Study On The Construction And Performance Of A Stimuli-Responsive Drug Delivery System Based On Nanoporous Materials

Stimuli-responsive drug delivery systems have become more and more fascinating and vital in the view of nanotechnology and nano medicine because they can change the pharmacokinetics of drugs,significantly improve the utilization of drugs,provide on-demand local drug delivery,and reduce toxic side-effects.As a typical representative,nanoporous materials with unique physical and chemical properties,such as abundant pore structure,low density,high surface area,tunable porous size,have displayed great promise in applications of industrial catalysis,gas adsorption,linear optics,electromagnetic materials,especially in stimuli-responsive delivery systems for the diagnosis and treatment of diseases.This thesis mainly focuses on some important scientific problems including further increasing the loading capacity of the nanocarrier,searching new release and targeting mechanism,reducing the biological toxicity,and developing multifunctional drug delivery systems.In this thesis,we carried out the research work by taking design of nanoporous materials-based drug delivery systems as the research content.The main works are listed as follows:1.Natural gelatin capped mesoporous silica nanoparticles for intracellular acid-triggered drug deliveryThis section proposed a natural gelatin capped mesoporous silica nanoparticles(MSN@Gelatin)based pH-responsive delivery system for intracellular anticancer drug controlled release.In this system,the gelatin,a proteinaceous biopolymer derived from the processing of animal collagen,was grafted onto the mesoporous silica nanoparticles(MSN)to form capping layer via temperature-induced gelation and subsequent glutaraldehyde mediated cross-linking,resulting in gelatin coated MSN.At neutral pH,gelatin capping layer could effectively prohibit the release of loaded drug molecules.However,the slightly acidic environment would lead to enhanced electrostatic repulsion between the gelatin and MSN,giving rise to uncapping and the subsequent controlled release of the entrapped drug.As a proof-of-the-concept,doxorubicin(DOX)was selected as the model anticancer drug.The loading and pH-responsive release experiments demonstrated that the system had excellent loading efficiency and almost no DOX was leaked at neutral.After putting in the slightly acidic condition,the DOX release from the DOX-loaded MSN@ Gelatin(DOX/MSN @ Gelatin)was occurred immediately.The cellular uptake and release studies indicated that the DOX/MSN@Gelatin could be endocytosed and accumulated within lysosomes.Triggered by acidic endosomal pH,the intracellular release of the loaded DOX was obviously eventuated.Further MTT assay results demonstrated that DOX/MSN@Gelatin exhibited dose-dependent toxicity and high killing efficacy,whereas the MSN@Gelatin showed negligible cytotoxicity.This biocompatible and effective delivery system will provide the great potential for developing delivery of cancer therapeutic agents.2.Programmed packaging of mesoporous silica nanocarriers for matrix metalloprotease 2-triggered tumor targeting and releaseThe development of multifunctional nanocarrier with each unit functioning at the correct time and location is a challenge for clinical applications.With this in mind,a type of intelligent mesoporous silica nanocarrier(PGFMSN)is proposed for matrix metalloprotease 2(MMP 2)-triggered tumor targeting and release by integrating programmed packing and MMP 2-degradable gelatin.MSN are first functionalized with folic acid(FA)as a target ligand to improve cell uptake.Then gelatin is introduced onto FA-MSN via temperature-induced gelation,where gelatin layer blocks drugs inside the mesopores and protects the targeting ligand.To prolong blood-circulation lifetime,polyethylene glycol(PEG)is further decorated to obtain PGFMSN.All units are programmatically incorporated in a simple way and coordinated in an optimal fashion.Cells,multicellular spheroids and in vivo results demonstrate that PGFMSN is shielded against nonspecific uptake.After circulating to tumor tissue,the up-regulated MMP-2 hydrolyzes gelatin layer to deshield PEG and switch on the function of FA,which facilitate the selective uptake by tumor cells through folate-receptor-mediated endocytosis.Meanwhile,the packaged drug is released due to the shedding of gelatin layer.It is shown that doxorubicin(DOX)-loaded exhibits superior tumor targeting,drug internalization,cytotoxicity,and antitumor efficacy over free DOX,non-PEGylated and non-targeted nanoparticles,which provides potential applications for targeted cancer therapy.3.A mannose-responsive controlled-release system based on con A-gated mesoporous silica nanocontainersIn this section.a novel delivery system based on Con A-gated glucose-functionalized mesoporous silica nanoparticle(MSN-Glc-Con A)was constructed for the mannose-responsive controlled release.In this system,glucose was firstly modified on the surface of MSN through the crosslinking reaction between glucosamine and cyanato-functionalized MSN.Concanavalin A(Con A),a lectin,was subsequently bound the functionalized glucose epitopes through multivalent carbohydrate-protein interactions,resulting in blockage of pores and inhibition of guest molecules release.In the presence of mannose,the Con A competitively bound with mannose and got away from the pore mouths because of higher affinity for mannose.Thus,the pores were uncapped and the entrapped guest molecules were released.The physical and chemical properties of the as-synthesized MSN were characterized by transmission electron microscopy,X-ray diffraction assay,Fourier transform infrared spectroscopy,Brunauer-Emmett-Teller and thermo gravimetric analysis.As a proof-of-principle,[Ru(bipy)3]Cl2 was selected as the model guest molecule,and the mannose-responsive loading and release of[Ru(bipy)3]Cl2 have been investigated.The results demonstrate that the system had excellent loading amount and good mannose-responsive release behavior.Release-profile studies in buffer showed that no[Ru(bipy)3]Cl2 leaked when the pore was closed and that release occurred immediately after adding mannose.The dye release percentage can reach 93%after treatment with mannose for 340 min.This lectin-gated MSN delivery system is a promising candidate for therapeutic agents delivery.4.Alizarin complexone functionalized mesoporous silica nanoparticles:a smart system integrating glucose-responsive double drugs release and real-time monitoring capabilitiesWe present a multifunctional delivery system that integrates both delivery/monitoring issues using glucose-triggered competitive binding scheme on alizarin complexone(ALC)functionalized mesoporous silica nanoparticles(MSN).In this system,ALC is modified on the surface of MSN as the signal reporter.Gluconated insulin(G-Ins)is then introduced onto MSN-ALC via benzene-1,4-diboronic acid(BA)mediated esterification reaction,where G-Ins not only blocks drugs inside the mesopores but also works as a hypoglycemic drug.In the absence of glucose,the sandwich-type boronate ester structure formed by BA binding to the diols of ALC and G-Ins remains intact,resulting in an fluorescence emission peak at 570 nm and blockage of pores.Following a competitive binding,the presence of glucose cause the dissociation of boronate ester between ALC and BA,which lead to the pores opening and disappearance of fluorescence.As proof of concept,rosiglitazone maleate(RSM),an insulin-sensitising agent,was doped into the MSN to form a multifunctional MSN(RSM@MSN-ALC-BA-Ins)integrating with double drugs loading,glucose-responsive performance and real-time monitoring capability.It has been demonstrated that the release of insulin and RSM in response to the glucose in buffer or in human serum can be real-time monitored through the changes of fluorescence signal.We believe that this developed multifunctional system will lead to a new generation of nanodevices for simultaneous optical diagnosis,self-regulated therapy,and non-invasive monitoring of the response to diabetes treatment.5.A metal-organic framework self-sacrificial template strategy to size tunable three-dimensional hollow mesoporous silica material for intracellular acid-triggered drug deliveryDesigning a general strategy to engineer hollow-structured materials with tunable size and specific shapes for emerging applications is still a daunting challenge in the view of nanoscience and nanotechnology.Here,we report a flexible and robust metal-organic frameworks(MOFs)self-sacrificial template strategy for the preparation of three-dimensional(3D)hollow mesoporous silica materials(HMSNs).In this strategy,an acid-sensitive MOF zeolitic imidazolate framework-8(ZIF-8)is coated with a layer of mesoporous silica and subsequently self-degraded under acidic condition to obtain HMSNs.The sizes and morphologies of HMSNs can be conveniently controlled by systematically regulating the synthetic conditions of ZIF-8 templates.A series of monodisperse HMSNs ranging from ca.80 nm to ca.3000 nm and nonspherical morphologies that give rare examples of cubic and polyhedral morphologies has been prepared.It is demonstrated that the as-made HMSNs possess well-defined mesopores,huge inner cavity and good biocompatibility,which make them suitable for delivery of small molecule as a nanocarrier.As a paradigm,the 360 nm HMSN was applied for pH-responsive intracellular anticancer drug controlled release by grafting ZIF-8 onto the HMSN as a novel pore blocker.Furthermore,on the basis of this strategy,multiple large-size functional nanoparticles can also be embedded into the inner cavity of HMSN to construct yolk-shell nanostructures.6.Facile fabrication of metal-organic frameworks with encapsulated Pd-Cu nanoalloy and antineoplastic agent for the chemo-photothermal synergistic cancer therapy.Metal-organic frameworks(MOFs)have great potential for drug delivery due to their advantages of variable composition and structure,facile preparation,biodegradable,easy modification,high porosity and large surface area.In this section,both anticancer drug DOX and Pd-Cu nanoalloy are encapsuled in pH-sensitive MOFs zeolitic imidazolate framework-8(ZIF-8)to develop a simple and powerful drug delivery system for chemo-photothermal synergistic tumor therapy.In this system,a novel Pd-Cu nanoalloy with distinguished photothermal conversion efficiency was successfully synthesized and characterized.Subsequently,the as-made Pd-Cu nanoalloy was introduced to ZIF-8 with DOX was encapsulated in ZIF-8 in a one-pot process.Under low-pH,the ZIF-8 is self-degraded.leading to the DOX release for cancer chemotherapy.In addtion,Pd-Cu nano alloy showed high efficiency for conversion of NIR light into heat,which provids the photothermal cancer therapy and also promots the DOX release under NIR irradiation.In vitro results demonstrated that that combined therapy mediated the highest rate of death of HT-29 cells compared to that of single chemotherapy or photothermal therapy,which opens new possibilities to construct multifunctional delivery systems for synergistic tumor therapy.