Construction Of Targeted Delivery System For Curcumin Loaded On Magneticα-Fe₂O₃/Fe₃O₄ Heterogeneous Nanotubes And Its Apoptosis Mechanism On MCF-7Cell

Curcumin（CUR）could regulate the microenvironment of various tumor cells,inhibited the proliferation,invasion metastasis,and induce the apoptosis.However,the poor of curcumin intestinal mucosa absorption,blood stability and solubility in water limited its application.In recent years,nanomedicine and life sciences had been greatly developed due to the research of nanomaterials.The novel nanocarriers could improve the water-solubility of insoluble drugs,protect the drugs from being phagocytic by human immune system,enhance drug stability and change the way of cell uptake.In this paper,magneticα-Fe₂O₃/Fe₃O₄ heterogeneous nanotubes were used as the carrier of curcumin,which was encapsulated by liposome（LIP）to construct the intelligent drug delivery system of novelty magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP,and the mechanism of its anti-tumor effect was further studied.The specific research outcomes were as follows.（1）Construction of magneticα-Fe₂O₃/Fe₃O₄ heterogeneous nanotubes.Magneticα-Fe₂O₃/Fe₃O₄ heterogeneous nanotubes were constructed by hydrothermal-calcination method using Fe Cl₃,K₂SO₄,NH₄H₂PO₄ as raw materials.Through SEM,TEM,VSM,XPS,XRD,EDS,BET,CV and EIS characterization techniques,the effects of process parameters on spatial structure,magnetic properties and phase composition of the products were investigated.It was found that the product changed from spindle-like to flake-like with increase of NH₄H₂PO₄ concentration,hollow structure gradually appeared with the increase of K₂SO₄ concentration,hydrothermal temperature and calcination time.When the concentration of NH₄H₂PO₄ and K₂SO₄ were 3 m M and 5 m M respectively,α-Fe₂O₃ nanotubes with hydrothermal temperature of 220℃for 48 h had large inner pore volume.The length of the nanotubes was about 240 nm,the outer and inner diameters were about 178 nm and 145 nm,respectively,and the saturation magnetization intensity was only 0.42 emu/g.α-Fe₂O₃ nanotubes and glucose were evenly mixed in a crucible,and then calcined in a furnace,α-Fe₂O₃/Fe₃O₄ heterogeneous nanotubes were obtained.The magnetic properties of the products increased firstly then decreased with augment of calcination temperature,calcination time and glucose mass,the maximum saturation magnetization was 50.1 emu/g.（2）Construction of magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP delivery system.A large number of CUR were loaded into hollow structure ofα-Fe₂O₃/Fe₃O₄ nanotubes as a drug carrier by vacuum ultrasonic method.α-Fe₂O₃/Fe₃O₄-CUR was successfully coated in liposomes by thin film hydration method.α-Fe₂O₃/Fe₃O₄-CUR@LIP nanocomposites with a saturation magnetization of 42.2 emu/g had strong magnetic response and could be induced by magnetic fields.The hydrodynamic particle size of magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP nanocomposites prepared by adjusting the ratio of different raw materials ranged from 228 nm to 276 nm,and the drug encapsulation rate was about 90%.The magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP nanocomposite had the characteristics of p H-sensitive and slow release.The effective concentration and colloidal stability of CUR in magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP nanocomposites could be maintained within 5 d.（3）Pharmacodynamic evaluation of magneticα-Fe₂O₃/Fe₃O₄-CUR@LIP delivery system.The effect and apoptotic mechanism of the magnetic nanotubes as effective carrier of CUR on breast cancer cells were evaluated.The results of MTT,AO/EB staining and flow cytometry confirmed the biocompatibility of the blank carrier.CUR andα-Fe₂O₃/Fe₃O₄-CUR@LIP had obvious killing effect on MCF-7 cells.The cytotoxicity ofα-Fe₂O₃/Fe₃O₄-CUR@LIP at magnetic field was higher than that of free CUR,and it was mainly achieved by inducing the late apoptosis of cells.The results of prussian blue staining and electrochemical experiments showed that the carrieres was aggregated and absorbed in MCF-7 cells.Western blotting was used to detect the expression of apoptosis-related proteins,andα-Fe₂O₃/Fe₃O₄-CUR@LIP up-regulated the proteins levels of Bax,p53,Caspase-3,while down-regulated hypoxia-inducible factor HIF-1αand the anti-apoptosis-related protein Bcl-2.The oxidative stress in the cells was detected,and it was confirmed that the nanoformulation induced the accumulation of intracellular ROS species and promoted the occurrence of cell apoptosis,which was verified by the active oxygen scavenger.The nanocomposites could activate the redox reaction in cancer cells,induce the production of endogenous ROS and cause cell apoptosis.