Ph-responsive T₁-T₂^* Dual-modal Contrast Agents Based On Magnetic Nanoparticles For Diagnosis

Cancer refers to malignant tumors,it performs a great threat to human health.Early diagnosis and right disease management,necessitate accurate diagnosis of pathological states of the disease.Magnetic resonance imaging(MRI)is one of the crucial noninvasive technological means belong to molecular imaging techniques involving computed tomography(CT),fluorescence optical imaging(FOI),ultrasonic imaging(US),and positron emission tomography(PET)and the like.It can be applied to cancer diagnosis and provide three-dimensional graphic of tissues at a high spatial resolution without radiation harm and penetration depth limitation which has attracted a lot of attentions.However,there is usually only a slight difference in the relaxation time between pathological tissue and normal tissue,which may confuse the diagnosis process.Therefore,magnetic resonance imaging requires contrast agents to improve the sensitivity and accuracy of diagnosis.Contrast agents are mainly used to shorten the relaxation time of protons in water and realize the regulation of magnetic resonance signals.In recent years,the application of nanoparticles in cancer diagnostic techniques such as magnetic resonance imaging has caused a great deal of research.Up to now,there have two categories of materials applied,one is paramagnetic gadolinium(Gd)-based coordination complexes(including Gd-DTPA and Gd-DOTA)which were used to reduce the longitudinal relaxation time of water protons as T1 contrast agents,and usually the other is the superparamagnetic iron oxide nanoparticles(such as Feridex and Resovist),which act on providing negative contrast as T2 contrast agents.Nevertheless,due to the low molecular weights,clinical used Gd-based MRI agents usually suffer from short blood circulation time.Moreover,the majority of Gd-based contrast agents are harmful to the organ such as kidney.On the other hand,iron oxide-based T2 contrast agents are limited by the calcification,bleeding,and the susceptibility artifacts.Just as the facts mentioned above,all the contrast agents now available have more or less drawbacks and limitations.In order to overcome above problems,some dual-modal contrast agents were designed to improve the MRI effect,which provided the integrated imaging information simultaneously.Not only the T1*-weighted signal provide accurate diagnostic,but also the T2*-weighted signal are contributed to lesions detecting.Paramagnetic manganese ions(Mn2+)can play a role in shortening the relaxation time of T1 and T2 simultaneously.It is a valuable contrast agent for magnetic resonance imaging.Meanwhile,Mn2+ is one of the essential elements of humans,it has a relatively high electron spin(5/2)and has less toxic than other paramagnetic metal ions.We have prepared two pH-responsive T1-T2*dual-modality contrast agents by gentle and simple hydrothermal process,Fe3O4@C@MnO2 and MnSiO3@Fe3O4@C nanoparticles can enhance T1-T2 imaging simultaneously and improve diagnostic accuracy.The work is as follows:(1)we have developed a simple,self-reduction process for in situ fabrication of core-shell structured Fe3O4@C@MnO2.Through coating MnO2 onto the surface of Fe3O4@C,the resulting Fe3O4@C@MnO2 NPs can be served as pH-reponsive T1-T2*dual-modal contrast agents.The release rate of Mn ions in acidic PBS(pH = 5.0)was approximately ten times to that in neutral condition(pH = 7.4).Benefiting from the excellent acid-sensitivity,which facilitates the release of ions from Fe3O4@C?MnO2 NPs at tumor region with acidic microenvironment and organelles,the diagnosis accuracy was commendably improved.After intravenous injection of Fe3O4@C@MnO2 NPs,a rapid contrast enhancement in tumors was achieved with a significant enhancement of 127%24 h after the administration.Moreover,a significant decreasement of 71%was witnessed in T2 MRI signal.It demonstrated that Fe3O4@C@MnO2 NPs can act as both positive and negative MRI contrast agents.Cytotoxicity assays,hemolysis assay and histology analysis demonstrated excellent biocompatibility of Fe3O4@C@MnO2 NPs.Therefore the Fe3O4@C@MnO2 is a safty dual-modal contrast agent for precisely diagnosis,will be highly promising for the development of multiplex diagnostic nanoplatform.We use SiO2@Fe3O4@C nanospheres as precursors.Then etch solid-state SiO2 nucleus through Na3C6H5O7·2H2O and MnSO4·H2O to transform the SiO2 from solid state to mesoporous MnSiO3,forming superparamagnetic core-shell MnSiO3@Fe3O4@C nanoparticles.The nanoparticles have a uniform particle size and mean diameter of about 125 nm Superparamagnetic Fe3O4 can act on T2*-weighted imaging to detect diseased tissue.MnSiO3@Fe3O4@C is eroded by hydrogen ions in acidic tumors.The released Mn2+ ions shorten the longitudinal relaxation of water protons and increase MR imaging sensitivity.