Etherlipid-containing multiple lipid liposomes

Abstract

Described herein are liposomes containing etherlipids of the formula: as well as a phosphatidylcholine, a sterol, and a headgroup-derivatized lipid. These liposomes are useful in a variety of therapeutic regimens, including the treatment of cancers and inflammatory disorders.

1. A liposome having a lipid bilayer which comprises: (a) a phosphatidylcholine; (b) a sterol; (c) a headgroup-derivatized lipid comprising a phosphatidylethanolamine linked at the ethanolamine group to a dicarboxylic acid; and, (d) an etherlipid having the formula: 
                 
 
       wherein R 1  is Y 1  Y 2 , Y 2  is CH 3  or CO 2 H, Y 1  is (CH 2 ) n1  (CH═CH) n2 (CH 2 ) n3 (CH═CH) n4  (CH 2 ) n5 (CH═CH) n6  (CH 2 ) n7 (CH═CH) n8 (CH 2 ) n9 , the sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 3 to 23, n1 is zero or an integer of from 1 to 23, n3 is zero or an integer of from 1 to 20, n5 is zero or an integer of from 1 to 17, n7 is zero or an integer of from 1 to 14, n9 is zero or an integer of from 1 to 11, and each of n2, n4, n6 and  8 n8  is independently zero or 1;
 wherein Z is oxygen or sulfur and R 2  is CH 3 ;  
 wherein R 3  is —O—P(O) 2 —O—CH 2 CH 2 N(CH 3 ) 3 ;  
 and wherein the phosphatidylethanolamine-dicarboxylic acid comprises from about 5 mole percent to about 20 mole percent of the lipid bilayer and the etherlipid comprises from greater than about 10 mole percent to less than about 30 mole percent of the lipid bilayer.  
 
     
     
       2. The liposome of  claim 1  which is a unilamellar liposome having a diameter of from greater than about 50 nm to less than about 200 nm. 
     
     
       3. The liposome of  claim 1 , wherein the phosphatidylcholine is an unsaturated or partially unsaturated phosphatidylcholine. 
     
     
       4. The liposome of  claim 3 , wherein the phosphatidylcholine is dioleoyl phosphatidylcholine. 
     
     
       5. The liposome of  claim 1 , wherein the sterol is cholesterol. 
     
     
       6. The liposome of  claim 1 , wherein the headgroup derivatized lipid comprises a phosphatidylethanolamine selected from the group consisting of dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and dioleoyl phosphatidylethanolamine. 
     
     
       7. The liposome of  claim 6 , wherein the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine. 
     
     
       8. The liposome of  claim 1 , wherein the headgroup-derivatized lipid comprises a dicarboxylic acid selected from the group consisting of glutaric acid, sebacic acid, succinic acid and tartaric acid. 
     
     
       9. The liposome of  claim 8 , wherein the dicarboxylic acid is glutaric acid. 
     
     
       10. The liposome of  claim 1 , wherein the headgroup-derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid. 
     
     
       11. The liposome of  claim 1 , wherein R 1  is (CH 2 ) n1 CH 3  and Z is O. 
     
     
       12. The liposome of  claim 11 , wherein the etherlipid is: 
                 
 
     
     
       13. The liposome of  claim 12 , wherein the phosphatidylcholine is dioleoyl phosphatidylethanolamine, the sterol is cholesterol and the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid. 
     
     
       14. The liposome of  claim 13 , wherein the bilayer comprises about 20 mole percent of the etherlipid, about 10 mole percent of the headgroup-derivatized lipid, about 30 mole percent cholesterol and about 40 mole percent dioleoyl phosphatidylcholine. 
     
     
       15. The liposome of  claim 1 , comprising an additional bioactive agent. 
     
     
       16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the liposome of  claim 1 . 
     
     
       17. A liposome having a lipid bilayer which comprises: ( a )  a phosphatidylcholine ; ( b )  a sterol ; ( c )  a headgroup - derivatized lipid comprising a phosphatidylethanolamine linked at the ethanolamine group to a dicarboxylic acid; and , ( d )  an etherlipid having the formula:                       wherein R   1    is Y   1    Y   2   , Y   2    is CH   3    or CO   2   H, Y   1    is  ( CH   2   )   n1 ( CH═CH ) n2 ( CH   2 ) n3 ( CH═CH ) n4 ( CH   2 ) n5 ( CH═CH ) n6 ( CH   2 ) n7 ( CH═CH ) n8 ( CH   2 ) n9   , the sum of n 1 + 2 n 2 +n 3 + 2 n 4 +n 5 + 2 n 6 +n 7 + 2 n 8 +n 9  is an integer of from  3  to  23 , n 1  is zero or an integer of from  1  to  23 , n 3  is zero or an integer of from  1  to  20 , n 5  is zero or an integer of from  1  to  17 , n 7  is zero or an integer of from  1  to  14 , n 9  is zero or an integer of from  1  to  11 , and each of n 2 , n 4 , n 6  and n 8  is independently zero or  1 ;        wherein Z is NH   2   ,C ( O ) O   2    or HNC ( O );      R   2    is CH   3 ;      R   3    is —O—P ( O ) 2   —O—CH   2   CH   2   N ( CH   3 ) 3   ; and        wherein the phosphatidylethanolamine - dicarboxylic acid comprises from about  5  mole percent to about  20  mole percent of the lipid bilayer and the etherlipid comprises from greater than about  10  mole percent to less than about  30  mole percent of the lipid bilayer.     
     
     
       18. The liposomes of  claim 17  which is a unilamellar liposome having a diameter of from greater than about  50  nm to less than about  200  nm. 
     
     
       19. The liposome of  claim 17 , wherein the phosphatidylcholine is an unsaturated or partially unsaturated phosphatidylcholine. 
     
     
       20. The liposome of  claim 19 , wherein the phosphatidylcholine is dioleoyl phosphatidylcholine. 
     
     
       21. The liposome of  claim 17 , wherein the sterol is cholesterol. 
     
     
       22. The liposome of  claim 17 , wherein the headgroup derivatized lipid comprises a phosphatidylethanolamine selected from the group consisting of dipalmitoyl phosphatidylethanolamine, palmitoyloleoyl phosphatidylethanolamine and dioleoyl phosphatidylethanolamine. 
     
     
       23. The liposome of  claim 22 , wherein the headgroup derivatized lipid comprises dioleoyl phosphatidylethanolamine. 
     
     
       24. The liposome of  claim 17 , wherein the headgroup- derivatized lipid comprises a dicarboxylic acid selected from the group consisting of glutaric acid, sebacic acid, succinic acid and tartaric acid.   
     
     
       25. The liposome of  claim 24 , wherein the dicarboxylic acid is glutaric acid. 
     
     
       26. The liposome of  claim 17 , wherein the headgroup- derivatized lipid comprises dioleoyl phosphatidylethanolamine and glutaric acid.   
     
     
       27. The liposome of  claim 17 , wherein R 1    is  ( CH   2 ) n1   CH   3    and Z is C ( O ) O.   
     
     
       28. The liposome of  claim 17 , wherein R 1    is  ( CH   2 ) n1   CH   3    and Z is NH.   
     
     
       29. The liposome of  claim 17 , wherein R 1    is  ( CH   2 ) n1   CH   3    and Z is HNC ( O ). 
     
     
       30. The liposome of  claim 17 , comprising an additional bioactive agent. 
     
     
       31. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the liposome of  claim 17 .