Method of delivering an anti-cancer agent to a cell

Abstract

There is provided a delivery vehicle comprising an anti-cancer agent together with a conjugate of a delivery agent containing a free aldehyde and a flavonoid, having the delivery agent conjugated at the C6 and/or the C8 position of the A ring of the flavonoid. The resulting delivery vehicles may be used to deliver an anti-cancer agent to a cell.

1 .- 32 . (canceled) 
     
     
         33 . A micellar nanocomplex comprising:
 an anti-cancer agent that is a protein; and   a conjugate of:
 (i) aldehyde-terminated polyethylene glycol; and 
 (ii) a flavonoid that is either monomeric (−)-epigallocatechin gallate or oligomeric (−)-epigallocatechin gallate, 
   the micellar nanocomplex having the polyethylene glycol conjugated at the C6 and/or the C8 position of the A ring of the flavonoid by attachment of the polyethylene glycol via reaction of the free aldehyde group with the C6 and/or C8 position of the A ring of the flavonoid, and exhibiting an anti-cancer effect on a cell as a result of a synergistic effect between the anti-cancer effect of the anti-cancer agent and the anti-cancer effect of the flavonoid,   wherein when the flavonoid is monomeric (−)-epigallocatechin gallate, the micellar nanocomplex further comprises non-conjugated oligomeric (−)-epigallocatechin gallate in an inner core of the micellar nanocomplex,   wherein the anti-cancer agent is complexed with either the conjugated or non-conjugated oligomeric (−)-epigallocatechin gallate, whichever is present.   
     
     
         34 . The micellar nanocomplex of  claim 33 , wherein the aldehyde-terminated polyethylene glycol is conjugated to oligomeric (−)-epigallocatechin gallate. 
     
     
         35 . The micellar nanocomplex of  claim 34 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through enzyme-catalyzed oxidative coupling. 
     
     
         36 . The micellar nanocomplex of  claim 34 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through aldehyde-mediated oligomerization. 
     
     
         37 . The micellar nanocomplex of  claim 34 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through a carbon-carbon linkage between the C6 or C8 position on the A ring of a first monomeric unit to the C6 or C8 position on the A ring of a second monomeric unit. 
     
     
         38 . The micellar nanocomplex of  claim 33 , wherein the aldehyde-terminated polyethylene glycol is conjugated to monomeric (−)-epigallocatechin gallate and the micellar nanocomplex comprises an inner core containing non-conjugated oligomeric (−)-epigallocatechin gallate. 
     
     
         39 . The micellar nanocomplex of  claim 38 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through enzyme-catalyzed oxidative coupling. 
     
     
         40 . The micellar nanocomplex of  claim 38 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through aldehyde-mediated oligomerization. 
     
     
         41 . The micellar nanocomplex of  claim 38 , wherein the oligomeric (−)-epigallocatechin gallate is formed from (−)-epigallocatechin gallate monomers that have been oligomerized through a carbon-carbon linkage between the C6 or C8 position on the A ring of a first monomeric unit to the C6 or C8 position on the A ring of a second monomeric unit. 
     
     
         42 . The micellar nanocomplex of  claim 33 , wherein the anti-cancer agent is a protein that is a peptide, an antibody, a hormone, an enzyme, a growth factor, or a cytokine. 
     
     
         43 . The micellar nanocomplex of  claim 33 , wherein the anti-cancer agent is a protein that is an antibody directed against a tumour cell-surface marker, an immunoregulatory peptide, a cytokine or a growth factor. 
     
     
         44 . The micellar nanocomplex of  claim 33 , wherein the anti-cancer agent is a protein that is a cytokine. 
     
     
         45 . The micellar nanocomplex of  claim 33 , wherein the anti-cancer agent is an antibody directed against a tumour cell-surface marker. 
     
     
         46 . A pharmaceutical composition comprising the micellar nanocomplex according to  claim 33 . 
     
     
         47 . A pharmaceutical composition comprising the micellar nanocomplex according to  claim 34 . 
     
     
         48 . A pharmaceutical composition comprising the micellar nanocomplex according to  claim 38 . 
     
     
         49 . A method of delivering trastuzumab to a cell comprising contacting the micellar nanocomplex of  claim 33  with the cell. 
     
     
         50 . The method according to  claim 48 , wherein the cell is in vitro. 
     
     
         51 . The method according to  claim 49 , wherein the cell is in vivo and the method comprises administering the micellar nanocomplex to a subject in need of anti-cancer treatment.