Design Of Functional Polymer Microspheres And Application As Tumor Microenviroment-triggered Drug Delivery Systems

At present,chemotherapy remains the cornerstones in the therapy of cancer.Almost all the anticancer drugs cause severe side effects on normal tissues due to their nonspecific delivery.Many researchers had been committed to develop the stimulus-responsive drug delivery systems(DDSs)with good biocompatibility and biodegradability in order to achieve targeted release in cancerous cells and reduce the premature release of drugs in normal cells.That way,the selective release of anti-cancer drugs was completed and the cancer patients would be freed from side effects with the enhanced treatment efficacy.The nonselective of anti-cancer drugs greatly affected its anticancer activity,which requires the synthesis of DDS with multiple stimuli responsiveness.In addition,different drug-loading ways would affect the drug release.Therefore,in this thesis,4-formylphenyl acrylate(FPA)was synthesized as hydrophobic monomer with aldehyde groups.Then,we prepared the mono-disperse microspheres by the emulsion copolymerication of FPA and methacrylic acid(MAA),poly(ethylene glycol)methyl ether methacrylate(PEGMA),and/or β-cyclodextrins-containing acrylic monomer.Then,the drug DDSs were prepared by different drug loading ways and the in-vitro drug release was researched.The research work of this thesis mainly includes the following three parts:1.A facile strategy was established for the pH/reductant dual-responsive FPA/PEGMA microspheres via emulsion polymerication.The DOX was conjugated onto the nanoparticles through reacting with the aldehyde groups to form the acid-labile Schiff base bond.The degradation behavior of the drug carrier was also studied.Due to the pH responsiveness of the Schiff base,the leakage of DOX can be controlled,and avoided release in the simulated normal physiological condition.It had a high release ratio with the synergetic effect of reductive agent and pH.The pH/reduction dual responsiveness had built a platform for the microspheres in the application of drug controlled release.2.To further study the influence of drug-loading method on drug release,mono-dispersed P(FPA-co-PEGMA-co-MAA)nanoparticles were prepared via emulsion copolymerization.The DOX could be loaded via the strong electrostatic interaction between the carboxyl groups of PMMA segments and the amino group of DOX.In addition,the aldehyde group of PFPA segments could conjugate with DOX via acid-labile Schiff base bond.So,three kinds of DDS were prepared by different drug-loading methods.According to in vitro simulated drug release experiments,the better biodegradability,pH/Redox stimuli-responsiveness make the nanoparticles a potential platform for the controlled release of anticarcinogens.3.The cyclodextrin-containing acrylic monomer ACD was synthesized by acryloyl chloride and β-cyclodextrin.Then,P(FPA-co-ACD)nanoparticles were prepared by emulsion polymerization.The formed nanoparticles were observed by DLS and TEM.DOX could be loaded through the hydrophobic effect of β-cyclodextrin and chemical bonding of PFPA segments.In vitro simulated drug release experiments,the drug release profile of microspheres showed the pH/Redox dual-responsiveness.Thus,this drug carrier could reach the goal of controlled smart release.