Metal-Modified Mesoporous Silica Nanoparticles For Chemodynamic Therapy And Tumor Deep Penetration

Currently,multidrug resistance(MDR)and the difficulty in tumor sites penetration induced by the tumor microenvironment are still challenging in cancer treatment.Development of nanotechnology provides new strategies to solve existing problems.Mesoporous silica nanoparticles(MSNs),as a popular nano carrier,possess good biocompatibility,high drug loading capacity,and ease of modification,but are relativlely poor in versatality.In contrast,metallic materials,both metal ions or metal-related nanoparticles,have been widely investigated in cancer therapy due to their diverse physicochemical properties.In this work,with zinc,copper,iron and platinum,we designed metal-doped MSNs and nanodot-attached nanocomposite for the pH-responsive drug controlled release conferred by metals,chemodynamic therapy(CDT),pHresponsive size transformation for deep penetration,reactive oxygen species(ROS)-responsive ultra-small platinum nanodot pre-drug to overcome MDR.First,zinc-,copper-or iron-doped mesoporous silica nanoparticles(ZnMSNs,Cu-MSNs or Fe-MSNs)with uniform particle size and ordered mesoporous structure were prepared by using a modified Stober method.Among them,Zn-MSNs and Cu-MSNs were spherical in shape,and their sizes were larger than MSNs,101.42 nm±15.88 nm and 110.95 nm±38.65 nm,respectively.The sphericity of Fe-MSNs is reduced and the particles tend to grow into short rods in the direction of the pore channel with an axial size of 116.32 nm±28.85 nm.The copper and iron co-doped mesoporous silica nanoparticles(Cu-Fe-MSNs)were prepared by introducing Cu(NO3)2 and Fe(NO3)3 metal sources simultaneously,which showed a Janus structure of small spheres attached to large spheres,and the Cu elements were mainly distributed in the large sphere part of the particles,while the Fe elements were concentrated in the small sphere part of the particles,and the overall particle size was reduced to 80.82 nm±23.02 nm.The Zn-MSNs,Cu-MSNs,Fe-MSNs and Cu-Fe-MSNs all maintain the main composition as SiO2 stable tetrahedral structure,with the local composition replaced by-Si-O-M-O-Si-structure(M corresponds to Zn,Cu and Fe,respectively).Subsequently,the properties and in vitro anti-tumor effects of Cu-Fe-MSNs were further investigated.Based on the siphoning effect of the mesoporous structure of MSNs,the drug loading and encapsulation rates of Cu-Fe-MSNs for doxorubicin(Dox)reached 10.05%and 93.13%,respectively.Due to the introduction of Cu and Fe,nitrogen atom in Dox could form pH-sensitive coordination bonds with Cu or Fe in-Si-O-Cu-O-Si-or-Si-O-Fe-O-Siframework on the pore wall,and the cumulative drug release rate was 16.72%±2.63%and 83.36%±0.50%at pH 7.4 and 5.0,respectively,which could effectively reduce the early drug leakage before reaching the target cells and improve the therapeutic accuracy.In addition,Cu-Fe-MSNs were biodegradable and slowly degraded to small fragments in the lysosomal environment,and released Cu2+and Fe3+,which catalyzed Fenton-like and Fenton reactions in the cells and showed ferreptosis properties,including increasing the ROS generation,glutathione/glutathione disulfide ratio change,and lipid peroxidation.The Hela cell survival rate was suppressed to 8.82%±1.64%after incurbated with Cu-Fe-MSNs at concentration of 160 μg/mL.Then,chitosan-capped ultrasmall platinum nanodots(CS/Pt)were rapidly prepared with a monodispersed particle size of 3.19 nm±0.72 nm by using a low molecular weight chitosan(CS)as the protective agent,chloroplatinic acid as the platinum source,and sodium borohydride as the strong reducing agent.The CS/Pt coated Zn-MSNs-Dox(Zn-MSNs-Dox@CS/Pt)were prepared with stable monodisperse,uniform CS coating,Pt nanodots scattered and particle size of around 100 nm.The early drug leakage from the CS/Pt-coating nanosystems was further reduced under neutral conditions,and the 24-h cumulative drug release rates were 10.06%±2.21%and 57.44%±3.56%at pH 7.4 and 5.0,respectively.Finally,morphology alteration function was verified by in vitro simulations.It is revealed that Zn-MSNs-Dox@CS/Pt has a pH-responsive,i.e.,the composite particles with a particle size of around 100 nm were maintained in a neutral environment to safeguard in vivo circulation and tumor enrichment,and the Pt nanodots with a particle size of less than 5 nm were dissociated in a weak acid environment to promote tumor deep penetration.The acid-dependent morphological changes were examined at the two-dimensional cellular culture,resulting in expanding the cellular gap and affecting intercellular junctions.At the three-dimensional cell cluster level,Zn-MSNs-Dox@CS/Pt was observed to carry Dox into the center of the cell cluster,while both free Dox and ZnMSNs-Dox stayed only at the surface of the cell cluster.In addition,Zn-MSNsDox@CS/Pt formed a synergistic effect,where Dox releasing induced ROS generation in cells,and high ROS levels triggered Pt2+leaching from Pt nanodots,which showed good inhibition on drug resistant cells MCF-7/ADR.Similarly,Zn-MSNs-Dox@CS/Pt significantly inhibited tumor growth in MCF-7/ADR-bearing nude mice,and the tumor volume and tumor weight of nude mice in the Zn-MSNs-Dox@CS/Pt treatment group were significantly lower than those of the remaining control group.In summary,this work successfully constructed nanocomposites in the form of metal-doped and metal-based nanodot attachment,and investigated(a)the application potential of Cu and Fe in chemodynamic therapy as well as ferrptosis according to the qualities of different metals;(b)the effect of responsive particle size variation nanosystems on tumor tissue penetration;and(c)the role of high ROS-responsive ultrasmall Pt nanodots as prodrugs in multidrug-resistant cells.The works conducted in this thesis could potentially be served as the fundamentals for the future development of responsive metal nanocomposites for cancer therapy.