Liposomal assembly for therapeutic and/or diagnostic use
Composition for diagnostic or therapeutic use which comprises an assembly comprising an active agent. The assembly comprises a liposome and a plurality of micellar components associated thereto, said micellar components being associated to the outer surface of the envelope of said liposome through a substantially electrostatic interaction, When an active compound is incorporated into the micelles, a substantial amount of said active compound can be linked to a singe liposome. Furthermore, the presence of the outer micellar layer allows to increase the residence time of said liposome in the blood stream.
1. A composition for diagnostic or therapeutic use which comprises an assembly comprising:
a) a liposome comprising a first amphiphilic compound bearing a first overall net charge, said liposome having a boundary envelope with a respective inner and an outer surface, said envelope defining an internal portion thereof; and
b) a plurality of micelles comprising: (i) a second amphiphilic compound; and (ii) an image enhancing compound; said second amphiphilic compound bearing a second overall net charge opposite in sign to said first net charge; said micelles being associated with the outer surface of the envelope of said liposome through a substantially electrostatic interaction.
2. A composition according to claim 1 wherein said second amphiphilic compound is a polymeric compound.
3. A composition according to claim 2 wherein said amphiphilic polymeric compound is a polymeric surfactant or a phospholipid bearing a hydrophilic polymeric moiety.
4. A composition according to claim 1 wherein said image enhancing compound is a MRI responsive compound.
5. A composition according to claim 4 wherein said MRI responsive compound is a paramagnetic metal ion complexed by a chelating molecule comprising a lipophilic moiety.
6. A composition according to claim 5 wherein said paramagnetic ion is selected from the group consisting of chromium (III), manganese (II), manganese (III), iron (II), iron (III), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III), gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), europium (III) and ytterbium (III).
7. A composition according to claim 5 wherein said chelating molecule is an amphipatic chelating agent comprising a chelating hydrophilic portion and a lipophilic portion.
8. A composition according to claim 7 wherein said chelating hydrophilic portion is a residue of a chelating acid selected from the group consisting of diethylenetriamine pentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), benzo-DOTA, dibenzo-DOTA, 1,4,7,-tricarboxymethyl 1,4,7,10 teraazacyclododecane triacetic acid (DO3A), 1,4,7,10-tetraazacyclo-dodecan-1-(2-hydroxypropyl)-4,7,10-triacetic acid (HP-DO3A), ethylenediamine-tetraacetic acid (EDTA), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), benzo-TETA, ethylenebis-(2-hydroxy-phenylglycine) (EHPG), 5-Cl-EHPG, 5Br-EHPG, 5-Me-EHPG, 5t-Bu-EHPG, and Ssec-Bu-EHPG, benzodiethylenetriamine pentaacetic acid (benzo-DTPA), dibenzo-DTPA, phenyl-DTPA, diphenyl-DTPA, benzyl-DTPA, dibenzyl DTPA, bis-2 (hydroxybenzyl)-ethylene-diaminediacetic acid (HBED), 1,4,7-triazacyclo-nonane N,N′,N″-triacetic acid (NOTA), benzo-NOTA, 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetra(methyl tetraacetic acid) (DOTMA), benzo-DOTMA, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-(methyl tetraacetic acid) (TETMA), benzo-TETMA, derivatives of 1,3-propylenediaminetetraacetic acid (PDTA), derivatives of triethylenetetraaminehexaacetic acid (TTHA), derivatives of 1,5,10-N,N′,N″-tris(2,3-dihydroxybenzoyl)-tricatecholate (LICAM), and derivatives of 1,3,5-N,N′,N″-tris(2,3-dihydroxybenzoyl) aminomethylbenzene (MECAM).
9. A composition according to claim 7 wherein said lipophilic portion is selected from the group consisting of a residue of a (C 1 -C 24 ) alcohol, an aromatic alcohol, a (C 1 -C 24 )alkyl linear aliphatic amine, an aromatic amine, or mixtures thereof.
10. A composition according to claim 9 wherein said lipophilic portion is a residue of n-decyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, n-octadecyl alcohol, benzyl alcohol, mono-, di- or tri-(C 1 -C 4 )alkyl-phenyl alcohols, n-decyl amine, n-dodecyl amine, n-tetradecyl amine, n-hexadecyl amine, n-octadecyl amine, benzyl amine, mono-, di- or tri-(C 1 -C 4 )alkyl-phenyl amine, or mixtures thereof.
11. A composition according to claim 5 wherein said MRI responsive compound is [10-[2-(dioctadecylamino)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (3-)]Gadolinium.
12. A composition according to claim 1 , wherein said micelles further comprises a targeting ligand.
13. A composition according to claim 1 wherein said liposome further comprises a therapeutic agent.
14. A composition according to claim 1 wherein said positively charged amphiphilic compound is selected from the group consisting of mono or di-esters of ethylphosphatidylcholine with or two fatty acid; alkylammonium salts comprising at least one (C 10 -C 20 ), alkyl chain; tertiary or quaternary ammonium salts comprising one or two (C 10 -C 20 ) acyl chain linked to the N-atom through a (C 3 -C 6 ) alkylene bridge; and mixtures thereof.
15. A composition according to claim 1 wherein said negatively charged compound is selected from the group consisting of fatty acid di-ester of phophatidylserine, fatty acid di-ester of phosphatidic acid, fatty acid di-ester of phosphatidylglycerol, fatty acid di-ester of phosphatidylinositol, polytheyleneglycol-modified fatty acid di-ester of phosphatidylethanolamine, bile acid salts, (C 12 -C 24 ) fatty acid salts, and mixtures thereof.
16. A composition according to claim 1 wherein said micelles further comprise an amphiphilic polymeric compound.
17. A method for preparing an assembly according to claim 1 , which comprises admixing a preparation comprising a liposome or a precursor thereof with a preparation comprising a micelle or a precursor thereof to be associated to said liposome.