Compositions and methods for enhancing contrast in imaging

Abstract

Example compositions of liposomes with hydrophilic polymers on their surface, and containing relatively high concentrations of contrast-enhancing agents for computed tomography are provided. Example pharmaceutical compositions of such liposomes, when administered to a subject, provide for increased contrast of extended duration, as measured by computed tomography, in the bloodstream and other tissues of the subject. Also provided are example methods for making the liposomes containing high concentrations of contrast-enhancing agents, and example methods for using the compositions.

We claim: 
     
       1. A composition for enhancing contrast of one or more areas of a subject for X-ray imaging when administered to the subject, the composition comprising:
 liposomes, the liposomes encapsulating one or more iodinated nonradioactive contrast-enhancing agents, and the liposomes comprising: cholesterol, at least one phospholipid, and at least one phospholipid which is derivatized with a polymer chain, 
 wherein the average diameter of the liposomes is less than 150 nanometers, wherein the liposomes encapsulate the one or more iodinated nonradioactive contrast enhancing agents such that the liposomes have an iodine concentration of at least 30 mg I/mL of liposome composition, and wherein the encapsulated one or more iodinated nonradioactive contrast enhancing agents represent at least 90% of the total iodine concentration of the composition. 
 
     
     
       2. The composition of  claim 1 , wherein the X-ray imaging is computed tomography. 
     
     
       3. The composition of  claim 1 , wherein the iodinated nonradioactive contrast-enhancing agents are selected from at least one of: iodinated ionic compounds, iodinated nonionic compounds, and mixtures thereof. 
     
     
       4. The composition of  claim 3 , wherein a suspension of the liposomes has a concentration of at least 30 milligrams of iodine per milliliter of the suspension. 
     
     
       5. The composition of  claim 1 , wherein the average diameter of the liposomes is less than 120 nanometers. 
     
     
       6. The composition of  claim 1 , wherein the composition is capable of being administered to the bloodstream of the subject. 
     
     
       7. The composition of  claim 6 , wherein the composition provides an enhanced contrast that remains detectable at least 30 minutes after administration. 
     
     
       8. The composition of  claim 6 , wherein the composition provides an enhanced contrast of at least 50 Hounsfield units in at least part of at least one of a vasculature and an organ of the subject. 
     
     
       9. The composition of  claim 1 , wherein the liposomes are PEGylated liposomes. 
     
     
       10. The composition of  claim 1 , wherein the liposomes are targeted liposomes. 
     
     
       11. A composition for enhancing contrast of one or more areas of a subject for X-ray imaging when administered to the subject, the composition comprising liposomes, the liposomes comprising:
 at least one first lipid or phospholipid; 
 at least one second lipid or phospholipid which is derivatized with one or more polymers; and 
 at least one sterically bulky excipient capable of stabilizing the liposomes; 
 wherein the average diameter of the liposomes is less than 150 nanometers, and wherein the liposomes encapsulate at least one iodinated nonradioactive contrast enhancing agent, and wherein the liposomes are contained in a suspension medium, at least some of the iodinated nonradioactive contrast enhancing agent that has not been encapsulated by the liposomes having been removed from the suspension medium. 
 
     
     
       12. The composition of  claim 11 , wherein the at least one first lipid or phospholipid comprises 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC). 
     
     
       13. The composition of  claim 11 , wherein the at least one second lipid or phospholipid which is derivatized with one or more polymers comprises N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (DSPL-MPLG2000). 
     
     
       14. The composition of  claim 11 , wherein the at least one sterically bulky excipient is selected from at least one of: sterols, fatty alcohols, fatty acids, and mixtures thereof. 
     
     
       15. The composition of  claim 11 , wherein the at least one sterically bulky excipient is cholesterol. 
     
     
       16. The composition of  claim 11 , wherein the liposomes are not autoclaved. 
     
     
       17. The composition of  claim 11 , wherein the liposomes are contained in a suspension medium, at least some of the iodinated nonradioactive contrast enhancing agent that has not been encapsulated by the liposomes having been removed from the suspension medium. 
     
     
       18. The composition of  claim 11 , wherein the at least one first lipid or phospholipid is present in the amount of from about 55 to about 75 mol %; the at least one second lipid or phospholipid which is derivatized with one or more polymers is present in the amount of from about 1 to about 20 mol %; and the at least one sterically bulky excipient is present in the amount of from about 25 to about 40 mol %. 
     
     
       19. The composition of  claim 18 , wherein the at least one first lipid or phospholipid is hydrogenated soy phosphatidylcholine; the at least one second lipid or phospholipid which is derivatized with one or more polymers is N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (DSPL-MPLG2000); and the at least one sterically bulky excipient is cholesterol. 
     
     
       20. The composition of claim 1, wherein the one or more iodinated nonradioactive contrast-enhancing agents comprise iodixanol and/or iohexol.  
     
     
       21. The composition of claim 1, wherein the at least one phospholipid comprises 1,2-dipalmatoyl-sn-glycero-3-phosphocholine (DPPC).  
     
     
       22. The composition of claim 1, wherein the at least one phospholipid which is derivatized with a polymer chain comprises N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (DSPE-MPEG2000).  
     
     
       23. A composition, comprising:
 (a) liposomes having an average diameter of less than 150 nanometers, the liposomes comprising:
 (i) 1,2-dipalmatoyl-sn-glycero-3-phosphocholine (DPPC); 
 (ii) N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (DSPE-MPEG2000); and 
 (iii) cholesterol, and 
   (b) an iodinated nonradioactive contrast enhancing agent, a fraction of the iodinated nonradioactive contrast enhancing agent being encapsulated by the liposomes and a lesser fraction of the iodinated nonradioactive contrast enhancing agent being unencapsulated.    
     
     
       24. The composition of claim 23, wherein sufficient iodinated nonradioactive contrast enhancing agent is encapsulated by the liposomes such that the liposomes have an iodine concentration of over 30 mg I/mL of liposome composition.  
     
     
       25. The composition of claim 23, with the proviso that the composition is exclusive of Soy PC (HSPC) and pure DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine).  
     
     
       26. A composition for obtaining X-ray images of a region of interest of a subject when administered to the subject, the composition comprising:
 liposomes, a plurality of the liposomes having an internal cavity and a bilayer, the bilayer comprising: cholesterol, a phospholipid, and a phospholipid which is derivatized with a polymer chain; and   an iodinated nonradioactive contrast enhancing agent, at least some of the iodinated nonradioactive contrast enhancing agent being encapsulated in the internal cavity such that the liposomes have an iodine concentration of at least 30 mg I/mL of liposome composition, wherein iodinated nonradioactive contrast enhancing agent that has not been encapsulated has been removed from the composition,   wherein the average diameter of the liposomes is less than 150 nanometers.    
     
     
       27. The composition of claim 26, wherein the iodinated nonradioactive contrast-enhancing agent comprises at least one of iodixanol and iohexol.  
     
     
       28. The composition of claim 26, wherein the phospholipid comprises 1,2-dipalmatoyl-sn-glycero-3-phosphocholine (DPPC).  
     
     
       29. The composition of claim 26, wherein the phospholipid which is derivatized with a polymer chain comprises N-carbamylmethoxypoly(ethylene glycol)-1,2-distearoyl-sn-glycerol-3-phosphoethanolamine (DSPE-MPEG2000).