Photosensitizers with ligand targeting properties for tumor therapy

Abstract

The present invention provides a drug delivery system wherein a “parachute” structure is coupled to a therapeutic compound. The “parachute” structure comprises hydrophilic branched molecular fragments, or a cyclodextrin moiety, with a defined action diameter. The complex (a parachute structure coupled with a therapeutic compound) is either fixed at a cell membrane or delivered to a defined distance from the membrane within the cell. The membrane-anchoring/localizing effect of the parachute is achieved by hydrophilic structures linked with a branching unit of desired therapeutic compounds. Furthermore, the parachute structures can be connected by a spacer (e.g. β-amino acids, γ-amino butyric acid, or poly-amino acids) instead of directly binding to the therapeutic compound, so that the therapeutic compounds can be localized within the cells at a defined distance from the cell membrane. A spacer containing a breaking point can determine the time span, during which the drug exhibits its therapeutic activity. The hydrophilic residues can also carry signals for targeting the parachute-therapeutic complex to a defined tissue type. This can be mediated by an antibody which is specific for a tumor marker. Alternatively, a biotin can be attached at C6 position of the sugar and then react with an avidin-labeled tumor-specific antibody. The parachute function may also be achieved by other, more bulky hydrophilic structures such as oligosaccharides connected to the branching unit. Such sugar oligomers have specific attachment points to cell selecting, and therefore do not need additional molecular structures to target a specific tumor tissue. The use of the parachute structure gives the advantages of being able to localize a photosensitizer or chemotherapeutic drug at the site within a cell where it can destroy the tumor cell most effectively. This reduces the level of necessary systemic doses of the drugs, promotes drug excretion, and therefore considerably reduces side effects of the therapy.

What is claimed is:  
     
         1 . A complex for delivery and application of drugs to cell membranes or a defined distance from the membrane within cells comprising: 
 at least one parachute structure, having a defined action diameter which hinders said structure from penetrating through a cell membrane; and    at least one therapeutic compound, which can penetrate said cell membrane..    
     
     
         2 . A complex according to    claim 1   , wherein said parachute structure comprises hydrophilic moieties, and said hydrophilic moieties are preferably sugar residues that have said defined action diameter, and wherein said action diameter can be achieved by a branching unit to which said hydrophilic moieties are bound.  
     
     
         3 . A complex according to    claim 2   , wherein said hydrophilic moieties are glucosamine molecules attaching to said branching unit.  
     
     
         4 . A complex according to    claim 2   , wherein said hydrophilic moieties may be monomers or oligomers with specific attachment points to selectins on specific cells so that the complex is targeted to said specific cells.  
     
     
         5 . A complex according to    claim 1   , wherein said parachute structure comprises a hydrophilic moiety and said hydrophilic moiety is a cyclodextrin.  
     
     
         6 . A complex according to    claim 1   , wherein said therapeutic compound is a photosensitizer.  
     
     
         7 . A complex according to    claim 1   , wherein said compound is a chemotherapeutic drug.  
     
     
         8 . A complex according to    claim 1   , wherein said parachute structure is directly bound to said therapeutic compound.  
     
     
         9 . A complex according to    claim 1   , wherein said parachute structure is connected with said therapeutic compound by a spacer, and wherein said spacer is preferably β-aminoacids, γ-amino butyric acid, or poly-aminoacids, and wherein type and number of said spacer used define the distance of said therapeutic agent to cell membranes or its localization within the cell.  
     
     
         10 . A complex according to    claim 9   , wherein said spacer is preferably an aliphatic, aromatic or heterocyclic molecule, or an amino acid sequence.  
     
     
         11 . A complex according to    claim 10   , wherein said amino sequence has an enzyme cleavable breaking point.  
     
     
         12 . A complex according to    claim 9   , wherein using different number or type of said spacers to connect said therapeutic compound and said parachute structure delivers said complex into subcellular compartments at a defined distance from surface of said compartments.  
     
     
         13 . A complex according to    claim 1   , wherein said parachute structures are modified with signals for targeting said complex to a defined tissue or cell type in an organism.  
     
     
         14 . A complex according to    claim 12   , wherein said modified signals contain bridging structures like a biotin-avidin system.  
     
     
         15 . A complex according to    claim 1   , wherein said complex can be used for destruction of cells, and wherein said cells are prokaryotic, preferably bacteria.  
     
     
         16 . A complex according to    claim 15   , wherein said cells are eukaryotic, preferably human and animal cells.  
     
     
         17 . A complex according to    claim 6   , wherein said photosensitiser is close to said membrane during time of activation to render said photosensitiser more effective compared to a similar photosensitiser without said parachute structure.  
     
     
         18 . A method for the selective destruction of eukaryotic or prokaryotic cells comprising the steps of: 
 a. administering a complex, wherein said complex contains at least one parachute structure and at least one photosensitizer; and    b. waiting for a interval to allow said complex to selectively localize at cell membranes or at a defined position within a cell; and    c. irradiating a region where said complex was administered for a defined time interval and intensity to activate said photosensitizer, wherein said time interval and intensity are sufficient to achieve selective destruction of desired cells.