Novel lipid formulations for delivery of therapeutic agents to solid tumors

Abstract

The present invention provides novel, serum-stable lipid particles comprising one or more active agents or therapeutic agents, methods of making the lipid particles, and methods of delivering and/or administering the lipid particles. More particularly, the present invention provides serum-stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (e.g., one or more interfering RNA molecules), methods of making the SNALP, and methods of delivering and/or administering the SNALP (e.g., for the treatment of cancer). In particular embodiments, the present invention provides tumor-directed lipid particles that preferentially target solid tumors. The tumor-directed formulations of the present invention are capable of preferentially delivering a payload such as a nucleic acid to cells of solid tumors compared to non-cancerous cells.

What is claimed is: 
     
         1 . A nucleic acid-lipid particle comprising:
 (a) a nucleic acid;   (b) a cationic lipid comprising from about 45 mol % to 60 mol % of the total lipid present in the particle;   (c) a non-cationic lipid comprising from 35 mol % to 45 mol % of the total lipid present in the particle, wherein the non-cationic lipid comprises a mixture of a phospholipid and cholesterol or a derivative thereof; and   (d) a conjugated lipid that inhibits aggregation of particles comprising from 5 mol % to 10 mol % of the total lipid present in the particle, wherein the conjugated lipid comprises a polyethyleneglycol (PEG)-lipid conjugate.   
     
     
         2 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises a single-stranded or double-stranded DNA. 
     
     
         3 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises a single-stranded or double-stranded RNA. 
     
     
         4 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises an interfering RNA. 
     
     
         5 . The nucleic acid-lipid particle of  claim 4 , wherein the interfering RNA comprises an siRNA. 
     
     
         6 . The nucleic acid-lipid particle of  claim 5 , wherein the siRNA silences the expression of a gene associated with a cell proliferative disorder. 
     
     
         7 . The nucleic acid-lipid particle of  claim 1 , wherein the phospholipid comprises from 5 mol % to 10 mol % of the total lipid present in the particle. 
     
     
         8 . The nucleic acid-lipid particle of  claim 1 , wherein the cholesterol or derivative thereof comprises from 25 mol % to 35 mol % of the total lipid present in the particle. 
     
     
         9 . The nucleic acid-lipid particle of  claim 1 , wherein the PEG has an average molecular weight of from about 550 daltons to about 10,000 daltons. 
     
     
         10 . The nucleic acid-lipid particle of  claim 1 , wherein the PEG has an average molecular weight of from about 1,000 daltons to about 5,000 daltons. 
     
     
         11 . The nucleic acid-lipid particle of  claim 1 , wherein the PEG-lipid conjugate is a member selected from the group consisting of a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG dialkyloxypropyl (PEG-DAA) conjugate, a PEG-phospholipid conjugate, a PEG-ceramide (PEG-Cer) conjugate, and a mixture thereof. 
     
     
         12 . The nucleic acid-lipid particle of  claim 11 , wherein the PEG-lipid conjugate comprises a PEG-DAA conjugate. 
     
     
         13 . The nucleic acid-lipid particle of  claim 12 , wherein the PEG-DAA conjugate comprises a PEG-dimyristyloxypropyl (PEG-DMA) conjugate. 
     
     
         14 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid is fully encapsulated in the nucleic acid-lipid particle. 
     
     
         15 . A pharmaceutical composition comprising a nucleic acid-lipid particle of  claim 1  and a pharmaceutically acceptable carrier.