Lapachone delivery systems, compositions and uses related thereto

Abstract

In part, the present invention is directed to a system comprising a lapachone or a prodrug thereof and a polymer, such as a biocompatible and optionally biodegradable polymer, methods for treatment using the subject polymer compositions, and methods of making and using the same. In another part, the present invention includes inclusion complexes of a lapachone or a prodrug thereof and a cyclodextrin, preferably a β-cyclodextrin, such as hydroxypropyl β-cyclodextrin, e.g., to improve the solubility of the lapachone or prodrug thereof.

1 - 28 . (canceled)  
     
     
         29 . A drug delivery composition selected from an implant, microparticles, and nanoparticles, wherein the composition comprises a prodrug of a lapachone incorporated in a biocompatible polymer having a molecular weight of about 2,000 or more daltons, and the lapachone has a structure of Formula I or II:  
       
         
           
           
               
               
           
         
         wherein R and R 1  each independently represent h, hydroxy, amino, amido, sulfhydryl, halogen, or substituted or unsubstituted alkyl, alkenyl, heteroalkyl, carbocyclic aliphatic, carbocyclic aliphatic alkyl, aryl, aralkyl, heterocyclic aliphatic, heterocyclic aliphatic alkyl, heteroaryl, heteroaralkyl, or alkoxy,  
         or a pharmaceutically acceptable salt thereof:  
       
     
     
         30 . The composition of  claim 29 , wherein the prodrug of the lapachone is admixed with the polymer.  
     
     
         31 . The composition of  claim 29 , wherein the composition is an implant.  
     
     
         32 . The composition of  claim 31 , wherein the implant is a millirod dimensioned to position two radiation seeds at a predetermined distance from one another.  
     
     
         33 . The composition of  claim 29 , wherein the composition is provided as microparticles.  
     
     
         34 . The composition of  claim 29 , wherein the composition is provided as nanoparticles.  
     
     
         35 . The composition of  claim 29 , further comprising hydroxypropyl β-cyclodextrin, wherein the prodrug of the lapachone is provided as an inclusion complex with the hydroxypropyl β-cyclodextrin.  
     
     
         36 . The composition of  claim 29 , wherein the prodrug of tie lapachone is a prodrug of β-lapachone.  
     
     
         37 . The composition of  claim 29 , wherein the polymer is biodegradable.  
     
     
         38 . The composition of  claim 29 , wherein the polymer comprises one or more of poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), polyethylene glycol (PEG), polysebacic acid (PSA), or a polyanhydride.  
     
     
         39 . A method of inhibiting proliferation of a cancerous cell in a patient, comprising administering to the patient the drug delivery composition of  claim 29 .  
     
     
         40 . The method of  claim 39 , wherein the cell overexpresses NQO1.  
     
     
         41 . The method of  claim 40 , wherein the cell is a lung cancer cell, a breast cancer cell, or a prostate cancer cell.  
     
     
         42 . The method of  claim 41 , wherein the cell is a non-small cell lung cancer cell.  
     
     
         43 . The method of  claim 42 , wherein the composition is delivered to the patient by inhalation of micro spheres comprising a pro drug of a lapachone and a biocompatible polymer.  
     
     
         44 . The method of  claim 39 , wherein the cell is a prostate cancer cell and the composition is delivered to the patient by implanting radioactive seeds spaced apart by at least one polymeric millirod comprising a prodrug of a lapachone and a biocompatible polymer.  
     
     
         45 . A composition of  claim 29 , wherein a therapeutic agent, a diagnostic agent, an imaging agent, or an adjuvant is also incorporated in the polymer.  
     
     
         46 . A kit comprising a prodrug of a lapachone, a β-cyclodextrin, and instructions for combining the prodrug of the lapachone and β-cyclodextrin to form a complex and administering the complex to a patient.  
     
     
         47 . A kit comprising at least two radioactive seeds, at least one millirod according to claim  4 , and instructions for administering the radioactive seeds and millirod to a patient.  
     
     
         48 . A composition of  claim 29 , wherein the biocompatible polymer has a molecular weight of about 2,000 to about 1,000,000 daltons.