Use of one or more metal carriers to selectively kill mammalian cells

Abstract

Compositions and methods for decreasing the viability of cells, particularly aberrant non-healthy cells, and most particularly cancer cells, are disclosed. The primary agent that causes cell death is a toxic metal atom or ion. Embodiments of the invention provide compositions and methods to ensure that the toxic metal is directed to the desired cell or tissue. In one embodiment, the metal is bound to a sulfur-rich peptide or protein carrier containing a targeting moiety. Such metal-protein complex is targeted to the selected cells or tissues to enrich the cell or tissue site with the metal-containing peptide or protein molecules followed by administering a dithiocarbonyl which carries the metal from the protein inside the cells to induce cell death.

1 . A pharmaceutical composition to induce cancer cell death in tumors, the pharmaceutical composition comprising:
 a metal ion bound to a dithiocarbonyl compound conjugated with one or more targeting molecules, wherein the dithiocarbonyl compound is represented by the formula:
   (R 1 ) m (R 2 )Z—C—(S)—S—Y 
   
       wherein:
 m is 0 or 1; 
 R 1  and R 2  may be independently hydrogen or C 1 -C 24  straight, branched, or cyclic alkyl, alkenyl, aryl, alkaryl, aralkyl, or alkoxy fragments, said fragments optionally substituted with ester, ether, halogen, sulfate, hydroxyl, or phosphate groups or wherein R 1  or R 2  may be optionally connected via a bridge comprising —(CH 2 ) n —, wherein n is 3-8, and wherein said bridge may be optionally substituted with C 1 -C 10  straight, branched, or cyclic alkyl, aryl, aryalkyl, or alkaryl groups, each of said groups optionally substituted with hydroxyl, halo, phosphate, sulfate, or sulfonate groups; 
 Z is oxygen or nitrogen with the proviso that if Z is oxygen then m is 0; and 
 Y is C 1 -C 12  amine or C 1 -C 12  carboxyl conjugated with a targeting moiety;
 wherein the targeted dithiocarbonyl compound releases the metal ion into the intracellular space to affect cell death. 
 
 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the dithiocarbonyl compound is a dithocarbamate that binds metal ions in an exchangeable manner. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the metal ion is cadmium (II), zinc (II), copper (I), silver (I), cobalt (II), mercury (II), iron (II), gold (I), bismuth (III), nickel (II), lead (II), or platinum (II). 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the metal ion is cadmium (II). 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the metal ion is zinc (II). 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is an antibody or antibody fragment that recognizes cancer cell antigens. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is a tumor-homing peptide that targets head and neck tumors, tumor lymphatics, or tumor derived blood vessels. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is a receptor binding agonist or antagonist including folic acid, transferrin, gambogic acid, or luteinizing hormone-releasing, hormone-derived short peptides. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is a receptor-binding fragment of epidermal growth factor. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is a lipid component of a targeted cell type. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is a 3′-NH 2 — modified nucleic acid ligand. 
     
     
         12 . The pharmaceutical composition of  claim 1 , wherein the targeting molecule is polyethylene glycol. 
     
     
         13 . The pharmaceutical composition of  claim 1 , further comprising a nanoparticle or nanocell, the nanoparticle or nanocell comprising the targeting molecule. 
     
     
         14 . The composition of  claim 13 , wherein the nanoparticle or nanocell further comprises polyethylene glycol. 
     
     
         15 . The pharmaceutical composition of  claim 1 , wherein the dithiocarbonyl compound is 3-aminopropylpiperidine-1-carbodithioate.HCl salt conjugated with a targeted moiety and/or polyethylene glycol. 
     
     
         16 . The pharmaceutical composition of  claim 1 , wherein R 1  and R 2  are connected via —(CH 2 ) n —, wherein n is 3-8, to form a heterocycle. 
     
     
         17 . A method of synthesizing 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3) comprising the steps of:
 a) dissolving piperidine in a mixture comprising sodium hydroxide and water to form a piperidine mixture;   b) cooling the piperidine mixture;   c) adding CS 2  in a drop-wise manner to the cooled piperidine mixture while simultaneously stirring the mixture;   d) stirring the piperidine mixture after the addition of CS 2  is complete to precipitate N-piperidinedithiocarbamic acid from the mixture;   e) removing impurities from the precipitated N-piperidinedithiocarbamic acid; and   f) mixing a solution comprising the N-piperidinedithiocarbamic acid with 3-chloropropylamine (HCL salt) to form and then precipitate 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3).   
     
     
         18 . The method according to  claim 17 , wherein the 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3) is 98-100% pure. 
     
     
         19 . The method according to  claim 17 , wherein the step of removing impurities from N-piperidinedithiocarbamic acid comprises the additional steps of:
 i) dissolving the precipitated N-piperidinedithiocarbamic acid in 200 mL of water mixed with 300 mL of acetone;   ii) filtering the dissolved precipitated N-piperidinedithiocarbamic acid;   iii) washing the dissolved precipitated N-piperidinedithiocarbamic acid with ice-cold acetone; and   iv) drying the N-piperidinedithiocarbamic acid precipitate.   
     
     
         20 . The method according to  claim 17 , wherein the step of mixing a solution comprising the N-piperidinedithiocarbamic acid with 3-chloropropylamine (HCL salt) to precipitate 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3) comprises:
 i) dissolving the N-piperidinedithiocarbamic acid in water;   ii) slowly mixing the dissolved N-piperidinedithiocarbamic acid with 0.011 mol of 3-chloropropylamine (HCL salt) to form and then precipitate the 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3); and   iii) removing impurities from the 3-aminopropylpiperidine-1-carbodithioate.HCl salt (CCK3) precipitate.