温度/pH响应性MPEG-b-PCL/PNVCL-b-PCL共聚物复合胶束的制备及载药性质

以基于亚胺键的嵌段共聚物为构筑单元的温度/pH响应性共聚物复合胶束(CMs), 由于具有亚胺键和核-壳-冠结构, 表现出较高的灵敏度和稳定性. 以聚乙二醇单甲醚(MPEG)、 N-乙烯基己内酰胺(NVCL)和ε-己内酯(ε-CL)为原料, 分别制备了端醛基聚乙二醇单甲醚(MPEG-CHO)、 端醛基聚N-乙烯基己内酰胺(PNVCL-CHO)和端氨基聚己内酯(H₂N-PCL), 利用希夫碱反应, 进一步制备了基于亚胺键的聚乙二醇单甲醚-b-聚己内酯(MPEG-b-PCL)和聚N-乙烯基己内酰胺-b-聚己内酯(PNVCL-b-PCL)嵌段共聚物, 对共聚物结构进行了确认. 以MPEG-b-PCL和PNVCL-b-PCL为构筑单元, 制备了共聚物复合胶束, 研究了复合胶束对阿霉素的包载、 释放性质和细胞毒性等. 研究结果表明, 室温下MPEG-b-PCL和PNVCL-b-PCL能够在水中自组装形成以PCL为核、 MPEG和PNVCL为混合壳的共聚物复合胶束, 在生理温度下, 温敏性PNVCL链段发生相变塌缩在PCL核表面, 能够防止药物扩散释放, 亲水性MPEG链段形成可控通道. 药物体外释放结果表明, 在弱酸性环境中, 亚胺键能够断裂, 胶束被破坏, 促进药物的释放, 噻唑蓝(MTT)实验表明, 复合胶束的细胞毒性较低.

Preparation and Drug Delivery Properties of Thermo/pH Dual Responsive Copolymer Composite Micelles of MPEG-b-PCL/PNVCL-b-PCL

Thermo/pH dual responsive copolymer composite micelles（CMs） based on the block copolymers with imine bonds show higher sensitivity and stability due to their imine linkage and core-shell-crown three la-yer structure. Using polyethylene glycol monomethyl ether（MPEG）， N-vinyl caprolactam（NVCL） and ε-caprolactone（ε-CL） as raw materials， the aldehyde-terminated poly（ethylene glycol） monomethyl ether（MPEG-CHO）， aldehyde-terminated poly（N-vinylcaprolactam）（PNVCL-CHO） and amino-terminated polycaprolactone（H₂N-PCL） were prepared respectively. Block copolymers， poly（ethylene glycol） monomethyl ether-b-poly（ε-caprolactone）（MPEG-b-PCL） and poly（N-vinylcaprolactam）-b-poly（ε-caprolactone） （PNVCL-b-PCL） based on imine bond， were synthesized by reaction of H₂N-PCL with MPEG-CHO and PNVCL-CHO. At room temperature， MPEG-b-PCL and PNVCL-b-PCL self-assembled to form CMs with PCL as the core and MPEG/PNVCL as the mixed shell in water. At the physiological temperature， thermo-responsive PNVCL collapsed on the PCL core， while MPEG still stretched to form core-shell-corona micelles， which might protect the drug encapsulated in the core. Studies on the in vitro drug release showed that a much faster release rate was observed at slightly acidic media， due to the disruption of imine bonds. 3-（4，5）-Dimethylthiahiazo（-z-y1）-3，5-di-phenytetrazoliumromide（MTT） assay demonstrated the low cytotoxicity of the composite micelles.