Preparation And Characterization Of Amphiphilic Star-shaped Copolymers And Properties Of Their Drug-load Micelles

Amphiphilic star-shaped copolymers tended to self-assemble into core-shell micelles with a hydrophobic core and a hydrophilic outer surface in aqueous solution.The core-shell structure of such assemblies was ideally suited to the biomedical applications such as controlled drug delivery.Compared to the linear copolymers,amphiphilic star-shaped copolymers have a smaller fluid mechanics volume and lower viscosity radius which can improve the bioavailability of drugs.In consequence,amphiphilic star-shaped copolymers had been widely studied.In the present study,the star-shaped PLLA was synthesized by ring-opening polymerization of L-lactide in the presence of sorbitol,xylitol and erythritol as initiator,severally.With the hydrophilic base reunite glycol(PEG),polyvinylpyrrolidone(PVP)and polyethylene glycol 1000 vitamin E succinate(TPGS)were grafted to the s-PLLA that preparation into amphiphilic star-shaped copolymers of 4s-PLLA-PEG,5s-PLLA-PVP and 6s-PLLA-TPGS,respectively.Then,ibuprofen(IBU),rifampicin(RIF)and indomethacin(IMC)regarded as hydrophobic model drug were hermeticed in the micelles of 4s-PLLA-PEG,5s-PLLA-PVP and 6s-PLLA-TPGS via dialysis method,respectively.The main content was structured as follows:(1)Preparation and characterization of four-arm amphiphilic s-PLLA-PEG copolymers and properties of their drug-load micellesThe four-arm star-shaped poly(L-lactide)(4s-PLLA)was prepared by ROP of erythritol as the core and Sn(Oct)2 as the catalyst.The star-shaped PLLA-PEG copolymer was synthesized using esterification reaction between of PEG-OH and s-PLLA-COOH.Then,ibuprofen,as a hydrophobic model drug,was encapsulated into the 4s-PLLA-PEG micelles via dialysis method.The crystallization property and thermal properties of the 4s-PLLA-PEG copolymers were adjusted by changing Mw of PEG;and the drug loading capacity(LC),drug encapsulation efficiency(EE),particle size,particle size distribution and in vitro release behavior of 4s-PLLA-PEG/IBU micelles were characterized by employing vltraviolet-visible spectroscopy(UVS),laser particle analyzer and TEM.The results shown that changing the molecular weight Mw of PEG can control the average diameters of 4s-PLLA-PEG micelles between 105 nm and 121 nm,and and the LC and EE of the 4s-PLLA-PEG/IBU micelles were controlled as well.The burst release behavior can be better suppressed by increasing the MW of the 4s-PLLA-PEG.(2)Preparation and characterization of five-arm amphiphilic s-PLLA-PVP copolymers and properties of their drug-load micellesThe star-shaped poly(L-lactide)(5s-PLLA)was prepared by the ring-opening polymerization for L-lactide with stannous octoate as a catalyst and xylitol as a multifunctional initiator.The carboxylic polyvinyl pyrrolidone group(PVP-COOH)was synthesized by free radical solution polymerization with N-vinyl pyrrolidone(NVP)as monomers and azodiisobutyronitrile(AIBN)as an initiator.The amphiphilic star-shaped 5s-PLLA-PVP copolymers were then synthesized using esterification reaction between the hydroxy group of 5s-PLLA and the carboxyl group of PVP-COOH at room temperature.Subsequently,RIF was used as a hydrophobic model drug,and RIF loaded the micelles of the 5s-PLLA-PVP copolymer was prepared by dialysis method.The drug loading capacity(LC),drug encapsulation efficiency(EE),particle size,particle size distribution and morphology of 5s-PLLA-PVP/RIF micelles were characterized by employing vltraviolet-visible spectroscopy(UVS),laser particle analyzer and TEM.The RIF micelles in vitro release characterization was investigated by applying UVS and constant temperature shock chamber.It is shown that the higher mole ratio monomer copolymerization of composited s-PLLA-PVP drug synthesis of micelle has the higher particle size distribution,LC and EE.Through the drug release curve,it can obtain that the micelle has low sudden release rate;and the Mw higher,slow and controllable cumulative release rate.Besides,the drug release curve corresponds to Baker-Lonsdable model.(3)Preparation and characterization of six-arm amphiphilic s-PLLA-TPGS copolymers and properties of their drug-load micellesThe star-shaped poly(L-lactide)(6s-PLLA)was generated by the ring-opening polymerization of L-lactide with sorbitol as a multifunctional initiator and stannous octoate as a catalyst;carboxylation of 6s-PLLA.At last,the star-shaped 6s-PLLA-TPGS copolymer was synthesized by the esterification of between TPGS and 6s-PLLA-COOH.The structure of copolymer was characterized via 1HNMR.Then,indometacin as a hydrophobic model drug and the micelles of the 6s-PLLA-TPGS copolymer was prepared by dialysis method.The LC,EE,partical size distribution,partical size and surface morphology were characterized via applying UVS,laser particle analyzer and TEM.The property of in vitro release of 6s-PLLA-TPGS/IMC micelles was studied by UVS,and the drug release curve was fitted via the dynamic model as well.The results shown that,the average diameters of 6s-PLLA-TPGS micelles between 116.3 nm and 132.7 nm can be prepared by varying the copolymers of monomer/initiator molar ratios.The drug release curve.of the EMC-loaded micelles shown that the 6s=PLLA-TPGS micelles has low burst release and controllable cumulative release rate.Besides,the release profiles of IMC from 6s-PLLA-TPGS followed the Baker-Lonsdale model equation.