Polyoxazoline-lipid conjugates and lipid nanoparticles and pharmaceutical compositions including same
POZ-lipid conjugates and lipid nanoparticles (LNPs) including POZ-lipid conjugates used to facilitate delivery of an encapsulated payload. LNPs including POZ-lipid conjugates and a nucleic acid payload such as, but not limited to, mRNA or modified mRNA are disclosed. Such LNPs have no immunogenicity or reduced immunogenicity as compared to a corresponding LNP containing a PEG-lipid.
1. A compound having one of the following formulae:
wherein m ranges from 0 to 2, n ranges from 1 to 1000, o ranges from 1 to 5, and p ranges from 1 to 10.
2. The compound of claim 1 , having a hydrolysis half-life in 50 percent human plasma of about 10 minutes or less.
3. The compound of claim 1 , having a hydrolysis half-life in 50 percent human plasma of about 120 hours or more.
4. The compound of claim 1 , exhibiting a decrease of about 30 percent to about 50 percent in POZ-DMA peak area over a range of UV wavelengths centered at 210 nm after overnight exposure to lipo-amidase at 37° C.
5. The compound of claim 1 , exhibiting a decrease of about 10 percent or less in POZ-DMA peak area UV wavelengths centered at 210 nm after overnight exposure to lipo-amidase at 37° C.
6. A composition comprising the compound of claim 1 .
7. The composition of claim 6 , further comprising a cationic or ionizable lipid.
8. A compound having one of the following formulae:
wherein m ranges from 0 to 2, n ranges from 1 to 1000, o ranges from 1 to 5, and p ranges from 1 to 10.
9. The compound of claim 8 , having a hydrolysis half-life in 50 percent human plasma of about 120 hours or more.
10. A composition comprising the compound of claim 8 .
11. The composition of claim 10 , further comprising a cationic or ionizable lipid.
12. A compound having the following formula:
wherein m ranges from 0 to 2, and wherein the compound has a rate of hydrolysis that is determined at least in part by an amidase-cleavable amide.
13. The compound of claim 12 , wherein m is 1.
14. A composition comprising the compound of claim 12 .
15. The composition of claim 14 , further comprising a cationic or ionizable lipid.
16. The compound of claim 12 , having a hydrolysis half-life in 50 percent human plasma of about 120 hours or more.
17. A lipid nanoparticle comprising:
a compound of one of the following formulae:
wherein m ranges from 0 to 2, n ranges from 1 to 1000, o ranges from 1 to 5, and p ranges from 1 to 10;
an ionizable or cationic lipid;
a helper lipid; and
a sterol lipid.
18. The lipid nanoparticle of claim 17 , further comprising a payload.
19. The lipid nanoparticle of claim 18 , wherein the payload comprises an oligonucleotide.
20. The lipid nanoparticle of claim 19 , wherein the oligonucleotide comprises DNA, siRNA, self-replicating mRNA, mRNA comprised of modified nucleosides, or mRNA comprised of naturally occurring nucleosides.
21. The lipid nanoparticle of claim 17 , wherein the helper lipid comprises 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), or 1-palmitoyl-2-oleoylsn-glycero-3-phosphoethanolamine (POPE).
22. The lipid nanoparticle of claim 21 , wherein the sterol lipid comprises cholesterol, the helper lipid is DSPC, and further comprising an oligonucleotide payload.