Targeted lipid-drug formulations for delivery of drugs to myeloid and lymphoid immune cells

Abstract

A method of preferentially delivering an active agent to an immune cell, such as a myeloid progenitor cell, a dendritic cell, a monocyte, a macrophage or a T-lymphocyte, or other cell type restricted to a functional organ system or an anatomic entity, of a mammalian subject by administering a lipid-drug complex to the subject. The lipid-drug complex is comprised of an active agent, such as a drug, and an outer surface with a targeting ligand that binds a marker on the surface of the immune cell or other cell type that is infected with or susceptible to infection with an infectious agent. The other cell type that is infected with or suspectible to infection with an infectious agent may belong to a malignant tumor or a part of the immune system contributing to the development, maintenance, or exacerbation of an autoimmune disease or chronic inflammatory disease.

1 . A method of preferentially delivering a drug to an immune cell of a mammalian subject, said cell being selected from the group consisting of a myeloid progenitor cell, a dendritic cell, a monocyte, a macrophage, and a T-lymphocyte, comprising: 
 administering to the mammalian subject a lipid-drug complex comprising the drug and further comprising, an outer surface comprising at least one targeting ligand that specifically binds a marker on the surface of the immune cell, the immune cell being infected with, or susceptible to infection with, an infectious agent.    
     
     
         2 . The method of  claim 1 , wherein the infectious agent is a virus.  
     
     
         3 . The method of  claim 1 , wherein the infectious agent is a bacterium, a fungus, a protozoan, or a prion.  
     
     
         4 . The method of  claim 2 , wherein the virus is selected from the group consisting of HIV, HSV, EBV, CMV, Ebola and Marburg virus, HAV, HBV, HCV and HPV.  
     
     
         5 . The method of  claim 1 , wherein the lipid-drug complex is a liposome-drug complex.  
     
     
         6 . The method of  claim 1 , wherein the drug is an anti-viral drug.  
     
     
         7 . The method of  claim 1 , wherein the drug is an anti-HIV drug.  
     
     
         8 . The method of  claim 7 , wherein the anti-HIV drug is a HIV-specific small interfering RNA (siRNA).  
     
     
         9 . The method of  claim 7 , wherein the anti-HIV drug is a HIV-specific anti-sense DNA.  
     
     
         10 . The method of  claim 7 , wherein the anti-HIV drug is a HIV-specific sense DNA.  
     
     
         11 . The method of  claim 7 , wherein the anti-HIV drug is a HIV-specific anti-sense RNA.  
     
     
         12 . The method of  claim 7 , wherein the anti-HIV drug is a HIV-specific sense RNA.  
     
     
         13 . The method of  claim 1 , wherein the drug is indinavir, saquinavir, nelfinavir, or tenofovir disoproxil fumarate.  
     
     
         14 . The method of  claim 1 , wherein the drug is an anticancer drug, an antifungal drug, an antibacterial drug, or an immunomodulatory agent.  
     
     
         15 . The method of  claim 1 , wherein the lipid-drug complex further comprises one or more secondary drugs.  
     
     
         16 . The method of  claim 1 , wherein the drug is a cytotoxic agent.  
     
     
         17 . The method of  claim 1 , wherein the drug is an immunomodulatory agent that is active in the immune cell.  
     
     
         18 . The method of  claim 1 , wherein the infectious agent is susceptible to the drug.  
     
     
         19 . The method of  claim 1 , wherein administering is by a transvascular route.  
     
     
         20 . The method of  claim 1 , wherein administering is by a subcutaneous, an intradermal, an intraperitoneal or a parenteral route.  
     
     
         21 . The method of  claim 1 , wherein the immune cell is a dendritic cell.  
     
     
         22 . The method of  claim 21 , wherein the dendritic cell is a myeloid dendritic cell, a plasmacytoid dendritic cell, or a follicular dendritic cell.  
     
     
         23 . The method of  claim 21 , wherein the targeting ligand specifically binds CD209 (DC-SIGN).  
     
     
         24 . The method of  claim 1 , wherein the T lymphocyte is a T-memory cell.  
     
     
         25 . The method of  claim 24 , wherein the lipid-drug complex comprises targeting ligands that specifically bind CD4 and targeting ligands that specifically bind CD45R0.  
     
     
         26 . The method of  claim 1 , wherein the outer surface of the lipid-drug complex further comprises a  Staphylococcus aureus  protein A adapted for specifically binding IgG.  
     
     
         27 . The method of  claim 26 , wherein the targeting ligand is a monoclonal or a polyclonal antibody specifically bound by the  Staphylococcus aureus  protein A.  
     
     
         28 . The method of  claim 1 , wherein the marker is a pathologically altered or mutated transcript of a major histocompatibility complex (MHC).  
     
     
         29 . The method of  claim 1 , wherein the drug is an expression vector for dendritic cell-mediated vaccination.  
     
     
         30 . The method of  claim 1 , wherein the drug is a natural substance.  
     
     
         31 . The method of  claim 30 , wherein the natural substance is plant-derived purified.  
     
     
         32 . The method of  claim 30 , wherein the natural substance is recombinantly produced.  
     
     
         33 . The method of  claim 30 , wherein the natural substance is leaf-derived IDS-30 extract.  
     
     
         34 . The method of  claim 30 , wherein the natural substance is rhizome-derived UDA lectin.  
     
     
         35 . The method of  claim 30 , wherein the natural substance is MHL.  
     
     
         36 . A targeted liposome, comprising on its external surface a targeting ligand that specifically binds CD209.  
     
     
         37 . A targeted liposome, comprising on its external surface a targeting ligand that specifically binds CD209 and a targeting ligand that specifically binds CD4.  
     
     
         38 . The targeted liposome of  claim 36  or  claim 37 , wherein the targeting ligand is a monoclonal antibody specifically bound by the  Staphylococcus aureus  protein A.  
     
     
         39 . A method of preferentially targeting a mammalian immune cell with a liposome, said cell being selected from the group consisting of a myeloid progenitor cell, a dendritic cell, a monocyte, a macrophage, and a T-lymphocyte, comprising: 
 administering to the immune cell a liposome comprising an active agent and further comprising, an outer surface comprising at least one targeting ligand that specifically binds a marker on the surface of the immune cell, the marker being selected from the group consisting of CD209, CD45R0, and CD4.    
     
     
         40 . The method of  claim 39 , wherein the active agent is a drug.  
     
     
         41 . The method of  claim 40 , wherein the drug is an anti-HIV drug.  
     
     
         42 . The method of  claim 40 , wherein the drug is indinavir, saquinavir, nelfinavir, or tenofovir disoproxil fumarate.  
     
     
         43 . The method of  claim 40 , wherein the drug is an antiviral drug, an anticancer drug, an antifungal drug, an antibacterial drug, or an immunomodulatory agent.  
     
     
         44 . The method of  claim 40 , wherein the drug is a cytotoxic agent.  
     
     
         45 . The method of  claim 39 , wherein the active agent is an immunomodulatory agent that is active in the immune cell.  
     
     
         46 . The method of  claim 45 , wherein the immunomodulatory agent is an immunosuppressant.  
     
     
         47 . The method of  claim 45 , wherein the immunomodulatory agent is an immunoactivating agent.  
     
     
         48 . The method of  claim 39 , wherein the liposome comprises on its outer surface a targeting ligand that specifically binds CD209 and a targeting ligand that specifically binds CD4.  
     
     
         49 . A method of preferentially delivering a drug to a cell type of an organ system or anatomic entity of a mammalian subject comprising: 
 administering to the mammalian subject a lipid-drug complex comprising the drug and further comprising, an outer surface comprising at least one targeting ligand that specifically binds a marker on the surface of the cell type, the organ system or anatomic entity being infected with, or susceptible to infection with, an infectious agent.