Non-liposomal systems for nucleic acid delivery

Abstract

The present invention provides novel, stable lipid particles having a non-lamellar structure and comprising one or more active agents or therapeutic agents, methods of making such lipid particles, and methods of delivering and/or administering such lipid particles. More particularly, the present invention provides stable nucleic acid-lipid particles (SNALP) that have a non-lamellar structure and that comprise 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 composition comprising:
 a plurality of nucleic acid-lipid particles, wherein each particle in the plurality of particles comprises:   (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 10 mol % of the total lipid present in the particle,   wherein at least about 95% of the particles in the plurality of particles have a non-lamellar morphology.   
     
     
         2 . The composition of  claim 1 , wherein the nucleic acid is an interfering RNA selected from the group consisting of siRNA, aiRNA, miRNA, Dicer-substrate dsRNA, shRNA, ssRNAi oligonucleotides, and combinations thereof. 
     
     
         3 . The composition of  claim 2 , wherein the interfering RNA is an siRNA. 
     
     
         4 . The composition of  claim 3 , wherein the siRNA comprises from about 15 to about 60 nucleotides. 
     
     
         5 . The composition of  claim 3 , wherein one or more of the nucleotides in the double-stranded region of the siRNA comprise modified nucleotides. 
     
     
         6 . The composition of  claim 5 , wherein the modified nucleotides comprise 2′-O-methyl (2′OMe) nucleotides. 
     
     
         7 . The composition of  claim 5 , wherein less than about 50% of the nucleotides in the double-stranded region comprise modified nucleotides. 
     
     
         8 . The composition of  claim 5 , wherein from about 20% to about 40% of the nucleotides in the double-stranded region comprise modified nucleotides. 
     
     
         9 . The composition of  claim 1 , wherein the cationic lipid comprises 1,2-dilinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dim ethyl aminopropane (DLenDMA), 1,2-di-γ-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA), 2,2-dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), or a mixture thereof. 
     
     
         10 . The composition of  claim 1 , wherein the cationic lipid comprises MC3, LenMC3, CP-LenMC3, γ-LenMC3, CP-γ-LenMC3, MC3MC, MC2MC, MC3 Ether, MC4 Ether, MC3 Amide, Pan-MC3, Pan-MC4, Pan MC5 or a mixture thereof. 
     
     
         11 . The composition of  claim 1 , wherein the non-cationic lipid is a phospholipid. 
     
     
         12 . The composition of  claim 1 , wherein the non-cationic lipid is cholesterol or a cholesterol derivative. 
     
     
         13 . The composition of  claim 1 , wherein the non-cationic lipid is a mixture of a phospholipid and cholesterol or a cholesterol derivative. 
     
     
         14 - 54 . (canceled) 
     
     
         55 . A method for introducing a therapeutic agent into a cell, the method comprising:
 contacting the cell with a composition of  claim 1 .   
     
     
         56 . The method of  claim 55 , wherein the cell is in a mammal. 
     
     
         57 . A method for the in vivo delivery of a therapeutic agent, the method comprising:
 administering to a mammal a composition of  claim 1 .   
     
     
         58 . The method of  claim 57 , wherein the administration is selected from the group consisting of oral, intranasal, intravenous, intraperitoneal, intramuscular, intra-articular, intralesional, intratracheal, subcutaneous, and intradermal. 
     
     
         59 . The method of  claim 57 , wherein the mammal is a human. 
     
     
         60 . A method for treating a disease or disorder in a mammal in need thereof, the method comprising:
 administering to the mammal a therapeutically effective amount of a composition of  claim 1 .   
     
     
         61 . The method of  claim 60 , wherein the disease or disorder is selected from the group consisting of a viral infection, a liver disease or disorder, and cancer. 
     
     
         62 . (canceled)