Nanomaterials containing constrained lipids and uses thereof

Patent metadata

Field	Value
Publication number	US-12569438-B2
Application number	US-202017630861-A
Country	US
Kind code	B2
Filing date	Jul 24, 2020
Priority date	Jul 29, 2019
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

Compositions for delivering nucleic acids to cells or tissue microenvironments are provided. In one embodiment, the compositions are lipid nanoparticle compositions formulated to have reduced splenic and hepatic clearance. It has been discovered that the chemical composition of lipid nanoparticles significantly influences the natural trafficking of the lipid nanoparticles. More specifically, it has been discovered that conformationally constrained ionizable lipids can modify the tropism and clearance profile of lipid nanoparticles without the need of a targeting ligand. It has also been discovered that tropism of the disclosed lipid nanoparticles is size-independent.

First claim

We claim:

1 . A lipid nanoparticle composition comprising:
an ionizable lipid having a structure according to

 or a pharmaceutically acceptable salt thereof;
a phospholipid;
a polyethylene glycol-lipid;
a cholesterol; and optionally
a nucleic acid.

2 . The lipid nanoparticle composition of claim 1 , wherein the amount of ionizable lipid present is in the range of about 35 to about 65 mole percent, based on total moles.

3 . The lipid nanoparticle composition of claim 1 , wherein the phospholipid is 1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC).

4 . The lipid nanoparticle composition of claim 1 , wherein the polyethylene glycol-lipid is C 14 PEG 2000 or C 18 PEG 2000 .

5 . The lipid nanoparticle composition of claim 1 , wherein the composition comprises about 30 mol % to about 70 mol % ionizable lipid, about 5 mol % to about 25 mol % phospholipid, about 25 mol % to about 45 mol % cholesterol, and about 0.1 mol % to about 5 mol % polyethylene glycol-lipid.

6 . The lipid nanoparticle composition of claim 1 , wherein the nucleic acid comprises RNA, DNA, single-stranded RNA, single-stranded DNA, double-stranded RNA, double stranded DNA, triple-stranded DNA, siRNA, shRNA, sgRNA, mRNA, miRNA, antisense DNA, or a combination thereof.

7 . The lipid nanoparticle composition of claim 1 , wherein the nucleic acid encodes a protein.

8 . The lipid nanoparticle composition of claim 1 , wherein the nucleic acid encodes an RNA-guided DNA endonuclease.

9 . The lipid nanoparticle composition of claim 8 , wherein the RNA-guided DNA endonuclease is Cas9, CasX, CasY, Cas13, or Cpf1.

10 . The nanoparticle composition of claim 1 , wherein the lipid nanoparticle has a hydrodynamic diameter in the range of from about 30 nm to about 170 nm.

11 . A lipid nanoparticle composition comprising:
an ionizable lipid having a structure according to

 or a pharmaceutically acceptable salt thereof;
1-2-distearoyl-sn-glycero-3-phosphocholine (DSPC);
C 14 PEG 2000 ;
cholesterol; and
siRNA.

12 . The lipid nanoparticle of claim 11 , wherein the ionizable lipid is 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof.

13 . The lipid nanoparticle of claim 11 , wherein C 14 PEG 2000 is present at about 2.0 to about 3.0 mole percent, DSPC is present at about 15 to about 17 mole percent, cholesterol is present at about 45 to about 47 mole percent, the ionizable lipid is present at about 33 to about 36 mole percent, and the siRNA is present at 5 to 20 mass ratio of total lipid to siRNA.

14 . The lipid nanoparticle of claim 11 , wherein C 14 PEG 2000 is present at about 2.5 mole percent, DSPC is present at about 16 mole percent, cholesterol is present at about 46.5 mole percent, and the ionizable lipid is present at about 35 mole percent.

15 . A pharmaceutical composition comprising the lipid nanoparticle composition of claim 1 , and a pharmaceutically acceptable excipient.

16 . A method of delivering a nucleic acid to a subject in need thereof, comprising, administering to the subject the lipid nanoparticle composition of claim 1 .

17 . The method of claim 16 , further comprising administering a second therapeutic agent to the subject.

18 . A method of delivering a nucleic acid to an immune cell in a subject in need thereof, comprising:
administering to the subject a lipid nanoparticle composition consisting of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof; DSPC; a polyethylene glycol-lipid; a cholesterol; and a nucleic acid, wherein the lipid nanoparticle composition delivers the nucleic acid to the immune cell in the subject.

19 . The method of claim 18 , wherein the lipid nanoparticle composition does not contain a targeting ligand that targets the lipid nanoparticle composition to the immune cell.

20 . The method of claim 18 , wherein the immune cell is a T cell.

21 . A method for increasing delivery of a nanoparticle composition to non-hepatocyte cells in a subject comprising formulating the nanoparticle composition to comprise an amount of an ionizable lipid that is effective to increase delivery of the nanoparticle composition to non-hepatocyte cells when administered to the subject, wherein the ionizable lipid has a structure according to either

or a pharmaceutically acceptable salt thereof.

22 . A method for reducing gene expression in an immune cell in a subject in need thereof, comprising:
administering to the subject a lipid nanoparticle composition consisting of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof; DSPC; a polyethylene glycol-lipid; cholesterol; and an inhibitory nucleic acid, wherein the lipid nanoparticle composition delivers the inhibitory nucleic acid to the immune cell in the subject.

23 . A method for editing a gene in an immune cell in a subject in need thereof, comprising:
administering to the subject a lipid nanoparticle composition comprising a first and second population of lipid nanoparticles, wherein the first population of lipid nanoparticles consists of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof, DSPC, a polyethylene glycol-lipid, cholesterol, and sgRNA specific for the gene, and wherein the second population of lipid nanoparticles consists of 3-[(1-Adamantanyl)acetoxy]-2-{[3-(diethylamino)propoxycarbonyloxy]methyl}propyl (9Z,12Z)-9,12-octadecadienoate, or a pharmaceutically acceptable salt thereof, DSPC, a polyethylene glycol-lipid, cholesterol, and mRNA encoding an RNA guided DNA endonuclease.

24 . A compound having a structure that is

or a pharmaceutically acceptable salt thereof.

25 . The compound of claim 24 , having a structure that is

or a pharmaceutically acceptable salt thereof.

26 . The compound of claim 24 , having a structure that is

or a pharmaceutically acceptable salt thereof.

Assignees

• Georgia Tech Res Inst

Inventors

• Dahlman James Everett
• Sago Cory Dane
• Gan Zubao

Classifications

• B82Y5/00

  Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery · CPC title

• A61K48/0033

  the non-active part being non-polymeric · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title