Click Chemical Synthesis Of Polycarbonate-based Core Crosslinked Micelles

Polymeric micelles are widely used in the research of anti-cancer treatments because they can improve the solubility of drugs,prolong the circulation time in the body,and enhance the penetration and retention effects and enhance tumor accumulation and reduce side effects.Drugs are usually encapsulated in polymer micelles by hydrophobic interaction.During the delivery of body fluids,the polymer micelles may be diluted and disintegrated in advance,leading to unnecessary side effects due to drug leakage.To solve this problem,cross-linking strategies have been adopted.Polycarbonate has low toxicity and good biocompatibility was often used as a drug delivery material.In order to improve the stability of polycarbonate micelles and prevent premature leakage of the loaded micelles during transportation,this thesis uses click chemistry reaction to synthesize two kinds of polycarbonate-based stimuli-responsive core cross-linked micelles by simple direct cross-linking method,and investigate their performance in anti-cancer drug delivery materials.(1)Using PEG_5kas a macroinitiator and DBU as a catalyst,PEG-PMPC was synthesized by ring-opening polymerization of cyclic carbonate The chemical structure of the polymer was detected using ¹H NMR,¹³C NMR,and FT-IR,the polymer were analyzed by GPC.(2)Through azide-alkyne click reaction between the alkynyl group of the side chain of the amphiphilic PEG-PMPC copolymer and the azido derivative containing thioketone bis(2-azidoethyl)3,3'-(propane-2,2-diylbis(Thiodialkyl))dipropionate(TK-N₃),a reactive oxygen(ROS)responsive polycarbonate core crosslinked(CCL)micelle was synthesized.Results showed that CCL micelle formed spherical micelles with average diameter of 146.4nm,possessing excellent stability against dilution and high DOX loading.The drug release can be achieved under the stimulation of H₂O₂(5 m M and 10 m M).In vitro toxicity tests showed that CCL micelles exhibit low toxicity and good biocompatibility(Cell viability?95%),and have good toxicity effects on cancer cells(He La cells:IC₅₀=3.74?g/m L,MCF-7 cells:IC₅₀=3.91?g/m L).CLSM and flow cytometry show excellent internalization efficiency and DOX release from CCL micelles.The obtained ROS responsive core crosslinked polycarbonate micelles have great potential for the delivery of anticancer drugs.(3)Using thiol derivative ethane-1,2-dialkylbis(3-mercaptopropionate)(EGDMPA)as cross-linker,p H-responsive core crosslinked polycarbonate micelles(CCLMs)were achieved via thiol-yne click reaction with amphiphilic PEG-PMPC.The results showed that the obtained CCLMs had a particle size of 136.4 nm,excellent dilution stability,and could slowly hydrolyze and release anticancer drugs at p H 5.0.In addition,it showed good biocompatibility and low toxicity in He La and MCF-7 cells Cell(viability?95%).Moreover,DOX loaded CCLMs showed good anticancer effect in He La and MCF-7 cells(He La cells:IC₅₀=2.03?g/m L,MCF-7 cells:IC₅₀=5.04?g/m L).CLSM and flow cytometry results showed that CCLMs had excellent internalization efficiency and could release encapsulated DOX in He La cells under acidic environment.