Polymalic acid-based nanobiopolymer compositions

Abstract

Nanobiopolymeric conjugates based on biodegradable, non-toxic and non-immunogenic poly (β-L-malic acid) PMLA covalently linked to molecular modules that include morpholino antisense oligonucleotides (AONa), an siRNA or an antibody specific for an oncogenic protein in a cancer cell, and an antibody specific for a transferrin receptor protein, are provided. Methods for treating a cancer in subject with nanobiopolymeric conjugates are described.

What is claimed is: 
     
         1 . A composition comprising:
 a polymalic acid-based scaffold;   a tyrosine kinase inhibitor covalently attached to the polymalic acid-based scaffold; and   a laminin-411 inhibitor covalently attached to the polymalic acid-based scaffold.   
     
     
         2 . The composition of  claim 1 , wherein the polymalic acid-based scaffold comprises poly(β-L-malic acid). 
     
     
         3 . The composition of  claim 1 , further comprising an endosomal escape unit. 
     
     
         4 . The composition of  claim 1 , further comprising an anti-TfR antibody. 
     
     
         5 . The composition of  claim 1 , further comprising polyethylene glycol. 
     
     
         6 . The composition of  claim 1 , wherein the tyrosine kinase inhibitor and the laminin-411 inhibitor are covalently attached to the polymalic acid-based scaffold via a glutathione-cleavable bond or via a disulfide bond. 
     
     
         7 . The composition of  claim 1 , wherein the laminin-411 inhibitor targets an α4 or β1 subunit of laminin-411. 
     
     
         8 . The composition of  claim 1 , wherein the laminin-411 inhibitor targets an α4 subunit of laminin-411, and wherein the composition further comprises a second laminin-411 inhibitor that targets a β1 subunit of laminin-411 and is covalently attached to the polymalic acid-based scaffold. 
     
     
         9 . The composition of  claim 1 , wherein the tyrosine kinase inhibitor targets HER2 or EGFR. 
     
     
         10 . The composition of  claim 9 , wherein the tyrosine kinase inhibitor comprises an antibody. 
     
     
         11 . The composition of  claim 1 , wherein the tyrosine kinase inhibitor comprises gefitinib. 
     
     
         12 . The composition of  claim 9 , wherein the tyrosine kinase inhibitor or the laminin-411 inhibitor comprises an oligonucleotide. 
     
     
         13 . The composition of  claim 12 , wherein the oligonucleotide comprises a morpholino antisense oligonucleotide or an siRNA. 
     
     
         14 . The composition of  claim 1 , wherein the tyrosine kinase inhibitor comprises a nucleotide sequence comprising 5′-AGGGAGCCGCAGCTTCATGTCTGTG-3′ (SEQ ID NO: 1), 5′-CATGGTGCTCACTGCGGCTCCGGC-3′ (SEQ ID NO: 2), 5′-TCGCTCCGGCTCTCCCGATCAATAC-3′ (SEQ ID NO: 3), 5′-CCUAUAAUGCUACGAAUAUtt-3′ (SEQ ID NO: 6), 5′-AUAUUCGUAGCAUUUAUGGag-3′ (SEQ ID NO: 7), 5′-GUUGGAUGAUUGACUCUGAtt-3′ (SEQ ID NO: 8), or 5′-UCAGAGUCAAUCAUCCAACat-3′ (SEQ ID NO: 9). 
     
     
         15 . The composition of  claim 1 , wherein the laminin-411 inhibitor comprises a nucleotide sequence comprising 5′-AGCTCAAAGCCATTTCTCCGCTGAC-3′ (SEQ ID NO:4) or 5′-CTAGCAACTGGAGAAGCCCCATGCC-3′ (SEQ ID NO:5). 
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of the polymalic acid-based scaffold of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , formulated for intravenous administration. 
     
     
         18 . A method of treating a cancer in a subject, by inhibiting the synthesis or activity of laminin-411 and HER2 or EGFR, the method comprising administering to a subject in need thereof the pharmaceutical composition of  claim 16 . 
     
     
         19 . The method of  claim 18 , wherein the cancer is breast cancer. 
     
     
         20 . The method of  claim 18 , wherein the administration inhibits a cancer stem cell marker comprising CD133 protein, c-myc protein, CD44 protein, Notch1 protein, or nestin protein.