可降解形状记忆交联聚酯网络合成及在药物缓释中的应用
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摘要
可降解形状记忆聚合物具有良好的机械性能、可降解性、形状记忆性等性能,在高分子医用材料领域有着广泛的应用前景(例如,手术缝合线、药物释放载体、支架等),已成为近年来研究的热点。本文合成了几种生物相容形状记忆聚氨酯或聚酯材料,并研究了材料的降解和药物缓释性能。
分别以乙醇酸和D,L-乳酸为原料,合成了乙交酯和丙交酯,其中丙交酯、乙交酯的产率分别超过55%和50%。再以乙交酯、丙交酯为原料,季戊四醇为引发剂,二丁基氧化锡(DBTO)或者辛酸亚锡(Sn(oct)2)为催化剂,开环聚合得到了一系列不同分子量和乙交酯含量的星形丙交酯/乙交酯共聚物(PLGA)。采用羟基滴定、FTIR、GPC、1HNMR等方法对合成的PLGA进行了表征。
PLGA与异氰酸酯反应得到了交联结构的无定型聚酯型聚氨酯材料(PU)。PU具有良好的形状记忆性能和机械强度,但是材料的亲水性和韧性相对较差。PU的转变温度(Ttrans)在一定程度上,可以通过改变PLGA相对分子质量或者乙交酯来调节。
合成了聚乙二醇双甲基丙烯酸酯(PEGDMA)和聚酯PLGA聚氨酯无定型互穿网络形状记忆聚合物材料。通过调节PEGDMA的含量,可以方便地调节形状记忆材料的Ttrans和亲水性来适用特殊潜在的医学和临床需要。
PLGA与丙烯酰氯反应得到了星型双键封端的PLGA大分子单体(PLGATA),并与PEGDMA在紫外光引发下,合成了具有良好形状记忆性能的材料(LP),不仅提高了材料的亲水性,而且材料的Ttrans也可以方便的调节。
PU材料在PBS溶液的降解结果表明:PU材料的降解过程大致可分为两个阶段:诱导期和加速期。材料的质量损失率和吸水率在诱导期缓慢增加;在加速期迅速增加。
负载模型药物阿司匹林(ASP)/地塞米松(DEX)形状记忆材料的体外释放结果表明:两种药物的释放都是扩散控制和降解控制两种机制共同作用的结果。但由于ASP呈酸性,导致体外释放过程相对较短,只有20天左右;而DEX释放过程则达120天左右,和没有负载药物的PU相比,材料的降解速度显著加快。
Biodegradable shape-memory polymers have been extensively investigated, which have excellent properties, such as good mechanical properties, and multifunctionalities, etc. They have drawn increasing attention as their potential applications for medical materials, such as surgical sutures, drug delivery carriers and scaffolds, etc. In this thesis, several kinds of biodegradable polyurethanes or polyesters with good shape-memory effect are synthesized. The degradation and drug release behaviors of these biodegradable networks are also studied.
Star-shaped oligo[(D,L-lactide)-co-glycolide] (PLGA) with different number-average molecular weights and glycolide content is synthesized through ring-opening polymerization of D,L-lactide and glycolide with dibutyl tin oxide (DBTO) or Stannous octoate (Sn(oct)2) as catalyst and pentaerythritol as an initiator. The obtained oligomers are characterized by hydroxy titration, Fourier transform infrared spectrometry (FTIR), gel permeation chromatography (GPC) and 1H proton nuclear magnetic resonance (1HNMR).
Biodegradable, amorphous polyesterurethanes (PU) are synthesized by the coupling reaction of PLGA and diisocyanate, which have good shape-memory and mechanical properties. But the hydrophilicity and toughness are very poor. The transition temperatures (Ttrans) of PU can be adjusted by changing the molecular weights and compositions of the PLGA.
Polyesterurethane/poly(ethylene glycol) dimethacrylate (PEGDMA) interpenetrating networks materials (IPNs) with shape-memory properties are synthesized. The hydrophilicity and transition temperatures of IPNs can be conveniently adjusted through variation of network compositions to match the promising potential clinical or medical applications.
Poly[(D,L-lactide)-co-glycolide] tetracrylate (PLGATA) is synthesized by PLGA and acrylic chloride. Shape-memory polyester materials (LP) are obtained through photopolymerization of PLGATA and PEGDMA. The hydrophilicity and Ttrans of LP can be conveniently adjusted.
The degradation behavior of the PU is investigated in PBS solution. The degradation process can be approximately divided into two phases: the induction course and the acceleration course. The water uptake and weight loss of PU samples increase slowly in the induction course and increase significantly in acceleration course.
The release behavior of model drug aspirin (ASP) and dexamethasone (DEX) from biodegradable polyesterurethane networks is also studied. The release result exhibits a typical erosion-controlled release mechanism, which is combined effect of degradation and diffusion. The drug release course of ASP from PU networks is shorter than from DEX for the acidity of ASP. The release course of ASP last about 20 days and it is 120 days for DEX. The degradation course of drug-loaded materials is accelerated faster than those of drug-free materials.
分别以乙醇酸和D,L-乳酸为原料,合成了乙交酯和丙交酯,其中丙交酯、乙交酯的产率分别超过55%和50%。再以乙交酯、丙交酯为原料,季戊四醇为引发剂,二丁基氧化锡(DBTO)或者辛酸亚锡(Sn(oct)2)为催化剂,开环聚合得到了一系列不同分子量和乙交酯含量的星形丙交酯/乙交酯共聚物(PLGA)。采用羟基滴定、FTIR、GPC、1HNMR等方法对合成的PLGA进行了表征。
PLGA与异氰酸酯反应得到了交联结构的无定型聚酯型聚氨酯材料(PU)。PU具有良好的形状记忆性能和机械强度,但是材料的亲水性和韧性相对较差。PU的转变温度(Ttrans)在一定程度上,可以通过改变PLGA相对分子质量或者乙交酯来调节。
合成了聚乙二醇双甲基丙烯酸酯(PEGDMA)和聚酯PLGA聚氨酯无定型互穿网络形状记忆聚合物材料。通过调节PEGDMA的含量,可以方便地调节形状记忆材料的Ttrans和亲水性来适用特殊潜在的医学和临床需要。
PLGA与丙烯酰氯反应得到了星型双键封端的PLGA大分子单体(PLGATA),并与PEGDMA在紫外光引发下,合成了具有良好形状记忆性能的材料(LP),不仅提高了材料的亲水性,而且材料的Ttrans也可以方便的调节。
PU材料在PBS溶液的降解结果表明:PU材料的降解过程大致可分为两个阶段:诱导期和加速期。材料的质量损失率和吸水率在诱导期缓慢增加;在加速期迅速增加。
负载模型药物阿司匹林(ASP)/地塞米松(DEX)形状记忆材料的体外释放结果表明:两种药物的释放都是扩散控制和降解控制两种机制共同作用的结果。但由于ASP呈酸性,导致体外释放过程相对较短,只有20天左右;而DEX释放过程则达120天左右,和没有负载药物的PU相比,材料的降解速度显著加快。
Biodegradable shape-memory polymers have been extensively investigated, which have excellent properties, such as good mechanical properties, and multifunctionalities, etc. They have drawn increasing attention as their potential applications for medical materials, such as surgical sutures, drug delivery carriers and scaffolds, etc. In this thesis, several kinds of biodegradable polyurethanes or polyesters with good shape-memory effect are synthesized. The degradation and drug release behaviors of these biodegradable networks are also studied.
Star-shaped oligo[(D,L-lactide)-co-glycolide] (PLGA) with different number-average molecular weights and glycolide content is synthesized through ring-opening polymerization of D,L-lactide and glycolide with dibutyl tin oxide (DBTO) or Stannous octoate (Sn(oct)2) as catalyst and pentaerythritol as an initiator. The obtained oligomers are characterized by hydroxy titration, Fourier transform infrared spectrometry (FTIR), gel permeation chromatography (GPC) and 1H proton nuclear magnetic resonance (1HNMR).
Biodegradable, amorphous polyesterurethanes (PU) are synthesized by the coupling reaction of PLGA and diisocyanate, which have good shape-memory and mechanical properties. But the hydrophilicity and toughness are very poor. The transition temperatures (Ttrans) of PU can be adjusted by changing the molecular weights and compositions of the PLGA.
Polyesterurethane/poly(ethylene glycol) dimethacrylate (PEGDMA) interpenetrating networks materials (IPNs) with shape-memory properties are synthesized. The hydrophilicity and transition temperatures of IPNs can be conveniently adjusted through variation of network compositions to match the promising potential clinical or medical applications.
Poly[(D,L-lactide)-co-glycolide] tetracrylate (PLGATA) is synthesized by PLGA and acrylic chloride. Shape-memory polyester materials (LP) are obtained through photopolymerization of PLGATA and PEGDMA. The hydrophilicity and Ttrans of LP can be conveniently adjusted.
The degradation behavior of the PU is investigated in PBS solution. The degradation process can be approximately divided into two phases: the induction course and the acceleration course. The water uptake and weight loss of PU samples increase slowly in the induction course and increase significantly in acceleration course.
The release behavior of model drug aspirin (ASP) and dexamethasone (DEX) from biodegradable polyesterurethane networks is also studied. The release result exhibits a typical erosion-controlled release mechanism, which is combined effect of degradation and diffusion. The drug release course of ASP from PU networks is shorter than from DEX for the acidity of ASP. The release course of ASP last about 20 days and it is 120 days for DEX. The degradation course of drug-loaded materials is accelerated faster than those of drug-free materials.
引文
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