Synthesis And Properties Of PLLA-based Temperature/reduction-responsive Single- And Double-end Triblock Polymers

In recent years,amphiphilic polymers composed of hydrophobic and hydrophilic segments are considered to be effective structural units for constructing self-assembled micelle nano-aggregates,which can be used in medicine and materials science applications.For example,they can be used as bone fixation implants,tissue scaffolds and nano-scale anti-tumor carriers.Particularly,polylactic acid(PLA)is a promising class of hydrophobic aliphatic polyesters of biodegradable hydroxyalkanoic acid,with excellent bioabsorbability and compatibility,and has been approved by the FDA for clinical use.These unique properties make PLA-based polymers have a wide range of applications in the biomedical field including sutures.The PLA have three kinds of isomers,namely L-polylactic acid(PLLA),D-polylactic acid(PDLA),and D,L-polylactic acid(PDLLA).PLLA and PDLA are semicrystalline polymers with good mechanical strength and are the main raw materials for the synthesis of hydrophobic segments of amphiphilic polymer.In all stimulus responsive monomers,the hydrophilic polyethylene glycol analogue,namely the oligomer ethylene glycol methyl ether methacrylate P(MEO2MA-co-OEGMA),has appealed to widespread attention because of its advantages in temperature sensitivity,water solubility,and biocompatibility.In addition,the suitable low critical solution temperature(LCST)of random polymer P(MEO2MA-co-OEGMA)can be adjusted the physiological temperature of the human body by controlling the content of OEGMA.What's more,since the concentration of reductive glutathione thioprotein(GSH,a cysteine-containing tripeptide)in tumor cells is 100-1000 fold that of normal cells,the disulfide bonds can be cleaved easily to form sulfhydryl groups by reducing agents.Therefore,in the design of nanocarriers,reducing functionalized disulfide bonds and other stimulus-responsive monomers(temperature,pH,light,etc.)are introduced to form the reduced polymers with multiple stimulus responsiveness,which are used to study the multifunctional controlled release behavior of drugs.According to the above research conditions,PLLA with good biocompatibility and the reducing substance 2,2'-dithiodiethanol(SS-DOH)are selected as the hydrophobic segment,and the temperature-sensitive homopolymer P(MEO2MA-co-OEGMA)is used as a hydrophilic segment in this work.Then,two double-end and single-end triblock high molecular copolymers with temperature-reduction dual stimulus response were designed and synthesized using ring-opening polymerization(ROP)and atom transfer radical polymerization(ATRP)technology.The specific work are as follows:1.The temperature/reduction dual stimulus response type double-end triblock copolymer,which are composed of PLLA-SS-PLLA containing disulfide bonds as the hydrophobic segment and P(MEO2MA-co-OEGMA)as the hydrophilic segment P(MEO2MA-co-OEGMA)-b-PLLA-SS-PLLA-b-P(MEO2MA-co-OEGMA)(SPMO)is designed and synthesized via ROP and ATRP technology.The successful synthesis of SPMO was proved by proton nuclear magnetic resonance spectroscopy(1H NMR)and Fourier transform infrared spectroscopy(FTIR).The test of size exclusive chromatography(SEC)shows that the polymer with a certain degree of polymerization has been successfully synthesized and proved to have a relatively narrow molecular weight distribution coefficient(DM ?1.50).The water solubility and transmittance of the polymers were tested by digital photos and UV-Vis spectrophotometer,which proved the SPMO had good hydrophilicity and suitable low critical solution temperature(LCST).Using surface tension method and fluorescent probe technology to determine the critical micelle concentration(CMC)of the polymeric micelles.Dynamic light scattering(DLS)and transmission electron microscopy(TEM)were used to characterize the particle size and morphology.The vial flip experiments was used to study the sol-gel(Sol-Gel)transition behavior of the polymers.Lastly,the hydrophobic anticancer drug doxorubicin(DOX)was used to research the in vitro release behavior of the drug-loaded micelles.The results show that the synthesized temperature/reduction responsive double-end triblock polymeric micelles can be used as a favorable drug carrier.In addition,they exhibit reductive responsiveness in the presence of the reducing agent glutathione(GSH)or the small molecule reducing agent dithiothreitol(DTT)and temperature responsiveness with temperature changes.2.The temperature/reduction dual stimulus response type single-end triblock copolymer,which are composed of PLLA-SS-containing disulfide bonds as the hydrophobic segment and P(MEO2MA-co-OEGMA)as the hydrophilic segment PLLA-SS-b-P(MEO2MA-co-OEGMA)(ST)is designed and synthesized via ROP and ATRP technology.The 1H NMR and FTIR proved the successful synthesis of the amphiphilic single-ended polymer ST.The SEC test proves that the single-ended polymer has a relatively narrow molecular weight distribution coefficient.The water solubility and light transmittance of the polymer were tested by digital photos and UV-Vis spectrophotometer,which proved that the single-ended polymer had better hydrophilicity and more suitable LCST value.The CMC value of the single-ended polymeric micelles were measured using fluorescent probe technology.DLS and TEM were used to characterize the particle size and morphology of polymeric micelles.Finally,the anticancer drug DOX was used to research the in vitro release behavior of the drug-loaded micelles.The results show that synthesized single-ended triblock polymeric micelles can be expected to become a favorable drug carrier.