Fundamental And Applied Research Into The Interactions Of Proteins With Drugs And Silica Materials

Protein is an important component of human cells and tissues and is the material basis of life activities.Albumins account for approximately half amount of the total proteins in blood,whose interaction with drug molecules and various biomedical materials is one of the important research contents in biomedical field.In this paper,the interactions of serum albumin with drug molecules and silica-based materials of different dimensions(including silica quantum dots,mesoporous silica nanorods,hierarchical zeolite microspheres,etc.)are systematically studied,which provides basic data and theoretical reference for the application of protein host-guest chemistry in drug design,drug delivery,protein separation and enzyme immobilization.The concrete contents of this paper are as follows:In Chapter 1,the research background of the subject is summarized.In Chapter 2,the molecular recognition behaviors of lamivudine(3TC),cryptotanshinone(CTSO),hypoxanthine nucleoside(HXR)by human serum albumin(HSA)are studied.According to the fluorescence quenching model,equilibrium constants,thermodynamic parameters,number of binding sites,and interaction forces between drugs with HSA at different temperatures are determined;The binding sites of drug molecules in HSA are determined by fluorescence probe technology;The influence of drugs on the secondary structure of HSA is analyzed by synchronous emission and circular dichroism;The structures of drug-protein complexes are presented by molecular docking calculation.In Chapter 3,N-1,3-benzothiazol-2-ylformamide(MABT)is prepared from 2-aminobenzothiazole(ABT).The protein-interacting mechanism,thermodynamics and geometric characteristics of ABT and MABT are comparatively investigated by means of spectrum,molecular simulation and DFT calculation.The difference in energy transfer efficiency between protein and two molecules is deciphered by frontier molecular orbital theory.Meanwhile,the difference in molecular orientation of MABT and ABT in new complexes is also explained by DFT calculation.The effect of carbamylation on protein binding activity of benzothiazole derivatives is systematically revealed,which provides valuable information for the structural design of N-substituted benzothiazole-based drugs and pesticides.In Chapter 4,amino functionalized blue light silica quantum dots(Si QDs)are synthesized by hydrothermal method without adding any reductant or catalyst.The structure,optical properties,albumin-binding and cell imaging performance are discussed by XRD,TEM,XPS,IR,UV,TG,surface potential,fluorescence lifetime,three-dimensional fluorescence,circular dichroism,molecular surface simulation and MTT assay.The results show that Si QDs bind with HSA through hydrogen bonds,which poses no obvious influence on the fluorescence lifetime of Si QDs.Furthermore,Si QDs show tiny cytotoxicity and thus can be used for fluorescence imaging.In Chapter 5,a p H sensitive drug delivery system is constructed by anchoring HSA on the surface of zwitterions-modified mesoporous silica nanorods(MSNR),and its release behavior in protein-containing medium is measured.Zwitterions effectively improve the dispersity and stability of MSNR,and inhibit its non-specific adsorption for proteins.The introduction of benzoimide bond achieves p H-responsive release of drug.The release processes of 3TC in protein-free and protein-containing simulated body fluids are measured by UV spectra and synchronous fluorescence quenching spectra,respectively.The results show that the protein in real body fluid can change the release behavior of drug,and the protein"gatekeeper"can effectively diminish the pre-mature release and improve the biocompatibility of the materials.In Chapter 6,the interactions of a hollow-structured zeolite microsphere(HSZ)and its functional derivatives(HSZ-OH,HSZ-NH₂ and HSZ-CHO)with BSA are studied.Owing to the unique cup-shaped pores on MWW-nanosheets,the included angles of nanosheets,the highly exposed outer surface and the abundant mesopores and macropores in the shell,HSZ materials exhibit higher BSA loading than familiar microporous zeolites.Furthermore,the loading and release property for BSA can be regulated by surface functionalization.The loading mechanisms of protein on HSZ are analyzed from the views of surface properties,interaction forces and thermodynamics.Finally,HSZ-NH₂ is tentatively applied to the immobilization of horseradish peroxidase.Chapter 7,conclusions and prospects are discussed.