Mesoporous Silica Composite Nanoparticles For Stimuli-responsive Tumor Diagnosis And Treatment

The risk of cancer is significantly increasing nowadays,which is a serious social and health problem threatening human beings.Early detection and effective treatment would reduce the incidence and mortality rates significantly.With the continuous improvements in our understanding of tumor characteristics and the developments of nanotechnology,multifunctional nanocomposites offer a route towards cancer diagnosis and treatment.Stimuli-responsive systems for tumor microenvironment?such as pH,hypoxia,redox,enzymes,etc.?or external field?such as light,electricity,magnetism,ultrasound,radiation,etc.?,which could be used for temporally and spatially controllable therapeutic platforms,have been widely investigated currently.Mesoporous silica nanoparticles?MSNs?are of special interest for cancer theranostics due to their excellent biocompatibility,high stability,rigid framework,well-defined pore structure,easily controllable morphology and tunable surface chemistry.Therefore,we carried out a series of researches based on the construction of mesoporous silica composite nanoparticles for stimuli-responsive cancer diagnosis and treatment from the basic research of materials science?including reaction mechanism analysis,nanocomposites design,microstructure characterization,etc.?and the exploration of biological applications?including biomarker detection,tumor microenvironment modulation,controlled drug release,integration of collaborative treatment,etc.?.The main contents are as follows:?1?Mesoporous silica nanoparticles with radial pore structure were prepared by the oil-water two-phase method.Experimental investigations were performed by changing the ratio of oil/water,the amount of styrene,the concentration of lysine and the stirring speed.The role of each component in the reaction was analyzed and the interfacial growth mechanism was summarized,which pave the way for further design and application of multifunctional nanocomposites.?2?We established a new method for synthesizing upconversion nanoparticles with amorphous shell.The precursor solution for upconversion compounds was diffused into the radial mesopores of silica nanotemplates by capillary effect,followed by the nucleation and growth of upconversion nanocrystals through thermo-decomposition method.The upconversion mesoporous silica nanoparticles(CaF₂:RE³⁺@MSN)synthesized do not only present uniform morphology,but also show high specific surface area and large pore volume,providing sufficient space and abundant active groups for subsequent surface modification and multifunctional integration.The excellent upconversion luminescence property also offered a wide range of potential possibility for optical applications.?3?Simultaneous detection of multiple types of microRNA?miRNA?is of great significance in early cancer diagnosis.We have investigated a photoluminescence-based approach for simultaneous sensitive detection of multiple breast cancer related miRNA biomarkers,based on rare-earth-doped CaF₂ upconversion nanocrystals embedded mesoporous silica nanoparticles(CaF₂:RE³⁺@MSN).The upconversion mesoporous silica nanoparticles(CaF₂:RE³⁺@MSN)synthesized do not only present uniform morphology,but also show high specific surface area and large pore volume,providing sufficient space and abundant active groups for subsequent surface modification.The detection system was fabricated by immobilizing oligonucleotide probe onto the surface of CaF₂:RE³⁺@MSN and coupled with Fe₃O₄ magnetic particles.Two different rare earth doped upconversion MSN with oligonucleotide probe matching different target miRNAs made it possible to obtain a multiple biosensing platform for the detection of different miRNA in the same solution.?4?We developed a more accurate miRNA detection system via the development of a composite membrane,consisting of thermoplastic polyurethane?TPU?@GO electrospun fibres and high surface area upconversion mesoporous silica nanoparticles?MSNs?.In this system,the upconversion MSNs,synthesized by an in-situ nanocrystalline growth method,showed high specific area and abundant active groups,which were favorable for modification via DNA probes.The electrospun TPU fibres were used as a substrate,which,when combined with a GO coating,shows strong affinity toward single-stranded oligonucleotides conjugated with upconversion MSNs.In the presence of target miRNA,the complementary interaction between the DNA probe and miRNA resulted in detachment of upconversion MSNs from the membrane,and a consequent reduction in upconversion luminescence intensity.This provided quantitative miRNA detection with a limit of 20 pM.The interlaced network of the membrane showed strong-capillary-action and hence enrichment effects,which improved the accuracy of miRNA detection.This flexible composite membrane therefore offers a novel approach for accurate miRNA detection and has potential for application in early cancer diagnosis.?5?The efficacy of the conventional photodynamic therapy?PDT?is markedly suppressed by limited penetration depth of light in biological tissues and oxygen depletion in the hypoxic tumor microenvironment.Therefore,we combined the upconversion MSNs with MnO₂ coating and loaded with the photosensitizer Ce6 to prepare a multifunctional nanocomposite?C@SMn-Ce6?for near-infrared?NIR?-triggered PDT and tumor hypoxia modulation.Within such nanocomposites,Mn²⁺ions doped into the lattice of CaF₂ crystals effectively enhance the near-infrared?NIR?-triggered red-light upconversion photoluminescence for exciting the adsorbed Ce6 via resonance energy transfer,enabling the improved photodynamic phenomenon.Meanwhile,the MnO₂ coating modulates the hypoxic tumor microenvironment by in situ generating O₂ through the reaction with tumor endogenous H₂O₂.Both mechanisms acting synchronously leads to the superior therapeutic outcome in NIR-triggered photodynamic tumor therapy.?6?Under the action of an electric field,we found that the Faraday cage effect would occur on the surface of platinum nanoparticles?PtNPs?and produces a hole-doping condition.Dissociation reaction of water molecules occurs subsequently,generating cytotoxic hydroxyl radicals??OH?with the assist of chlorine ions.Based on this phenomenon,we present a new conceptual approach for cancer treatment,namely“electrodynamic therapy?EDT?”,utilizing the electro-driven catalytic reaction occurred on PtNPs under the square-wave alternating current?AC?electric field.Based on the experimental verification and computational simulation,we demonstrated that PtNPs have the ability to catalyze water molecule decomposition to produce ROS in the presence of chlorine ions.This mechanism induces the death of cancer cells and could be employed for local ablation of large size solid tumors.This work thus presents a nanotechnology-based EDT strategy as a new type of cancer treatment method with high potency and minimal invasiveness.?7?As a continuous study on the concept of previously proposed EDT,we designed mesoporous silica-based nanocomposites decorated with PtNPs and loaded with anticancer drug doxorubicin?DOX?for synergistic electrodynamic-chemotherapy?Silica-DOX@Chitosan-Pt,SDCP?.MSNs carriers with ordered radical pore structure and high specific surface area were fabricated first.Chitosan coating was utilized to prevent the early release of loaded anticancer drugs doxorubicin?DOX?.PtNPs were directly attached to the surface of chitosan-silica hybrid nanoparticles by in-situ chemical reductive growth.when the SDCP nanoparticles are internalized by cancerous cells via endocytosis and reach the acidic organelles such as lysosomes?pH⁵.0?,the swelling behavior of chitosan occurs and the release of loaded DOX molecules would be accelerated.Such silica-based nanocomposites could enable homogenous killing of large-sized tumors?over 500mm³?and realize remarkable tumor destruction efficacy at a relatively low quantity of electricity.To our best knowledge,this is the first study to combine EDT and chemotherapy to develop a synergetic nanoplatform,which will open a new dimension for the design of other EDT-based anticancer strategies.