Compounds for targeting drug delivery and enhancing siRNA activity

Patent metadata

Field	Value
Publication number	US-9393315-B2
Application number	US-201213492424-A
Country	US
Kind code	B2
Filing date	Jun 8, 2012
Priority date	Jun 8, 2011
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

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 (targeting molecule) m -linker-(targeting molecule) n , wherein the targeting molecule consists of a retinoid or a fat soluble vitamin having a specific receptor on the target cell; wherein m and n are independently 1, 2, or 3; wherein m+n=4-6; and wherein the linker comprises one or more elements selected from a polyethylene glycol (PEG), glutarate (Glu), hexyl, Gly 3 , and 4-aminobutanoate (GluNH).

2. The compound of claim 1 , wherein the retinoid is selected from vitamin A, retinoic acid, tretinoin, adapalene, 4-hydroxy(phenyl)retinamide (4-HPR), retinyl palmitate, retinal, saturated retinoic acid, and saturated, demethylated retinoic acid.

3. The compound of claim 1 , wherein the fat-soluble vitamin is vitamin D, vitamin E, or vitamin K.

4. The compound of claim 1 , wherein the compound is selected from (retinoid) 2 -PEG-(retinoid) 2 , (retinoid) 2 -bis-amido-PEG-(retinoid) 2 , and (retinoid) 2 -Lys-bis-amido-PEG-Lys-(retinoid) 2 .

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

6. The compound of claim 5 , wherein the compound has the structure of formula

wherein q, r, and s are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. The compound of claim 5 , wherein the compound has the structure of formula

8. The compound of claim 1 , wherein the PEG is mono disperse.

9. A stellate-cell-specific drug carrier comprising a stellate cell specific amount of a retinoid molecule consisting of the structure (retinoid) m -linker-(retinoid) n ; wherein m and n are independently 1, 2, or 3; wherein the linker comprises one or more elements selected from a polyethylene glycol (PEG), glutarate (Glu), hexyl, Gly 3 , and 4-aminobutanoate (GluNH).

10. The drug carrier of claim 9 , further comprising a liposomal composition.

11. The drug carrier of claim 10 , wherein the liposomal composition comprises a lipid vesicle comprising a bilayer of lipid molecules.

12. The drug carrier of claim 10 , wherein the retinoid molecule is at least partially exposed on the exterior of the drug carrier before the drug carrier reaches the stellate cell.

13. The drug carrier of claim 11 , wherein the retinoid is 0.1 mol % to 20 mol % of the lipid molecules.

14. The compound of claim 1 , wherein the polyethylene glycol has a molecular weight of about 550 to about 2000.

15. A compound for facilitating drug delivery to a target cell, consisting of the structure (targeting molecule) m -linker-(targeting molecule) n , wherein the targeting molecule consists of a retinoid or a fat soluble vitamin having a specific receptor on the target cell; wherein m and n are 1 or 2; wherein m+n=3; and wherein the linker comprises one or more elements selected from bis-amido-polyethylene glycol (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, PEG-Glu, glutarate (Glu), hexyl, Gly 3 , and 4-aminobutanoate (GluNH).

16. The compound of claim 1 , wherein the linker comprises one or more elements selected from 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, PEG-Glu, glutarate (Glu), hexyl, Gly3, and 4-aminobutanoate (GluNH).

17. The drug carrier of claim 9 , wherein the linker comprises one or more elements selected from 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, PEG-Glu, glutarate (Glu), hexyl, Gly3, and 4-aminobutanoate (GluNH).

Assignees

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

• C07C2601/16

  the ring being unsaturated · CPC title

• C07F9/10

  Phosphatides, e.g. lecithin · CPC title

• A61K47/551

  one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid · CPC title

• A61K31/07

  Retinol compounds, e.g. vitamin A (retinoic acids A61K31/203) · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title