Tannine-iron(Ⅲ) Modified Mesoporous Silica Nanoparticles For Tumor Chemotherapy/Photothermal Therapy

Research background and purpose:Cancer is one of the major diseases that seriously threaten human life and health,and chemotherapy is the main treatment method.However,the nonspecific cytotoxicity of chemotherapy,leakage during transportation,and low concentrations in tumor tissue greatly affect patient life.The high permeability,long-term retention,increased drug solubility,and high bioavailability of nanomaterials to tumor blood vessels have become the focus of current research.However,nanoparticles used for targeted therapy cannot achieve early accurate diagnosis and real-time monitoring of therapeutic effects.Therefore,in order to meet the needs of clinical diagnosis,nanotechnology is used to deliver targeted magnetic resonance imaging contrast agents,photoacoustic imaging contrast agents,and fluorescent imaging agents to tumor tissue,which can further localize and diagnose malignant tumors and achieve the integration of cancer diagnosis and treatment.Tannic acid（TA）,as a natural plant polyphenol,can chelate with metal particles to form a complex.In addition,TA-Fe（Ⅲ）complexes have excellent photothermal effects under near-infrared light,and have good application potential in the biomedical field.Therefore,this thesis utilizes the photothermal conversion ability of tannic acid iron（Ⅲ）to select mesoporous silica（MSNs）with good biocompatibility to load doxorubicin（DOX）and modify its surface with TA-Fe（Ⅲ）.In order to further improve the biocompatibility of nanoparticles,BSA complexes were modified on their surfaces to achieve the synergistic treatment of tumor with photothermal and chemotherapy.Materials and Methods:1.Mesoporous silica nanoparticles（MSNs）were prepared by the sol gel method.The experimental parameters were optimized by changing the reaction speed,temperature and feed ratio,and the optimal synthesis process was selected.Aminoated mesoporous silica nanoparticles（MSN-NH₂）were prepared by amination modification of 3-aminopropyltriethoxysilane（APTES）and loaded with doxorubicin（DOX）.Then,p H responsive tannic acid iron modified drug loaded mesoporous silica nanoparticles（TA-Fe（Ⅲ）@MSN@DOX）were prepared using polyphenol metal protein coordination self-assembly.The morphology of nanoparticles was characterized by scanning electron microscopy（SEM）and transmission electron microscopy（TEM）;The particle size distribution and potential were characterized by dynamic light scattering nano particle size analyzer（DLS）;Fourier transform infrared spectroscopy（FITR）was used to characterize the functional group changes on the surface of nanoparticles,X-ray photoelectron spectroscopy（XPS）was used for elemental analysis,and inductively coupled plasma spectroscopy（ICP）was used to investigate the Fe（Ⅲ）content of nanoparticles;UV spectrophotometry was used to determine the drug loading rate（DL）of the drug,and fluorescence spectrophotometry was used to investigate the drug release from nanoparticles at different p H conditions.2.The safety of blank nanoparticles and the inhibitory effect of drug loaded nanoparticles on the proliferation of human MCF-7 breast cancer cells were evaluated by CCK 8 and live/head cell staining experiments.The uptake of nanoparticles by human MCF-7 breast cancer cells was compared through cell uptake experiments.3.The 4T1 tumor-bearing mice model was established,and the photothermal effect of nanoparticles in vivo was investigated by injecting nanoparticles into the tail vein and irradiating them with near-infrared light.4.The 4T1 tumor-bearing mice model was established,and the antitumor efficacy and safety of nanoparticles were further investigated by injecting nanoparticles into the tail vein and conducting pharmacodynamic experiments in vivo to investigate the antitumor efficacy of nanoparticles in vivo.The tissue sections were stained with hematoxylin and eosin（H&E staining）.with near infrared irradiation.Result:1.The nanoparticles constructed in this study are regular spherical in shape,with uniform particle size distribution,and have a significant Tindall effect.The average particle size is 465±44.95 nm,the potential is-30.1 m V,and the polydispersity coefficient（PDI）is 0.201.The results of in vitro release experiments show that nanoparticles have p H responsive ability;In vitro photothermal experiments show that nanoparticles have good photothermal conversion capabilities.2.Cytotoxicity experiments and live/dead cell staining showed that empty nanoparticles（TA-Fe（Ⅲ）@MSN）were safe at experimental doses,while drug-loaded nanoparticles（TA-Fe（Ⅲ）@MSN@DOX）were safe at experimental doses.It can significantly inhibit the proliferation of mouse MCF-7 breast cancer cells.Cell photothermal experiments showed that the photothermal efficacy of TA-Fe（Ⅲ）@MSN nanoparticles against MCF-7 cells increased with increasing infrared irradiation power and nanoparticles concentration@MSN@DOX The infrared irradiation group had good chemotherapy and photothermal synergistic anti-tumor efficacy.Cell uptake experiments show that nanoparticles（TA-Fe（Ⅲ）@MSN）can enter the cell within about 4 hours.3.In vivo photothermal experiments have shown that nanoparticles can rise to46.7℃after 5 minutes of near-infrared laser irradiation,It has been proved that it has good photothermal effect in tumor bearing mice.4.In vivo anti-tumor experiments have shown that nanoparticles can effectively inhibit tumor growth in 4T1 tumor bearing mice,and the introduction of photothermal therapy can enhance the anti-tumor effect of nanoparticles,enabling tumor ablation.The safety test in vivo showed that the nanoparticles had no obvious damage to all important organs（heart,liver,spleen,lung and kidney）of mice,indicating that the nanoparticles were safe.Conclusion:This study successfully designed and prepared a diagnostic and therapeutic integrated drug loaded nanoparticles（TA-Fe（Ⅲ）@MSN@DOX）Nanoparticles have good acid responsive release ability and photothermal performance in vitro.In vitro and in vivo experiments have confirmed that the nanoparticles have good synergistic anti-tumor effects of photothermal therapy and chemotherapy,providing a new idea for the development of new diagnostic and therapeutic integrated nanoparticles with photothermal imaging and chemotherapy functions.