Enhanced oral transcompartmental delivery of therapeutic or diaganostic agents

Abstract

The invention is directed to pharmaceutical compositions and methods for delivery of a therapeutic or diagnostic agent from one bodily compartment to one or more other bodily compartment by administering one of the following conjugates: a polymer having multiple functional groups at least one of which is covalently bound to a therapeutic or diagnostic agent, and at least one cell uptake promoter covalently bound to the therapeutic or diagnostic agent; or a polymer and at least one cell uptake promoter bound thereto; the polymer further comprising multiple functional groups at least one of which is covalently bound a therapeutic or diagnostic agent.

1 .- 27 . (canceled) 
     
     
         28 . A transcompartmental delivery promoting composition comprising:
 a) a pharmaceutically acceptable polymer comprising multiple functional groups, at least one therapeutic or diagnostic agent covalently bound to a functional group, and at least one cell uptake promoter selected from the group consisting of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor covalently bound to said therapeutic or diagnostic agent; or   b) a pharmaceutically acceptable polymer comprising multiple functional groups, at least one cell uptake promoter selected from the group consisting of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor covalently bound to a functional group; and at least one therapeutic or diagnostic agent covalently bound to a functional group.   
     
     
         29 .- 35 . (canceled) 
     
     
         36 . The composition of  claim 28 , wherein said functional group comprises a ketone, an ester, a carboxylic acid, an aldehyde, an alcohol, a thiol, or an amine. 
     
     
         37 . The composition of  claim 36 , wherein said functional group is a thiol. 
     
     
         38 . The composition of  claim 28 , wherein said multiple functional groups are derived from a thiol compound bound to said polymer. 
     
     
         39 . The composition of  claim 38 , wherein said thiol compound is cysteamine, 1-amino-2-methyl-2-propanethiol, or 1-amino-2-propanethiol. 
     
     
         40 .- 68 . (canceled) 
     
     
         69 . The composition of  claim 28 , wherein the polymer has at least 3 arms comprising a functional group. 
     
     
         70 . The composition of  claim 28 , wherein the polymer has at least 4 arms comprising a functional group. 
     
     
         71 . The composition of  claim 28 , wherein the polymer has at least 8 arms comprising a functional group. 
     
     
         72 . The composition of  claim 71 , wherein the polymer has at least 8 arms comprising a functional group, and the same or different moiety capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor is attached to at least two of the arms. 
     
     
         73 . The composition of  claim 72 , wherein the polymer has at least 8 arms comprising a functional group, and the same or different moiety capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor is attached to four of the arms. 
     
     
         74 . The composition of  claim 28 , wherein at least two same or different therapeutic agents selected from the group consisting of SEQ ID NOS: 1-8 are independently bound to a functional group on an arm of the polymer. 
     
     
         75 . The composition of  claim 28 , consisting of (A) a polymer having 8 arms, (B) at least two same or different moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor, each independently covalently bound to a functional group on an arm of said polymer, and (C) a therapeutic agent selected from the group consisting of SEQ ID NOS: 1-8 covalently bound to a functional group on an arm of said polymer. 
     
     
         76 . The composition of  claim 28 , consisting of (A) a polymer having 8 arms, (B) at least four same or different moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor, each independently covalently bound to a functional group on a polymer arm, and (C) at least one of the therapeutic agents selected from the group consisting of SEQ ID NOS: 1-8, each independently covalently bound to a functional group on an arm of said polymer. 
     
     
         77 . The composition of  claim 28 , wherein four therapeutic agents independently selected from the group consisting of SEQ ID NOS: 1-8 are each covalently bound to a functional group on an arm of said polymer. 
     
     
         78 . The composition of  claim 28 , wherein the polymer size is about 20 kDa. 
     
     
         79 . The composition of  claim 28 , comprising a plurality of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor. 
     
     
         80 . The composition of  claim 28 , comprising a plurality of therapeutic agents or diagnostic agents. 
     
     
         81 . The composition of  claim 28 , comprising a plurality of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor and therapeutic agents or diagnostic agents. 
     
     
         82 . The composition of  claim 28 , comprising a plurality of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor and therapeutic agents and diagnostic agents. 
     
     
         83 . The composition of  claim 28 , wherein the moiety capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor is a formyl-methionyl-leucyl-phenylalanine (fMLF) peptide. 
     
     
         84 . The composition of  claim 28 , wherein the therapeutic agent is a tat inhibitory peptide. 
     
     
         85 . The composition of  claim 84 , wherein the tat inhibitory peptide is selected from the group consisting of SEQ ID NOS: 1-8. 
     
     
         86 . The composition of  claim 28  wherein the polymer is polyethylene glycol (PEG). 
     
     
         87 . The composition of  claim 86  wherein the PEG comprises a plurality of PEGS co-polymerized with a diamine, a dicarboxylic acid or an amino acid further comprising an amine, carboxylic acid, hydroxyl or thiol group for covalent attachment of moieties capable of binding to the formyl-methionyl-leucyl phenylalanine (fMLF) receptor, therapeutic agents and diagnostic agents. 
     
     
         88 . The composition of  claim 86  wherein the PEG is a functionalized multi-arm PEG. 
     
     
         89 . The composition of  claim 28 , wherein said polymer of (a) or (b) is selected from the group consisting of carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, an amino acid homopolymer, polypropylene oxide, a copolymer of ethylene glycol/propylene glycol, an ethylene/maleic anhydride copolymer, an amino acid copolymer, a copolymer of polyethylene glycol and an amino acid, a polypropylene oxide/ethylene oxide copolymer, and a polyethylene glycol/thiomalic acid copolymer; and any combination thereof.