Fucoidans as Ligands for the Diagnosis of Degenerative Pathologies

Abstract

The present invention relates to the diagnosis of clinical conditions characterized by undesirable and/or abnormal selectin expression. In particular, the invention provides for the use of fucoidans for the detection of selectins using imaging techniques including ultrasonography, scintigraphy and MRI. Selectin-targeted imaging agents are provided that comprise at least one fucoidan moiety associated with at least one detectable moiety. Methods and kits are described for using these imaging agents in the diagnosis of clinical conditions such as thrombosis, myocardial ischemia/reperfusion injury, stroke and ischemic brain trauma, neurodegenerative disorders, tumor metastasis and tumor growth, and rheumatoid arthritis.

1 . An imaging agent comprising at least one fucoidan moiety associated with at least one detectable moiety, wherein the imaging agent is selectin-targeted. 
     
     
         2 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one fucoidan moiety binds to at least one human selectin selected from the group consisting of P-selectin, L-selectin and E-selectin, with a dissociation constant of between about 0.1 nM and about 500 nM. 
     
     
         3 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one detectable moiety comprises a metal-chelating moiety complexed to a detectable metal moiety. 
     
     
         4 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one detectable moiety is detectable by planar scintigraphy (PS), Single Photon Emission Computed Tomography (SPECT), Positron Emission Tomography (PET), contrast-enhanced ultrasonography (CEUS), Magnetic Resonance Imaging (MRI), fluorescence spectroscopy, Computed Tomography, ultrasonography, X-ray radiography, or any combination thereof. 
     
     
         5 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one detectable moiety comprises a member of the group consisting of: ultrasmall superparamagnetic iron oxide particles (USPIOs), technetium-99m ( 99m Tc), gallium-67 ( 67 Ga), yttrium-91 ( 91 Y), indium-111 ( 111 In), rhenium-186 ( 186 Re), thallium-201 ( 201 T1), carbon-11 ( 11 C), nitrogen-13 ( 13 N), oxygen-15 ( 15 O), fluorine-18 ( 18 F), gadolinium III (Gd 3+ ), chromium III (Cr 3+ ), dysprosium III (Dy 3+ ), europium (Eu 3+ ), iron III (Fe 3+ ), manganese II (Mn 2+ ), ytterbium III (Yb 3+ ), europium (Eu 3+ ), quantum dots, Texas red, fluorescein isothiocyanate (FITC), phycoerythrin (PE), rhodamine, carboxycyanine, Cy-3, Cy-5, Cy5.5, Cy7, DY-630, DY-635, DY-680, Atto 565 dyes, merocyanine, styryl dye, oxonol dye, BODIPY dyes, acoustically active microbubbles, acoustically active liposomes, iodine, and analogues thereof, derivatives thereof, and combinations thereof. 
     
     
         6 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one fucoidan moiety has an average molecular weight of about 2000 to about 8000 Da. 
     
     
         7 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one fucoidan moiety has an average molecular weight of about 20,000 to about 70,000 Da. 
     
     
         8 . The selectin-targeted imaging agent according to  claim 1  wherein the at least one fucoidan moiety has an average molecular weight of about 100,000 to about 500,000 Da. 
     
     
         9 . The selectin-targeted imaging agent according to  claim 1 , wherein the at least one detectable moiety comprises an ultrasmall superparamagnetic iron oxide particle (USPIO) and the at least one fucoidan moiety and where the fucoidan moiety constitutes a shell around the at least one USPIO. 
     
     
         10 . A pharmaceutical composition comprising an effective amount of at least one selectin-targeted imaging agent according to  claim 1 , or a physiologically tolerable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein the at least one selectin-targeted imaging agent is a selectin-targeted imaging agent of  claim 9 . 
     
     
         12 . A method for diagnosing a clinical condition associated with selectins in a patient, said method comprising steps of:
 administering to the patient an effective amount of a pharmaceutical composition according to  claim 1 , and   detecting any selectin bound to the imaging agent using an imaging technique.   
     
     
         13 . The method according to  claim 12 , wherein the clinical condition associated with selectins is a member of the group consisting of thrombosis, myocardial ischemia/reperfusion injury, stroke and ischemic brain trauma, neurodegenerative disorders, tumor metastasis, tumor growth, and rheumatoid arthritis. 
     
     
         14 . A method for detecting the presence of abnormal selectins in a biological system, the method comprising steps of:
 contacting the biological system with an effective amount of a selectin-targeted imaging agent of  claim 1 , and   detecting any selectin bound to the imaging agent using an imaging technique.   
     
     
         15 . The method according to  claim 14 , wherein the biological sample is selected from the group consisting of a cell, a biological fluid and a biological tissue. 
     
     
         16 . The method according to  claim 15 , wherein the biological sample originates from a patient suspected of having a clinical condition associated with selectins, and said method is used to diagnose the clinical condition associated with selectins. 
     
     
         17 . The method according to  claim 16 , wherein the clinical condition associated with selectins is a member of the group consisting of thrombosis, myocardial ischemia/reperfusion injury, stroke and ischemic brain trauma, neurodegenerative disorders, tumor metastasis, tumor growth, and rheumatoid arthritis. 
     
     
         18 . The method according to  claim 14 , wherein the biological sample originates from a patient who has received a treatment for a clinical condition associated with selectins, and said method is used to monitor the response of the patient to the treatment. 
     
     
         19 . The method according to  claim 18 , wherein the clinical condition associated with selectins is a member of the group consisting of thrombosis, myocardial ischemia/reperfusion injury, stroke and ischemic brain trauma, neurodegenerative disorders, tumor metastasis, tumor growth, and rheumatoid arthritis. 
     
     
         20 . A kit for the diagnosis of a clinical condition associated with selectins in a patient or for the detection of abnormal selectins in a biological system, the kit comprising:
 a selectin-targeted imaging agent according to  claim 1 , or   a fucoidan moiety, a detectable moiety, and instructions for preparing a selectin-targeted imaging agent according to  claim 1 .   
     
     
         21 . The kit according to  claim 20 , further comprising instructions for diagnosing the clinical condition associated with selectins using the selectin-targeted imaging agent. 
     
     
         22 . The kit according to  claim 21 , wherein the clinical condition associated with selectins is a member of the group consisting of thrombosis, myocardial ischemia/reperfusion injury, stroke and ischemic brain trauma, neurodegenerative disorders, tumor metastasis, tumor growth, and rheumatoid arthritis. 
     
     
         23 . The kit according to  claim 21 , further comprising instructions for detecting abnormal selectins in the biological system using the selectin-targeted imaging agent.