Functionalized Magnetic-mesoporous Silica Nanoparticles For Combined Cancer-targeted Therapy

In recent years,nanotechnology is widely used in nanomedicine,especially in anti-tumor studies.Combination therapy or multimodality imaging can be realized by integrating different therapeutic agents or diagnostic agents into one platform.Mesoporous silica nanoparticles?MSNs?have received considerable attention for cancer therapy due to their simple synthesis,tunable pore size and volume,controllable diameter,and significant biocompatibility.The large surface area and pore volume provide a high drug loading capacity allowing adsorption of many different types of molecules.Facile silane chemistry allows simple surface modification of MSNs with variety of functional groups,making them amemable to diverse applications.With these prominent properties,the study of MSNs on cancer theranostics has increased dramatically.In this study,we focus on developing cancer therapeutic and diagnostic system based on MSNs,including using MSNs for combination therapy and theranostic.We explored the endocytic uptake pathways of MSNs,using magnetic MSNs as T₂ MR imaging contrast agents and how to endow MSNs the target function for improving cell uptake to enhance the antitumor effect.In chapter one,we summarized the application of MSNs in cancer therapies and diagnosis.We discuss their advantages and disadvantages,and look forward their prospects.In chapter two,we synthesized polyethylenimine?PEI?-moodified Fe₃O₄@SiO₂nanoparticles,which could electrostatically absorb VEGF shRNA?denoted as Fe₃O₄@SiO₂/PEI/VEGFshRNA?.Thenanocomplexesshowedexcellent hemocompatibility and biocompatibility,they could be internalized by MCF-7 cells and exhibited significant inhibition of VEGF gene expression in vitro.The nanocomplexes have significant knockdown efficiency when the concentration of nanocomposites reached 60?g/mL,but almost no cytotoxicity was detected.We also showed that the Fe₃O₄@SiO₂/PEI/VEGF shRNA nanocomposites had the potential for VEGF shRNA delivery and MR imaging simultaneously.In chapter three,we designed folate?FA?receptor targeted magnetic mesoporous silica nanoparticles for co-delivery of DOX and VEGF shRNA?denoted as M-MSN?DOX?/PEI-FA/VEGF shRNA?.The nanocomplexes have magnetic and FA dual targeting function,which can highly efficient delivery of DOX and VEGF shRNA.The RNAi efficiency and antiangiogenic effects were further investigated.It was expected that the MSN?DOX?/PEI-FA/VEGF shRNA nanocomplexes could be employed as an efficient and safe codelivery nanoplatform for antitumor studies.In chapter four,we loaded chemotherapy drug Irinotecan and NIR dyes onto hollow mesoporous silica nanoparticles for combination of chemotherapy and photothermal therapy?denoted as HMII?.The potential antitumor effect through PTT and chemotherapy in vivo were evaluated in EMT-6 cell bearing mice.The results demonstrated that HMII have superior antitumor effect over drug mixtures or monotherapies.Thus,the HMII would be a potential biomedical nanosystem for combination of chemotherapy and photothermal therapy.