Targeted dendrimer-drug conjugates
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.
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.