
注:实施例14未接枝侧链;表中碳酸钙的含量来自于CO2(CaCO3)和残重之和。
图9为实施例14~16制备的碳酸钙的X-射线衍射图。由图可知,载药后的碳酸钙仍然为球霰石为主的结构。图10为实施例10(未载药)和实施例16(载药)所制备的碳酸钙的形貌图,扫描电镜显示二者均为球形形貌,粒径差别不大,说明球霰石微晶粒之间的空隙可用于包裹药物;透射电镜图显示所制备颗粒边界模糊,微晶粒之间有微弱的阴影,这些阴影可归属为PEI和所包裹的药物。
实施例17-25
本组实施例进一步合成各种结构的接枝聚乙烯亚胺,然后合成碳酸钙。其中实施例18、20和22用的是线性PEI,其余实施例用的是支化PEI;实施例17~22所用的侧链的结构见图11。表5为各实施例所用接枝PEI的结构以及所合成碳酸钙的组成、晶型和粒径等数据。
实施例17~21所接枝的侧链为疏水链,并且侧链均含有环氧基,首先合成相应的接枝PEI:将聚乙烯亚胺(PEI)加入反应釜中,并向反应釜中加入四氢呋喃,使PEI的质量浓度约为20%,在搅拌条件下将PEI完全溶解,然后加入相应的缩水甘油醚化合物(表5,侧链类型),所加入的质量使侧链的百分含量符合表5所列数值(比如实施例15,侧链质量含量为15%,则加入85质量份PEI,15质量份C8-EPO,其余实施例类似),在50℃搅拌反应10小时,得到接枝PEI(缩水甘油醚和PEI的反应可以达到100%,无需提出产物)。其次,在所得溶液中通入CO2,搅拌条件下反应24h,得到接枝PEI的CO2加合物悬浮液(半透明,经动态光散射测试,其粒径为100~400nm;得到的为内部亲水的外部疏水的纳米粒子,内部为PEI的CO2加合物,外部为疏水链)。最后,向所得接枝PEI的CO2加合物悬浮液滴加Ca(OH)2的饱和水溶液,所加的质量份为PEI质量份的100倍,滴加完毕后得到白色沉淀,继续搅拌反应1h,过滤得到膏状物;将所得膏状物用100份四氢呋喃重新悬浮,再次过滤,最后100份水洗,过滤得膏状物。将膏状物进行冷冻干燥,研磨成粉末,置于高压釜中,在0.6MPa CO2气氛下保压24h,使CaCO3中的PEI与CO2中充分反应,即得到接枝PEI的CO2加合物合成的碳酸钙。所得碳酸钙可以在有机溶剂(四氢呋喃、氯仿、乙醚等)中悬浮。
表5
注:表中V和C分别表示球霰石和方解石;“80V+20C”表示含80%球霰石和20%方解石,依次类推。
实施例22~25所接枝的侧链为亲水链(表5),并且侧链均含有羧基,对侧链类型说明如下:PMPC为丙烯酸和2-甲基丙烯酰氧基乙基磷酰胆碱的共聚物,分子量3000,每个分子链平均含有1.2各丙烯酸链节;RGD肽为RGDGGGGG八肽结构,甘氨酸G为细胞粘附肽(RGD)的间隔基,G端为羧基端;西妥昔单抗为可识别肿瘤细胞的单克隆抗体,为一种蛋白质分子,其分子链上含有羧基侧基;PEG+AS1411中,AS1411为商品化的可识别肿瘤细胞的一种核酸适配体,接枝量为1%,其核酸序列结构为5′-GGT GGT TGT GGT GG-3′(thiol),其中3v端基接枝有巯基,便于偶联到聚乙二醇(PEG)链上,实施例25所用的PEG为一端带马来酰亚胺,另一端为N-羟基琥珀酰亚胺(NHS)酯的PEG(Mal-PEG-NHS),分子量为3000,其接枝量为20%。
合成相应的接枝PEI。对于实施例22~24的合成工艺为:称取1质量份的PEI,溶于水,配成10%的水溶液;另外称取适当的侧链分子,使侧链的质量百分含量如表5所示,均匀分散在水中,加入和侧链等摩尔的1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC),活化40min后,滴加进PEI水溶液反应24h,得到接枝PEI水溶液。对于实施例25的合成工艺为:1质量份的PEI溶于5质量份的磷酸缓冲液(PBS,pH=7.2)中,加入0.2质量份的Mal-PEG-NHS,室温搅拌反应6h,加入1质量份的AS1411,室温搅拌反应6h得到接枝PEI的水溶液。其次,向所得接枝PEI的水溶液通入CO2反应24h,合成接枝PEI的CO2加合物水溶液。最后,向所得接枝PEI的CO2加合物溶液液滴加100质量份的Ca(OH)2的饱和水溶液,滴加完毕后得到白色乳液,继续搅拌反应1h;离心洗涤,冷冻干燥,即得到接枝PEI的CO2加合物合成的碳酸钙颗粒;将所得碳酸钙颗粒研磨并放进高压釜,在0.5MPa CO2气氛保压24h,得到最终的碳酸钙产物。所得碳酸钙颗粒可以在水中稳定的悬浮,形成胶体。
表5列出了所得产物的碳酸钙含量、粒径和晶型等数据。由表可知所得的碳酸钙颗粒主要为球霰石结构,碳酸钙含量为50%以上。除分子量较小的PEI外(如200到2000),其余PEI的CO2加合物合成的碳酸钙粒径小于1微米,适合作药物载体。
以上实施例充分说明单独的PEI的CO2加合物或者接枝改性的PEI的CO2加合物均可用于合成碳酸钙,还可以在合成碳酸钙的过程中包含治疗性的药物或者生物分子,不会影响碳酸钙的晶型和形貌。在合成碳酸钙以后,还可以进一步对颗粒进行接枝改性。本发明合成的碳酸钙可以是球霰石或者方解石,晶型稳定,粒径均匀,同时还具有在水中的胶体稳定性(PEI亲水接枝)或者在有机物中的可分散性(PEI疏水接枝)。需要说明的是PEI的接枝链,或者所包裹的药物或者生物分子是可替换的。本领域技术人员可以根据特定需要对接枝链或者所包裹的药物(或者生物分子)进行替换,但本质上都是利用聚乙烯亚胺的CO2加合物来合成碳酸钙,来控制碳酸钙的晶型,因此这些替换均属于本发明的保护范围。
以上内容是结合具体的/优选的实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,其还可以对这些已描述的实施例做出若干替代或变型,而这些替代或变型方式都应视为属于本发明的保护范围。
Claims (1)
1.一种聚乙烯亚胺和/或接枝改性聚乙烯亚胺的二氧化碳加合物作为原料制备碳酸钙的用途,其特征在于所述接枝改性聚乙烯亚胺的接枝侧链包括但不限于以下结构的至少一种:
(1)聚乙二醇、聚乙烯醇、聚甲基丙烯酸羟乙酯、聚丙烯酸羟乙酯、聚2-甲基丙烯酰氧基乙基磷酰胆碱等电中性的亲水性链段;
(2)叶酸、亲和体、RGD(精氨酸-甘氨酸-天冬氨酸)肽、肿瘤细胞表皮生长因子GE11肽(多肽序列结构为YHWYGYTPQNVI)、精氨酸八肽(R8肽)等具有肿瘤细胞靶向的小分子和多肽;
(3)肿瘤细胞表皮生长因子、西妥昔单抗、利妥昔单抗、卡瑞珠单抗、阿特利珠单抗、帕博利珠单抗等具有肿瘤靶向的生长因子和抗体;
(4)核酸适配体;
(5)碳原子数1到22的烷基链;
(6)含有至少一个丙二醇重复单元的聚丙二醇链;
(7)碳原子数为4以上的硅烷;
(8)含有至少一个重复单元的聚二甲基硅氧烷;
(9)碳原子数为1到22的含氟烷基。
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