Design,Preparation And Properties Of Star-shaped Amphiphilic Block Copolymers As Drug Delivery Systems For Controlled Release

In the past several decades,star-shaped amphiphilic block copolymers have attracted considerable attention as drug carriers due to their unique branching structure.They could form unimolecular micelles with enhanced stability to survive the high dilution-associated deformation and subsequently premature drug release in the body fluids and blood during circulation.However,only a few literature reported the effect of star architectures on their in vitro drug release behaviors.In addition,it is worth pointing out that permanently stable micelles are undesirable as well because the effective release of cargoes in the intracellular environment is also required to achieve an ideal therapeutic efficiency.In view of the above problems,three star-shaped amphiphilic block copolymers with the same compositions but different arm numbers were synthesized to investigate the effect of star architecture on their bioproperties as well as biomedical applications as drug carriers.The optimal star-shaped copolymers with the best performance for in vitro drug loading and drug release were therefore screened based on a comparision study.In the next study,a reduction-responsive star-shaped amphiphilic block copolymer with the optimal star structure were prepared by incorporating reducible disulfide links to connect the hydrophobic poly(?-caprolactone)(PCL)and hydrophilic poly(oligoethyleneglycol methacrylate)(POEGMA)blocks.This formulation was further used as drug carries for reduction-trigerred drug delivery.The conten of this master thesis are as follows:1.Three different branched alcohols,2-(hydroxymethyl)propane-1,3-diol,pentaerythritol and dipentaerythritol with 3,4 and 6 respective hydroxyl groups were chosen as the starting core to generate the target star-shaped amphiphilic block copolymers composed of hydrophobic poly(?-caprolactone)(PCL)and hydrophilic poly(oligoethyleneglycol methacrylate)(POEGMA)with 3,4 and 6 corresponding star arms by a combination of ring-opening polymerization(ROP)and atom transfer radical polymerization(ATRP).Dynamic light scattering(DLS)measurements and pyrene fluorescence probe technique confirmed the capability of resultant star-shaped amphiphilic copolymers to form unimolecular micelles with average diameters smaller than 60 nm in an aqueous phase.A comparison of the drug loading capacity revealed that the micelles of 4s-PCL-POEGMA exhibited the highest drug loading content(DLC)of all the three formulations.More importantly,in vitro doxorubicin(DOX)release study showed unique pH-mediated release behaviors,i.e.,dramatically accelerated release at pH 6.0 but a much slower profile at p H 7.4,from these generally recognized “p H-insensitive” multiarm star-shaped micelles.Taken together,4s-PCL-POEGMA micelles show the best performance in vitro drug release behaviors of all the three formulations.2.4s-PCL-SS-POEGMA was successfully prepared by incorporating reducible disulfide links to connect the hydrophobic poly(?-caprolactone)(PCL)and hydrophilic poly(oligoethyleneglycol methacrylate)(POEGMA)blocks.Dynamic light scattering(DLS)measurements and transmission electron microscope(TEM)results showed that the 4s-PCL-SS-POEGMA formed micelle aggregates above the concentration of 0.25 mg/ml but existed as unimolecular micelles with hydrodynamic diameter less than 80 nm below the concentration.The in vitro doxorubicin(DOX)release study showed dramatically accelerated release and up to 79% cumulative release in 72 h in a reducing environment(in the presence of 10 mM TCEP)but much slower profiles in the physiological pH or a tunmor acidic pH conditions,confirming that the reduction-triggerred dissembly of 4s-PCL-SS-POEGMA micelles promotes the drug release with enhanced therapeutic efficacy.This formulation has therefore great potential as smart carriers for controlled drug delivery.