NOVEL LIPID FORMULATIONS FOR DELIVERY OF THERAPEUTIC AGENTS TO SOLID TUMORS
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.
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.