Metal Oxide Nanoparticle-Based T1-T2 Dual-Mode Magnetic Resonance Imaging Contrast Agent

Abstract

The present invention relates to a magnetic resonance imaging (MRI) contrast agent, particularly a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent that can be used not only as a T1 MRI contrast agent but also as a T2 MRI contrast agent, and a method for producing the same. The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent can provide more accurate and detailed information associated with disease than single MRI contrast agent by the beneficial contrast effects in both T1 imaging with high tissue resolution and T2 imaging with high feasibility on detection of a lesion.

1 . A metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent, wherein the agent is used not only as a T1 MRI contrast agent but also as a T2 MRI contrast agent. 
     
     
         2 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 1 , wherein the metal oxide is superparamagnetic metal oxides. 
     
     
         3 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 2 , wherein the superparamagnetic metal oxides are at least one selected from the group consisting of iron oxide, cobalt oxide and nickel oxide. 
     
     
         4 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 2 , wherein the superparamagnetic metal oxides are formed with at least one shape selected from the group consisting of octahedral, cross-shaped, urchin-shaped, and cubic. 
     
     
         5 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 2 , wherein the superparamagnetic metal oxides comprise the doped metal ions of T1 contrast material. 
     
     
         6 . A method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent that has a core of T1 contrast material and a porous shell of T2 contrast material on the core, comprising the following steps:
 A) synthesizing metal oxide nanoparticles of T1 contrast material under inert gas environment;   B) forming an epitaxial layer of metal oxide of T2 contrast material on the surface of metal oxide nanoparticles of T1 contrast material under inert gas environment;   C) maintaining the formation of the layer of metal oxide of T2 contrast material under dry air environment to form multilayer nanoparticles having a core and porous shell structure; and   D) coating multilayer nanoparticles with a biocompatible polymer.   
     
     
         7 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the metal oxide nanoparticles of T1 contrast material are at least one selected from the group consisting of manganese oxide nanoparticle, chromium oxide nanoparticle and gadolinium oxide nanoparticle. 
     
     
         8 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the metal oxide nanoparticles of T1 contrast material are synthesized with at least one shape selected from the group consisting of octahedral, cross-shaped, urchin-shaped, and cubic. 
     
     
         9 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the metal oxide of T2 contrast material is superparamagnetic metal oxides. 
     
     
         10 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 9 , wherein the superparamagnetic metal oxides are at least one selected from the group consisting of iron oxide, cobalt oxide and nickel oxide. 
     
     
         11 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the layer of metal oxide of T2 contrast material comprises the doped metal ions of T1 contrast material. 
     
     
         12 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the multilayer nanoparticles have the core of T1 contrast material and the shell of T2 contrast material having at least one shape selected from the group consisting of octahedral, cross-shaped, urchin-shaped, and cubic. 
     
     
         13 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 6 , wherein the biocompatible polymer is at least one selected from the group consisting of biopolymers such as chitosan, elastin, hyaluronic acid, alginate, gelatin, collagen, and cellulose; and synthetic polymers such as polyethylene glycol (PEG), polyethylene oxide (PEO), polycaprolactone (PCL), polylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolic) acid (PLGA), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polydioxanone (PDO), poly(L-lactide-co-caprolactone), poly(ester urethane) (PEU), poly(L-lactide-co-D-lactide), poly(ethylene-co-vinyl alcohol), poly(acrylic acid) (PAA), polyvinyl alcohol) (PVA), polyvinylpyrrolidone (PVP), polystyrene (PS) and polyaniline (PAN). 
     
     
         14 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 13 , wherein the biocompatible polymer can be modified by conjugation with targeting moieties or diagnostic moieties. 
     
     
         15 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 14 , wherein the targeting moiety can be selected from the group consisting of antibodies, antibody fragments, aptamers, and various ligands binding to receptors displayed on the surface of target cell. 
     
     
         16 . The method for producing a metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 14 , wherein the diagnostic moiety can be selected from the group consisting of diagnostic imaging moieties such as fluorophores, optical reporters and quantum dots; computed tomography (CT) probes such as iodine-based compounds and gold nanoparticles; and nonmetallic radioisotopes such as indium (In), technetium (Tc) and fluorine (F). 
     
     
         17 . A metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent prepared by the method of  claim 6 . 
     
     
         18 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 17 , the nanoparticle has a core of metal oxide of T1 contrast material and a porous shell of metal oxide of T2 contrast material. 
     
     
         19 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 18 , wherein the metal oxide of T1 contrast material is at least one selected from the group consisting of manganese oxide, chromium oxide and gadolinium oxide. 
     
     
         20 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 18 , wherein the metal oxide of T2 contrast material is superparamagnetic metal oxides. 
     
     
         21 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 20 , wherein the superparamagnetic metal oxides are at least one selected from the group consisting of iron oxide, cobalt oxide and nickel oxide. 
     
     
         22 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 21 , wherein the superparamagnetic metal oxides are formed with at least one shape selected from the group consisting of octahedral, cross-shaped, urchin-shaped, and cubic. 
     
     
         23 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 20 , wherein the superparamagnetic metal oxides comprise the doped metal ions of T1 contrast material. 
     
     
         24 . The metal oxide nanoparticle-based T1-T2 dual-mode MRI contrast agent according to  claim 23 , wherein the doped metal ions of T1 contrast material is at least one selected from the group consisting of manganese ion, chromium ion and gadolinium ion.