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

Dendritic polymers-based unimolecular micelles with enhanced stability are attractive carriers.However,the preparation of dendrimers or dendrons with higher generation remains substantially synthetic challenge due to the increased steric hindrance,multistep and tedious preparation,and low yields.The adoption of Boltorn H40,a commercially available dendritic polymer of Boltorn family containing multiple hydroxyl groups with various functionalities as a dendrimer-based starting core template for the generation of hyperbranched polymers offers a straightforward solution to address this problem.To develop universal strategies toward H40-based amphiphilic block copolymers,the“grafting from”and“grafting to”approaches were both applied in this study.The reduction-insensitive block copolymers,H40-b-poly（ε-caprolactone）-b-poly（oligo（ethylene glycol）monomethyl ether methacrylate）（H40-b-PCL-b-POEGMA）were synthesized by“grafting from”including sequential ring-opening polymerization（ROP）and atom transfer radical polymerization（ATRP）.The core structure as well as the polymer composition of the non-reducible amphiphilic hyperbranched block copolymers was optimized toward better properties and performance for drug delivery applications,and H40-PCL₁₅-b-POEGMA₂₃3 was screened as the best polymer construct relative to H20-PCL₁₅-b-POEGMA₂₃3 and H40-PCL₁₅-b-POEGMA₃₂ in terms of micelle stability and drug loading capacity.Therefore,the reducible H40-b-PCL-SS-POEGMA with an identical core and polymer composition to that of H40-PCL₁₅-b-POEGMA₂₃ was further prepared by“grafting to”using click coupling between H40-PCL-azide and P（OEGMA）-alkyne.The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX-loaded reducible micelles of H40-PCL₁₅-SS-POEGMA₂₃3 produced greater cytotoxicity in cancer cells than in normal cells and macrophages,therefore are promising carriers for anti-cancer drug delivery.To investigate the effect of architecture on their bioproperties as well as biomedical applications as drug carriers.The optimal hyperbranched 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 hyperbranched amphiphilic block copolymer with the optimal structure were prepared by incorporating reducible disulfide links toconnectthehydrophobicpoly（ε-caprolactone）（PCL）andhydrophilic 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.Two different Boltorn H40 and Boltorn H20 were chosen as the core to generate the target hyperbranched amphiphilic block copolymers composed of hydrophobic poly（ε-caprolactone）（PCL）and hydrophilic poly（oligoethyleneglycol methacrylate）（POEGMA）with different arms by“grafting from”method.Dynamic light scattering（DLS）measurements and pyrene fluorescence probe technique confirmed the capability of resultant hyperbranched amphiphilic copolymers（H40-PCL-POEGMA&H20-PCL-POEGMA）to form unimolecular micelles with average diameters smaller than 70 nm in an aqueous phase.A comparison of the drug loading capacity（DLC）revealed that the unimolecular micelles of H40-PCL₁₅-b-POEGMA₂₃ exhibited the highest drug loading content（DLC）of all the three kind of formulations.2.The reducible H40-PCL-SS-POEGMA with disulfide links in the block junctions of PCL and POEGMA were prepared by“grafting to”using click coupling between H40-PCL-azide and P（OEGMA）-alkyne.Dynamic light scattering（DLS）measurements and transmission electron microscope（TEM）results showed that the H40-PCL-SS-POEGMA formed micelle above the concentration of 0.25 mg/ml and the unimolecular micelles with hydrodynamic diameter less than 50 nm.The in vitro doxorubicin（DOX）release study showed dramatically accelerated release and up to 87%cumulative release in 72 h in a reducing environment（in the presence of 10 mM GSH）but much slower profiles in the physiological pH or a tunmor acidic pH conditions,confirming that the reduction-triggerred dissembly of H40-PCL-SS-POEGMA micelles promotes the drug release with enhanced therapeutic efficacy.In vitro cytotoxicity study further confirmed higher inhibition of cellular proliferation against HeLa cells for DOX-loaded reduction-sensitive H40-PCL-SS-POEGMA micelles relative to the reduction-insensitive counterparts.The delivery efficacy evaluated by an in vitro cytotoxicity study revealed that the resulting DOX-loaded reducible micelles of H40-PCL-SS-POEGMA produced greater cytotoxicity in cancer cells than in normal cells and macrophages,therefore are promising carriers for anti-cancer drug delivery.Taken together,the reduction-responsive unimolecular micelles developed herein are promising biomaterials to address the stability vs high therapeutic efficacy dilemma for cancer therapy.