Lanthanide Nanoparticle Conjugates and Uses Thereof

Abstract

The present disclosure is directed generally to lanthanide nanoparticle conjugates, such as gadolinium nanoparticle conjugates, nanoparticle conjugates including polymers, conjugation to targeting agents and therapeutic agents, and their use in targeting, treating, and/or imaging disease states in a patient.

1 - 14 . (canceled) 
     
     
         15 . A lanthanide nanoparticle conjugate comprising:
 a lanthanide nanoparticle, and   a polymer, polymer precursor, or initiator grafted onto the nanoparticle, wherein the polymer, polymer precursor, or initiator comprises a functional group that is the point of attachment to the lanthanide nanoparticle.   
     
     
         16 . The nanoparticle conjugate of  claim 15 , wherein the lanthanide is select from gadolinium, lanthanum, erbium, ytterbium, neodymium, europium, terbium, cerium, thulium, praseodymium, promethium, samarium, dysprosium, holmium, and lutetium. 
     
     
         17 . The nanoparticle conjugate of  claim 15 , wherein the functional group is selected from thiolates, thioethers, thioesters, carboxylates, amines, amides, halides, phosphonates, phosphonate esters, phosphinates, sulphonates, sulphates, porphyrins, nitrates, pyridine, pyridyl based compounds, nitrogen containing ligands, oxygen containing ligands, and sulfur containing ligands. 
     
     
         18 . The nanoparticle conjugate of  claim 15 , further comprising a second functional group not grafted onto said gadolinium nanoparticle. 
     
     
         19 . The nanoparticle conjugate of  claim 15 , wherein the second functional group is selected from the group consisting of carboxylic acids and carboxylic acid salt derivatives, acid halides, sulfonic acids and sulfonic acid salts, anhydride derivatives, hydroxyl derivatives, amine and amide derivatives, silane derivations, phosphate derivatives, nitro derivatives, succinimide and sulfo-containing succinimide derivatives, halide derivatives, alkene derivatives, morpholine derivatives, cyano derivatives, epoxide derivatives, ester derivatives, carbazole derivatives, azide derivatives, alkyne derivatives, acid containing sugar derivatives, glycerol analogue derivatives, maleimide derivatives, protected acids and alcohols, and acid halide derivatives. 
     
     
         20 . The nanoparticle conjugate of  claim 15 , further comprising a therapeutic agent covalently bonded to said polymer. 
     
     
         21 . The nanoparticle conjugate of  claim 15 , further comprising a targeting agent covalently bonded to said polymer. 
     
     
         22 . The nanoparticle conjugate of  claim 15 , wherein the conjugate retains twice the amount of lanthanide as the lanthanide nanoparticle when each of the conjugate and the nanoparticle is digested under physiological conditions. 
     
     
         23 . The nanoparticle conjugate of  claim 22  wherein the polymer is poly(N-isopropylacrylamide) (PNIPAM). 
     
     
         24 . The nanoparticle conjugate of  claim 15 , wherein the conjugate increases cell viability compared to the lanthanide nanoparticle when each of the conjugate and the nanoparticle is administered to cells. 
     
     
         25 . The nanoparticle conjugate of  claim 24  wherein the polymer is poly(N-isopropylacrylamide) (PNIPAM). 
     
     
         26 . A pharmaceutical composition comprising:
 a nanoparticle conjugate of  claim 15 , and   a pharmaceutically acceptable carrier.   
     
     
         27 . A method of making the nanoparticle conjugate of  claim 15  comprising:
 contacting a compound of Formula III or salt thereof with a compound of Formula (V) or a salt thereof to form a compound of Formula (VI): 
 
       
         
           
           
               
               
           
         
          and 
         contacting the compound of Formula (VI) with the lanthanide nanoparticle to form the lanthanide nanoparticle conjugate; 
         wherein n is an integer, and 
         R 2 , R 3 , R 4 , R 7 , and R 8  are each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy. 
       
     
     
         28 . The method of  claim 27 , further comprising:
 contacting the compound of Formula VI with a reducing agent in the presence of the nanoparticle.   
     
     
         29 . A method of making the nanoparticle conjugate of  claim 15  comprising:
 contacting a compound of Formula (II) or salt thereof with a compound of Formula (V) or a salt thereof to form the compound of Formula (VI): 
 
       
         
           
           
               
               
           
         
          and 
         contacting the compound of Formula (VI) with the lanthanide nanoparticle to form the lanthanide nanoparticle conjugate; 
         wherein n is an integer, and 
         R 2 , R 3 , R 4 , R 5 , and R 8  are each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroalkyloxy, substituted heteroalkyloxy, heteroaryloxy and substituted heteroaryloxy. 
       
     
     
         30 . The method of  claim 29 , further comprising:
 contacting the compound of Formula VI with a reducing agent in the presence of the nanoparticle.   
     
     
         31 . A method of imaging a target tissue comprising:
 administering an effective amount of the nanoparticle conjugate of  claim 15  to a patient; and   imaging the target tissue with an imaging technique to obtain an image of the patient or of a portion of said patient.   
     
     
         32 . The method of  claim 31 , wherein the imaging technique is magnetic resonance imaging or fluorescent imaging. 
     
     
         33 . A method of increasing the stability of a lanthanide nanoparticle conjugate comprising:
 grafting a polymer having one of the following formulas:   
       
         
           
           
               
               
           
         
         onto a lanthanide nanoparticle to form a lanthanide nanoparticle conjugate, wherein the lanthanide nanoparticle conjugate is twice as resistant to digestion as the lanthanide nanoparticle. 
       
     
     
         34 . The method of  claim 33 , wherein the digestion is under physiological conditions.