Therapeutic liposome composition and method of preparation

Abstract

Reagents for use in preparing a therapeutic liposome composition sensitized to a target cell are described. The reagents include a liposomal composition composed of pre-formed liposomes having an entrapped therapeutic agent and a plurality of targeting conjugates composed of a lipid, a hydrophilic polymer and a targeting ligand. The therapeutic, target-cell sensitized liposome composition is formed by incubating the liposomal composition with a selected conjugate.

1 . A treatment method, comprising 
 determining the expression status of a receptor on a cell;    selecting a conjugate consisting essentially of (i) a lipid having a polar head group and a hydrophobic tail, (ii) a hydrophilic polymer having a proximal end and a distal end, said polymer attached at its proximal end to the head group of the lipid, and (iii) a targeting ligand having binding affinity for said receptor, said ligand attached to the distal end of the polymer;    inserting said conjugate into a liposome to form a targeted liposome; and    administering said targeted liposome to a subject.    
     
     
         2 . The method of  claim 1 , wherein said determining comprises determining from a biopsy specimen expression status of a growth factor receptor on a cell.  
     
     
         3 . The method of  claim 2 , wherein said determining comprises determining express status of a growth factor receptor selected from the group consisting of c-erbB-2 protein product of the HER2/neu oncogene, epidermal growth factor receptor, basic fibroblast growth factor receptor and vascular endothelial growth factor receptor.  
     
     
         4 . The method of  claim 1 , wherein said determining comprises determining from a biopsy specimen c-erb-2 receptor expression status on a cell.  
     
     
         5 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand is an antibody or an antibody fragment.  
     
     
         6 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand binds to an extracellular domain of a growth factor receptor.  
     
     
         7 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand binds a receptor selected from the group consisting of E-selectin receptor, L-selectin receptor, P-selectin receptor, folate receptor, CD4 receptor, CD19 receptor, αβ integrin receptors and chemokine receptors.  
     
     
         8 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand binds a receptor on a malignant B-cell or T-cell, said receptor selected from the group consisting of CD19, CD20, CD22, CD4, CD7 and CD8.  
     
     
         9 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand is selected from the group consisting of folic acid, pyridoxal phosphate, vitamin B12, sialyl Lewis x , transferrin, epidermal growth factor, basic fibroblast growth factor, vascular endothelial growth factor, VCAM-1, ICAM-1, PECAM-1, RGD peptides and NGR peptides.  
     
     
         10 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said targeting ligand is selected from the group consisting of water soluble vitamins, apolipoproteins, insulin, galactose, Mac-1, PECAM-1/CD31, fibronectin, osteopontin, RGD sequences of matrix proteins, HIV GP 120/41 domain peptomers, GP120 C4 domain peptomers, T cell tropic isolates, SDF-1 chemokines, Macrophage tropic isolates, anti-cell surface receptor antibodies or fragments thereof, pyridoxyl ligands, biotin, RGD peptide mimetics, YIGSRG protein, a v B 5 , IL-8, anti-E-selectin Fab.  
     
     
         11 . The method of  claim 1 , wherein said selecting comprises selecting a conjugate wherein said hydrophilic polymer is polyethylene glycol.  
     
     
         12 . The method of  claim 1 , wherein said inserting comprises incubating said conjugate with liposomes.  
     
     
         13 . The method of  claim 1 , wherein said inserting comprises incubating said conjugate with liposomes having an entrapped drug.  
     
     
         14 . The method of  claim 13 , wherein said entrapped drug is a cytotoxic drug.  
     
     
         15 . The method of  claim 14 , wherein said cytotoxic drug is an anthracycline antibiotic.  
     
     
         16 . The method of  claim 1 , wherein said administering is via injection.