Preparation Of Innovative Magnetic Nanoparticles For Biomedical Applications

Due to their unique magnetic properties and comparable size to functional biomolecules,magnetic nanoparticles(MNPs)have been considered as one of the most promising materials for biomedical applications.Magnetic iron oxide nanoparticles as MRI contrast agent have been developed by many companies around the world.In 1996,the US Food and Drug Administration(FDA)approved Feridex developed by Advanced Magnetics as liver contrast agent in clinic.With increasing demand in effectual treatment and noninvasive,real-time disease diagnosis,MNPs can enhance magnetic resonance imaging(MRI)sensitivity,magnetic heating efficiency,and deep tissue penetration of the magnetic field,making MNPs particularly attractive for constructing high-performance contrast/hyperthermia agents for diagnostic and therapeutic applications.Despite the stated advantages of MNPs,the main challenges to their use from bench to bed are low MR sensitivity and relatively poor energy transfer efficiency.In order to improve the performance of nano-agents,significant effort has been dedicated on the preparation of MNPs to control the size,shape,composition,surface functionalization,and magnetic properties of MNPs.This thesis identifies critical issues and newly available strategies for controlling synthesis of MNPs and modifying MNP surfaces to significantly improve their performance as contrast/hyperthermia agents.1.Magnetic hyperthermia based on nanoparticle suspension has become a powerful and non-invasive technique for various biomedical applications,where clinically approved single-domain superparamagnetic iron oxides are widely used.However,the paradox of superparamagnetism facilitating good suspension and improved magnetic properties for high application performance has been a long standing problem.Here,we have developed a ferrimagnetic vortex-domain iron oxide nanorings(FVIOs)suspension with significant efficient property for thermal induction.The unique magnetic vortex structure has been proved to possess negligible remanance and relatively large hysteresis loss,which not only promoting the colloid stability and but also maximizing the specific absorption rate(SAR).The obtained FVIOs suspension have demonstrated superior magnetic heating ability with a high SAR value(3050 W/g),one order of magnitude higher than that of commercial superparamagnetic Resovist(280 W/g),which allow in vitro trials on MCF-7 breast cancer cells carried out at low dosage with cell viability of about 20%recorded after 10 min treatment.Combined with enhanced permeability and retention effect arising from relatively large particle size,FVIOs also demonstrated remarkable antitumor efficacy on a nude mice tumor without any severe toxicity.The FVIOs suspension provides a new class of heat mediator for thermally active applications in biomedical system.2.Highly monodispersed magnetite nanoparticles with controlled particle size and mPEG surface coating have been successfully synthesized as a model system to investigate the effect of surface coating on the specific absorption rate(SAR)under an alternating magnetic field.Enhanced SAR with decreased surface coating thickness was observed and ascribed to the increased Brownian loss,improved thermal conductivity as well as improved dispersibility.By elaborate optimization of the surface coating and particle size,a significant increase of SAR(up to 74%)could be achieved with a minimal variation of the saturation magnetization(<5%).In particular,the 19nm@2000 sample exhibited the highest SAR of 930 W/g among the samples.Furthermore,this high heating capacity can be maintained in various simulated physiological conditions.Our results provide a general strategy for surface coating optimization of magnetic cores for high performance hyperthermia agents.3.Superparamagnetic nanoparticles with superhigh T2 relaxivity and cellular uptake are strongly desired for ultrasensitive magnetic resonance imaging(MRI).Towards this end,highly monodispersed manganese ferrite nanoparticles(MNPs,6 nm)with mPEG-g-PEI and PEG coatings as model system are employed in this study to investigate the coating engineering for simultaneously high T2 relaxivity and cellular uptake.The quantitative evaluations of the intracellular uptake indicate that mPEG-g-PEI modified MNPs possess highly efficient cellular uptake,2.4-fold larger than that with mPEG coating.More signifi cantly,this coating simultaneously leads to a remarkably high T2 relaxivity up to 331.8 mM-1s-1,which is 4 times larger than that of the mPEG control and the largest value reported for superparamagnetic iron oxides with similar size.Modeling analysis reveals that the superior relaxivity is mainly attributed to the largely reduced diffusivity of water molecules trapped in the mPEG-g-PEI net.Further MRI of MDA-MB-231 breast cancer cells loaded MNPs with mPEG-g-PEI coating demonstrated the strong MR contrast in vitro effect with a T2 relaxivity as high as 92.6 mM-1s-1,2.5-folds larger than reported 10 nm MNPs.This study provides a universal strategy of coating engineering of various magnetic nanoparticles for highly sensitive MRI.4.Uniform magnetic nanoparticle-loaded polymer nanospheres with different loading contents of manganese ferrite nanoparticles were successfully synthesized using a flexible emulsion process.The MnFe2O4-loaded polymer nanospheres displayed an excellent dispersibility in both water and phosphate buffer saline.The effect of loading ratio and size of MnFe2O4 nanoparticles within the nanospheres on the specific absorption rate(SAR)under an alternating magnetic field was investigated.Our results indicate that a large size(here 18 nm)and a low loading ratio are preferable for a high SAR.For a smaller particle size(6 nm),the low loading ratio did not result in an enhancement of the SAR value,while a very low SAR value is expected for 6 nm.In addition,the SAR of low-content MnFe2O4(18 nm)-loaded polymer nanospheres in the agarose gel which is simulated for in vivo environment is the highest among the samples and does not change substantially in physiological environments.This differs largely from the behaviour of singly dispersed nanoparticles.Our results have paved the way for the design of MnFe2O4-loaded polymer nanospheres as magnetic hyperthermia agents for in vivo bio-applications.5.Human-like collagen(HLC)coated monodispersed superparamagnetic Fe3O4 nanoparticles have been successfully prepared to investigate its effect on heat induction property and cell toxicity.After coating HLC,the sample shows a faster speed of raising temperature under an alternating magnetic field although it has a reduced saturation magnetization.This may result from the effective heat conduction and good colloid stability due to many charges of HLC on its surface.In addition,compared with Fe3O4 nanoparticles before coating HLC,HLC-coated Fe3O4 nanoparticles do not induce notable cytotoxic effect at higher concentration and indicates that HLC-coated Fe3O4 nanoparticles could improve biocompatibility.Our results make clear that Fe3O4 nanoparticles after coating HLC not only possess effective heat induction for cancer treatment,but also have improved biocompatibility for biomedicine applications.