新型可降解树枝状大分子及抗肿瘤前药的合成与表征
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摘要
药物的控制释放和在人体内的靶向性给药研究是当今化学、医学和药学领域中的一项热点。如何使药物快速准确的到达病灶部位和使药物在安全疗效范围内长效释放是当今给药技术的一个重要课题。大分子前药是以大分子化合物为载体的一种新的药物传输体系。其结构主要包括:大分子载体、小分子活性药物、连接基和定位基。生物可降解高分子,由于它们在体内可以降解,降解产物可以被机体吸收或代谢,不存在积累在体内的危险,因此成为药物释放体系的载体的首选材料。作为药物载体的材料应包括以下几个优点:良好的生物相容性,结构精确可控,分子量分布较窄,低的毒性和免疫性,可生物降解性和有高效的药物装载能力。
树枝状大分子高支化度、球形外状、表面的多官能化和尺寸的精确可控性等都为其作为药物载体提供了得天独厚的条件。树枝状大分子是一类新型高效的非生物载体,在医药领域有着极为广阔的应用前景,通过化学合成可以使树枝状大分子具有精确的结构和形态,可以明显提高单分子药物载体的载药量,使得给药过程在纳米尺度上得到实现。但是,目前的树枝状大分子作为药物载体,存在着生物相容性较差,毒性大,不可降解等问题,限制了其应用。
我们设计了一种由丙三醇和羟基乙酸齐聚物等生物毒性低的材料组成的树枝状大分子,由于其中间以酯键相连接,具有良好的可降解性。将树枝状大分子键接上具有良好生物形容性和水溶性的PEG后,可以形成一种具有良好生物相容性、低的生物毒性、分子量分布较宰的和具有可降解性的药物载体。通过合成不同长度的羟基乙酸齐聚物,可以控制其药代动力学行为,期望其能作为一种优秀的药物载体。
本文设计制备了以丙三醇及羟基乙酸齐聚物为模版的哑铃型树枝状聚合物,及以聚乙二醇-树枝状大分子为载体的聚合物胶束给药系统。本论文对树枝状大分子、两亲性树枝状大分子聚合物的合成、表征,以及载药胶束的形态尺寸等都进行了研究。具体内容摘要如下:
1、采用基团保护的方法成功合成了结构精确可控的羟基乙酸齐聚物,其中以叔丁基作为羧基保护基团。以丙三醇和羟基乙酸齐聚物为模版,采用收敛法合成了不同代数的树枝状大分子。最后,以癸二酸为核,采用收敛法合成了三代的哑铃型树枝状大分子并采用质子核磁共振(1H NMR)对其结构进行了表征。
2、MPEG的端羟基与丁二酸酐在4,4'-二甲基氨基吡啶存在下反应,便得到端羧基的MPEG。以二环己基碳二亚胺(DCC)为缩合剂、4,4'-二甲基氨基吡啶(DMAP)作催化剂,制得了端基为羧基的聚乙二醇单甲醚-三代树枝状大分子两嵌段共聚物。进一步将嵌段聚合物接上紫杉醇,制备出结构精确的抗肿瘤前药。并采用质子核磁共振(1H NMR)以及凝胶色谱仪(GPC)对其进行了表征。
3、采用荧光探针法测定了聚合物前药的临界胶束浓度(CMC),考察了其胶束化行为。
Controlled drug release is one of the most important tasks in pharmaceutics. Great progress has been made in this field, and many materials and systems have been developed to satisfy the requirements for controlled delivery of a variety of drugs. Prodrug is a new drug delivery system (DDS) based on polymer compounds. Its structure includes polymer carrier, active drug, spacer and targeting moiety. With the development of biodegradable polymers which are degradable, resorbable and metabolizable in human body without danger of accumulation, they have become the preferred candidates for DDS carriers. The candidates as carriers for drug delivery systems should include these advantages: excellent biocompatibility, the precise and well-defined structure, the low polydispersity.
The unique properties of dendrimers, such as their high degree of branching, globular architecture, multivalency, and well-defined molecular weight, make them promising new scaffolds for drug delivery. Dendrimers are a new class of high-efficiency nonbiological vectors with very broad application prospects in the pharmaceutical field. By the stepwise synthesis of dendrimers affords molecules with a highly regular stucture and a well-defined morphology, drug loading with a significant increase and the administration process with reflections in nano-scale. But because of the bad biocompatibility, toxicity and undegradability, the application of dendriemrs for drug delivery has been limited.
So a low toxicity and degradabable dendrimer from glycerol and glycolic acid oligomer was prepared, and it was well biodegradble because of the ester between the repit units.The conjugation of the well-defined MPEG to the dendrimer was to improve its biocompatibility, so a low toxicity, well-defined architecture, degradabable and excellent biocompatable drug carrier was prepared. The pharmacokinetics behavior could be controlled and changed by synthesis of the precise oligmers of glycolic acids with different repeat units; it is expected to be an excellent drug carrier candidate.
The dumbbell-shape dendrimers composed of glycerol and oligomers of glycolic acid and the polymeric micelle formed with amphiphilic MPEG-dendrimer as carrier were prepared. The preparation and characterization of dendrimers and amphiphilic block copolymers, the morphology and size of drug-loaded micelles were studied. The research was mainly concerned with the following aspects:
1.The precise oligomers of glycolic acid were synthesized by group protection methods. The protection was accomplished with tert-butyl- as the carboxyl protecting group.By using glycerol and oligomers of glycolic acid as templates, dendrimers with different generations were synthesized via a convergent method.At last,the third generation dumbbell-shape dendrimer based on sebacic acid as core and the convergent method was synthesized, and the structure was confirmed by 1H NMR.
2.The hydroxyl group of MPEG was converted into a carboxyl group by reacting with the diglycolic anhydride in the presence of dimethylaminopyridine (DMAP).The carboxyl-terminated MPEG-dendrimer was prepared by esterification using coupling agent dicyclohexyl carbodiimide (DCC) and the catalyst DMAP.Then the carboxyl-terminated MPEG-dendrimer was reacted with paclitaxel to prepare prodrugs. The products were confirmed by 1H NMR and GPC.
3.The micellization behavior of the MPEG-G3-paclitaxel prodrug was examined by using fluorescent probe technique to determinate critical micelle concentration (CMC).
树枝状大分子高支化度、球形外状、表面的多官能化和尺寸的精确可控性等都为其作为药物载体提供了得天独厚的条件。树枝状大分子是一类新型高效的非生物载体,在医药领域有着极为广阔的应用前景,通过化学合成可以使树枝状大分子具有精确的结构和形态,可以明显提高单分子药物载体的载药量,使得给药过程在纳米尺度上得到实现。但是,目前的树枝状大分子作为药物载体,存在着生物相容性较差,毒性大,不可降解等问题,限制了其应用。
我们设计了一种由丙三醇和羟基乙酸齐聚物等生物毒性低的材料组成的树枝状大分子,由于其中间以酯键相连接,具有良好的可降解性。将树枝状大分子键接上具有良好生物形容性和水溶性的PEG后,可以形成一种具有良好生物相容性、低的生物毒性、分子量分布较宰的和具有可降解性的药物载体。通过合成不同长度的羟基乙酸齐聚物,可以控制其药代动力学行为,期望其能作为一种优秀的药物载体。
本文设计制备了以丙三醇及羟基乙酸齐聚物为模版的哑铃型树枝状聚合物,及以聚乙二醇-树枝状大分子为载体的聚合物胶束给药系统。本论文对树枝状大分子、两亲性树枝状大分子聚合物的合成、表征,以及载药胶束的形态尺寸等都进行了研究。具体内容摘要如下:
1、采用基团保护的方法成功合成了结构精确可控的羟基乙酸齐聚物,其中以叔丁基作为羧基保护基团。以丙三醇和羟基乙酸齐聚物为模版,采用收敛法合成了不同代数的树枝状大分子。最后,以癸二酸为核,采用收敛法合成了三代的哑铃型树枝状大分子并采用质子核磁共振(1H NMR)对其结构进行了表征。
2、MPEG的端羟基与丁二酸酐在4,4'-二甲基氨基吡啶存在下反应,便得到端羧基的MPEG。以二环己基碳二亚胺(DCC)为缩合剂、4,4'-二甲基氨基吡啶(DMAP)作催化剂,制得了端基为羧基的聚乙二醇单甲醚-三代树枝状大分子两嵌段共聚物。进一步将嵌段聚合物接上紫杉醇,制备出结构精确的抗肿瘤前药。并采用质子核磁共振(1H NMR)以及凝胶色谱仪(GPC)对其进行了表征。
3、采用荧光探针法测定了聚合物前药的临界胶束浓度(CMC),考察了其胶束化行为。
Controlled drug release is one of the most important tasks in pharmaceutics. Great progress has been made in this field, and many materials and systems have been developed to satisfy the requirements for controlled delivery of a variety of drugs. Prodrug is a new drug delivery system (DDS) based on polymer compounds. Its structure includes polymer carrier, active drug, spacer and targeting moiety. With the development of biodegradable polymers which are degradable, resorbable and metabolizable in human body without danger of accumulation, they have become the preferred candidates for DDS carriers. The candidates as carriers for drug delivery systems should include these advantages: excellent biocompatibility, the precise and well-defined structure, the low polydispersity.
The unique properties of dendrimers, such as their high degree of branching, globular architecture, multivalency, and well-defined molecular weight, make them promising new scaffolds for drug delivery. Dendrimers are a new class of high-efficiency nonbiological vectors with very broad application prospects in the pharmaceutical field. By the stepwise synthesis of dendrimers affords molecules with a highly regular stucture and a well-defined morphology, drug loading with a significant increase and the administration process with reflections in nano-scale. But because of the bad biocompatibility, toxicity and undegradability, the application of dendriemrs for drug delivery has been limited.
So a low toxicity and degradabable dendrimer from glycerol and glycolic acid oligomer was prepared, and it was well biodegradble because of the ester between the repit units.The conjugation of the well-defined MPEG to the dendrimer was to improve its biocompatibility, so a low toxicity, well-defined architecture, degradabable and excellent biocompatable drug carrier was prepared. The pharmacokinetics behavior could be controlled and changed by synthesis of the precise oligmers of glycolic acids with different repeat units; it is expected to be an excellent drug carrier candidate.
The dumbbell-shape dendrimers composed of glycerol and oligomers of glycolic acid and the polymeric micelle formed with amphiphilic MPEG-dendrimer as carrier were prepared. The preparation and characterization of dendrimers and amphiphilic block copolymers, the morphology and size of drug-loaded micelles were studied. The research was mainly concerned with the following aspects:
1.The precise oligomers of glycolic acid were synthesized by group protection methods. The protection was accomplished with tert-butyl- as the carboxyl protecting group.By using glycerol and oligomers of glycolic acid as templates, dendrimers with different generations were synthesized via a convergent method.At last,the third generation dumbbell-shape dendrimer based on sebacic acid as core and the convergent method was synthesized, and the structure was confirmed by 1H NMR.
2.The hydroxyl group of MPEG was converted into a carboxyl group by reacting with the diglycolic anhydride in the presence of dimethylaminopyridine (DMAP).The carboxyl-terminated MPEG-dendrimer was prepared by esterification using coupling agent dicyclohexyl carbodiimide (DCC) and the catalyst DMAP.Then the carboxyl-terminated MPEG-dendrimer was reacted with paclitaxel to prepare prodrugs. The products were confirmed by 1H NMR and GPC.
3.The micellization behavior of the MPEG-G3-paclitaxel prodrug was examined by using fluorescent probe technique to determinate critical micelle concentration (CMC).
引文
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