Thermo-sensitive N-isopropyl Acrylamide Block Copolymers Prepared By RAFT Polymerization And Their Appliations

Micelles and nanoparticles prepared by self-assembly of thermo-sensitive block copolymers have many excellent properties such as nano-size effect etc.,and have a wide range of potential applications in controlled drug release and other fields.In this thesis,block copolymers of N-isopropyl acrylamide(NIPAM)and hydrophobic monomers were prepared by reversible addition-fragmentation chain transfer polymerization(RAFT).The obtained copolymers were diluted in aqueous solutions to prepare thermo-sensitive nanoparticles or micelles,and their potential applications in controlled drug release were investigated.Using S,S'-bis(?,?'-dimethyl-?"-acetic acid)-trithiocarbonate(BDAAT)as RAFT agents,stearyl methacrylate(SMA)homopolymers(the macromolecular RAFT reagents required for subsequent reactions)were synthesized.The effects of temperature and theoretical molecular weight on the polymerization reaction were systematically studied,and the kinetics of the polymerization reaction process was analyzed.What's more,the relationship between reaction rates and temperature and molecular weight was analyzed by Arrhenius equation.RAFT polymerization could well control the SMA homo-polymerization reaction,and PSMA homopolymers of pre-determined molecular weight were obtained.The initial stage of the reactions followed first-order reaction kinetics law,and molecular weight distribution could be lowered by increasing temperature.In the condition of obtaining targeted and narrowly distributed polymers,the temperature for the subsequent RAFT solution polymerization to prepare block copolymers of NIP AM and SMA was determined to be 70?C.At the suitable reaction temperature,two kinds of PSMA-b-PNIPAM thermo-sensitive block copolymers were synthesized by RAFT polymerization.They had different chemical structures and terminal groups:one was diblock copolymers with hydrophobic terminal groups,and the other one was triblock copolymers with hydrophilic terminal groups.They self-assembled into stable micelles in aqueous solutions.The chemical structure of the obtained polymers was characterized by nuclear magnetic resonance proton spectrum and carbon spectrum,and it was confirmed that the obtained products were strict block copolymers.RAFT polymerization could well regulate the synthesis of NIP AM and SMA block copolymers.PSMA-b-PNIPAM block copolymers could undergo jmicrophase separation in selective solvents,and the micelles obtained by their self-assembly were spherical particles with thermo-sensitivity.The diameters of the micelles decreased with increasing temperature.The hydrophobic chain segment PSMA and hydrophobic terminal groups made the lower critical solution temperature(LCST)of the diblock copolymers lower than that of the PNIPAM homopolymer;while the hydrophilic terminal groups and hydrophobic chain segment of the triblock copolymer had opposite effects on the LCST.The LCST of the triblock copolymers was close to that of the PNIPAM homopolymer.The hydrophobic drug ibuprofen and the hydrophilic drug procaine were loaded into PSMA-b-PNIPAM block copolymer micelles to investigate the drug loading efficiency of the micelles and the controlled release of the two drugs.The two drugs not only interacted with the PSMA-b-PNIPAM block copolymer micelles,but also interacted with each other.In the case that the two drugs were loaded separately,when the temperature was lower than the LCST of the micelles,the drug loading efficiency of the hydrophilic drug procaine was higher;when the temperature was higher than the LCST of the micelles,the drug loading efficiency of the hydrophobic drug ibuprofen was higher.When both drugs were loaded at the same time,the drug loading efficiency decreased.By changing conditions such as temperature,PSMA-b-PNIPAM micelles could achieve controlled release of hydrophilic and hydrophobic drugs.In order to further increase drug loading efficiency of hydrophilic drugs and better control the release of drugs,PSMA-b-PNIPAM injectable hydrogels were prepared in situ by RAFT emulsion polymerization.By changing the initial contents of oil phase,the state of the PSMA-b-PNIPAM emulsion could be adjusted,and the phase transition of the sample from liquid to solid could be achieved.With the increase of the initial contents of oil phase,the latex particles gradually aggregated together from single spherical particles,the fluidity of the emulsion became weaker,and the emulsion gradually transformed from emulsion to gel.When the temperature was higher than the LCST of the samples,the PNIPAM chain segment became hydrophobic,phase separation took place and the gel shrunk to squeeze out the water,at the same time the procaine dissolved in the water was released.When the temperature was lower than the LCST of the samples,less than 10%of the procaine was released;when the temperature was raised above the LCST of the samples,approximately 50-60%of the procaine was released.It was confirmed that PSMA-b-PNIPAM injectable hydrogels could well control the release of procaine,and play a role of "switch".In addition,3-methacryloxypropyl trimethoxy silane(MPS)was introduced into the PNIPAM temperature-sensitive block copolymer systems to prepare organic-inorganic silicon-containing nanoparticles.Targeted molecular weight PMPS-b-PNIPAM block copolymers were prepared in an anhydrous and anaerobic environment by RAFT living polymerization,and the molecular weight distribution was narrow.The longer the PNIPAM chain segment in the block copolymers,the easier it was to form nanoparticles;and under different pH conditions,it was easier to form nanoparticles in alkaline environments than in acidic environments.Both the acidic and alkaline environments could reduce the LCST of the PMPS-b-PNIPAM block copolymers;however,the alkaline environments would reduce the temperature sensitivity,and the acidic environments would enhance it.