| Metal organic frameworks(metal-organic frameworks MOFs)is currently the subject of much attention as a new type of porous materials,organic-inorganic hybrid formation of MOFs in the structure height can be cut and the characteristics of function is incomparable for other inorganic materials;abundant spatial topological structure,structure formation with specific surface area and high.In addition,porous MOFs can loaded drug and has characteristics of high dosage and control drug release,with the advantages of MOFs in drug carrier gradually been excavated,became a target to pass the drug carrier has broad application prospects in the new carrier and began to be widely studied.And the size has been reduced to nano size,known as the nano metal organic skeleton(NMOF).Considering the Zn2 + is the trace elements necessary for human body,the former laboratory using zinc acetate(Zn(OAC)2.2H2O)as a metal ion,with terephthalic acid(NH2-BDC)as ligand synthesis of the nano size and is suitable for human application of nano metal organic frameworks(IRMOF-3).RGD peptide is a kind of widely exist in organisms of various extracell?lar matrix organization and blood in a class by arginine glycine aspartic acid(Arg-Gly-Asp)peptide sequence composition,is the recognition of integrin and its ligand protein interaction sites.Integrin family is a similar by many structural and functional proteins of the composition of the membrane receptor family,is important in both cell surface adhesion and signal transduction receptor.av?3 or?v?5is an important molec?le of integrin family,is expressed at high level in the surface of lung cancer,breast cancer,prostate cancer,bladder cancer,glioblastoma and other solid tumor cells.RGD is a kind of non-toxic,water-soluble polypeptide is good,highly selective and integrin binding,are the important active targeting ligand.Cantharidin(CTD)is the representative of the anti tumor cytotoxicity more classical Chinese medicine,at present the preparation of derivatives of caps?le,injection is widely used for the treatment of gastric cancer,colon cancer,liver cancer and other diseases,the toxicity of CTD is strong,effective dose is close to the toxic dosage,limit its clinical application.IRMOF-3 has high drug loading rate and prolong the drug release,will be loaded in CTD IRMOF-3 in the pore characteristics,can extend the role of CTD in vivo time and improve the toxicity,the study in this field has not been reported.So this topic in human RGD and IRMOF-3 coupling(RIR)on the basis of success,with RIR as a drug carrier,taking CTD as a model drug,to investigate its in vitro drug release,drug loading,rats and lung cancer cells within the pharmacokinetics,as drug carrier to lay the foundation for IRMOF-3 application open.Objective1.the success of RGD coupled IRMOF-3 and characterization of drug loaded in vitro.2.containing CTD on RIR(CTD-RIR)to study the drug release in vitro3.on CTD-RIR for pharmacokinetic studies in mouse tumor cells in vivo and lung in rats 4.For in vitro and in vivo evaluation of CTD-RIRMethod and resplts1.In drug loading and by response surface method optimization of drug loading conditions,drug concentration,drug loading time,stirrer temperature,stirrer speed as factors,to load quantity and package sealing rate as the evaluation index,get the drug loading conditions for:drug concentration was 55%;drug loading time 96h;stirred tank reactor temperature 27.5 ?,the speed of agitator 999.5r/min;according to the best process of preparation nanoparticles of 3 batches of CTD-RIR.The indicators of stability,process reproduce well;in CTD-RIR characterization,through the contrast before and after drug loading scanning electron spectra and XRD patterns and found drug loading had no effect on load shape state,functional groups and structures.2.In vitro drug release,through positive dialysis and retrodialysis two methods to study CTD-RIR in normal cells(pH 7.4)and tumor cells(pH5.0)released under two conditions.Positive dialysis res?lts show:the free drug in pH 5.0 and pH 7.4 under two conditions were released very soon,when 5h sampling points,in the pH 5.0 and pH 7.4 under the two conditions of dissolution reached 88.87%and87.76%,the basic release complete.The release of CTD-RIR nanoparticles significantly slowed down,the front half part of drug release process of two-phase,and adsorbed on the RIR surface diffusion of drug into the medium on,then the steady release,after 36h,two kinds of release medium of release were about 60%,release complete.The release res?lts in the release of res?lts reverse dialysis method and positive dialysis were not obviously.3.Through the study of CTD-RIR,in rats in vivo pharmacokinetic res?lts showed:three doses of CTD on the pharmacokinetics of rats conformed to two compartment model of W=1/C2,with the increase of the dose,the elimination half-life was significantly prolonged,distribution half-life is prolonged significantly in the high dose group,with three different doses after administration of CTD,the linear relationship between the pharmacokinetics in rats in vivo.Between the three dose groups of CTD-IRMOF-3 and CTD-RIR t1/2,AUCO-t,AUCO-inf,MRTO-inf,AUMCO-inf,CL no significant difference,but there are significant differences between the low dose group and the TC,showed that the nanoparticles prolonged drug in vivo residence time.4.Through the compartment model and volume integral method of CTD-RIR nanoparticles were studied,res?lts showed that:the correlation between in vivo CTD-RIR nanoparticles have good correlation between in vitro and in vivo,in vitro experiments can be used for the quality evaluation of CTD-RIR nanoparticles.Conclusion:RIR is loaded into the CTD,through the response surface optimization method to optimize the optimum process conditions are obtained,the drug loading and encaps?lation rate is high of CTD-RIR,the in vitro release effect is good,the role of time can be extended in vivo,can significantly improve the characteristics of CTD toxicity,short half-life.The innovative point of the study:Get the IRMOF-3 coupling of RGD after RIR has high porosity and surface area,good stability,good biocompatibility,high drug loading rate,drug controlled release and targeting tumor characteristics,is a good carrier of anti tumor.Loading CTD,can improve the toxicity of CTD and prolong the time of drug action in vivo and in tumor cells. |
PDF Full Text Request