Nanocomplexes for delivery of saporin

Abstract

A nanocomplex, of particle size 50 nm to 1000 nm, containing saporin and a lipid-like compound, in which saporin binds to the lipid-like compound via non-covalent interaction or covalent bonding. The lipid-like compound has a hydrophilic moiety, a hydrophobic moiety, and a linker joining the hydrophilic moiety and the hydrophobic moiety. The hydrophilic moiety is optionally charged and the hydrophobic moiety has 8 to 24 carbon atoms. Also disclosed is a pharmaceutical composition containing such a nanocomplex and a pharmaceutically acceptable carrier. The nanocomplex is useful in treating diseases, such as cancer.

1 . A nanocomplex comprising saporin and a lipid-like compound, wherein the nanocomplex has a particle size of 50 nm to 1000 nm; the saporin binds to the lipid-like compound via non-covalent interaction or covalent bonding; and the lipid-like compound has a hydrophilic moiety, a hydrophobic moiety, and a linker joining the hydrophilic moiety and the hydrophobic moiety, the hydrophilic moiety being optionally charged and the hydrophobic moiety having 8 to 24 carbon atoms. 
     
     
         2 . The nanocomplex of  claim 1 , wherein the hydrophilic moiety is 
       
         
           
           
               
               
           
         
       
       each of R a , R a ′, R a ″, and R a ′″, independently, being a C 1 -C 20  monovalent aliphatic radical, a C 1 -C 20  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z being a C 1 -C 20  bivalent aliphatic radical, a C 1 -C 20  bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical. 
     
     
         3 . The nanocomplex of  claim 2 , wherein the hydrophobic moiety is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical, and the linker is O, S, Si, C 1 -C 6  alkylene, 
       
         
           
           
               
               
           
         
       
       in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, a C 1 -C 10  oxyaliphatic radical, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical. 
     
     
         4 . The nanocomplex of  claim 3 , wherein the hydrophobic moiety is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical, and the linker is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The nanocomplex of  claim 2 , wherein the hydrophilic moiety is 
       
         
           
           
               
               
           
         
       
       in which each of R a  and R a ′, independently, is, H, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z is a C 1 -C 10  bivalent aliphatic radical, a C 1 -C 10  bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical. 
     
     
         6 . The nanocomplex of  claim 5 , wherein the hydrophobic moiety is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical, and the linker is O, S, Si, C 1 -C 6  alkylene, 
       
         
           
           
               
               
           
         
       
       in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, a C 1 -C 10  oxyaliphatic radical, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical. 
     
     
         7 . The nanocomplex of  claim 6 , wherein the hydrophobic moiety is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical, and the linker is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The nanocomplex of  claim 1 , wherein the linker is O, S, Si, C 1 -C 6  alkylene, 
       
         
           
           
               
               
           
         
       
       in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, a C 1 -C 10  oxyaliphatic radical, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical. 
     
     
         9 . The nanocomplex of  claim 8 , wherein the hydrophobic moiety is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical. 
     
     
         10 . The nanocomplex of  claim 9 , wherein the hydrophobic moiety is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical. 
     
     
         11 . The nanocomplex of  claim 8 , wherein the linker is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The nanocomplex of  claim 11 , wherein the hydrophobic moiety is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical. 
     
     
         13 . The nanocomplex of  claim 12 , wherein the hydrophobic moiety is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical. 
     
     
         14 . The nanocomplex of  claim 1 , wherein the hydrophobic moiety is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical. 
     
     
         15 . The nanocomplex of  claim 14 , wherein the hydrophobic moiety is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical. 
     
     
         16 . The nanocomplex of  claim 1 , wherein
 the hydrophobic moiety is a heteroaliphatic radical containing one or more —S—S— groups and 8 to 24 carbon atoms;   the hydrophilic moiety is an aliphatic or heteroaliphatic radical containing one or more hydrophilic groups and 1-20 carbon atoms, each of the hydrophilic groups being amino, alkylamino, dialkylamino, trialkylamino, tetraalkylammonium, hydroxyamino, hydroxyl, carboxyl, carboxylate, carbamate, carbamide, carbonate, phosphate, phosphite, sulfate, sulfite, or thiosulfate; and   the linker is O, S, Si, C 1 -C 6  alkylene,   
       
         
           
           
               
               
           
         
       
       in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, a C 1 -C 10  oxyaliphatic radical, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical. 
     
     
         17 . The nanocomplex of  claim 1 , wherein the lipid-like compound has additional one to three hydrophilic moieties, additional one to three hydrophobic moieties, and additional one to seven linkers. 
     
     
         18 . The nanocomplex of  claim 17 , wherein the lipid-like compound is a compound of formula (I): B 1 —K 1 -A-K 2 —B 2 , in which
 A, the hydrophilic moiety, is 
 
       
         
           
           
               
               
           
         
       
       each of R a , R a ′, R a ″, and R a ′″, independently, being a C 1 -C 20  monovalent aliphatic radical, a C 1 -C 20  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z being a C 1 -C 20  bivalent aliphatic radical, a C 1 -C 20  bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
 each of B 1 , the hydrophobic moiety, and B 2 , also the hydrophobic moiety, independently, is a C 12-20  aliphatic radical or a C 12-20  heteroaliphatic radical; and 
 each of K 1 , the linker, and K 2 , also the linker, independently, is O, S, Si, C 1 -C 6  alkylene, 
 
       
         
           
           
               
               
           
         
       
       in which each of m, n, p, q, and t, independently, is 1-6; W is O, S, or NR c ; each of L 1 , L 3 , L 5 , L 7 , and L 9 , independently, is a bond, O, S, or NR d ; each of L 2 , L 4 , L 6 , L 8 , and L 10 , independently, is a bond, O, S, or NR e ; and V is OR f , SR g , or NR h R i , each of R b , R c , R d , R e , R f , R g , R h , and R i , independently, being H, OH, a C 1 -C 10  oxyaliphatic radical, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical. 
     
     
         19 . The nanocomplex of  claim 18 , wherein
 A is   
       
         
           
           
               
               
           
         
       
       in which each of R a  and R a ′, independently, is, H, a C 1 -C 10  monovalent aliphatic radical, a C 1 -C 10  monovalent heteroaliphatic radical, a monovalent aryl radical, or a monovalent heteroaryl radical; and Z is a C 1 -C 10  bivalent aliphatic radical, a C 1 -C 10  bivalent heteroaliphatic radical, a bivalent aryl radical, or a bivalent heteroaryl radical;
 each of B 1  and B 2 , independently, is a C 14-18  aliphatic radical or a C 14-18  heteroaliphatic radical; and 
 each of K 1  and K 2 , independently, is 
 
       
         
           
           
               
               
           
         
       
     
     
         20 . The nanocomplex of  claim 19 , wherein the lipid-like compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       in which each of j1 and j2, independently, is 8, 9, 10, 11, or 12; and each of k1, k2, k3, and k4, independently, is 12, 13, 14, 15, or 16. 
     
     
         21 . A pharmaceutical composition comprising a nanocomplex of  claim 1  and a pharmaceutical carrier. 
     
     
         22 . A method of treating a disease comprising administering an effective amount of a nanocomplex of  claim 1  to a patient in need thereof, wherein the disease is cancer, arthritis, neurodegenerative/cognitive disorders, an infection, chronic pain, or a sleeping disorder. 
     
     
         23 . The method of  claim 22 , wherein the disease is cancer.