Delivery of agents to inflamed tissues using folate-targeted liposomes

Abstract

The invention described herein pertains to folate-receptor targeted agents comprising therapeutic agents useful for the treatment of inflammatory disease, including folate-receptor targeted liposomes (folate-targeted liposomes) containing entrapped therapeutic agents and folate-receptor targeted dendrimers conjugated to therapeutic agents (folate-targeted dendrimer conjugates), useful for the treatment of inflammatory disease, including auto-immune disease, as well as to folate-targeted liposomes containing entrapped imaging agents and dendrimer conjugates conjugated to imaging agents, for use in the diagnosis and monitoring of treatment in such disease.

1 . A folate-receptor targeted agent comprising a therapeutic agent useful for the treatment of inflammatory disease which is a folate-targeted liposomal composition comprising an anti-inflammatory agent as an entrapped agent wherein the lipid bilayer is primarily composed of DSPC/cholesterol with a mol ratio of about 56:40. 
     
     
         2 - 3 . (canceled) 
     
     
         4 . The liposomal composition of  claim 1  wherein the lipid bilayer comprises a comprises a folate-targeting conjugate composed of (a) a lipid having a polar head group and a hydrophobic tail, (b) a hydrophilic polymer having a first end and a second end, said polymer attached at its first end to the head group of the lipid, and (c) a folate ligand (Fol) attached to the second end of the polymer, and wherein the folate ligand is a folic acid residue or an analog or derivative thereof, wherein the hydrophilic polymer of the folate targeting conjugate is a PEG having an average molecular weight of about 200-5000 in which the end groups, prior to attachment, are independently amino, hydroxy, thiol or carboxy; and wherein the folate targeting conjugate is present at about 0.01 mol % to about 1 mol % in the lipid bilayer. 
     
     
         5 - 6 . (canceled) 
     
     
         7 . The liposomal composition of  claim 4  wherein the lipid bilayer further comprises a hydrophilic coating composed of (a) a lipid having a polar head group and a hydrophobic tail and (b) a hydrophilic polymer having a first end and a second end, said polymer attached at its first end to the head group of the lipid and optionally capped at its second end, wherein the hydrophilic coating is a polyethylene glycol (PEG), a polylactic acid (PLA), a polyglycolic acid (PGA) or a polyvinyl alcohol (PVA). 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The liposomal composition of  claim 4  wherein the entrapped agent is an anti-inflammatory steroid. 
     
     
         11 . The liposomal composition of  claim 1  wherein the entrapped agent is a drug useful in the treatment of rheumatoid arthritis or other autoimmune disease including an antiproliferative, immunomodulator or immunosuppresant agent. 
     
     
         12 . A method of treatment of an inflammatory disease in a subject in need thereof, comprising administering an effective amount of a liposomal composition as described in  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising a liposomal composition comprising an anti-inflammatory agent as an entrapped agent as described in  claim 1  and further comprising at least one pharmaceutically acceptable carrier or excipient. 
     
     
         14 . A composition comprising a folate-targeted liposomal composition comprising an imaging or visualizing agent as an entrapped agent and further comprising at least one pharmaceutically acceptable carrier or excipient, wherein the lipid bilayer of the liposomal composition is primarily composed of DSPC/cholesterol with a mol ratio of about 56:40 and, wherein the hydrophilic polymer of the folate targeting conjugate is a PEG having an average molecular weight of about 200-5000 in which the end groups, prior to attachment, are independently amino, hydroxy, thiol or carboxy; and wherein the folate targeting conjugate is present at about 0.01 mol % to about 1 mol % in the lipid bilayer. 
     
     
         15 . A method of using a folate-targeted liposomal composition comprising an imaging or visualizing agent as an entrapped agent as described in  claim 14  for diagnosis or monitoring the treatment of an inflammatory disease in an inflamed tissue region in the body in a subject in need thereof. 
     
     
         16 . A kit comprising a folate-targeted liposomal composition comprising an imaging or visualizing agent as an entrapped agent as described in  claim 14  and instructions for diagnosis or monitoring the treatment of an inflammatory disease. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . A folate-targeting dendrimer conjugate comprising a folate-targeted dendrimer conjugated to an anti-inflammatory agent wherein the folate-targeting ligand (Fol) is a folic acid residue or an analog or derivative thereof, a hydrophilic coating, and a conjugated anti-inflammatory agent; and wherein the folate targeting conjugate is present at about 12-25% of the dendrimeric termini; the hydrophilic coating residue is present at about 25-40% of the dendrimeric termini; and the conjugated to anti-inflammatory agent is present at about 3-13% of the dendrimeric termini. 
     
     
         20 . (canceled) 
     
     
         21 . The folate-targeted dendrimer conjugate of  claim 19  wherein the hydrophilic coating is a polyethylene glycol (PEG), a polylactic acid (PLA), a polyglycolic acid (PGA) or a polyvinyl alcohol (PVA). 
     
     
         22 . (canceled) 
     
     
         23 . The folate-targeted dendrimer conjugate of  claim 19  wherein the conjugated anti-inflammatory agent is an anti-inflammatory steroid. 
     
     
         24 . The folate-targeted dendrimer conjugate of  claim 19  wherein the conjugated anti-inflammatory agent is a drug useful in the treatment of rheumatoid arthritis or other autoimmune disease including an antiproliferative, immunomodulator or immunosuppresant agent. 
     
     
         25 . A method of treatment of an inflammatory disease in a subject in need thereof, comprising administering an effective amount of a folate-targeted dendrimer conjugate as described in  claim 19 . 
     
     
         26 . A pharmaceutical composition comprising a folate-targeted dendrimer conjugate comprising an anti-inflammatory agent as described in  claim 19  and further comprising at least one pharmaceutically acceptable carrier or excipient. 
     
     
         27 . A composition comprising a folate-targeted dendrimer conjugate comprising an imaging or visualizing agent as a conjugated agent, wherein the folate-targeting ligand (Fol) is a folic acid residue or an analog or derivative thereof, a hydrophilic coating, and a conjugated anti-inflammatory agent; and wherein the folate targeting conjugate is present at about 12-25% of the dendrimeric termini; the hydrophilic coating residue is present at about 25-40% of the dendrimeric termini; and further comprising at least one pharmaceutically acceptable carrier or excipient. 
     
     
         28 . A method of using a folate-targeted dendrimer conjugate comprising an imaging or visualizing agent as a conjugated agent as described in  claim 27  for diagnosis or monitoring the treatment of an inflammatory disease in an inflamed tissue region in the body in a subject in need thereof. 
     
     
         29 . A kit comprising a composition comprising a folate-targeted dendrimer conjugate comprising an imaging or visualizing agent as a conjugated agent as described in  claim 27  and instructions for diagnosis or monitoring the treatment of an inflammatory disease. 
     
     
         30 . A kit comprising a folate-targeted dendrimer conjugate comprising an anti-inflammatory agent as described in  claim 19 , or a pharmaceutical composition thereof, and an imaging agent for the inflammatory condition.