新型两亲性分子的合成及作为药物载体的初步研究

Preliminary study on synthesis of novel amphiphilic molecules and their application as drug vectors

目的:合成三分枝低聚乙二醇(TEG)为亲水部分和分别以6个碳(R1),8个碳(R2),12个碳(R3)的脂肪链为疏水部分的3种两亲性分子(TEG-R1,TEG-R2,TEG-R3),并对其作为难溶性药物载体进行研究。方法:通过苯磺酰化、取代反应、还原反应、酯化后形成酰胺成功合成3个化合物,通过核磁进行结构表征,应用芘荧光探针法进行临界胶束浓度的测定,透射电镜观察其自组装形态。自组装溶剂蒸发法制备载药鬼臼毒素胶束,对载药胶束进行粒径表征,并考察3种两亲性分子的溶血性。结果:核磁证明3种两亲性分子均成功合成,TEG-R1,TEG-R2,TEG-R3的临界胶束浓度分别为50,50,10mg·L-1。电镜观察呈20～50nm的类球形状态。3种两亲性分子均能制备成载药胶束且粒径分布在100～200nm。溶血性实验证明接枝6碳脂肪链的两亲性分子中TEG-R1不会引起溶血。结论:3种两亲性分子在水溶液中均具有胶束化行为,且均能作为难溶性药物载体;其中TEG-R1不会引起溶血有望成为新型的药物载体。

Objective： To synthesize three amphiphilic molecules （TEG-R1, TEG-R2, TEG-R3 ）, with branched oligo polyethylene glycol as hydrophilic fractions and aliphatic chains （containing six, eight and twelve carbon atoms respectively） as hydrophobic fractions, and study them as insoluble drug vectors. Method： Three compounds were successfully through acylation, substitution reaction, reduction reaction and esterification. Their structures were verified by NMR analysis; and the critical micelle concentrations （CMC） of TEG-R1 , TEG-R2, TEG-R3 were determined by pyrene fluorescence probe spectrometry. Transmission electronic microsco- py （TEM） photos displayed the state of the aqueous solution. The self-assembly solution evaporation method was adopted to prepare drug loading podophyllotoxin mieelles, and characterize their grain size, in order to detect the hemolysis of the three amphiphilic mole- cules. Result： Nuclear magnetism showed the successful synthesis of three amphiphilic molecules, with critical micelle concentrations of TEG-R1, TEG-R2, TEG-R3 of 50, 50, 10 mg · L -1, respectively. Transmission electronic microscopy （TEM） photos displayed a spherical-like state, with diameter of 20-50 rim. All of the three amphiphilic molecules could be prepared into drug-loading micelles, with the range of grain sizes between 100-200 nm. Hemdytic experiment showed that, among the amphiphilic molecules of the graft sixcarbon aliphatic chain, TEG-R1 could not cause hemolysis. Conclusion： All of the three amphiphilic molecules are micellized in water solution, and can be used as insoluble drug vectors. Among them, TEG-R1 could not cause hemolysis, and is expected to become a new-type drug vector.