Chlorotoxin-labeled nanoparticle compositions and methods for targeting primary brain tumors

Abstract

Chlorotoxin-labeled nanoparticles that target primary brain tumors, compositions that include the nanoparticles, methods of imaging tissues using the nanoparticles, and methods for treating tissues using the nanoparticles.

1 . A chlorotoxin-labeled particle, comprising: 
 (a) a core having a surface, the core comprising a material having magnetic resonance imaging activity;    (b) a chlorotoxin; and    (c) a linker covalently coupling the chlorotoxin to the surface.    
   
   
       2 . The particle of  claim 1 , wherein the material having magnetic resonance imaging activity comprises a metal oxide selected from the group consisting of ferrous oxide, ferric oxide, silicon oxide, polycrystalline silicon oxide, aluminum oxide, germanium oxide, zinc selenide, tin dioxide, titanium dioxide, indium tin oxide, gadolinium oxide, and mixtures thereof.  
   
   
       3 . The particle of  claim 1 , wherein the core comprises a material selected from the group consisting of silicon nitride, stainless steel, titanium, nickel titanium, and mixtures thereof.  
   
   
       4 . The particle of  claim 1 , wherein the chlorotoxin is selected from the group consisting of native chlorotoxin, synthetic chlorotoxin, recombinant chlorotoxin, and fragments and variants thereof having chlorotoxin binding activity.  
   
   
       5 . The particle of  claim 1 , wherein the chlorotoxin-labeled particle has from about 1 to about 50 chlorotoxins/particle.  
   
   
       6 . The particle of  claim 1 , wherein the linker comprises a polyalkylene oxide moiety.  
   
   
       7 . The particle of  claim 1 , wherein the linker comprises a polyethylene oxide moiety.  
   
   
       8 . The particle of  claim 1 , wherein the chlorotoxin-labeled particle further comprises a fluorescent moiety.  
   
   
       9 . The particle of  claim 8 , wherein the chlorotoxin-labeled particle has from about 1 to about 10 fluorescent moieties/particle.  
   
   
       10 . The particle of  claim 8 , wherein the fluorescent moiety is selected from the group consisting of near infrared emitting fluorescent moiety.  
   
   
       11 . The particle of  claim 8 , wherein the fluorescent moiety is a cyanine moiety.  
   
   
       12 . The particle of  claim 8 , wherein the fluorescent moiety is a Cy5.5 moiety.  
   
   
       13 . The particle of  claim 1 , wherein the core has a diameter of from about 2 mn to about 25 nm.  
   
   
       14 . The particle of  claim 1 , wherein labeled particle has a diameter of from about 15 nm to about 200 nm.  
   
   
       15 . A pharmaceutical composition, comprising a chlorotoxin-labeled particle of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       16 . A pharmaceutical composition, comprising a pharmacologically effective amount of a chlorotoxin-labeled particle of  claim 1  to treat a patient suffering from a glioma.  
   
   
       17 . A method for differentiating neuroectodermal-derived tumor cells from non-neoplastic brain tissue, comprising: 
 (a) contacting a tissue of interest with a chlorotoxin-labeled nanoparticle having affinity and specificity for neuroectodermal-derived tumor cells; and    (b) measuring the level of binding of the chlorotoxin-labeled nanoparticle, wherein an elevated level of binding, relative to normal tissue, is indicative that the tissue is neoplastic.    
   
   
       18 . A method for detecting neuroectodermal-derived tumor cells in a patient, comprising: 
 (a) contacting a tissue of interest with a chlorotoxin-labeled nanoparticle having affinity and specificity for neuroectodermal-derived tumor cells; and    (b) measuring the level of binding of the chlorotoxin-labeled nanoparticle, wherein an elevated level of binding, relative to normal tissue, is indicative that the tissue is neoplastic.    
   
   
       19 . A method for detecting a tissue expressing matrix metalloproteinase (MMP-2) protein complex, comprising: 
 (a) contacting a tissue of interest with a chlorotoxin-labeled nanoparticle having affinity and specificity for matrix metalloproteinase (MMP-2) protein complex; and    (b) measuring the level of binding of the chlorotoxin-labeled nanoparticle, wherein an elevated level of binding, relative to normal tissue, is indicative of the presence of a tumor expressing matrix metalloproteinase (MMP-2) protein complex.    
   
   
       20 . The method of  claim 17 , wherein measuring the level of binding of the chlorotoxin-labeled nanoparticle comprises magnetic resonance imaging.  
   
   
       21 . The method of  claim 17 , wherein the chlorotoxin-labeled nanoparticle further comprises a fluorescent moiety.  
   
   
       22 . The method of  claim 21 , wherein measuring the level of binding of the chlorotoxin-labeled nanoparticle comprises fluorescence imaging.  
   
   
       23 . A method for determining the location of glioma cells in a patient preoperatively, intraoperatively, and postoperatively, comprising: 
 (a) administering a pharmaceutical composition to a patient, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and an amount of a fluorophore/chlorotoxin-labeled nanoparticle sufficient to image glioma cells in vivo;    (b) measuring the level of binding of the fluorophore/chlorotoxin-labeled nanoparticle by magnetic resonance imaging pre-operatively to determine the location of glioma cells, wherein an elevated level of binding, relative to normal tissue, is indicative of the presence of glioma cells;    (c) surgically removing from the patient at least some glioma cells located by magnetic resonance imaging;    (d) measuring the level of binding of the fluorophore/chlorotoxin-labeled nanoparticle by fluorescence imaging intra-operatively to determine the location of residual glioma cells, wherein an elevated level of binding, relative to normal tissue, is indicative of the presence of residual glioma cells;    (e) surgically removing from the patient at least some residual glioma cells located by fluorescence imaging; and    (f) measuring the level of binding of the fluorophore/chlorotoxin-labeled nanoparticle by magnetic resonance imaging post-operatively to determine the location of glioma cells, wherein an elevated level of binding, relative to normal tissue, is indicative of the presence of glioma cells.    
   
   
       24 . A method for treating a glioma in a patient, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a chlorotoxin-labeled nanoparticle of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       25 . A method for treating a neuroectodermal tumor, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a chlorotoxin-labeled nanoparticle of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       26 . A method for treating a tumor expressing matrix metalloproteinase (MMP-2) protein complex, comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising a chlorotoxin-labeled nanoparticle of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       27 . A method for inhibiting invasive activity of neoplastic cells, comprising administering to neoplastic cells an effective amount of a pharmaceutical composition comprising a chlorotoxin-labeled nanoparticle of  claim 1  and a pharmaceutically acceptable carrier.