Gene delivery carrier
Disclosed are methods, compositions, reagents, systems, and kits to prepare and utilize poly (β-amino ester) (PBAE) polymers, which are synthesized via Michael addition reactions of diacrylates and amines disclosed herein. Various embodiments utilize lactones and lactone derivatives to generate the diacrylate compounds. The PBAE polymers are shown to be effective biodegradable carriers for the delivery of an agent such as an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, or an immunological agent.
1. A polymer of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
is a single bond or a double bond;
A is hydrogen or —XR 3 ;
each B independently is a diradical of the formula:
each D independently is:
E is —XR 4 ;
R is C 2 -C 6 alkyl;
R′ is C 2 -C 20 alkyl, optionally substituted with a group selected from alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, trialkylamino, acylamino, cyano, hydroxy, halo, mercapto, nitro, carboxyaldehyde, carboxy, alkoxycarbonyl, and carboxamide;
R″ cyclic or acyclic aliphatic, cyclic or acyclic heteroaliphatic, or a combination thereof, wherein each aliphatic or heteroaliphatic is optionally substituted with a C 1-6 alkyl;
each R a independently is hydrogen or C 1-6 alkyl;
each R 1 independently is selected from hydrogen, C 1 -C 10 alkyl, and C 1 -C 20 heteroalkyl, wherein the alkyl and heteroalkyl groups are optionally substituted with halogen, hydroxyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, or 5-14 membered heteroaryl;
R 3 and R 4 independently are selected from hydrogen, C 1 -C 20 alkyl, C 1 -C 10 heteroalkyl, C 3-10 carbocyclyl, and 3-14 membered heterocyclyl;
X is O, S, NH, or NR X , wherein R X is C 1-6 alkyl;
X′ is O;
each m independently is an integer between 3 and 10, inclusive; and
n is an integer between 1 and 10,000, inclusive.
2. The polymer of claim 1 , having the structure of Formula (II):
3. The polymer of claim 1 , wherein B is of the formula:
4. The polymer of claim 1 , wherein m is an integer between 3 and 7, inclusive.
5. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
each R 1 is independently
at least one R 1 is
and
at least one R 1 is
6. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
each R 1 is independently
at least one R 1 is
and
at least one R 1 is
7. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
each R 1 is independently
at least one R 1 is
and
at least one R 1 is
8. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
each D is independently
at least one D is
and
at least one D is
9. The polymer of claim 1 , wherein the polymer has a molecular weight between 1-100 kDa.
10. A composition comprising a polymer of claim 1 and an excipient.
11. The composition of claim 10 , wherein the composition further comprises an agent.
12. The composition of claim 11 , wherein the agent is a polynucleotide.
13. The composition of claim 12 , wherein the polynucleotide is DNA.
14. The composition of claim 12 , wherein the polynucleotide is RNA.
15. The composition of claim 14 , wherein the RNA is dsRNA, siRNA, shRNA, miRNA, mRNA, or antisense RNA.
16. The composition of claim 14 , wherein the RNA is mRNA.
17. The composition of claim 16 , wherein the mRNA encodes an antigen.
18. The composition of claim 12 , wherein the polynucleotide carries out RNA interference.
19. The composition of claim 10 , wherein the composition is in the form of a particle.
20. The composition of claim 19 , wherein the particle encapsulates an agent.
21. The polymer of claim 5 , wherein:
m=3, n is about 5, each X is —NH—, and R 3 and R 4 are both
m=5, n is about 5, each X is —NH—, and R 3 and R 4 are both
or
m=7, n is about 5, each X is —NH—, and R 3 and R 4 are both
22. The polymer of claim 6 , wherein:
m=3, n is about 5, each X is —NH—, and R 3 and R 4 are both
m=5, n is about 5, each X is —NH—, and R 3 and R 4 are both
or
m=7, n is about 5, each X is —NH—, and R 3 and R 4 are both
23. The polymer of claim 7 , wherein:
m=3, n is about 5, each X is —NH—, and R 3 and R 4 are both
m=5, n is about 5, each X is —NH—, and R 3 and R 4 are both
or
m=7, n is about 5, each X is —NH—, and R 3 and R 4 are both