Dendrimer compositions and their use in treatment of diseases of the eye

Abstract

The present invention provides compositions comprising PAMAM dendrimers conjugated with one or more biologically active agents, and their use systemically to target activated microglia/macrophages in retina/choroid and generally, inflammatory and/or angiogenic diseases of the eye.

1 . A dosage formulation formulated for systemic delivery comprising hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers covalently linked to at least one or more therapeutic, prophylactic or detectable agents, which can be the same or different, in an amount effective to label or treat an inflammatory and/or angiogenic disease in the eye. 
     
     
         2 . The dosage formulation of  claim 1 , wherein the at least one or more agents are selected from the group consisting of proteins, oligonucleotides, siRNAs, microRNAs, vitamin A, vitamin C, vitamin E, beta-carotene, and small molecules. 
     
     
         3 . The dosage formulation of  claim 2 , wherein the agents are anti-inflammatory agents selected from the group consisting of triamcinolone acetonide, methyl prednisone, dexamethasone, COX-2 inhibitors, gold compound anti-inflammatory agents, salicylate anti-inflammatory agents, N-acetyl cysteine, minocycline, aflibercept, rapamycin, and anti-VEGF agents. 
     
     
         4 . The dosage formulation of  claim 1 , wherein the inflammatory disease of the eye is selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa, optic neuritis, infection, uveitis, sarcoid, sickle cell disease, retinal detachment, temporal arteritis, retinal ischemia, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, hypotension, diabetic retinopathy, macular edema, and choroidal neovascularization. 
     
     
         5 . The dosage formulation of  claim 1 , wherein the dendrimers are included in liposomes, microcapsules, nanoparticles, or nanocapsules. 
     
     
         6 . The dosage formulation of  claim 1 , wherein the PAMAM dendrimer is a G3, G4, G5, G6, G7, GB, G9 or G10 PAMAM dendrimer. 
     
     
         7 . A method for diagnosing and/or treating an inflammatory and/or angiogenic disease in the eye of a subject comprising administering to the subject systemically a dendrimer composition, in an effective amount, to label or treat the inflammatory and/or angiogenic disease in the eye of the subject,
 wherein the dendrimer composition comprises hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers covalently linked to one or more therapeutic, prophylactic or detectable agents, which can be the same or different.   
     
     
         8 . The method of  claim 7 , wherein the inflammatory disease of the eye is selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa, optic neuritis, infection, uveitis, sarcoid, sickle cell disease, retinal detachment, temporal arteritis, retinal ischemia, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, hypotension, diabetic retinopathy, macular edema, and choroidal neovascularization. 
     
     
         9 . The method of  claim 8 , wherein the composition is administered to the subject in a time period selected from the group consisting of daily, weekly, biweekly, monthly, and bimonthly. 
     
     
         10 . The method of  claim 7 , wherein the composition is administered in conjunction with at least one or more additional agents. 
     
     
         11 . The method of  claim 7 , wherein the one or more agents are selected from the group consisting of proteins, oligonucleotides, siRNAs, microRNAs, vitamin A, vitamin C, vitamin E, beta-carotene, and small molecules. 
     
     
         12 . The method of  claim 11 , wherein the agents are anti-inflammatory agents selected from the group consisting of triamcinolone acetonide, methyl prednisone, dexamethasone, COX-2 inhibitors, gold compound anti-inflammatory agents, salicylate anti-inflammatory agents, N-acetyl cysteine, minocycline, aflibercept, rapamycin, and anti-VEGF agents. 
     
     
         13 . The method of  claim 11 , wherein the agent is an antibody selected from the group consisting of daclizumab, basiliximab, ranibizumab, and pegaptanib sodium. 
     
     
         14 . The dosage formulation of  claim 1 , wherein the at least one or more agents are selected from the group consisting of enzymes, receptor antagonists or agonists, hormones, growth factors, and antibodies. 
     
     
         15 . The dosage formulation of  claim 1  formulated for subcutaneous injection. 
     
     
         16 . The dosage formulation of  claim 1  formulated for intramuscular injection. 
     
     
         17 . The dosage formulation of  claim 1  formulated for intravenous injection. 
     
     
         18 . The method of  claim 7 , wherein the at least one or more agents are selected from the group consisting of enzymes, receptor antagonists or agonists, hormones, growth factors, and antibodies. 
     
     
         19 . The method of  claim 7 , wherein the one or more detectable agents are selected from the group consisting of carbocyanine, indocarbocyanine, oxacarbocyanine, thüicarbocyanine and merocyanine, polymethine, coumarine, rhodamine, xanthene, fluorescein, boron-dipyrromethane.