Alpha-aminoamidine polymers and uses thereof
α-Aminoamidine polymers and methods of preparing a-aminoamidine polymers by reacting by reacting one or more amines with one or more isocyanides and one or more aldehydes are described. Methods of preparing a-aminoamidine polymers from commercially available starting materials are also provided, wherein the starting materials are racemic or stereochemically pure. a-Aminoamidine polymers or salt forms thereof are preferably biodegradable and biocompatible and may be used in a variety of drug delivery systems and for other purposes as well such as, for example, coatings, additives, excipients, plastics, and materials, etc. Given the amino moiety of these α-aminoamidine polymers, they are particularly suited for the delivery of polynucleotides. Complexes, micelles, liposomes or particles containing the inventive α-aminoamidine polymers and polynucleotides can be prepared. The inventive α-aminoamidine polymers may also be used in preparing microparticles for drug delivery. They are particularly useful in delivering labile agents given their ability to buffer the pH of their surroundings.
1. A polymer of Formula (I):
or a pharmaceutically acceptable salt or isomer thereof;
wherein:
R 1 is a linking group comprising one or more combinations of substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl; optionally interrupted by one or more groups independently selected from —O—, —S—, —OSi(R 7 R 8 )O—, —SiR 7 R 8 —, and —NR 10 —;
R 2 is hydrogen; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
R 3 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
each instance of R 4 , R 5 , and R 10 is, independently, hydrogen; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; acyl; sulfonyl; or a nitrogen protecting group;
or R 4 and R 1 optionally form a cyclic structure;
or R 5 and R 1 optionally form a cyclic structure;
each of R 7 and R 8 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic; substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl;
each E is independently, hydrogen or a group of formula R 4 or R 5 ;
G is
and
n is an integer from 2 to 100, inclusive.
2. The polymer of claim 1 , wherein the polymer is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
3. A particle comprising a polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof.
4. The particle of claim 3 , wherein the particle further comprises one or more stabilizing agents and/or one or more amino acids.
5. The particle of claim 4 , wherein the stabilizing agents are selected from the group consisting of polyethylene glycol (PEG), cholesterol, cholesterol analogs, and poloxamers.
6. The particle of claim 4 , wherein the stabilizing agents are selected from the group consisting of 3β-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DC-cholesterol), PLURONIC® F127 (poloxamer 407), and 2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (DMG-PEG).
7. The particle of claim 4 , wherein the one or more amino acids comprise H (histidine).
8. A composition comprising a polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof.
9. The composition of claim 8 , wherein the composition is a pharmaceutical composition, a cosmetic composition, a nutraceutical composition, or a composition with non-medical application.
10. The composition of claim 8 , wherein the composition further comprises an agent.
11. The composition of claim 10 , 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.
12. The composition of claim 10 , wherein the agent is a polynucleotide.
13. The composition of claim 9 , wherein the composition is in the form of a particle.
14. The composition of claim 13 , wherein the particle is a nanoparticle or microparticle.
15. The composition of claim 13 , wherein the particle is a micelle, liposome, or lipoplex.
16. The composition of claim 13 , wherein the particle encapsulates an agent.
17. A method of delivering a polynucleotide to a cell, comprising:
providing a composition comprising an polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, and a polynucleotide; and
exposing the composition to the cell under conditions sufficient to facilitate delivery of the polynucleotide into the interior of the cell.
18. The polymer of claim 1 , wherein the polymer is of the formula:
wherein R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
19. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
20. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
21. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
22. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
23. The polymer of claim 1 , wherein the polymer is of the formula:
wherein:
R 2 is of the formula:
and R 3 is of the formula:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
R 2 is of the formula:
and R 3 is of the formula:
R 2 is of the formula:
and R 3 is of the formula:
or R 2 is of the formula:
and R 3 is of the formula:
or a pharmaceutically acceptable salt or isomer thereof.
24. The composition of claim 10 , wherein the agent is a polynucleotide that encodes a protein or peptide.
25. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic.
26. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic interrupted by one or more groups independently selected from —O— and —SiR 7 R 8 —.
27. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic.
28. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 is a linking group comprising one or more substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic, and one or more substituted or unsubstituted aryl.
29. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 2 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic.
30. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 2 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
31. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 3 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic, or substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 heteroaliphatic.
32. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 3 is substituted or unsubstituted aryl.
33. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 4 is hydrogen.
34. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 4 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic.
35. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 5 is hydrogen.
36. The polymer of claim 1 , or a pharmaceutically acceptable salt or isomer thereof, wherein R 5 is substituted or unsubstituted, branched or unbranched, cyclic or acyclic C 1-20 aliphatic.
37. The composition of claim 12 , wherein the polynucleotide is DNA.
38. The composition of claim 12 , wherein the polynucleotide is RNA.
39. The composition of claim 38 , wherein the RNA is RNAi, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.
40. The polymer of claim 1 , wherein:
R 1 is
R 2 is
R 3 is
R 4 is hydrogen; and
R 5 is hydrogen.