Study On The Synthesis And Properties Of Linear And Star-shaped Temperature-sensitive Block Copolymers Based On PCL/PEG Polymers

Stimuli-responsive polymers have important research value in gene delivery,tissue engineering,artificial muscle’s and biomarkers and other fields.Among them,temperature-sensitive polymers are considered as a kind of important stimuli-responsive polymers due to their ability to respond to the physiological temperature of the human body.Micelles and physical gels formed from their polymers are widely used in drug delivery and tissue Engineering.Polycaprolactone(PCL)is a hydrophobic polymer with good biocompatibility and biodegradability and harmless to the human body and its degradation products do not lead to acid environment.The hydrophobic chain of PCL is modified with hydrophilic chain modifications to obtain amphiphilic block polymers containing hydrophobic PCL blocks as cores and hydrophilic blocks as shells in aqueous solution,which improved PCL-based polymers are advantageous for drug delivery systems,enabling the hydrophobic drug to be wrapped in the hydrophobic PCL core,allowing rapid and effective drug delivery and cellular targeting in the human body.The PEG analogues poly 2-(2-methoxyethoxy)ethyl methacrylate(PMEO2MA)and polyoligo(ethylene glycol)methyl ether methacrylate(POEGMA)as new members of the temperature sensitive family have aroused widespread concern,MEO2MA and OEGMA can be randomly composed of copolymer P(MEO2MA-co-OEGMA).The low critical solution temperature(LCST)values of PMEO2MA and POEGMA are 26 ℃ and 90 ℃,respectively.The LCST value of the copolymers can be adjusted accurately between 26 ℃ and 90 ℃ by changing the comonomer feed ratio.Copolymer P(MEO2MA-co-OEGMA)has been widely studied due to its great temperature responsiveness,good hydrophilicity,outstanding biocompatibility and non-toxicity,and is attractive for targeted drug delivery and other fields.In this paper,two types of temperature responsive block polymers have been designed and synthesized by using hydrophobic PCL,hydrophilic and temperature-sensitive P(MEO2MA-co-OEGMA)with biocompatibility.Two types of thermo-sensitive block polymers,the linear polymer L-PCL-P(MEO2MA-co-OEGMA)and the star-shape copolymer S-PCL-P(MEO2MA-co-OEGMA)were designed and synthesized by ring-opening polymerization(ROP)and reversible addition-fragmentation chain transfer radical polymerization(RAFT),which the aqueous solution properties of the polymer,micellization and the release behavior of the drug loaded micelles were emphatically studied.Specific work is as follows:1.Well-defined novel linear biodegradable amphiphilic thermo-responsive block copolymers L-PCL-P(MEO2MA-co-OEGMA)(tBPs),were synthesized via a combination of ROP and RAFT.The successful synthesis of linear block copolymers was characterized using Fourier transform infrared spectroscopy(FT-IR),proton nuclear magnetic resonance(1H NMR)and gel permeation chromatography(GPC).The water solubility and low critical solution temperature(LCST)of the copolymer were studied by digital photo and transmittance measurement.The micelles of self-assembly thermo-responsive of the amphiphilic block copolymers were obtained in water medium and the self-assembly behaviors of amphiphilic linear block copolymers were investigated by a fluorescence probe method,dynamic light scattering(DLS)and transmission electron microscopy(TEM)analyses.A hydrophobic drug,anethole,was encapsulated in micelles by using dialysis method.The average particle sizes of drug loaded micelles were determined by dynamic light scattering measurement.In vitro the sustained release of the anethole was performed in pH=7.4 PBS at different temperatures.Results showed that the linear block copolymers micelles were quite effective in the encapsulation and controlled release of anethole.The sol-gel transition behavior of linear block copolymers under temperature induction was observed by vial inversion test.All these results indicate that the linear block copolymers have good temperature sensitivity and have great potential in medicine as potential carriers for hydrophobic drugs.2.A novel biodegradable amphiphilic temperature responsive four-armed star-shape block copolymer S-PCL-P(MEO2MA-co-OEGMA)(sBPs)was synthesized ROP and RAFT.The successful synthesis of star-shaped block copolymers was characterized using 1H NMR,FT-IR and GPC.The thermal sensitivity and reversible behavior of the polymer were investigated by transmittance test.The micellization behavior of the block copolymers was studied by CMC and DLS analyze.The morphology of the micelles was observed by TEM.The hydrophobic drug anethole was encapsulated in micelles by dialysis.The average diameter of drug-loaded micelles was determined by DLS.In vitro,the cumulative release of anethole from drug-loaded micelles in pH=7.4 and pH=5.5 PBS were determined respectively,and the results showed that the star-shaped block copolymers micelles could effectively encapsulate and release the anethole.All these results showed that the temperature-responsive star-shaped block copolymers micelles are expected to be applied in biomedicine and clinical medicine as an efficient drug carrier.