Studies Of Intelligent Responsive Nanoplatforms Based On Mesoporous Silica Nanoparticles/MOF And DNA Origami For Cancer Therapy

With the rapid development of nanotechnology,the technology of diagnosis and therapy of cancer is developing rapidly.As nanomaterials ha s some special properties,such as size effect,interface effect,especially high penetration and retention effect in tumor tissue,the application of nanomaterials in cancer diagnosis and therapy is widespread.Due to the complexity of cancer,normal cance r treatment methods have some defects,such as poorly targeted ability,side effects to the human body,as well as the metastasis and recurrence of cancer,it is difficult to treat cancer effectively.Recently the evolution of molecular biology has improve d the deep understanding of the mechanism of cancer occurrence and development and promoted the development of the precise diagnosis and treatment of cancer at the molecular level.A new cancer therapy field “precise medicine” has emerged with clinical significance and challenges.To address these challenges,we should develop new materials to construct a cancer-targeted and responsive drug delivery platform for precise cancer therapy.Mesoporous silica nanoparticles(MSNs)is a kind of excellent drug delivery carrier.The outstanding properties of mesoporous silica nanoparticles,such as high surface area,adjustable pore size,easy surface functionalization,and excellent biocompatibility,make it an ideal material for the development of stimuli-responsive drug delivery vehicles.In Chapter 2,we prepared a Dox-MSN@ZIF-8 composite nanoparticles that are stable in a neutral environment(p H = 7.4)and easily degraded in a slightly acidic environment(p H < 6.0).We initially synthesized mesoporous silicon nanoparticles with a diameter of ?80 nm,and then after optimizing the functional groups on the mesoporous silicon surface and the reaction temperature and time,an ultrathin ZIF-8 shell was synthesized in situ on the silicon surface to prepare a core-shell composite nanoparticle MSN@ZIF-8.The composite nanoparticles can be used for loading the chemotherapeutic drug Dox and have the p H-responsive drug release property,it can be used for constructing a tumor microenvironment responsive drug delivery system(DDS)for controllable drug release.Multidrug resistance(MDR)is one of the main causes of tumor chemotherapy failure.In Chapter 3,we designed a p H-responsive MSN-COOH@ZIF-8 nanoparticle for co-delivery of chemotherapy drugs and small interfering RNA(siR NA)for enhanced treatment of drug-resistant cancer cells.As mesoporous silicon has excellent biocompatibility and drug storage properties,ZIF-8 has a strong positive charge,it can effectively adsorb negatively charged siRNA and prevent siRNA from degradation by nuclease for the steric hindrance effect.In particular,the acid degradation of ZIF-8 can make the composite nanoparticle have p H-responsive drug release properties.Combining the excellent properties of these two kinds of nanomaterials,a MSNCOOH@ZIF-8 composite nanoparticle was constructed,and the chemotherapeutic drug doxorubicin(Dox)was loaded into MSNs,and then ZIF-8 encapsulated mesoporous silicon was used for adsorption of Bcl-2 siRNA for co-delivery of chemotherapeutic drugs and Bcl-2 siRNA to overcome drug resistance for enhanced cancer therapy.DNA origami is an excellent platform for constructing multifunctional nanodevices.In Chapter 4,we designed a DNA origami-based nanorobot for signal amplified detection of miR-21 and the release of antisense DNA cargo.The DNA origami nanorobot consists of a rectangular DNA origami and a DNAzyme-based DNA walker.After incubation with miR-21,the Mg Z robot at the start point of the DNA origami is activated and begins to cyclically cleave the substrate DNA,and could produce a green fluorescent signal(FAM),the Mg Z robot could walk along the substrate DNA path and reach the destination on origami to release Bcl2 antisense DNA cargo,and then produce a red fluorescent signal(Cy5).Thus,in the present of miR-21,the DNA origami robot(DNA origami nanorobot,DONR)can be activated to achieve the dual functions of signal amplified detection of miR-21 and simultaneously release of antisense cargo(Bcl2 antisense).In Chapter 5,we applied the DNA origami nanorobot for the precise diagnosis and treatment of cancer cells.In the experiment,we used DONR for intelligent diagnosis and treatment of cancer cells(MCF-7,Hela)and normal cells L02.Because cancer cells MCF-7 and Hela express high level of miR-21,normal cells L02 are miR-21 negative expression cells,the nanorobot can not only recognize cancer cells and normal cells but also release Bcl2 antisense DNA strands for the t reatment of cancer cells under the trigger of tumor marker miR-21.The nano-robot provides a research foundation for the development of an intelligent diagnosis and treatment platform based on DNA nanomachines.Antisense oligonucleotides(ASOs)are a kind of very effective technology for the treatment of drug-resistant cancer cells.In Chapter 6,we designed a DNA origamibased platform to deliver chemotherapy drugs Dox and ASOs.ASOs are used for enhanced treatment of cancer-resistant cells.By assembly of MUC1 aptamers on the two sides of DNA origami,the nano-platform can target cancer cells.To silence the drug-resistant genes Bcl2 and P-gp ASOs,we designed two kinds of ASOs on DNA origami.With the anchor strands on origami for loading Bcl2 and P-gp ASOs,it is very easy to load many Bcl2 and P-gp ASO strands on DNA origami by DNA strand hybridization.And the disulfide bonds on Bcl2 and P-gp ASOs make rapid release of ASOs from origami in the presence of glutathione(GSH).Since the concentration of GSH in cancer cells is much higher than that of normal cells,it can realize the stimulation-response release of ASOs.Besides,the chemotherapeutic drug Dox can be loaded by electrostatic adsorption on origami,so that Dox and ASOs can be delivered together into the cancer cells to enhance the therapeutic effect for drug-resistant cancer cells.