Application Of Micelles Based On Brush-type Polymer With Acid-degradable Backbone In Drug Delivery System

Stimulus-responsiveness polymeric nanoparticles can greatly improve the efficacy of drugs and reduce the damage to normal tissues due to the prolonged circulation time and highly passive targeting ability to tumor via the enhanced permeability and retention(EPR)effect.Therefore,various stimuli-sensitive drug carriers have been developed in recent years based on polymeric nanoparticles.In the field of stimulus-responsive systems,pH-sensitive polymers have shown their broad potential applications including drug and gene delivery systems.The pH value of the environment in tumor tissue is often 0.5–1.0 units lower than that in healthy tissue.Moreover,a larger pH shift happens during the process of cellular uptake,which ranges from 7.2–7.4 of blood or extracellular spaces to 4.0–6.5 of various intracellular compartments.This can be employed to design functional intracellular drug delivery carriers.Biodegradable brush-type polymers based on cleavable polyacetal backbones,PHF-g-(PCL-PEG)and PHF-g-(PCL-PEG-PBA),were prepared in this thesis.Polyacetal PHF was the redox reduction of dextran.The side-chain PCL was grafted onto the hydroxyl groups of PHF via ring-opening polymerization(ROP)of ?-CL.Further,PHF-g-PCL was modified with MPEG or phenylboronic acid-conjugated PEG(PEG-PBA).These particular structures were directional to facilitate the formation of spherical or rod-shaped micelles.Flow cytometry results of PHF-g-(PCL-PEG)micelles showed that rod-shaped micelles displayed enhanced cellular uptake compared to those of spherical ones.Rod-shaped micelles were selected to investigate the drug delivery abilities in detail.In vitro experiments verified the pH responsiveness of the polyacetal backbones.The drug release rate and the cumulative release of DOX(%)at pH 5.0 were much greater than those at pH 7.4.In the analysis of drug-release kinetic,a double-exponential model achieved the best fit.The cellular uptake ability of DOXloaded PHF-g-(PCL-PEG-PBA)micelles was found to be superior to DOX-loaded PHF-g-(PCL-PEG)micelles due to the boronic acid-mediated endocytosis.The attachment of targeting group phenylboronic acid did not affect the pH responsiveness of polyacetal.The blank micelles appeared to be almost nontoxic,while the DOX-loaded systems showed equivalent cytotoxicity against HepG2 cells compared to DOX at high concentration.The results indicated that the pH-sensitive brush-type polymer micelles based on polyacetal could be a potential carrier in drug delivery.