Compounds for targeting drug delivery and enhancing siRNA activity

Patent metadata

Field	Value
Publication number	US-10000447-B2
Application number	US-201615177269-A
Country	US
Kind code	B2
Filing date	Jun 8, 2016
Priority date	Jun 8, 2011
Publication date	Jun 19, 2018
Grant date	Jun 19, 2018

Abstract

Here described are compounds consisting of the structure

(targeting molecule) m -linker-(targeting molecule) n ,

wherein the targeting molecule is a retinoid or a fat soluble vitamin having a specific receptor on the target cell; wherein m and n are independently 0, 1, 2 or 3; and wherein the linker comprises a polyethylene glycol (PEG) or PEG-like molecule, as well as compositions and pharmaceutical formulations including these compounds which are useful for the targeting and delivery of therapeutic agents; and methods of using these compositions and pharmaceutical formulations.

First claim

What is claimed:

1. A compound, consisting of the structure (lipid) m -linker-(retinoid) n wherein m is 1, 2, or 3, and n is 1, 2, 3, 4 or 6; and wherein the linker comprises a polyethylene glycol (PEG), glutarate (Glu), hexyl, Gly 3 , 4-aminobutanoate, or GluNH.

2. The compound of claim 1 , wherein the lipid is selected from one or more of the group consisting of DODC, HEDODC, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and (6-(14-azanyl)hexanoyl)azanediyl)bis(ethane-2,1-diyl) ditetradecanoate (DC-6-14)

3. The compound of claim 2 , wherein the retinoid is selected from the group consisting of vitamin A, retinoic acid, tretinoin, adapalene, 4-hydroxy(phenyl)retinamide, retinyl palmitate, retinal, saturated retinoic acid, and saturated, demethylated retinoic acid.

4. The compound of claim 2 , wherein the linker comprises bis-amido-PEG, tris-amido-PEG, tetra-amido-PEG, Lys-bis-amido-PEG Lys, Lys-tris-amido-PEG-Lys, Lys-tetra-amido-PEG-Lys, Lys-PEG-Lys, PEG2000, PEG1250, PEG1000, PEG750, PEG550, Glu, PEG-Glu, hexyl, Gly 3 , 4-aminobutanoate, or Glu-NH.

5. The compound of claim 4 , selected from the group consisting of DSPE-PEG-VA, DSPE-PEG2000-Glu-VA, DSPE-PEG550-VA, DOPE-Glu-VA, DOPE-Glu-NH-VA, and DOPE-Gly 3 -VA.

6. A composition comprising the compound of claim 1 .

7. The composition of claim 6 , further comprising additional lipid molecules.

8. The composition of claim 7 , in the form of a liposomal composition.

9. The composition of claim 8 , wherein the compound is at least partially exposed on the exterior of the liposomal composition.

10. The composition of claim 8 , wherein the compound is 0.2 mol % to 20 mol % of the lipid molecules.

11. The composition of claim 7 , wherein the lipid molecules comprise one or more lipids selected from the group consisting of HEDC, DODC, HEDC, HEDODC, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and (6-(14-azanyl)hexanoyl)azanediyl)bis(ethane-2,1-diyl) ditetradecanoate (DC-6-14)

12. The composition of claim 11 , wherein the lipid molecules further comprise S104

13. The composition of claim 7 , further comprising a nucleic acid.

14. The composition of claim 13 , wherein the nucleic acid is an siRNA that is capable of knocking down expression of hsp47 mRNA in the stellate cell.

15. The composition of claim 6 , wherein the linker comprises bis-amido-PEG, tris-amido-PEG, tetra-amido-PEG, Lys-bis-amido-PEG Lys, Lys-tris-amido-PEG-Lys, Lys-tetra-amido-PEG-Lys, Lys-PEG-Lys, PEG2000, PEG1250, PEG1000, PEG750, PEG550, Glu, PEG-Glu, hexyl, Gly 3 or 4-aminobutanoate.

16. The composition of claim 15 , wherein the compound is selected from the group consisting of DSPE-PEG-VA, DSPE-PEG2000-Glu-VA, DSPE-PEG550-VA, DOPE-Glu-VA, DOPE-Glu-NH-VA, and DOPE-Gly 3 -VA.

Assignees

• Nitto Denko Corp

Inventors

• Niitsu Yoshiro
• Payne Joseph E
• Gaudette John A
• Hou Zheng
• Knopov Victor
• Witte Richard P
• Ahmadian Mohammad
• Perelman Loren A
• Tanaka Yasunobu
• Akopian Violetta

Classifications

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• Y10S977/907

  Liposome · CPC title

• C07C2601/16

  the ring being unsaturated · CPC title

• C07C237/22 Primary

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title

• Y10S977/773

  Nanoparticle, i.e. structure having three dimensions of 100 nm or less · CPC title