Environment Responsive Silica-Based Drug Delivery Systems For Tumour Therapy

Drug delivery system is one of the most important fields in the cancer therapy works.Among the wildly used drug carrier materials,such as liposome,polymer nanoparticles,dendrimers,and inorganic nanoparticles,silica nanoparticles have been recived numbers of researches.Slica nanoparticles have large pore volume,high surface area,and could be easily modified with functional groups to achieve the goals like targeting,controlled release,imaging and therapy.Although traditional silica nanoparticles have many advantages,it could be hardly degradabled in vivo,which hinder the further applications of clinical.In this study,we designed and constructed a series of novel silica-based drug delivery systems for targeted tumour therapy,which included dual drug delivery system based on biodegradable organosilcia core-shell architectures,drug delivery platform with an“AND”logic gate,and the combination of microbiota suppression and chemotherapy for orthotopic colorectal cancer.The details were described as follow:In chapter one,the microenvironment of tumour,and the usually used drug vehicles were introduced.A brief introduction of the history,the classifications,advantages and disadvantages of silica nanoparticles was given.The applications of silica nanoparticles in the field of drug delivery were described,which were distinguished by the types of simulation-resopnisve-triggers.In chapter two,biodegradable organosilica-based core-shell-structured nanocapsules were designed and used as dual stimuli-responsive drug carriers.Biodegradable organosilica shell coated outside the macromolecule model drug“core”would be disrupted by high glutathione(GSH)levels inside tumor cells,resulting in the escape of the entrapped drugs.Small-molecule drugs capping on the surface of the organosilica shell via pH-responsive imine bonds can be cut and released in the acidic lysosomal environment.Drug release curves were taken in vitro.Transmission electron microscopy showed the degradation of the framework of the organosilica shell,in the GSH solution.Cyctotoxicity of the nanoparticles was measured.Confocal imaging confirmed the release of small-molecule and macromolecular from the nanoparticles,in the cancer cells.This system will serve as an efficient shuttle for multidrug delivery and also provide a potential strategy to overcome drug resistance.The carriers could be degradabled in the cancer cells,lead to decrease of the retention time.In chapter three,a novel modular theranostic platform based on an“AND”logic gate was designed to control the stimuli-responsive drug release.As patch boards,mesoporous silica nanoparticles(MSN)were functionalized with linear pH-responsive benzimidazole(Bz)-polyethylene glycol(PEG)chains containing a redox-responsive ferrocene(Fc)oxide stopper at the end.As the plug,theβ-CD ring was initially located at the Bz position.In an acidic tumor microenvironment,the pH sensitive Bz was protonated and the complex formation constant between Bz andβ-CD was decreased.In a redox environment containing high concentration of GSH,Fc oxide could be redoxed to Fc,and the complex formation constant between Fc andβ-CD was increased.Only in the acidic and reductive environment,the constant between Fc andβ-CD could be greater than the constant between Bz andβ-CD,which resulted in the leave ofβ-CD,and the release of DOX.Drug release cruves were measured in different conditions,hemolysis experiment was proved the biocompatibility of the drug delivery system DOX@FAMSN.Normal and tumour cells were used for the cyctotoxicity assessment of DOX@FAMSN,in different environments.A confocal laser scanning microscope was used to study the cellular uptake of DOX@FAMSN in COS7 and KB cells,and the long-term anti-tumour efficacy was studied by using BALB/c mice.The in vivo metabolic analysis was measured by ~1H-MRS.To demonstrate the therapy efficacy of cancer,parameters of energy metabolism such as glucose,lactate,choline/lipid ratio were calculated from the result of ~1H-MRS.The“AND”logic gate could delivery drugs to the tumour more accurately,make the therapy efficacy increased and toxicity of organs decreased.In the chapter four,MSN which were coated by metal-polyphenol networks,were chosen and designed as drug delivery systems.5-fluorouracil and metronidazole were loaded into the MSN respectively.The drug vectors could control the intestinal microbiota,suppress the growth of the orthotopic colorectal cancer,achieve the goal of combination therapy.In vitro and in vivo studies showed the antitummour and antimicrobiota property of the system.The carriers were absorbed from intestinal perfusion,which would not enter the blood circulation,could take the toxicity of organs decreased.