Construction And Evaluation Of PH Responsive Nitrogen-Containing Metal-Organic Frameworks As Oral Drug Carriers

Metal-organic framework（MOF）is a porous material composed of metal ions/clusters and organic ligands.It has attracted much attention due to its high specific surface area,good biocompatibility,chemical modifiability,and diversity of components.However,due to the weak coordination bonds between many metal clusters and organic ligands,the stability of MOF cannot be guaranteed as drug carriers.Among many MOF,zirconium-based MOF are particularly suitable for biological applications due to their optimal stability and low toxicity to hydrolysis.In this study,three nitrogen containing zirconium based Ui O-66 series MOF were synthesized.The anionic drug loxoprofen（LOX）was selected as the model drug to explore a series of behaviors and mechanisms of p H responsive nitrogen containing MOF as oral drug carriers.Three Metal-organic frameworks,namely,Ui O-66-PDC,Ui O-66-NH₂ and Ui O-66-NO₂,were synthesized with different organic ligands and centered on metal Zr ion clusters,and loaded with loxoprofen.The three MOF were characterized by scanning electron microscopy,infrared spectroscopy,thermogravimetry,differential scanning calorimetry and X-ray scattering techniques.The results showed that all three MOF were able to successfully load drugs and maintain intact crystal structure before and after drug loading,with Ui O-66-PDC having the best loading effect.The release behavior of three drug loaded MOF was evaluated using artificial gastric juice,small intestine,and colon juice.The results showed that all three MOF improved the stability of LOX in the gastrointestinal environment,with Ui O-66-PDC better protecting LOX from the gastric acid environment to the intestinal environment and releasing a large number of drugs in the intestine.We also measured the cumulative release of organic ligands in MOF,and further evaluated the chemical stability of the drug loading system.Using computer simulation methods to study the adsorption and release behavior between LOX and three types of MOF from a molecular perspective.The optimal adsorption sites and adsorption energy results between LOX and MOF jointly indicate that the three oxygen atoms within LOX molecules will generate hydrogen bond interactions with the hydrogen atoms on the nitrogen and carbon atoms of the organic ligand,and also form electrostatic binding forces with zirconium ion clusters.The adsorption energy between Ui O-66-PDC and LOX is the highest,indicating that the binding between Ui O-66-PDC and LOX is the most stable and consumes the least energy.The ideal loading capacity and in vitro release molecular dynamics calculations of three MOF on LOX indicate a strong electrostatic interaction between the anionic drug LOX and Ui O-66-PDC.In the stomach acid environment,the drug release is inhibited due to strong electrostatic attraction.However,when it enters the intestine,the nitrogen atom of its heterocycle has more negative charges than the carbon in benzene,which repels the anionic drug loxoprofen and releases more drugs.The results of pharmacokinetic experiments in rats indicate that,LOX@Ui O-66-PDC The peak time of the group was longer than that of the LOX group,the peak concentration was lower than that of the raw material group,the blood drug concentration curve was smoother,the half-life was significantly prolonged,and the area under the drug time curve increased.The above results indicate that,LOX@Ui O-66-PDC The drug delivery system can improve the bioavailability of LOX and have a certain degree of sustained release effect.LOX@Ui O-66-PDC The results of the rat everted intestinal sac test showed that LOX was best absorbed in the duodenum,followed by the jejunum and ileum,and the colon was the smallest.Finally,the study was conducted using chemical inhibitor methods LOX@Ui O-66-PDC The endocytosis pathway proves that its main uptake pathway is mediated by cellular megakaryocytosis and lipid rafts/caveolin structures.The above results prove that LOX@Ui O-66-PDC It is expected to become a new type of oral drug delivery system.