Targeted dendrimer-drug conjugates

Patent metadata

Field	Value
Publication number	US-9345781-B2
Application number	US-201213493691-A
Country	US
Kind code	B2
Filing date	Jun 11, 2012
Priority date	Dec 11, 2009
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The invention provides for dendrimer conjugates useful for liver-specific delivery of therapeutic agents. The therapeutic agent is associated to the dendrimer through a enzyme-cleavable covalent linkage.

First claim

What is claimed is:

1. A dendrimer conjugate comprising a structure of

wherein X is NCH 3 and Y is H or OCH 3 ,
or a structure of

wherein X is O and Y is OCH 3 wherein the agent is a therapeutic agent or an imaging agent.

2. A pharmaceutical composition comprising a dendrimer conjugate of claim 1 and a pharmaceutically acceptable carrier.

3. A method of delivering a therapeutic agent to liver cells of a subject comprising contacting liver cells with a dendrimer conjugate of claim 1 , or a composition or pharmaceutical composition comprising the same under conditions sufficient to deliver the therapeutic agent to the liver cells wherein the dendrimer conjugate comprises a therapeutic agent.

4. A method of imaging a liver cell of a liver tissue, comprising administering to the subject a dendrimer conjugate of claim 1 , or a composition or pharmaceutical composition comprising the same, in an amount effective to image the liver cell, wherein the dendrimer conjugate comprises an imaging agent.

5. The dendrimer conjugate of claim 1 , further comprising a hepatocyte-specific targeting molecule, a PEG chain, or a combination thereof.

6. The dendrimer conjugate of claim 5 , wherein the hepatocyte-specific targeting molecule is a ligand of the asialoglycoprotein receptor (ASGPR).

7. The dendrimer conjugate of claim 6 , wherein the ligand of the ASGPR is N-acetyl-galactosamine.

8. The dendrimer conjugate of claim 5 , wherein the hepatocyte-specific targeting molecule is attached to the dendrimer through a thiourea moiety, a urea moiety, a carbamate moiety, a linkage from terminal epoxide opening, an amide linkage through peptide coupling, a linkage by formation of the Shiff base, a linkage formed by reduction of Shiff base, a linkage generated by “click” chemistry, or is attached to the dendrimer through linkage to a PEG chain which is linked to the dendrimer.

9. The dendrimer conjugate of claim 5 , wherein the PEG chain is attached to the dendrimer through an acid hydrolysable linkage.

10. The dendrimer of claim 5 , wherein a first end of the PEG chain is attached the dendrimer and a second end of the PEG chain is attached to one or more hepatocyte-specific targeting molecules.

11. The dendrimer conjugate of claim 1 , wherein the dendrimer is a poly(amidoamine) (PAMAM) polymer.

12. The dendrimer conjugate of claim 11 , wherein the dendrimer is acetylated, labeled, or both acetylated and labeled.

13. The dendrimer conjugate of claim 1 , wherein the therapeutic agent is an anti-cancer therapeutic agent.

14. The dendrimer conjugate of claim 13 , wherein the anti-cancer therapeutic agent is doxirubicin.

15. The dendrimer conjugate of claim 1 , wherein the dendrimer is a G5 dendrimer.

Assignees

• El-Sayed Mohamed E H
• Ensminger William
• Shewach Donna
• Univ Michigan

Inventors

• El-Sayed Mohamed E H
• Ensminger William
• Shewach Donna

Classifications

• A61K47/595

  Polyamides, e.g. nylon (polyamino acids A61K47/62) · CPC title

• A61K51/06

  Macromolecular compounds {, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules (peptides, proteins, polyamino acids A61K51/08; antibodies A61K51/10)} · CPC title

• A61K49/0054

  Macromolecular compounds, i.e. oligomers, polymers, dendrimers · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K47/59

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes · CPC title