Inhibiting proliferation of arterial smooth muscle cells

Abstract

The present invention provides methods and compositions for inhibiting the proliferation of smooth muscle cells at a site of vascular injury. The methods include intravascular administration of a reactive compound to the site of injury, without the requirement for activation or sustained release of the compound.

What is claimed is:  
     
         1 . A method for inhibiting restenosis, the method comprising local administration of an alkylating compound to a site of vascular recanalization, wherein said alkylating compound comprises a nucleic acid binding ligand.  
     
     
         2 . The method of    claim 1   , wherein the alkylating compound comprises a chemical group which forms a covalent bond with a nucleic acid.  
     
     
         3 . The method of    claim 2   , wherein the chemical group is selected from the group consisting of mustards, mustard intermediates and mustard equivalents.  
     
     
         4 . The method of    claim 3   , wherein the mustard is an aliphatic mustard.  
     
     
         5 . The method of    claim 2   , wherein the nucleic acid binding ligand is selected from the group consisting of intercalators, minor groove binders, major groove binders, electrostatic binders, nucleic acids, and derivatives thereof.  
     
     
         6 . The method of    claim 5   , wherein the intercalator is an acridine or acridine derivative.  
     
     
         7 . The method of    claim 6   , wherein the compound is a quinacrine mustard.  
     
     
         8 . The method of    claim 2   , wherein the nucleic acid binding ligand is covalently bonded to a frangible linker, wherein the frangible linker is covalently bonded to the chemical group.  
     
     
         9 . The method of    claim 8   , wherein said frangible linker is selected from the group consisting of esters, thioesters, thionoesters, dithioic acids, sulfates, sulfonates, phosphates, phosphonates, and amides.  
     
     
         10 . The method according to    claim 9   , wherein the alkylating compound is β-alanine, N-(acridin-9-yl), 2-[bis(2-chloroethyl)amino]ethyl ester.  
     
     
         11 . The method according to    claim 1   , wherein administration is achieved through the use of a system selected from the group consisting of catheters, stents, and endoluminal paving.  
     
     
         12 . The method according to    claim 11   , wherein administration is achieved through the use of an intravascular drug delivery catheter.  
     
     
         13 . The method of    claim 12   , wherein the catheter is selected from the group consisting of an infusion sleeve catheter, a pressure-driven catheter and a double balloon catheter.  
     
     
         14 . The method of    claim 1   , wherein the method further comprises administration of a quencher.  
     
     
         15 . The method of    claim 14   , wherein the quencher is administered locally.  
     
     
         16 . The method of    claim 14   , wherein the quencher is administered systemically.  
     
     
         17 . The method of    claim 14   , wherein the quencher is a thiol containing molecule.  
     
     
         18 . The method of    claim 17   , wherein the quencher is glutathione.  
     
     
         19 . The method of    claim 1   , wherein the vascular recanalization is achieved by angioplasty.  
     
     
         20 . The method of    claim 1   , wherein the local administration is of a non sustained release formulation.  
     
     
         21 . The method of    claim 20   , wherein the alkylating compound is delivered at a concentration of less than about 100 μM.  
     
     
         22 . The method of    claim 20   , wherein the alkylating compound is delivered at a concentration of less than about 1 μM.