Dendrimers for sustained release of compounds

Abstract

Dendrimer-based compositions and methods are provided, that are useful for administering pharmaceutical compositions to target cells and tissues for treatment of ocular diseases including macular degeneration, diabetic retinopathy, and retinitis pigmentosa.

1 - 36 . (canceled) 
     
     
         37 . A composition comprising a polyamidoamine (PAMAM) dendrimer with free hydroxyl terminal groups, and one or more biologically active agents bound to the hydroxyl terminal groups. 
     
     
         38 . The composition of  claim 37 , wherein the biologically active agent is selected from the group consisting of anti-inflammatory agents, anti-oxidants, growth factors, neurostimulants, neuroprotectants, anti-oncogenic agents, anti-angiogenic agents, tumor suppressor agents, anti-microbial agents, and apoptotic factors. 
     
     
         39 . The composition of  claim 37 , wherein the biologically active agent is selected from the group consisting of corticosteroids, cytokines, and chemotherapeutic agents. 
     
     
         40 . The composition of  claim 39 , wherein the corticosteroid is selected from the group consisting of fluocinolone acetonide, methylprednisone, and dexamethasone. 
     
     
         41 . The composition of  claim 38 , wherein the biologically active agent is selected from the group consisting of pegaptanib, ranibizumab, bevacizumab, vascular endothelial growth factor (VEGF)-trap, anecortave acetate, and Combretastatin A4 prodrug. 
     
     
         42 . The composition of  claim 37 , wherein the biologically active agent is selected from the group consisting of polypeptides, peptides, amino acids, nucleic acids, and small molecules. 
     
     
         43 . The composition of  claim 42 , wherein the biologically active agent is a nucleic acid, wherein the nucleic acid is selected from the group consisting of RNA, DNA, cDNA, siRNA, microRNA, and synthetic nucleic acid analogs. 
     
     
         44 . The composition of  claim 37 , wherein the biologically active agent is bound to the hydroxyl terminal group via one or more spacers selected from the group consisting of a peptide, amino acid and polyethylene glycols (PEG). 
     
     
         45 . The composition of  claim 37 , wherein the polyamidoamine (PAMAM) dendrimer is selected from the group consisting of PAMAM generation 1 (G1), PAMAM generation 2 (G2), PAMAM generation 3 (G3), PAMAM generation 4 (G4), PAMAM generation 5 (G5), PAMAM generation 6 (G6), PAMAM generation 7 (G7), PAMAM generation 8 (G8), PAMAM generation 9 (G9), and PAMAM generation 10 (G10) dendrimers. 
     
     
         46 . The composition of  claim 45 , wherein the polyamidoamine (PAMAM) dendrimer is PAMAM generation 4 (G4) or PAMAM generation 5 (G5). 
     
     
         47 . The composition of  claim 37 , wherein the dendrimer has a diameter of between 1.5 nanometers and 14.5 nanometers, inclusive. 
     
     
         48 . The composition of  claim 47 , wherein the dendrimer has a diameter of between 2 nanometers and 10 nanometers, inclusive. 
     
     
         49 . The composition of  claim 37 , wherein the dendrimer is encapsulated in a formulation selected from the group consisting of polymer matrices, microparticles, nanoparticles, liposomes, microcapsules, nanocapsules, hydrogels, and controlled-release implants. 
     
     
         50 . The composition of  claim 37 , wherein the formulation releases the biological agent over a period selected from the group consisting of several hours, several days, several weeks or several months. 
     
     
         51 . The composition of  claim 49 , wherein the formulation is a biodegradable polymeric nanoparticle. 
     
     
         52 . The composition of  claim 37  in an amount effective to treat one or more symptoms of neuroinflammation or inflammation in a subject in need thereof. 
     
     
         53 . A method of treating one or more symptoms of neuroinflammation or inflammation comprising administering an effective amount of a composition comprising a polyamidoamine (PAMAM) dendrimer with free hydroxyl terminal groups, and one or more biologically active agents bound to the hydroxyl terminal groups, wherein the biological agents are selected from the group consisting of anti-inflammatory agents, anti-oxidants, growth factors, neurostimulants, and neuroprotectants, anti-oncogenic agents, anti-angiogenic agents, tumor suppressor agents, anti-microbial agents, and apoptotic factors. 
     
     
         54 . The method of  claim 53 , wherein the composition is administered by intravitreal, and/or intrathecal administration. 
     
     
         55 . The method of  claim 53  wherein the biological agents are selected from the group consisting of anti-inflammatory agents, anti-oxidants, neurostimulants, and neuroprotectants and wherein the neuroinflammation or inflammation is caused by one or more of age-related macular degeneration (ARMD), retinitis pigmentosa, macular degeneration, cerebral palsy, optic neuritis, blunt and penetrating injuries, infections, 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, stroke, Alzheimer's disease, Parkinson's disease, brain or spinal cord trauma, AIDS dementia, age-related loss of cognitive function, memory loss, amyotrophic lateral sclerosis, seizure disorders, alcoholism, aging, and neuronal loss. 
     
     
         56 . The method of  claim 55 , wherein the neuroinflammation or inflammation is ocular neuroinflammation. 
     
     
         57 . The method of  claim 53 , wherein the composition delivers the biologically active agent to one or more cell types selected from the group consisting of activated microglia, glia, neurons, astrocytes, oligodendrocytes, Mueller cells, macrophages, photoreceptors or retinal pigment epithelial cells. 
     
     
         58 . The method of  claim 55 , wherein the neuroinflammation and/or inflammation is caused by one or more selected from the group consisting of retinitis pigmentosa, age-related macular degeneration, cerebral palsy optic neuritis, blunt and penetrating injuries, infections, 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, stroke, uveitis, photoreceptor degeneration, autoimmune retinopathy, inherited photoreceptor degeneration, myopic retinal degeneration, retinal pigment epithelial degeneration, diabetic retinopathy, central serous retinopathy, acute zonal outer occult retinopathy, acute multifocal placoid pigment epitheliopathy, multiple evanescent white dot syndrome, cancer associated retinopathy, retinal vasculitis, Alzheimer's disease, Parkinson's disease, brain or spinal cord trauma, AIDS dementia, age-related loss of cognitive function, memory loss, amyotrophic lateral sclerosis, seizure disorders, alcoholism, aging, and neuronal loss. 
     
     
         59 . The method of  claim 53  for treating progressive vision loss in a subject in need thereof, comprising administering to the eye of the subject. 
     
     
         60 . The method of  claim 59 , wherein the progressive vision loss is associated with at least one condition selected from the group consisting of uveitis, age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa.