US2007254022A1PendingUtilityA1

Cationic liposome delivery of taxanes to angiogenic blood vessels

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Individually held — no corporate assignee on recordPriority: Mar 12, 1997Filed: Apr 13, 2007Published: Nov 1, 2007
Est. expiryMar 12, 2017(expired)· nominal 20-yr term from priority
Inventors:Donald M. McdonaldJohn W. McleanO. Gavin Thurston
A61K 9/1272A61K 49/0032A61K 9/1271A61K 47/54A61K 31/337A61K 49/0041C12N 15/88A61K 31/335A61K 47/543A61P 9/10
68
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Claims

Abstract

Angiogenic endothelial cells are selectively targeted with lipid/DNA complexes or cationic liposomes containing a substance which affects the targeted cells by inhibiting or promoting their growth. A site of angiogenesis can be precisely located by administering cationic liposomes containing a detectable label. The complexes may comprise nucleotide constructs which are comprised of promoters which are selectively and exclusively activated in the environment of an angiogenic endothelial cell.

Claims

exact text as granted — not AI-modified
1 . A method of selectively affecting angiogenic endothelial cells, comprising the steps of: 
 administering to a mammal a composition comprising cationic lipids and a substance that inhibits angiogenesis; and    allowing the composition to associate with angiogenic endothelial cells of an angiogenic blood vessel for a time and in a manner such that the composition enters the angiogenic endothelial cells.    
   
   
       2 . The method of  claim 1 , wherein the composition is administered by injection into the circulatory system and further wherein the composition has, in blood, two-fold or greater affinity for angiogenic endothelial cells as compared to corresponding normal endothelial cells.  
   
   
       3 . The method of  claim 2 , wherein affinity is measured on an angiogenic endothelial cell to non-angiogenic endothelial cell basis.  
   
   
       4 . The method of  claim 3 , wherein affinity is measured ex vivo.  
   
   
       5 . The method of  claim 2 , wherein the injected composition has, in blood, ten-fold or greater affinity for angiogenic endothelial cells as compared to corresponding normal endothelial cells and further wherein the composition is comprised of 5 mole % or more cationic lipids and the composition is injected intraarterially.  
   
   
       6 . The method of  claim 1 , wherein the substance inhibits angiogenesis and is a taxane.  
   
   
       7 . The method of  claim 6 , wherein the composition comprising catibnic lipids and a taxane is associated with a liposome.  
   
   
       8 . The method of  claim 6 , wherein taxane is selected from the group consisting of paclitaxel, docetaxel, a 10-desacetyl analog of paclitaxel, a 3′N-desbenzoyl-3′N-t-butoxycarbonyl analog of paclitaxel, a galactose or mannose derivative of a taxane, a piperazino derivative of a taxane, a 6-thio or a sulfenamide derivative of a taxane, and a taxane attached to a hydrophobic moiety.  
   
   
       9 . The method of  claim 6 , wherein said taxane is paclitaxel.  
   
   
       10 . A cationic liposome, comprising: 
 cationic lipids; and    a taxane in a lipid bilayer of the liposome, wherein the liposome comprises substantially no taxane crystals, and wherein the taxane does not substantially partition from the lipid bilayer.    
   
   
       11 . The cationic liposome of  claim 10 , further comprising a detectable label.  
   
   
       12 . The cationic liposome of  claim 10 , further comprising a water-soluble taxane in an aqueous compartment of the liposome.  
   
   
       13 . The cationic liposome of  claim 10 , wherein the taxane is a pharmaceutically acceptable derivative.  
   
   
       14 . The cationic liposome of  claim 10 , wherein the taxane is paclitaxel.  
   
   
       15 . The cationic liposome of  claim 10 , wherein the taxane is docetaxel.  
   
   
       16 . The cationic liposome of  claim 10 , wherein the liposome comprises less than about 20 mole percent taxane or a taxane derivative and greater than about 20 mole percent cationic lipid.  
   
   
       17 . The cationic liposome of  claim 16 , wherein the liposome comprises from about 2 mole % to about 10 mole % taxane, and from about 40 mole % to about 98 mole % cationic lipid.  
   
   
       18 . The cationic liposome of  claim 10 , wherein said cationic liposome further comprises a neutral lipid.  
   
   
       19 . The cationic liposome of  claim 18 , wherein the liposome comprises from about 2 mole % to about 10 mole % taxane, from about 40 mole % to about 98 mole % cationic lipid, and from about 2 mole % to about 50 mole % neutral lipid.  
   
   
       20 . The cationic liposome of  claim 19 , wherein the neutral lipid is selected from the group consisting of a phosphatidylcholine (PC), a phosphatidylethanolamine (PE), and a mixture of a PC and a PE.  
   
   
       21 . The cationic liposome of  claim 20 , wherein the liposome comprises DOTAP, egg phosphatidyl choline, and paclitaxel in a 50:48:2 molar ratio.  
   
   
       22 . The cationic liposome of  claim 20 , wherein the liposome comprises DOTAP, DOPC, and paclitaxel in a 50:47:3 molar ratio.  
   
   
       23 . The cationic liposome of  claim 20 , wherein the liposome comprises DOTAP, DOPE, and paclitaxel in a 50:47:3 molar ratio.  
   
   
       24 . The cationic liposome of  claim 20 , wherein the liposome comprises DOTAP, MOPC, and paclitaxel in a 50:47:3 molar ratio.  
   
   
       25 . A cationic liposome, comprising: 
 cationic lipids; and    a taxane in an aqueous compartment of the liposome, wherein the liposome comprises substantially no taxane crystals.    
   
   
       26 . A method of reducing an atherosclerotic plaque, comprising: 
 administering to a mammal a composition comprising cationic lipids and a substance that reduces angiogenesis; and    allowing the composition to associate with angiogenic endothelial cells of an angiogenic blood vessel for a time and in a manner such that the composition enters the angiogenic endothelial cells, wherein reduction of angiogenesis results in reduction of atherosclerotic plaque formation.    
   
   
       27 . The method of  claim 26 , wherein the composition is administered by injection into the circulatory system and further wherein the composition has, in blood, two-fold or greater affinity for angiogenic endothelial cells as compared to corresponding normal endothelial cells.  
   
   
       28 . The method of  claim 26 , wherein the injected composition has, in blood, ten-fold or greater affinity for angiogenic endothelial cells as compared to corresponding normal endothelial cells and further wherein the composition is comprised of 5 mole % or more cationic lipids and the composition is injected intraarterially.  
   
   
       29 . The method of  claim 26 , wherein the composition comprises cationic lipids and a substance that reduces angiogenesis is associated with a liposome.  
   
   
       30 . The method of claim. 26, wherein the substance that reduces angiogenesis is a taxane.  
   
   
       31 . A method of reducing atherosclerotic plaque formation in a patient, comprising the steps of: 
 removing an atherosclerotic plaque from a circulatory vessel of the patient; and    administering to the patient a therapeutically effective amount of a composition comprising a cationic liposome and an active ingredient which inhibits angiogenesis.

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