Preparation And Properties Of Biodegradable Fe₃O₄-Au Hybrid Nanomedicine

There are huge risks and toxic side effects of traditional cancer treatment methods including chemotherapy,radiation therapy,surgical resection,etc.At present,new non-invasive cancer treatment methods such as drug sustained release,photothermal,and photodynamic development based on nanomaterials have become new research directions.Among them,Fe₃O₄ nanomaterials are widely used as drug carriers due to their advantages such as non-toxicity,good biocompatibility,magnetic targeting,magnetocaloric effect,and magnetic resonance imaging.Combining Fe₃O₄ with a variety of functional nanomedicines can achieve multiple imaging and synergistic therapy in tumor sites,so the development of new diagnostic and therapeutic integrated drugs around Fe₃O₄ nanomaterials has become a current research hotspot.Recent studies have shown that nanoparticles with a diameter of less than 6-8 nm can be metabolized and cleared by the kidneys.So at present,Fe₃O₄ and its composite nanomedicine are faced with the problem of being unclearable due to its large size and stable structure.At the same time,small-sized nanoparticles?such as 6-8 nm?cannot provide multiple diagnostic and therapeutic functions,and their short circulation time in the blood and weak EPR effect result in low uptake efficiency at the tumor site.How to construct multifunctional degradable nanomedicine is a problem and challenge facing researchers.Currently,the development of degradable nanomedicine in response to external stimuli?such as magnetic field,laser?or tumor microenvironment?such as low PH,high GSH,etc.?has become the focus of research.Based on the weak acidic property of tumor microenvironment,this article proposes to modifythe dense Fe₃O₄ cores based on the difficult degradation of Fe₃O₄ based hybird nanomedicine to form the loose mesoporous skeleton structure by in-situ etching in advance to improve its acid response characteristics,and the mesoporous structure formed by the etching is conducive to drug loading.Based on this,gold nanoparticles are introduced on the mesoporous Fe₃O₄ microspheres to develop a magnetically targeted and biodegradable integrated multi-functional nanomedicine for diagnosis and treatment.The main research contents are as follows:?1?Superparamagnetic Fe₃O₄ microspheres are closely packed with grains of different sizes and have good stability in acid solutions.In order to improve its acid dissolution performance,an acid etching strategy is proposed,using citric acid as an etchant,and ethylene glycol as a protective solvent.Based on the relationship between the grain diameter and the dissolution performance,small particles are preferentially removed using citric acid.Large grains are left to form a loose mesoporous framework structure.The effects of etching conditions on the formation of mesoporous structures and the dissolution performance of the etching products in weak acid buffer?p H = 5?were systematically studied to optimize the mesoporous framework structure of Fe₃O₄ microspheres.On this basis,the modified polyimide molecules on the surface of mesoporous Fe₃O₄ microspheres were introduced with gold nanoparticles?4nm?,and the light absorption performance in the near-infrared region was improved by adjusting the gold nanoparticle loading amount to synthesize mesoporous Fe₃O₄-Au?MFA?multifunctional nanomedicine.It was found that the saturation magnetization of MFA is 38 emu/g,which has good magnetic targeting ability.The maximum drug loading ratio of DOX:MFA is 18.15%.When the concentration is 200 ?g/ml,the 1.5W/cm2,808 nm laser is used to irradiate for 5 minutes,the temperature can be raised up to 56.4?,and the photothermal stability is good.In vitro cell experiments show that MFA nano-microspheres can be degraded within 6 days in both the in vitro tumor microenvironment experiment and the in vitro cancer cellexperiment.When the concentration is 200 ?g/ml,the survival rate of tumor cells in combination with thermo-chemotherapy is about 9.51%.In vivo and in vitro MRI results show that MFA nano-microspheres have good contrast effects and imaging capabilities for real-time monitoring;in vivo treatment experiments have shown that MFA nano-microspheres successfully accumulate in tumor sites in mice,and the tumor ablation rate is more than 90% in combination with thermo-chemotherapy.?2?Based on the above-mentioned acid etching pore-forming strategy,it is further proposed to use Fe₂O₃@Fe₃O₄ microspheres as precursors,and simultaneously etch the Fe₂O₃ easily-dissolved core and the dense shell of Fe₃O₄ to synthesize Fe₃O₄ microspheres with hollow mesoporous structure.Aiming at the leakage of mesoporous Fe₃O₄ nano-microspheres during drug delivery,a mixture of drugs and phase-change reagents was introduced into the hollow mesoporous Fe₃O₄ microspheres,and the temperature of the drugs was controlled by laser irradiation to achieve the light-controlled release of the drugs.As in the previous chapter,Au nanoparticles were introduced to synthesize hollow mesoporous Fe₃O₄-Au?HMFA?multifunctional nanomedicine.Characterization revealed that HMFA nano-microspheres can be degraded within 5 days in both in vitro tumor microenvironment experiments and in vitro cancer cell experiments.The saturation magnetization is 20 emu/g and they have good magnetic targeting ability.When the concentration is 200 ?g/ml,a 808 nm laser?1.5 W/cm2?was selected for 5 min,the temperature can be raised to 58.8? and the photothermal stability is good.The results of in vitro drug release experiments and in vitro cell experiments and in vivo treatment experiments show that when nanomedicines reached the tumor site,laser irradiation can be used to control the temperature of Pent to dissolve and release DOX.In vitro after chemo-photothermal combined therapy,the survival rate of tumor cells is only about 4.19%,which may be because HMFA nano-microspheres have more strong photothermal effect,and at the same time,due to the concentrated release of DOX,the synergistic effectwith the photothermal effect is enhanced.Photothermal experiments in mice confirm that nano-microspheres can rise to the phase transition temperature of phase change materials in vivo.Thermal phase change materials not only avoid the leakage of DOX,but also improve the synergistic effect of chemo-photothermal therapy through light-controlled release.In vivo treatment experiments have shown that HMFA nanospheres successfully accumulate in tumor sites in mice,and the tumor ablation rate is also more than 90% in combination with thermo-chemotherapy.