Rna interference compositions and methods for malignant tumors

Abstract

This invention provides compositions for use in distributing active agents for treating a malignant tumor in a subject. The compositions contain RNAi molecules targeted to a human GST-π, along with RNAi molecules targeted to a human p21, and a pharmaceutically acceptable carrier. The carrier can include nanoparticles composed of an ionizable lipid, a structural lipid, one or more stabilizer lipids, and a lipid for reducing immunogenicity of the nanoparticles. This invention further provides methods for preventing or treating a malignant tumor by administering a therapeutically effective amount of an RNAi composition.

What is claimed is: 
     
         1 . A method for preventing, treating or ameliorating one or more symptoms of a malignant tumor in a subject in need, the method comprising administering to the subject an effective amount of RNAi molecules targeted to a human GST-π, and an effective amount of RNAi molecules targeted to a human p21. 
     
     
         2 . The method of  claim 1 , wherein each of the RNAi molecules targeted to GST-π has an antisense strand SEQ ID NOs:131 and a sense strand SEQ ID NOs:157. 
     
     
         3 . The method of  claim 1 , wherein each of the RNAi molecules targeted to p21 has an antisense strand SEQ ID NOs:341 and a sense strand SEQ ID NOs:355. 
     
     
         4 . The method of  claim 1 , wherein each of the RNAi molecules targeted to GST-π has an antisense strand SEQ ID NOs:156 and a sense strand SEQ ID NOs:182. 
     
     
         5 . The method of  claim 1 , wherein each of the RNAi molecules targeted to p21 has an antisense strand SEQ ID NOs:343 and a sense strand SEQ ID NOs:357. 
     
     
         6 . The method of  claim 1 , wherein one or more of the nucleotides in the antisense strand or sense strand of the RNAi molecules is modified or chemically-modified. 
     
     
         7 . The method of  claim 6 , wherein the modified or chemically-modified nucleotides are 2′-deoxy nucleotides, 2′-O-alkyl substituted nucleotides, 2′-deoxy-2′-fluoro substituted nucleotides, phosphorothioate nucleotides, locked nucleotides, or any combination thereof. 
     
     
         8 . The method of  claim 1 , wherein each of the RNAi molecules contains a 2′-deoxynucleotide in one or more of positions 2 to 8 from the 5′ end of the antisense strand. 
     
     
         9 . The method of  claim 1 , wherein the antisense strand of each of the RNAi molecules has deoxynucleotides in a plurality of positions, the plurality of positions being one of the following:
 each of positions 4, 6 and 8, from the 5′ end of the antisense strand;   each of positions 3, 5 and 7, from the 5′ end of the antisense strand;   each of positions 1, 3, 5 and 7, from the 5′ end of the antisense strand;   each of positions 3-8, from the 5′ end of the antisense strand; or   each of positions 5-8, from the 5′ end of the antisense strand.   
     
     
         10 . The method of  claim 1 , wherein the RNAi molecules are encapsulated in a liposome nanoparticle. 
     
     
         11 . The method of  claim 1 , wherein the malignant tumor is associated with KRAS mutation, the method further comprising identifying a tumor cell in the subject, the tumor cell comprising at least one of: (i) a mutation of the KRAS gene, and (ii) an aberrant expression level of KRAS protein. 
     
     
         12 . The method of  claim 1 , wherein the malignant tumor overexpresses GST-p. 
     
     
         13 . The method of  claim 1 , wherein the malignant tumor is colon cancer, pancreatic cancer, kidney cancer, lung cancer, breast cancer, or fibrosarcoma. 
     
     
         14 . The method of  claim 1 , wherein the malignant tumor is lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas, or colorectal carcinoma. 
     
     
         15 . The method of  claim 1 , wherein the administration is intravenous injection, intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, oral, topical, infusion, or inhalation.