CN108456298A - 一种可溶性不对称酞菁修饰的两亲性聚合物及合成方法 - Google Patents
一种可溶性不对称酞菁修饰的两亲性聚合物及合成方法 Download PDFInfo
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Abstract
一种用不对称酞菁修饰的两亲性有机聚合物，是有机聚合物材料，其特征在于：亲水部分是聚乙二醇单甲醚；亲油部分是聚乳酸和酞菁，两者利用双硫键相连接。该两亲性分子可以用于癌症的治疗，属于有机高分子领域。本发明首先合成可溶性的不对称锌酞菁：然后利用聚乙二醇单甲醚引发L‑丙交酯开环聚合形成嵌段聚合物；两者利用双硫键相连接形成双亲性的聚合物。但当聚合物处于水溶液中可以自组装成为胶束，内部可以包裹化疗药物作为药物载体；聚合物本身也可对癌细胞做出被动响应的，此为光动力治疗；总的来说此聚合物可以做为化疗与光动力治疗的联合治疗药物。
Description
技术领域
本发明属于材料领域，特别涉及一种由可溶性不对称酞菁修饰的两亲性聚合物及合成方法，该两亲性聚合物能于水溶液中自组装成为胶束粒子。
技术背景
随着癌症成为人们生命健康安全的最大威胁之一，寻找有效的治疗癌症的手段已经成为人们研究的重点。目前相较于传统的化疗手段，光动力治疗具有生物毒性低，受到人们的热烈关注。在光动力治疗中光敏剂作为重要的组成部分，一直是人们研究的重点。酞菁作为第二代光敏剂中的佼佼者，一直受到人们的青睐，但是由于其溶解性的问题，以至于它的用途受到限制，因而我们期待做出一种溶解性好易于修饰改性的酞菁，以便于对这种光敏剂进行修饰。在本专利中，设计了一种对酞菁分子环上进行增长碳链的手段来改善酞菁的溶解性，使其有利于对它的进一步修饰。在本专利中的酞菁是一种可溶性的不对称酞菁，利用具有被动靶向性的双硫键将酞菁与嵌段共聚物聚乙二醇单甲醚-聚乳酸结合形成两亲性聚合物，进一步可以自组装形成胶束，可以自身治疗癌症，也可以负载化疗药物协同治疗癌症。
发明内容
本发明利用增长碳链的方法对酞菁前驱体进行改性，而后形成溶解性极佳的不对称酞菁，利用双硫键与嵌段共聚物聚乙二醇单甲醚-聚乳酸(mPEG-b-PLA)结合，形成两亲性酞菁聚合物，可自组装形成胶束粒子。
实施方法中，利用4-癸氧基邻苯二腈和4-[2-(2-溴乙氧基-吡喃)]邻苯二腈合成可溶性的不对称酞菁，其结构为：
实施方案中，利用聚乙二醇单甲醚作为引发剂，其醇羟基可在无水无氧条件下引发丙交酯进行开环聚合，获得嵌段聚合物mPEG-b-PLA，聚合度控制在100-140之间，其结构为：
实施方案中，将mPEG-b-PLA与不对称酞菁利用双硫键结合形成两亲性的有机聚合物，结构为：
有益效果
本发明所述的技术方案与现有技术相比，能够取得以下有益效果：本发明提供了一种可溶性不对称酞菁修饰的两亲性聚合物及其制备方法，这种由不对称酞菁修饰的两亲性聚合物，生物相容性性好、生物毒性低，由于具有可形成胶束能力，因此可用于化疗药物载体，增强癌症的治疗效果，使其功能性进一步的增强的同时，毒副作用比单纯化疗药物小很多。
附图说明
图1为ZnPC-OH的合成路线图
图2为ZnPC-S-S-COOH的合成路线图
图3为mPEG-b-PLA的合成路线图
图4为mPEG-b-PLA-S-S-ZnPC的合成路线图
图5为mPEG-b-PLA-S-S-ZnPC的核磁氢谱图
图6为胶束mPEG-b-PLA-S-S-ZnPC的扫描电镜图
具体实施方法
本发明的可溶性不对称酞菁两亲性嵌段聚合物聚乙二醇单甲醚-聚乳酸(mPEG-b-PLA-S-S-ZnPC)具有对水溶液有不同的亲和力，因此可以自组装形成纳米胶束粒子，这个聚合物的优点在于并不限制于本身的光动力治疗，也可以联合化疗药物如阿霉素协同治疗癌症。
3-乙氧基羟基-10,17,24-三癸氧基酞菁锌(ZnPC-OH)的合成
3-乙氧基羟基-10,17,24-三癸氧基酞菁锌(ZnPC-OH)的合成路线见图1。取经高温处理后冷却的单口圆底烧瓶，加入4-癸氧基邻苯二腈(0.568g，2mmol)和4-[2-(2-乙氧基吡喃)]邻苯二腈(0.182g,0.67mmol)，然后加入10ml正戊醇，反应24h，去除保护基，再经过提纯即可得到蓝绿色产物42mg，产率5.8％。Elemental Analysis:C,69.35；H,7.19；N,10.02。
ZnPC-S-S-COOH的合成
ZnPC-S-S-COOH的合成路线见图2。将ZnPC-OH(110.6mg，0.1mmol)和3,3'-二硫代二丙酸(168mg，0.8mmol)加入到5mL DCM中，4-二甲氨基吡啶(DMAP)与二环己基碳二亚胺(DCC)作用下。在室温下搅拌过夜。再利用DCM萃取和水洗涤，蒸发除去DCM后，粗产物经过分离提纯后，得出ZnPc-S-S-COOH，45mg，产率34.7％。Elemental Analysis:C,64.72；H,6.83；N,8.63。
嵌段共聚物聚乙二醇单甲醚-聚乳酸(mPEG-b-PLA)的合成
嵌段共聚物mPEG-b-PLA的合成路线见图3。在N2的条件下，在烧瓶内加入30ml甲苯，再将1g mPEG-5000和1.73gL-丙交酯加入到两口烧瓶内，搅拌均匀后加入50μL辛酸亚锡，置于油浴内反应10h。结束之后沉降得白色固体，真空干燥得到两嵌段聚合物2.7g。以聚苯乙烯为标准参照物，用凝胶渗透色谱对得到的聚合物进行分析，得到聚乙二醇单甲醚-聚乳酸的数均分子量为1.65万。
mPEG-b-PLA-S-S-ZnPC的合成
mPEG-b-PLA-S-S-ZnPC的合成路线如图4所示，将ZnPC-S-S-COOH(60mg，0.046mmol)，mPEG-b-PLA(450mg，0.03mmol)加入到20ml二氯甲烷，而后在4-二甲氨基吡啶(DMAP)与二环己基碳二亚胺(DCC)的作用下，在室温下搅拌过夜。除去其中的杂质后，再经过透析得到最终的产物198mg，产率41％。以聚苯乙烯为标准参照物，用凝胶渗透色谱对得到的聚合物进行分析，得到聚乳酸的数均分子量为1.8万。从图5的核磁氢谱图中在化学位7.5～9.5ppm相对应的为酞菁环上质子氢的位移，5.16ppm处对应PLA重复单元亚甲基的质子峰，3.64ppm处对应mPEG组分亚甲基质子峰，从而证明出已经和长处目的产物。从图6的扫描电镜图片可以看出胶束粒子的形成趋于球形，这与最初的设计思想相符合。
以上实施例的说明仅是本发明的优选实施方案及其核心思想，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (3)
1.一种用不对称酞菁修饰的两亲性有机高分子聚合物，其特征在于：亲水部分是聚乙二醇单甲醚；亲油部分是聚乳酸和酞菁，两者利用双硫键相连接，形成两亲性的聚合物。兼具光动力治疗和作为化疗药物载体的作用，本身作为光动力治疗时可以减小对生物体的毒性，也可以通过负载化疗药物来联合治疗增强治疗效果。
2.根据权利要求1所述的两亲性有机高分子聚合物制备方法，其特征在于，用溶剂热法制备3-乙氧基羟基-10,17,24-三癸氧基酞菁锌，通过酯化与3,3＇-二硫代二丙酸反应生成末端由二硫化物修饰的羧基酞菁(ZnPC-S-S-COOH)；合成嵌段聚合物聚乙二醇单甲醚-聚乳酸(mPEG-b-PLA)，利用酯键将ZnPC-S-S-COOH接枝到聚合物上最终获得两亲性的有机高分子聚合物。
3.根据权利要求2所述的两亲性的有机高分子聚合物，自身可以作为光动力治疗的材料，也可作为药物载体，来增强治疗癌症的效果，更为值得的注意的是其自身具有被动的靶向性来减少生物毒性。
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| CN110960686A (zh) * | 2019-12-26 | 2020-04-07 | 中国医学科学院生物医学工程研究所 | 一种用于肿瘤靶向荧光成像和光动力治疗的酞菁类化合物 |
| CN111040180A (zh) * | 2020-01-15 | 2020-04-21 | 重庆大学 | 一种生物级联反应式光动力集成生物聚合物及其制备方法和应用 |
| CN111303167A (zh) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | 一种显色材料、滤光片及其制备方法 |
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| JP6347684B2 (ja) * | 2014-07-07 | 2018-06-27 | 京セラ株式会社 | 半導体接着用熱硬化型樹脂組成物及び半導体装置 |
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| CN111040180B (zh) * | 2020-01-15 | 2021-12-07 | 重庆大学 | 一种生物级联反应式光动力集成生物聚合物及其制备方法和应用 |
| CN111303167A (zh) * | 2020-03-30 | 2020-06-19 | Tcl华星光电技术有限公司 | 一种显色材料、滤光片及其制备方法 |
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