Polymer-lipids and compositions
The present disclosure relates to improvements in the selection and formulation of PBAE polymers using a design of experiment approach, in which statistical methods are used to limit possible experimental conditions. The present disclosure relates to improved PBAE polymers and formulations.
1. A composition comprising a polymer of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
each A independently is A 1 or A 2 ;
A 1 is
A 2 is
B is
and
D is selected from:
each R independently is hydrogen or optionally substituted aliphatic; and
n is 1-10000;
wherein the composition further comprises:
a PEG lipid in an amount of 1-10 mol % with reference to the polymer;
a phospholipid in an amount of up to 20 mol % with reference to the polymer; and
a polynucleotide.
2. The composition of claim 1 , wherein the PEG portion of the PEG lipid has an average molecular weight in the range of 1000-5000 Da.
3. The composition of claim 1 , wherein the PEG lipid is present in the amount of 1-5 mol % with reference to the polymer.
4. The composition of claim 1 , wherein the composition further comprises a steroid.
5. The composition of claim 4 , wherein the steroid is present in the amount of 1-50 mol % with reference to the polymer.
6. The composition of claim 1 , wherein the phospholipid is present in the amount of about 20 mol % with reference to the polymer.
7. The composition of claim 1 , wherein the composition is characterized as having an N/P ratio of 25-100.
8. The composition of claim 1 , wherein the composition is a pharmaceutical composition.
9. A method of delivering a polynucleotide to a cell, comprising exposing the cell to a composition of claim 1 .
10. A method of treating a disease, disorder, or condition from which a subject suffers, comprising administering to the subject in need thereof an effective amount of a composition of claim 1 .
11. The composition of claim 7 , wherein the composition is characterized as having an N/P ratio of 50-100.
12. The composition of claim 1 , wherein the polynucleotide is DNA.
13. The composition of claim 1 , wherein the polynucleotide is RNA.
14. The composition of claim 13 , wherein the RNA is dsRNA, siRNA, shRNA, miRNA, mRNA, or antisense RNA.
15. The composition of claim 1 , wherein the polynucleotide encodes a protein or peptide.
16. The composition of claim 15 , wherein the protein is an antigen.
17. The composition of claim 1 , wherein D is
18. The composition of claim 1 , wherein the composition is in the form of a particle.
19. The composition of claim 18 , wherein the particle is a nanoparticle.
20. The composition of claim 8 , wherein the pharmaceutical composition is formulated for intravenous administration.
21. The composition of claim 1 , wherein the PEG lipid is C18-PEG2000.
22. The composition of claim 4 , wherein the steroid is cholesterol.
23. The composition of claim 1 , wherein the phospholipid is selected from distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), phosphatidylglycerols, cardiolipins, diacylphosphatidylserines, diacylphosphatidic acids, N-dodecanoyl phosphatidylethanolamines, N-succinyl phosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, and palmitoyloleyolphosphatidylglycerol (POPG).
24. The composition of claim 23 , wherein the phospholipid is DOPE.
25. The composition of claim 13 , wherein the polynucleotide is mRNA.
26. The composition of claim 1 , wherein the polynucleotide is chemically modified.
27. The method of claim 9 , wherein the polynucleotide is DNA.
28. The method of claim 9 , wherein the polynucleotide is RNA.
29. The method of claim 28 , wherein the RNA is dsRNA, siRNA, shRNA, miRNA, mRNA, or antisense RNA.
30. The method of claim 9 , wherein the polynucleotide is mRNA.
31. The method of claim 9 , wherein the polynucleotide is chemically modified.
32. The method of claim 9 , wherein the polynucleotide encodes a protein or peptide.
33. The method of claim 32 , wherein the protein is an antigen.
34. The method of claim 10 , wherein the disease, disorder, or condition is selected from the group consisting of proliferative disorders, inflammatory disorders, autoimmune disorders, painful conditions, and diseases of the lung, spleen, and liver.