Application Of Superparamagnetic Iron Oxide Nanoparticles In Tumor Therapy And Imaging

Monodispersed SPIONs(superparamagnetic iron oxide nanoparticles)co-coated with PEG and PEI polymers were prepared by an improved polyol method.To accomplish specific targeting properties,Tween 80 or FA(folic acid)was then modified on the SPIONs.The magnetic nanoparticles as a potential platform for dual targeted(receptor-mediated and magnetic-guided)drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site.Doxorubicin hydrochloride(DOX·HCl)was selected as a model anticancer drug to investigate the in vitro drug release and antiproliferative effect of tumor cells in vitro and in vivo.The key points are as follows:(1)Delivery of therapeutic or diagnostic agents across an intact blood-brain barrier(BBB)remains a major challenge.Superparamagnetic iron oxide nanoparticles(SPIONs)coated with poly(ethylene glycol)(PEG),poly(ethylene imine)(PEI)and polysorbate 80(Tween 80)(Tween 80-SPIONs)were prepared.We demonstrate the effective passage of tail-vein injected Tween 80-SPIONs across normal BBB in rats under an external magnetic field.The quantitative analyses show significant accumulation of SPIONs in the cortex near the magnet,with progressively lower accumulation in brain tissues far from the magnet.A transmission electron microscopy picture of an ultra-thin section of the rat brain displays Tween 80-SPIONs crossing the BBB.The comparative study confirms that both the Tween-80 modification and the external magnetic field play important roles in the effective passage of SPIONs across the intact BBB.Only the external magnetic field cannot drag the SPIONs coated with PEG/PEI polymers through the BBB.The results indicate the Tween 80-SPIONs cross the BBB via an active penetration facilitated by the external magnetic field.This work is encouraging for further study on the delivery of diagnostic and therapeutic agents into the brain parenchyma for the treatment of neurological disorders by using Tween 80-SPIONs carriers under an external magnetic field.(2)Multifunctional nanoparticles combining therapy and imaging have the potential to improve cancer treatment by allowing personalized therapy.In this study,we propose the concept of smart,multifunctional nanoparticles,which can intergerate magnetic field-induced targeting,drug-carrying vehicles and MRI contrast into one to tracking tumor progression.Here,the multifunctional PEG/PEI superparamagnetic iron oxide nanoparticles(SPIONs)modified by polysorbate 80(Ps 80)was prepared to encapsulate DOX for therasonic effect of giloma under magnetic field.The in vitro cell model study demonstrated that the multifunctional SPIONs significantly enhance the apoptotic and cytotoxic effects of DOX against C6 GBM cells.MRI monitoring images of glioblastoma(GBM)rat model showed that the multifunctional SPIONs was passively targeted in glioblastoma lesions at two hours post-administration by magnetic field.The ex vivo fluorescence images showed that the multifunctional SPIONs delivered the higher DOX molecules into glioblastoma tissues,which suggested its efficient targeting effect.In vivo antitumor effect study showed that tumor growth inhibition of the multifunctional SPIONs was more obvious than that of free DOX.And the median survival period of the multifunctional SPIONs treatment was significantly extend from 32 days of free DOX treatment to 79 days.TUNEL assay of glioblastoma tissues demonstrated the multifunctional SPIONs induced the more tumor apoptotic cells than free DOX.In conclusion,the multifunctional SPIONs may be a potential theranostic carriers for the treatment of CNS malignancies.(3)Monodispersed SPIONs(superparamagnetic iron oxide nanoparticles)cocoated with PEG and PEI polymers were prepared by an improved polyol method.To accomplish cancer-specific targeting properties,FA(folic acid)was then modified on the SPIONs via EDC/NHS method(FA-SPIONs).Doxorubicin(DOX)as an example anticancer drug was loaded into FA-SPIONs(DOX@FA-SPIONs),the DOX release rate of DOX@FA-SPIONs was much high in low pH PBS.The SPIONs,FA-SPIONs and DOX@FA-SPIONs with mean hydrodynamic diameters of 23,40 and 67 nm,respectively,performed excellent colloidal stability in PBS.Confocal laser scanning microscope(CLSM)study implicated that the FA-SPIONs targeted MCF-7 cells efficiently through the FA receptor-mediated endocytosis.DOX@FA-SPIONs were tested in nude mice with xenograft MCF-7 breast tumor though tail intravenous injection and were found inhibiting tumor growth more efficiently.The application of a magnetic field(MF)greatly improved the growth inhibiting efficiencies of DOX@FA-SPIONs on MCF-7 cells in vitro and on xenograft MCF-7 breast tumor of nude mice in vivo.The aggregation of SPIONs in tumor was monitored by magnetic resonance imaging(MRI)as the DOX@FA-SPIONs exhibited high r2 relaxivity(81.77 mM-1S-1).Histology on liver,Lung,kidney and heart in mice showed no significant toxicity of DOX@FA-SPIONs on mice organs after 35-day treatment.The FA-SPIONs are high efficient drug delivery nanoplatform for advanced cancer theranostics.