Biodegradable poly (beta-amino esters) and uses thereof

Patent metadata

Field	Value
Publication number	US-9700627-B2
Application number	US-201514811613-A
Country	US
Kind code	B2
Filing date	Jul 28, 2015
Priority date	Oct 10, 2000
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

Poly(β-amino esters) prepared from the conjugate addition of bis(secondary amines) or primary amines to a bis(acrylate ester) are described. Methods of preparing these polymers from commercially available starting materials are also provided. These tertiary amine-containing polymers are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems. Given the poly(amine) nature of these polymers, they are particularly suited for the delivery of polynucleotides. Nanoparticles containing polymer/polynucleotide complexes have been prepared. The inventive polymers may also be used to encapsulate other agents to be delivered. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings.

First claim

What is claimed is:

1. A polymer of the formula:

or a salt thereof, wherein:
linker A and linker B are each independently selected from the group consisting of carbon chains of 1 to 30 carbon atoms, heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which is optionally independently substituted with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups; and
n is an integer between 5 and 10,000;
provided that the polymer comprises at least two different types of

moieties.

2. The polymer of claim 1 , wherein the linker A is polyethylene or polyethylene glycol.

3. The polymer of claim 1 , wherein the linker B is polyethylene or polyethylene glycol.

4. The polymer of claim 1 , wherein the molecular weight of the polymer is between 1,000 g/mol and 100,000 g/mol.

5. A pharmaceutical composition comprising an agent to be delivered and a polymer of claim 1 .

6. The pharmaceutical composition of claim 5 , wherein the agent is a small molecule.

7. The pharmaceutical composition of claim 5 , wherein the agent is an antisense agent.

8. The pharmaceutical composition of claim 5 , wherein the agent is a peptide or protein.

9. The pharmaceutical composition of claim 5 , wherein the agent is a polynucleotide.

10. The pharmaceutical composition of claim 9 , wherein the polynucleotide is DNA or RNA.

11. The pharmaceutical composition of claim 9 , wherein the polynucleotide is plasmid DNA.

12. The pharmaceutical composition of claim 9 , wherein the polynucleotide is RNAi.

13. The pharmaceutical composition of claim 9 , wherein the polynucleotide encodes a protein or peptide.

14. The polymer of claim 1 , wherein the polymer is prepared by a method comprising reacting at least two different types of bis(secondary amine) monomers with one or more types of bis(acrylate ester) monomers under suitable conditions.

15. The polymer of claim 14 , wherein at least one bis(acrylate ester) monomer is of the formula

16. A method of synthesizing a polymer of claim 14 , the method comprising
reacting at least two different types of bis(secondary amine) monomers with one or more types of bis(acrylate ester) monomers under suitable conditions to form the polymer.

17. The polymer of claim 14 , wherein at least one bis(secondary amine) monomer is N,N′-dimethylethylenediamine or 1,2-bis(N-ethylamino)ethylene.

18. The polymer of claim 1 , wherein linker A is a carbon chain of 1 to 15 carbon atoms.

19. The polymer of claim 1 , wherein linker B is a carbon chain of 1 to 15 carbon atoms.

20. The polymer of claim 1 , wherein linker B is a heteroatom-containing carbon chain of 1 to 15 atoms long.

21. The polymer of claim 1 , wherein at least one instance of R 1 is hydrogen or branched or unbranched alkyl.

22. The polymer of claim 1 , wherein at least one instance of R 2 is hydrogen or branched or unbranched alkyl.

23. The polymer of claim 1 , wherein each of R 3 and R 6 is hydrogen.

24. The polymer of claim 1 , wherein each of R 4 , R 5 , R 7 , and R 8 is hydrogen.

25. The polymer of claim 1 , wherein n is an integer between 10 and 500.

26. The polymer of claim 1 , wherein linker A is a heteroatom-containing carbon chain of 1 to 15 atoms long.

27. The polymer of claim 1 , wherein the molecular weight of the polymer is between 4,000 g/mol and 50,000 g/mol.

28. A polymer of the formula:

or a salt thereof, wherein:
linker A and linker B are each independently selected from the group consisting of carbon chains of 1 to 30 carbon atoms, heteroatom-containing carbon chains of 1 to 30 atoms, and carbon chains and heteroatom-containing carbon chains with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which is optionally independently substituted with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, amino, alkylamino, dialkylamino, trialkylamino, aryl, ureido, heterocyclic, aromatic heterocyclic, cyclic, aromatic cyclic, halogen, hydroxyl, alkoxy, cyano, amide, carbamoyl, carboxylic acid, ester, carbonyl, carbonyldioxyl, alkylthioether, and thiol groups;
each of R 9 and R 10 is independently selected from the group consisting of hydrogen, branched and unbranched alkyl, branched and unbranched alkenyl, branched and unbranched alkynyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carboxyl ester, carbonyldioxyl, amide, thiohydroxyl, alkylthioether, amino, alkylamino, dialkylamino, trialkylamino, cyano, ureido, a substituted alkanoyl group, cyclic, cyclic aromatic, heterocyclic, and aromatic heterocyclic groups, each of which is optionally independently substituted with at least one substituent selected from the group consisting of branched and unbranched alkyl, branched and unbranched

Assignees

• Massachusetts Inst Technology

Inventors

• Langer Robert S
• Lynn David M
• Putnam David A
• Amiji Mansoor M
• Anderson Daniel Griffith

Classifications

• A61K47/34 Primary

  Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence) · CPC title

• A61K31/711

  Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links · CPC title

• B82Y5/00 Primary

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

• C08G73/0273

  Polyamines containing heterocyclic moieties in the main chain · CPC title

• A61K9/5146

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides · CPC title