Lipid-polymer based complexation and delivery of nucleic acids

Patent metadata

Field	Value
Publication number	US-12344693-B2
Application number	US-202217892637-A
Country	US
Kind code	B2
Filing date	Aug 22, 2022
Priority date	Apr 16, 2019
Publication date	Jul 1, 2025
Grant date	Jul 1, 2025

Abstract

The invention provides novel polymers, crosslinked polymer-nucleic acid complexes, lipid-polymer-nucleic acid-based complexation and nanoassemblies, and nanoassembly-based intracellular delivery of nucleic acids and controlled release thereof upon degradation of the nanoassemblies in response to specific microenvironment in the cell, and compositions and methods of preparation and use thereof.

First claim

The invention claimed is:

1. A molecular assembly, comprising:
a crosslinked polymer-nucleic acid complex comprising a nucleic acid encapsulated in a crosslinked polymer network; and
a coating on the crosslinked polymer-nucleic acid complex, wherein the coating comprises a zwitterionic lipid and a PEGylated lipid.

2. The molecular assembly of claim 1 , wherein the crosslinked polymer-nucleic acid complex comprises:
a crosslinked block or random copolymer comprising structural units of:

wherein
each of R 1 and R′ 1 is independently a hydrogen, C 1 -C 12 alkyl group, or halogen;
each of R 2 , R′ 2 , R 3 , and R′ 3 is independently a hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkyloxy, or halogen;
each of L 1 and L 2 is independently a linking group;
each of S 1 and S 2 is independently a single bond or a spacer group;
W is a hydrophobic group; and
X is a group comprising a crosslinking moiety; and

a nucleic acid molecule entrapped in the crosslinked block or random copolymer.

3. The molecular assembly of claim 2 , wherein the block or random copolymer further comprises the structural unit of:

wherein
R″ 1 is a hydrogen, C 1 -C 12 alkyl group, or halogen;
each of R″ 2 and R″ 3 is independently a hydrogen, C 1 -C 16 alkyl, C 1 -C 16 alkyloxy, or halogen;
L 3 is a linking group;
S 3 is a single bond or a spacer group; and
Y is a non-crosslinking group.

4. The molecular assembly of claim 2 , wherein X comprises a crosslinked group.

5. The molecular assembly of claim 2 , wherein X comprises a group capable of forming a crosslinking bond.

6. The molecular assembly of claim 2 , wherein the nucleic acid molecule is selected from single-standed or double-stranded RNA or DNA, and derivatives or anologs thereof.

7. The molecular assembly of claim 2 , wherein the nucleic acid molecule is selected from dsRNA, siRNA, mRNA, ncRNA, microRNA, catalytic RNA, gRNA, DNAs, oligonucleotides, aptamers, genes, plasmids, and derivatives or anologs thereof.

8. The molecular assembly of claim 7 , wherein the nucleic acid molecule is an siRNA.

9. The molecular assembly of claim 2 , wherein the copolymer is a random copolymer.

10. The molecular assembly of claim 2 , wherein the copolymer is a block copolymer.

11. The molecular assembly of claim 2 , wherein W comprises a C 1 -C 30 linear or branched alkyl group.

12. The molecular assembly of claim 2 , wherein each of L 1 , L 2 and L 3 is independently a

group.

13. The molecular assembly of claim 2 , wherein X comprises a disulfide group.

14. The molecular assembly of claim 2 , wherein the block or random copolymer further comprises the structural unit of:

wherein X′ comprises a group selected from:

wherein R is a C 1 -C 15 alkyl group, and Z is a counter ion.

15. The molecular assembly of claim 2 , being crosslinked both inter-molecularly and intra-molecularly.

16. The molecular assembly of claim 2 , wherein the zwitterionic lipid comprises a zwitterionic group selected from the group consisting of:

wherein each R is hydrogen or a C 1 -C 15 alkyl group; n is independently an integer from about 1 to about 12.

17. The molecular assembly of claim 16 , wherein each n is independently an integer from about 2 to about 6.

Assignees

• Univ Massachusetts

Inventors

• Thayumanavan Sankaran
• Dutta Kingshuk

Classifications

• A61K47/543 Primary

  Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine · CPC title

• A61K47/58

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin · CPC title

• B82Y5/00

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

• C08F220/385

  and containing nitrogen · CPC title

• C08F2438/03

  Use of a di- or tri-thiocarbonylthio compound, e.g. di- or tri-thioester, di- or tri-thiocarbamate, or a xanthate as chain transfer agent, e.g . Reversible Addition Fragmentation chain Transfer [RAFT] or Macromolecular Design via Interchange of Xanthates [MADIX] · CPC title