Appropriate Size Of Magnetic Nanoparticles For Various Bioapplications In Cancer Diagnostics And Therapy

Cancer is one of the major diseases that endanger human life and health,and tumor therapy has always been a difficult problem in the field of medical research.Nanomedicine has offered new strategies for cancer treatment due to their unique advantages of nanoparticles over small molecules.The intrinsic optical,thermal,electrical,or magnetic properties of the nanoparticles can be utilized for imaging or therapeutic purposes.Interest in constructing multifunctional nanoparticles has recently grown rapidly.Nanoparticles can be utilized for simultaneous delivery of therapeutic agents to the tumor area,real-time tracking of their biodistribution and fate in vivo,and evaluation of the therapeutic efficacy.Multifunctional bio-applications of the nanoparticles largely depended on their physiochemical properties(especially particle size).The optimized size range may be different for the bio-application of each function associated with multifunctional nanoparticles.It is difficult to best optimize each function simultaneously for multifunctional nanoparticles of a fixed size.The optimized size of the multifunctional nanoparticles should be chosen based on the greatest ability to perform each function.Therefore,it is necessary to investigate every optimized size range for each function of the nanoparticles before making a decision regarding size.Unfortunately,few studies have focused on studying every appropriate size range for each bio-function of multifunctional nanoparticles ahead and then choosing the final size.Iron oxide nanoparticles,which have been widely used in biomedical research,have multiple functions,such as molecular imaging,drug delivery,magnetic targeting,and photothermal therapy.The effect of size on the bio-applications of iron oxide nanoparticles has been often reported but only limited in the field of magnetic resonance imaging(MRI),and the investigated size was also limited to a narrow range.An investigation of iron oxide nanoparticles over a larger size range and of the size effect on diverse biofunctional applications is needed.Firstly,we synthesized a series of monodisperse Fe3O4 nanoparticles with identical surface properties ranging in size from 60 to 310 nm and systematically investigated their bio-behavior and application.The diameters of these nanoparticles were 60 nm,120 nm,200 nm and 310 nm,respectively,and they were referred to Fe3O4-60,Fe3O4-120,Fe3O4-200,and Fe3O4-310.Our data indicate that compared to their large counterparts,small Fe3O4 nanoparticles exhibited greater cellular internalization and deeper penetration into multicellular spheroids,thus enabling a higher photothermal ablation efficacy in vitro.Interestingly,larger Fe3O4 nanoparticles showed greater accumulation in tumors,thereby inducing more efficient tumor growth inhibition.In addition,120 nm may be the optimal diameter of Fe3O4 nanoparticles for magnetic resonance imaging and photoacoustic tomography in vitro.However,more efficient in vivo imaging mediated by Fe3O4 nanoparticles will predominantly depend on their high accumulation.Then,we synthesized Fe3O4-10 particles with the diameter of about 10 nm,and studied the biological effects of magnetic targeting in vitro and in vivo with the previous four types of magnetic nanoparticles.In the study of magnetic targeting effect in vitro,we first studied the magnetic responsiveness of blank and drug loaded Fe3O4-10,Fe3O4-60,Fe3O4-120,Fe3O4-200 and Fe3O4-310 nanoparticles in static solution and simulated in vivo environment.It was found that,except for Fe3O4-10,the nanoparticles in each solution could be enriched to the target site under the function of external magnetic field with the prolongation of time.When the particle size becomes larger,the adsorption rate of it will be faster.The magnetic responsiveness of the nanoparticles will be lower if the solution viscosity become higher.Cellular uptake experiments also showed that,the increase of intracellular uptake for the nanoparticles with larger size was the most enhanced under the function of an external magnetic field.In vivo magnetic targeting efficiency was determined with the bilateral tumor model mice.The results of in vivo fluorescence imaging and magnetic resonance imaging also showed that nanoparticles with larger particle size exhibited higher tumor retention and a stronger in vivo magnetic targeting effect.In addition,it is noteworthy that,in all of the above magnetic targeting efficiency experiments in vivo and in vivo,not only the nanoparticles themselves could be remained in the targeted site,the drug molecules on the nanoparticles could also be carried to the same location.It is suggested that the drug concentration could be improved effectively through the magnetic targeting strategy,and the toxicity of the nanomaterials to the normal tissue could be reduced.In this study,the relationship between the size effect and the biological behavior of magnetic nanomaterials was studied in depth and systematically,including cellular uptake,penetration in multicellular spheroids,biodistribution,magnetic resonance imaging,photoacoustic imaging,magnetic responsiveness and in vivo photothermal therapy.Our work presents a different appropriate size range for each biofunction of Fe3O4 nanoparticles,which could be a valuable reference for future nanoparticle design and clinical nanomedicine.