Control Of Surface PEGylation Of Polymeric Nanoparticles And Its Application For Drug Delivery

Nano drug carriers can be passively accumulated in tumors through enhanced permeability and retention effect(EPR effect)and have potential application prospects for enhanced drug efficacy and reduced toxicity.After a nanocarrier enters the blood circulation,it is easily recognized and taken up by the mononuclear phagocytic system(MPS)leading to clearance.The polyethylene glycol(PEG)modification of the surface of the nanocarriers can reduce the protein adsorption in the blood through steric hindrance.The nanoscale carriers,which have been listed on the market and have the prospect of clinical transformation,are almost all modified by PEG,such as Genexol-PM micellar paclitaxel,polyethylene glycol polyaspartic acid block polymer coated paclitaxel nano micelle NK105,which can significantly prolong the circulation time and reduce anaphylaxis through PEG.The degree of PEGylation(such as surface PEG length and density)of nanocarriers has a significant impact on their biological behavior,but the control of the degree of PEGylation on the surface of polymeric nanocarriers has not been effectively solved.It is difficult to accurately evaluate the degree of PEGylation of macromolecular nanocarriers on fate in the body.The purpose of this dissertation is to regulate the degree of surface PEGylation of polymeric nanomedicine carriers,reduce the influence of other nano properties,study the effect of PEGylation on the biological effects of nanocarriers on the surface,and to apply it to the study of drug delivery.The main contents and conclusions of the thesis are as follows:1.We successfully prepared nanocarriers with different surface PEG densities but same other nanoparticle properties.By incorporating PCL homopolymer into the PEG-PCL block copolymer and varying the adding ratio,the particle size of polymeric nanoparticles and the surface PEG density were adjusted.The nanoparticle volume was positively correlated with the mole ratio of CL/EG,and the surface PEG density also increased with it.By studying the in vivo pharmacokinetics of these different surface PEG density nanocarriers,it was found that high PEG density prolonged the circulation time of nanoparticles in vivo and increased the concentration of nanoparticles in the tumor.High PEG density in vitro was not beneficial for tumor cells to uptake nanoparticle,but the use of the MDA-MB-231-GFP tumor model in vivo demonstrated that high PEG density promoted uptake of nanoparticles by tumor cells.Therefore,the high surface PEG density modified nanoparticles accumulated at the tumor site by long circulation effect,so as to make up for the insufficient uptake ability of tumor cells,exerted a better therapeutic effect,and provided guidance for the development of cancer therapeutic drugs.2.A series of nanoparticles with different surface PEG lengths but similar other nano properties were obtained.The effect of surface PEG length on the biological behavior of nanoparticles was studied.On the basis of the previous observations,by changing the molecular weight of PEG in the PEG-PCL block copolymer,a nanoparticle library was obtained whose surface properties such as PEG length,PEG density,and particle size can be changed,thereby obtaining different PEG lengths but the same other nano properties.Using similar nanoparticles by excluding the interference of other nano-properties,it was found that the in vivo biological behavior of the nanoparticles did not vary monotonically with the increase of the PEG length on the surface of the particles.The terminal PEG density was?0.40 PEG/nm2,frontal PEG density was?0.16 PEG/nm2,hydrodynamic diameters were all?100 nm and the surface potential was-2 mV for nanoparticles.When the molecular weight of PEG was increased from 3400 to 8000 Da,the in vivo terminal elimination half-life of the nanoparticles showed a significantly prolonged circulation time.Docetaxel delivery by these nanoparticles in MDA-MB-231-GFP breast cancer mice model and the subcutaneous implant model of B16 melanoma led to a drastic shortening of tumors.The corresponding drug accumulation content in the tumor tissue and its anti-tumour effect trend was the same as its in vivo circulation time.When the molecular weight of PEG was 5000 Da,the interaction between nanoparticles and serum albumin was low,and the capture by MPS was reduced,with longer blood circulation time and tumor accumulation,and the curative effect was good.3.In this work,PEGylated cationic lipid-assisted nanoparticles were used to deliver immunosuppressive molecules to relieve dextran sulfate sodium(DSS)-induced acute colitis in mice.Co-assembly of polyethylene glycol-polylactic acid(PEG-PLA),cationic lipids(DOTAP,BHEM-Chol)and small molecule immunosuppressive molecules(tacrolimus,FK506)into cationic lipid-assisted nanoparticles(CLAN),with a size of about 110 nm,a surface potential of 35 mV,and a surface PEG density of 0.8 PEG/nrrm2.The nanoparticles were stable under simulated pH conditions of gastric juice and intestinal fluid,can effectively release the loaded drug;after intragastric administration.CLAN interacted with negatively charged mucin,effectively stayed in the inflamed colon,and penetrated the intestinal epithelial cell layer.Enhanced the effect of immunosuppressive drugs,eased the symptoms of intestinal inflammation,reduced the secretion of myeloperoxidase(MPO)and tumor necrosis factor(TNF-?),and suppressed the weight loss caused by enteritis in mice.