Remote Assembly of Targeted Nanoparticles Using H-Phosphonate -ENE/-YNE Hydrophosphonylation Reactions

Abstract

The present invention provides phosphonate compounds and methods of preparing the phosphonate compounds so as to allow, for example, increased capability to modify nanoparticles for targeted drug delivery applications.

1 - 35 . (canceled) 
     
     
         36 . A compound of formula: 
       
         
           
           
               
               
           
         
         wherein:
 the bond identified by   is a single or double bond; 
 each of L 1 , L 2  and L 3  is a bond or a linking group; 
 each of R 1 , R 2  and R 3  is independently selected from the group consisting of: a nanoparticle, an attachment component, a targeting agent, a diagnostic agent and a stealth agent; 
 
         wherein
 the nanoparticle is selected from the group consisting of: a liposome, a micelle, a lipoprotein, a lipid-coated bubble, a block copolymer micelle, a polymersome, a noisome, a quantum dot, an iron oxide particle, a gold particle, a dendrimer and a silica particle; 
 the attachment component is selected from the group consisting of: a C 8 -C 36  alkyl and cholesterol; and 
 the stealth agent is selected from the group consisting of: polyalkylene oxide, polyethylene glycol, a dendrimer, polyvinyl alcohol, polycarboxylate, a polysaccharide and hydroxyalkyl starch; and 
 
         R 4  is a selected from the group consisting of: H and —P(═O)(OL 1 -R 1 )(OL 2 -R 2 ), wherein when R 4  is other than H the bond identified by   is a single bond. 
       
     
     
         37 . The compound of  claim 36 , wherein L 1 , L 2  or L 3  is a hydrophilic, non-immunogenic, water soluble linking group 
     
     
         38 . The compound of  claim 37 , wherein the hydrophilic, non-immunogenic, water soluble linking group is selected from the group consisting of: polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polycarboxylate, polysaccharide and dextran. 
     
     
         39 . The compound of  claim 36 , wherein the targeting agent is an aptamer. 
     
     
         40 . The compound of  claim 36 , wherein the diagnostic agent is selected from the group consisting of: a radioactive agent, a fluorescent agent and a contrast agent. 
     
     
         41 . The compound of  claim 36 , wherein each of R 1  and R 2  is an attachment component selected from the group consisting of: a saturated or unsaturated C 10-24  alkyl group, a substituted saturated or unsaturated C 10-24  alkyl group and cholesterol. 
     
     
         42 . The compound of  claim 36 , wherein the stealth agent is selected from the group consisting of: PEG 500 , PEG 2000  and PEG 5000 . 
     
     
         43 . The compound of  claim 36 , having any one of the following:
 wherein L 3  is a linking group and R 3  is a stealth agent;   wherein each of R 1  and R 2  is independently selected from the group consisting of a targeting agent, a diagnostic agent and a stealth agent, R 3  is a nanoparticle or an attachment component attached to a nanoparticle; and R 4  is H;   wherein each of L 1  and L 2  is a bond; each of R 1  and R 2  is an attachment component selected from a saturated or unsaturated C 10-24  alkyl group, a substituted saturated or unsaturated C 10-24  alkyl group, and cholesterol; R 4  is —P(═O)(OL 1 -R 1 )(OL 2 -R 2 ) and the bond identified by   is a single bond; or   wherein R 3  is an attachment component selected from a saturated or unsaturated C 10-24  alkyl group, a substituted saturated or unsaturated C 10-24  alkyl group, and cholesterol; each of R 1  and R 2  is independently selected from the group consisting of: a targeting agent, a diagnostic agent and a stealth agent; R 4  is —P(═O)(OL 1 -R 1 )(OL 2 -R 2 ) and the bond identified by   is a single bond.   
     
     
         44 . A targeted delivery composition comprising a compound of  claim 36 , having any one of the following:
 wherein at least one of R 1  and R 2  is a targeting agent; and R 3  is a nanoparticle or an attachment component attached to a nanoparticle; or   wherein each of R 1  and R 2  is an attachment component that is attached to a nanoparticle and R 3  is selected from the group consisting of: a targeting agent, a diagnostic agent and a stealth agent.   
     
     
         45 . The targeted delivery composition of  claim 44 , wherein the nanoparticle is a liposome and the attachment component is a C 8 -C 36  alkyl or cholesterol associated with a bilayer of the liposome. 
     
     
         46 . A method for treating or diagnosing a cancerous condition in a subject, comprising administering to the subject a targeted delivery composition of  claim 44 , wherein the composition comprises a therapeutic or a diagnostic agent that is sufficient to treat or diagnose the condition. 
     
     
         47 . The method of  claim 46  wherein the nanoparticle is a liposome and the therapeutic agent is encapsulated in, embedded in, or tethered to the liposome. 
     
     
         48 . The method of  claim 46 , wherein the therapeutic agent is an anticancer agent selected from the group consisting of: doxorubicin, cisplatin, oxaliplatin, carboplatin, 5-fluorouracil, gemcitibine and a taxane. 
     
     
         49 . A method of determining the suitability of a subject for a targeted therapeutic treatment, comprising:
 administering to the subject a targeted delivery composition of  claim 44 , wherein R 1 , R 2  or R 3  is a diagnostic agent or the nanoparticle comprises a diagnostic agent; and   imaging the subject to detect the diagnostic agent.   
     
     
         50 . A method of preparing a phosphonate compound, the method comprising:
 combining a H-phosphonate compound having the formula:   
       
         
           
           
               
               
           
         
         and an alkyne compound having the formula: 
       
       
         
           
           
               
               
           
         
         in the presence of a catalyst to form the phosphonate compound having the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein
 the bond identified by   is a single or double bond; 
 each of L 1 , L 2  and L 3  is a bond or a linking group; and 
 each of R 1 , R 2  and R 3  is independently selected from the group consisting of: a nanoparticle, an attachment component, a targeting agent, a diagnostic agent and a stealth agent; 
 
         
         wherein
 the nanoparticle is selected from the group consisting of: a liposome, a micelle, a lipoprotein, a lipid-coated bubble, a block copolymer micelle, a polymersome, a noisome, a quantum dot, an iron oxide particle, a gold particle, a dendrimer and a silica particle; 
 the attachment component is selected from the group consisting of: a C 8 -C 36  alkyl and cholesterol; and 
 the stealth agent is selected from the group consisting of: polyalkylene oxide, polyethylene glycol, a dendrimer, polyvinyl alcohol, polycarboxylate, a polysaccharide, and hydroxyalkyl starch; and
 R 4  is a member selected from the group consisting of H and —P(═O)(OL 1 -R 1 )(OL 2 -R 2 ), wherein when R 4  is other than H the bond identified by   is a single bond. 
 
 
       
     
     
         51 . The method of  claim 50 , having any one of the following:
 wherein R 3  is an attachment component selected from the group consisting of: a saturated or unsaturated C 10-24  alkyl group, a substituted saturated or unsaturated C 10-24  alkyl group and cholesterol; or   wherein each of R 1  and R 2  is an attachment component independently selected from the group consisting of: a saturated or unsaturated C 10-24  alkyl group, a substituted saturated or unsaturated C 10-24  alkyl group and cholesterol.   
     
     
         52 . The method of  claim 51 , wherein R 1 , R 2  or R 3  are attached to a nanoparticle.