Systems and methods for high-resolution in vivo imaging of biochemical activity in a living organism

Abstract

This invention relates to multifunctional detection agents useful for providing high-resolution, in vivo imaging of biochemical activity in a living organism. Methods of using these multifunctional detection agents may comprise administering them into a living organism, and then estimating the localization of the detection agent using one modality (i.e., MRI), while concurrently estimating the level of biological activity using a second modality (i.e., optical imaging). One of the multifunctional detection agents comprises a magnetic resonance component and an optical imaging component. The magnetic resonance component comprises a contrast agent that is always activated or “on”. The optical imaging component comprises a plurality of activatable contrast agents or dyes, at least two of which are different from one another, wherein at least one of the activatable contrast agents can be activated or turned “on” only in the presence of a particular event.

1 . A multifunctional detection agent comprising:
 a magnetic resonance imaging component; and   a plurality of activatable optical imaging components, at least two of which are different from one another; wherein the magnetic resonance imaging component and the optical imaging component are contained in a single multifunctional detection agent, and wherein at least one activatable optical imaging component is activated only in the presence of a predetermined event.   
     
     
         2 . The multifunctional detection agent of  claim 1 , wherein the magnetic resonance imaging component comprises at least one of: a paramagnetic material and a superparamagnetic material. 
     
     
         3 . The multifunctional detection agent of  claim 2 , wherein the paramagnetic material comprises at least one of: a chelated gadolinium complex, a chelate of a paramagnetic ion, and a coated iron nanoparticle. 
     
     
         4 . The multifunctional detection agent of  claim 3 , wherein the paramagnetic ion comprises at least one of: manganese (Mn), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb) and lutetium (Lu). 
     
     
         5 . The multifunctional detection agent of  claim 2 , wherein the superparamagnetic material comprises a chelate of a superparamagnetic ion. 
     
     
         6 . The multifunctional detection agent of  claim 5 , wherein the superparamagnetic ion comprises at least one of: manganese (Mn), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb) and lutetium (Lu). 
     
     
         7 . The multifunctional detection agent of  claim 1 , wherein the plurality of activatable optical imaging components comprises at least one optical dye. 
     
     
         8 . The multifunctional detection agent of  claim 7 , wherein the plurality of activatable optical imaging components further comprises at least one quencher. 
     
     
         9 . The multifunctional detection agent of  claim 1 , wherein the magnetic resonance imaging component is covalently linked to the plurality of activatable optical imaging components. 
     
     
         10 . The multifunctional detection agent of  claim 1 , wherein the predetermined event comprises the presence of light of a predetermined wavelength and at least one of: the presence of a predetermined enzyme, enzymatic cleavage at fluorescence activation sites, when temperature exceeds a predetermined value, when temperature falls below a predetermined value, when pH exceeds a predetermined value, and when pH falls below a predetermined value. 
     
     
         11 . The multifunctional detection agent of  claim 1 , wherein the magnetic resonance imaging component is always activated. 
     
     
         12 . The multifunctional detection agent of  claim 1 , wherein the plurality of activatable optical imaging components is a dye or pigment selected from the group consisting of anthranones and their derivatives; anthraquinones and their derivatives; croconines and their derivatives; fluorescein and its derivatives; rhodamine and its derivatives such as tetramethylrhodamine; eosin and its derivatives; erythrosine and its derivatives; coumarin and its derivatives such as methyl-coumarins; pyrene and its derivatives; monoazos, disazos, trisazos and their derivatives; benzimidazolones and their derivatives; diketo pyrrole pyrroles and their derivatives; dioxazines and their derivatives; diarylides and their derivatives; indanthrones and their derivatives; isoindolines and their derivatives; stilbene and its derivatives; isoindolinones and their derivatives; naphtols and their derivatives; perinones and their derivatives; perylenes and their derivatives such as perylenic acid anhydride or perylenic acid imide; ansanthrones and their derivative; dibenzpyrenequinones and their derivatives; pyranthrones and their derivatives; bioranthorones and their derivatives; isobioranthorone and their derivatives; diphenylmethane, and triphenylmethane, type pigments; cyanine and azomethine type pigments; indigoid type pigments; bisbenzoimidazole type pigments; azulenium salts; pyrylium salts; thiapyrylium salts; benzopyrylium salts; phthalocyanines and their derivatives, pryanthrones and their derivatives; quinacidones and their derivatives; quinophthalones and their derivatives; squaraines and their derivatives; squarilylums and their derivatives; leuco dyes and their derivatives, deuterated leuco dyes and their derivatives; leuco-azine dyes; acridines; di- and tri-arylmethane, dyes; quinoneamines; o-nitro-substituted arylidene dyes, aryl nitrone dyes, and a combination comprising at least one of the foregoing dyes and pigments. 
     
     
         13 . A multifunctional detection agent comprising:
 a first component capable of enhancing anatomical information in a living organism; and   a plurality of activatable second components capable of enhancing functional information in a living organism, wherein the first component and the plurality of activatable second components are contained in a single multifunctional detection agent, and wherein the activatable second component is activated only in the presence of a predetermined event.   
     
     
         14 . The multifunctional detection agent of  claim 13 , wherein the first component is always activated. 
     
     
         15 . The multifunctional detection agent of  claim 13 , wherein the functional information comprises metabolic information. 
     
     
         16 . The multifunctional detection agent of  claim 13 , wherein the predetermined event includes the presence of light of a predetermined wavelength and at least one of: the presence of a predetermined enzyme, enzymatic cleavage at fluorescence activation sites, when temperature exceeds a predetermined value, when temperature falls below a predetermined value, when pH exceeds a predetermined value, and when pH falls below a predetermined value. 
     
     
         17 . A method of obtaining high-resolution, in vivo imaging of biochemical activity in a living organism, comprising the steps of:
 obtaining an image of anatomical information of the living organism; and   obtaining an image of functional information of the living organism,   
       wherein a multifunctional detection agent is present within the living organism, wherein the multifunctional detection agent comprises a first component capable of enhancing anatomical information of the living organism and a plurality of activatable second components capable of enhancing functional information of the living organism, and wherein the plurality of activatable second components is activated only upon the occurrence of a predetermined event. 
     
     
         18 . The method of  claim 17 , wherein the multifunctional detection agent is administered to the living organism before the obtaining steps are performed. 
     
     
         19 . The method of  claim 17 , wherein the multifunctional detection agent is administered in at least one of the following ways: intravenously, orally and intramuscularly. 
     
     
         20 . The method of  claim 17 , wherein the image of the anatomical information of the living organism is obtained via at least one of: computed tomography, positron emission tomography, and magnetic resonance imaging and wherein the image of the functional information of the living organism is obtained via optical imaging. 
     
     
         21 . The method of  claim 17 , wherein the obtaining an image of anatomical information and the obtaining an image of functional information are performed concurrently. 
     
     
         22 . A system for obtaining high-resolution, in vivo images of biochemical activity in a living organism, comprising:
 a first imaging device capable of detecting a first imaging component of a multifunctional detection agent to obtain images of anatomical information of the living organism; and   a second imaging device capable of detecting an activatable second imaging component of the multifunctional detection agent to obtain images of functional information of the living organism, wherein the activatable second imaging component of the multifunctional detection agent is activated only in the presence of a predetermined event; the multifunctional detection agent comprising a plurality of activatable second imaging components at least two of which are different from one another.   
     
     
         23 . The system of  claim 22 , wherein the functional information comprises metabolic information.