Preparation And Properties Of Mixed Micelles Based On Imine Bonds

The mixed micelle drug carrier can improve the bioavailability of the drug,reduce the side effects of the drug,and achieve controlled release of the drug.In this paper,two kinds of mixed micelles based on dynamic acid-sensitive imine linkages with polyethylene glycol monomethyl ether（MPEG）and poly-N-vinylcaprolactam（PNVCL）mixed shells were designed and synthesized.The properties of two kinds of micelles on the encapsulation and release of doxorubicin（DOX）as well as their cytotoxicity were studied.MPEG has good hydrophilicity and biocompatibility,which can avoid phagocytosis of proteins during blood circulation and increase the chance of drugs reaching the lesion.When the temperature-responsive segment PNVCL was in the extended state,the micelles had a core-shell structure,which can realize the entrapment of the drug.When the PNVCL collapses,the micelle becomes a core-shell-crown structure,which improves the stability of the mixed micelles and reduces the drug toxicity.The pH-sensitive imine bonds between the core and the shell enable intelligent release of the drug.The results showed that the mixed micelles drug carrier prepared in this paper has stimuli-responsive,and the release rate could be adjusted by the ratio of MPEG and PNVCL in the mixed shell.It had good biocompatibility and was easy to enter the cell interior.It was a mixed micelles drug carrier with application prospect.The contents are as follows:1.Mercaptoethanol（HSCH₂CH₂OH）aschaintransferagent,azobisisobutyronitrile（AIBN）initiated polymerization of vinyl caprolactam（NVCL）,and the resulting polymer hydroxyl-terminated N-vinylcaprolactam（PNVCL-OH）reacted with 4-hydroxybenzaldehyde to synthesize the poly（N-vinylcaprolactam）（PNVCL-CHO）.MPEG and 4-hydroxybenzaldehyde were used to synthesize hydroxyl-terminated polyethylene glycol（MPEG-CHO）.Stannous octoate was used as catalyst and N-（tert-butoxycarbonyl）ethanolamine is used as initiator to trigger the ring-opening polymerization of D,L lactide andε-caprolactone respectively.Then the tert-butoxycarbonyl polylactic acid（PCL-NHBoc）and tert-butoxycarbonyl polycaprolactone（PLA-NHBoc）were obtained.Then both of them were treated with trifluoroacetic acid to remove the protecting group to obtain the polymer amino-terminated polycaprolactone（PCL-NH₂）and the polymer amino-terminated polylactic acid（PLA-NH₂）.By the reaction of amino group and aldehyde group,PNVCL-CHO,MPEG-CHO,PCL-NH₂ and PLA-NH₂ were used to synthesize polyethylene glycol-b-polycaprolactone（MPEG-b-PCL）,poly N-vinylcaprolactam-b-polylactic acid（PNVCL-b-PLA）and polyethylene glycol-b-Polylactic acid（MPEG-b-PLA）.Results showed that PNVCL-b-PCL and PNVCL-b-PLA are temperature sensitive.2.The copolymers PNVCL-b-PCL and MPEG-b-PCL were self-assembled in aqueous solution to form mixed shell micelles in which PCL was hydrophobic core and PNVCL was hydrophilic shell.At the same time,copolymers PNVCL-b-PLA and MPEG-b-PLA in aqueous solution were self-assembled to form mixed micelles which PLA was hydrophobic core and PNVCL was hydrophilic shell.The morphology of the micelles was characterized by transmission electron microscopy（TEM）and the results were shown to be spherical.The results of drug-loading experiments showed that the mixed micelles had temperature/pH dual responsiveness.The results of encapsulation and release of doxorubicin showed that the release rate of mixed micelles in acidic environment（pH=5.0）was much higher than that in neutral environment（pH=7.4）.In a neutral environment of pH=7.4,the release rate at 25°C is higher than the release rate at 37°C.Changing the ratio of MPEG to PNVCL in the hybrid shell could change the release rate of the drug.MTT experiments showed that the two mixed micelles systems were less toxic to BGC-823 cells,and in vitro endocytosis experiments showed that the micelles can easily enter the cells.