Lipid formulations for delivery of therapeutic agents to solid tumors
View Patent ↗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 50 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, and wherein the PEG has an average molecular weight of from 550 daltons to 1000 daltons.
2. The nucleic acid-lipid particle of claim 1 , wherein the nucleic acid comprises an interfering RNA.
3. The nucleic acid-lipid particle of claim 2 , wherein the interfering RNA comprises an siRNA.
4. The nucleic acid-lipid particle of claim 3 , wherein the siRNA comprises a double-stranded region of about 19 to about 25 nucleotides in length.
5. The nucleic acid-lipid particle of claim 3 , wherein one or more of the nucleotides in the double-stranded region of the siRNA comprise modified nucleotides.
6. The nucleic acid-lipid particle of claim 5 , wherein the modified nucleotides comprise 2′-O-methyl (2′OMe) nucleotides.
7. The nucleic acid-lipid particle of claim 5 , wherein less than about 50% of the nucleotides in the double-stranded region comprise modified nucleotides.
8. The nucleic acid-lipid particle of claim 3 , wherein the siRNA comprises a 3′ overhang in one or both strands of the siRNA.
9. The nucleic acid-lipid particle of claim 8 , wherein one or more of the nucleotides in the 3′ overhang of one or both strands comprise modified nucleotides.
10. The nucleic acid-lipid particle of claim 9 , wherein the modified nucleotides comprise 2′-O-methyl (2′OMe) nucleotides.
11. The nucleic acid-lipid particle of claim 3 , wherein the siRNA silences the expression of a gene associated with a cell proliferative disorder.
12. 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, and wherein the cholesterol or derivative thereof comprises from 25 mol % to 35 mol % of the total lipid present in the particle.
13. The nucleic acid-lipid particle of claim 1 , wherein the PEG has an average molecular weight of about 750 daltons.
14. The nucleic acid-lipid particle of claim 1 , wherein the PEG-lipid conjugate is 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
15. The nucleic acid-lipid particle of claim 14 , wherein the PEG-lipid conjugate comprises a PEG-DAA conjugate.
16. The nucleic acid-lipid particle of claim 15 , wherein the PEG-DAA conjugate comprises a PEG-dimyristyloxypropyl (PEG-DMA) conjugate.
17. The nucleic acid-lipid particle of claim 1 , wherein the nucleic acid is fully encapsulated in the nucleic acid-lipid particle.
18. A pharmaceutical composition comprising a nucleic acid-lipid particle of claim 1 and a pharmaceutically acceptable carrier.