摘要
通过水溶低聚乙二醇异腈(OEG-NC)与(E)-4-氧杂-2-丁烯酸的Passerini多组分聚合反应以及聚合物的氢化反应制备了两种新型的水溶性聚(4-羟基丁酸)衍生物.利用核磁共振(NMR)和凝胶渗透色谱详细研究了这两种聚合物在水溶液中的降解行为,结果表明,在37℃的磷酸缓冲溶液中(pD 7.4),聚合物的分子量随时间延长逐步下降,同时生成唯一的γ-丁内酯衍生物,其数量逐渐增加, 1 d后降解达到85%.进一步比较了它们在磷酸缓冲溶液(pD 6.8)及混合溶液(pD 7.4缓冲溶液/丙酮)中的降解行为,发现γ-丁内酯衍生物仍是唯一的降解产物,但由于降解环境pH或极性的降低,降解速度明显减慢.模拟聚合物的重复单元、端基以及降解产物结构,设计合成了三种模型小分子化合物,详细研究了它们在相同条件下的水解行为,证明实验条件下酯键不会发生无规水解断裂,确定了这类聚合物在磷酸缓冲溶液中的降解机理,聚合物首先以从头到尾内环化的方式快速解聚合为γ-丁内酯衍生物,随后该内酯化合物缓慢水解开环生成4-羟基丁酸盐类化合物.
Biodegradable aliphatic polyesters have been widely used in biomedical fields owing to their good biocompatibility. One big challenge is to precisely modulate their degradation rate and degradation products under physiological conditions. In this work, we designed and synthesized two types of poly(4-hydroxybutyric acid)derivatives that can quickly depolymerize via intramolecular cyclization into corresponding γ-butyrolactone derivatives under physiological conditions. The polymers were synthesized by the Passerini multicomponent polymerization of OEG-NC and ethyl(E)-4-oxo-but-2-enoate, followed by hydrogenation. Nuclear magnetic resonance(NMR) and gel permeation chromatography(GPC) were used to follow the degradation of these polyesters under physiological conditions(pD 7.4 buffer solution, 37 ℃). It was demonstrated that the molar mass of the polyester gradually decreased with time together with the increase of the amount of corresponding γ-butyrolactone derivatives as the only degradation product. After 1 d, 85% of the polyester was degraded. When the pH of the buffer was decreased to 6.8 or a mixture of buffer and acetone was used as the degradation media, the degradation was slowed down, but γ-butyrolactone derivatives are still the only degradation products, implying that increase of the medium polarity and pH can accelerate the degradation. Three small model molecules that mimic the polymer repeating unit, end group, and degradation product were synthesized and their hydrolysis were investigated under identical conditions. Based on these results, we confirm that under physiological conditions, no random degradation via hydrolysis of the polyester backbone occurred.The degradation mechanism was thus elucidated. The first step is the fast head-to-tail depolymerization of the polyester via intramolecular cyclization, forming γ-butyrolactone derivatives as the only products. Then, slow hydrolysis of γ-butyrolactone derivatives into 4-hydroxy butyrate occurred. This type of polyester is the first reported depolymerizable polyester with simple structure under physiological conditions. Our current efforts are end-capping these polymers with various stimuli-responsive functional groups to develop new self-immolative polymers that can be used in biomedical fields as drug carriers.
作者
阚晓伟
张丽晶
李昭玥
杜福胜
李子臣
Xiao-Wei Kan;Li-Jing Zhang;Zhao-Yue Li;Fu-Sheng Du;Zi-Chen Li(Beijing National Laboratory for Molecular Sciences,Key Laboratory of Polymer Chemistry and Physics of Ministry of Education,College of Chemistry and Molecular Engineering,Peking University,Beijing 100871,China)
出处
《中国科学:化学》
CAS
CSCD
北大核心
2020年第10期1449-1459,共11页
SCIENTIA SINICA Chimica
基金
国家重点研发计划(编号:2016YFA0201400)
国家自然科学基金(编号:21534001)资助项目。