Polymeric conjugates and uses thereof

Abstract

Polymeric conjugates comprising a polymeric matrix having associated therewith an agent that down-regulates an activity or expression of a polypeptide associated with onset or progression of melanoma, and optionally and preferably, an additional agent that acts in synergy with said agent, are provided. Synthetic methodologies for preparing these conjugates and uses thereof in treating melanoma and other cancerous diseases are also provided.

What is claimed is: 
     
         1 . A polymeric conjugate comprising a polymeric matrix having associated therewith a first agent, said first agent down-regulates an activity or expression of a polypeptide associated with onset or progression of melanoma, wherein said polymeric matrix comprises a plurality of particles and said first agent is associated with at least a first portion of said particles. 
     
     
         2 . The polymeric conjugate of  claim 1 , wherein said polypeptide associated with onset or progression of melanoma is selected from MEK, BRAF and c-kit. 
     
     
         3 . The polymeric conjugate of  claim 1 , wherein said first agent is an agent that down-regulates MEK and/or BRAF. 
     
     
         4 . The polymeric conjugate of  claim 3 , wherein said first agent is selected from the group consisting of selumetinib, debrafenib, vemurafenib, PD318088, pimasertib, cobimetinib, sorafenib, LGX818, GDC 0879, imatinib, dasatinib and a structural analog thereof. 
     
     
         5 . The polymeric conjugate of  claim 1 , wherein said polymeric matrix further comprises an additional agent associated therewith, said additional agent acts in synergy with said first agent in the treatment of melanoma. 
     
     
         6 . The polymeric conjugate of  claim 5 , wherein said additional agent that acts in synergy with said first agent is associated with at least a second portion of said particles. 
     
     
         7 . The polymeric conjugate of  claim 5 , wherein said additional agent that acts in synergy with said first agent is associated with said at least a first portion of said particles. 
     
     
         8 . The polymeric conjugate of  claim 5 , wherein said additional agent is a second agent that down-regulates an activity or expression of a polypeptide associated with onset or progression of melanoma. 
     
     
         9 . The polymeric conjugate of  claim 5 , wherein said additional agent is a second agent that down-regulates MEK and/or BRAF, said second agent being different from said first agent. 
     
     
         10 . The polymeric conjugate of  claim 9 , wherein said second agent is selected from the group consisting of selumetinib, debrafenib, vemurafenib, PD318088, Pimasertib, GDC 0879 and a structural analog thereof. 
     
     
         11 . The polymeric conjugate of  claim 9 , wherein each particle in said first portion comprises as said first agent an agent that downregulates an activity of MEK and as second agent, an agent that downregulates an activity of BRAF. 
     
     
         12 . The polymeric conjugate of  claim 11 , wherein said agent that downregulates an activity of MEK and said agent that downregulates an activity of BRAF act in synergy. 
     
     
         13 . The polymeric conjugate of  claim 9 , wherein each particle in said first portion comprises as said first agent an agent that downregulates an activity of MEK, the polymeric conjugate further comprises a second portion of said particles, wherein each particle in said second portion comprises an agent that downregulates an activity of BRAF. 
     
     
         14 . The polymeric conjugate of  claim 11 , wherein said agent that downregulates an activity of MEK and said agent that downregulates an activity of BRAF act in synergy. 
     
     
         15 . The polymeric conjugate of  claim 5 , wherein said additional agent is an anti-angiogenesis agent. 
     
     
         16 . The polymeric conjugate of  claim 5 , wherein said additional agent is temozolomide or campothecin. 
     
     
         17 . The polymeric conjugate of  claim 1 , wherein said particles comprise PLGA. 
     
     
         18 . The polymeric conjugate of  claim 1 , further comprising a targeting moiety attached to at least a portion of said particles, said targeting moiety being a ligand of a cell-surface receptor expressed in melanoma cells. 
     
     
         19 . A pharmaceutical composition comprising the polymeric conjugate of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         20 . A method of treating a cancerous disease associated with a polypeptide that is associated with onset or progression of melanoma in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the polymeric conjugate of  claim 1 . 
     
     
         21 . The method of  claim 20 , wherein said disease is melanoma. 
     
     
         22 . The method of  claim 21 , wherein said melanoma is CNS-metastasizing melanoma.