IP Library › Granted Patent US 12,390,528
Granted Patent B2
US 12,390,528 · App. 17/122,068 · Granted Aug 19, 2025

Conjugated lipomers and uses thereof

Inventors: James E. Dahlman (Cambridge, MA); Avraham D. Schroeder (Newton, MA); Daniel Griffith Anderson (Framingham, MA); Robert S. Langer (Newton, MA); Christopher G. Levins (Flemington, NJ)
Assignee: Massachusetts Institute of Technology
A61K47/22A61K9/0019A61K9/1272A61K47/34A61K47/543A61K47/59A61K47/6907A61K47/6911A61K47/6921C07D257/02C07D273/00C07D273/08C07D295/084C08G73/10C12N15/1137C12N15/1138C12N2310/14C12N2320/32
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Quick Facts
Patent No.
US 12,390,528
App. No.
17/122,068
Granted
Aug 19, 2025
Kind
B2
Abstract

The present invention provides inventive conjugated polyethyleneimine (PEI) polymers and conjugated aza-macrocycles (collectively referred to herein as “conjugated lipomers” or “lipomers”) containing one or more groups of the formula (iii): wherein R 3 and R 4 are as defined herein. Also provided are compositions comprising the inventive conjugated lipomers, and methods of preparation and use.

Claims (56)

1. A conjugated lipomer of the Formula (II):

or salt thereof; wherein:

each instance of L 1 is independently formula:

provided that at least one L 1 is formula (ii) and at least one L 1 is formula (iii);

n is an integer between 3 and 45, inclusive;

each instance of R 2 is independently hydrogen; acyl; silyl; sulfonyl; an amino protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted polyethyleneimine; or a group of the formula (iii′):

or the two R 2 groups are joined to form a substituted or unsubstituted heterocyclyl;

each instance of R 3 is —C 13 H 27 ;

each instance of R 4 is independently hydrogen, acyl; silyl; a hydroxyl protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

A is —N(R 5 ) 2 , wherein each instance of R 5 is hydrogen; and

Z is hydrogen; acyl; silyl; sulfonyl; an amino protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl, or a group of the formula (iii′):

or Z and the nitrogen atom to which it is attached form a substituted or unsubstituted heterocyclyl group.

2. The conjugated lipomer of claim 1 , or salt thereof, wherein the conjugated lipomer is prepared from a polyethyleneimine polymer having a number average molecule weight (Mn) of less than 800 g/mol.

3. The conjugated lipomer of claim 1 , or salt thereof, wherein n is an integer between 3 and 5, inclusive.

4. The conjugated lipomer of claim 1 , or salt thereof, wherein each instance of R 2 is independently hydrogen; a substituted or unsubstituted polyethyleneimine; or a group of the formula (iii′).

5. A composition comprising one or more conjugated lipomers of claim 1 , or salt thereof, and, optionally, an excipient.

6. The composition of claim 5 , wherein the composition is a pharmaceutical composition or a cosmetic composition.

7. The composition of claim 5 , wherein the composition further comprises an agent.

8. The composition of claim 7 , wherein the agent is an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, or an immunological agent.

9. The composition of claim 8 , wherein the agent is a polynucleotide, and the polynucleotide is DNA or RNA.

10. The composition of claim 9 , wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

11. A method of preparing a conjugated lipomer of claim 1 , or salt thereof, the method comprising contacting a compound of the Formula (I), or salt thereof, with an epoxide of the formula (xii):

wherein each instance of R 1 is independently hydrogen or a group of the formula (ii′):

to provide the conjugated lipomer of the Formula (II), or salt thereof.

12. A conjugated lipomer, or salt thereof, prepared by contacting a compound of Formula (I):

or salt thereof, with one or more different epoxides of the formula (xii):

wherein:

n is an integer between 3 and 45, inclusive;

each instance of R 1 is independently selected from hydrogen or a group of the formula (ii′):

A is —N(R 5 ) 2 , wherein each instance of R 5 is hydrogen;

Z is hydrogen; acyl; silyl; sulfonyl; an amino protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; or Z and the nitrogen atom to which it is attached form a substituted or unsubstituted heterocyclyl group;

each instance of R 2 is independently hydrogen; acyl; silyl; sulfonyl; an amino protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; a substituted or unsubstituted polyethyleneimine; or a group of the formula (iii′):

or the two R 2 groups are joined to form a substituted or unsubstituted heterocyclyl;

each instance of R 3 is —C 13 H 27 ;

each instance of R 4 is independently hydrogen, acyl; silyl; a hydroxyl protecting group; substituted or unsubstituted alkyl; substituted or unsubstituted alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted heteroalkyl; substituted or unsubstituted heteroalkenyl; substituted or unsubstituted heteroalkynyl; substituted or unsubstituted carbocyclyl; substituted or unsubstituted heterocyclyl; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;

provided that the number average molar mass (Mn) of the compound of Formula (I) does not exceed 2000 g/mol (about 2 kDa).

13. The conjugated lipomer of claim 1 , or salt thereof, wherein each instance of R 4 is hydrogen.

14. The conjugated lipomer of claim 4 , or salt thereof, wherein the polyethyleneimine is of formula (iv):

wherein:

t is 1;

P is hydrogen or a group of the formula (iii′):

R 6 is hydrogen or a group of formula (iii′), wherein:

each instance of R 3 is —C 13 H 27 ; and

each instance of R 4 is hydrogen.

15. The conjugated lipomer of claim 1 , or salt thereof, wherein each instance of formula (iii) is

16. The conjugated lipomer of claim 1 , or salt thereof, wherein each instance of L 1 is independently of formula (ii) or (iii), wherein each instance of formula (ii) is

and each instance of formula (iii) is

17. The conjugated lipomer of claim 1 , or salt thereof, wherein:

each instance of L 1 is independently formula (ii) or (iii);

n is an integer between 10 and 15, inclusive;

each instance of R 2 is independently a substituted polyethyleneimine, or a group of formula (iii′);

each instance of R 4 is hydrogen; and

Z is a group of formula (iii′).

18. The conjugated lipomer of claim 12 , or salt thereof, wherein each instance of R 2 is independently hydrogen; a substituted or unsubstituted polyethyleneimine; or a group of the formula (iii′).

19. The conjugated lipomer of claim 12 , or salt thereof, wherein Z is hydrogen.

20. The conjugated lipomer of claim 1 , or salt thereof, wherein Z is hydrogen or a group of the formula (iii′).

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2022
From: DAHLMAN, JAMES E.; SCHROEDER, AVRAHAM D.; ANDERSON, DANIEL GRIFFITH; LANGER, ROBERT S.; LEVINS, CHRISTOPHER G.
To: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Reel/Frame 059159/0180 →
Continuity (5)
Continuation 16181109 · Nov 5, 2018
Continuation 14995842 · Jan 14, 2016
Continuation 13428695 · Mar 23, 2012
Provisional Application 61468455 · Mar 28, 2011
Related Publication 20210260195A1 · Aug 26, 2021
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