Novel lipid formulations for nucleic acid delivery

Abstract

The present invention provides novel, 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 stable nucleic acid-lipid particles (SNALP) comprising a nucleic acid (such as one or more interfering RNA), methods of making the SNALP, and methods of delivering and/or administering the SNALP.

1 . A nucleic acid-lipid particle comprising:
 (a) a nucleic acid;   (b) a cationic lipid comprising from about 50 mol % to about 85 mol % of the total lipid present in the particle;   (c) a non-cationic lipid comprising from about 13 mol % to about 49.5 mol % of the total lipid present in the particle; and   (d) a conjugated lipid that inhibits aggregation of particles comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the particle.   
     
     
         2 . The nucleic acid-lipid particle of  claim 1 , wherein the nucleic acid comprises a small interfering RNA (siRNA). 
     
     
         3 . The nucleic acid-lipid particle of  claim 2 , wherein the siRNA comprises from about 15 to about 60 nucleotides. 
     
     
         4 . The nucleic acid-lipid particle of  claim 2 , wherein the siRNA comprises at least one modified nucleotide. 
     
     
         5 . The nucleic acid-lipid particle of  claim 2 , wherein the siRNA comprises at least one 2′-O-methyl (2′OMe) nucleotide. 
     
     
         6 . The nucleic acid-lipid particle of  claim 1 , wherein the cationic lipid comprises 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), or a mixture thereof. 
     
     
         7 . The nucleic acid-lipid particle of  claim 1 , wherein the cationic lipid comprises 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA). 
     
     
         8 . The nucleic acid-lipid particle of  claim 1 , wherein the cationic lipid comprises from about 56.5 mol % to about 66.5 mol % of the total lipid present in the particle. 
     
     
         9 . The nucleic acid-lipid particle of  claim 1 , wherein the cationic lipid comprises from about 52 mol % to about 62 mol % of the total lipid present in the particle. 
     
     
         10 . The nucleic acid-lipid particle of  claim 1 , wherein the non-cationic lipid comprises cholesterol or a derivative thereof. 
     
     
         11 . The nucleic acid-lipid particle of  claim 10 , wherein the cholesterol or derivative thereof comprises from about 31.5 mol % to about 42.5 mol % of the total lipid present in the particle. 
     
     
         12 . The nucleic acid-lipid particle of  claim 1 , wherein the non-cationic lipid comprises a phospholipid. 
     
     
         13 . The nucleic acid-lipid particle of  claim 1 , wherein the non-cationic lipid comprises a mixture of a phospholipid and cholesterol or a derivative thereof. 
     
     
         14 . The nucleic acid-lipid particle of  claim 13 , wherein the phospholipid comprises dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), or a mixture thereof. 
     
     
         15 . The nucleic acid-lipid particle of  claim 13 , wherein the phospholipid comprises from about 4 mol % to about 10 mol % of the total lipid present in the particle and the cholesterol comprises from about 30 mol % to about 40 mol % of the total lipid present in the particle. 
     
     
         16 . The nucleic acid-lipid particle of  claim 13 , wherein the phospholipid comprises from about 10 mol % to about 30 mol % of the total lipid present in the particle and the cholesterol comprises from about 10 mol % to about 30 mol % of the total lipid present in the particle. 
     
     
         17 . The nucleic acid-lipid particle of  claim 1 , wherein the conjugated lipid that inhibits aggregation of particles comprises a polyethyleneglycol (PEG)-lipid conjugate. 
     
     
         18 . The nucleic acid-lipid particle of  claim 17 , wherein the PEG-lipid conjugate comprises a PEG-diacylglycerol (PEG-DAG) conjugate, a PEG-dialkyloxypropyl (PEG-DAA) conjugate, or a mixture thereof. 
     
     
         19 . The nucleic acid-lipid particle of  claim 18 , wherein the PEG-DAA conjugate comprises a PEG-dimyristyloxypropyl (PEG-DMA) conjugate, a PEG-distearyloxypropyl (PEG-DSA) conjugate, or a mixture thereof. 
     
     
         20 . The nucleic acid-lipid particle of  claim 19 , wherein the PEG has an average molecular weight of about 2,000 daltons. 
     
     
         21 - 46 . (canceled)