Poly(amine-co-ester) polymers and polyplexes with modified end groups and methods of use thereof

1. A method of administering one or more therapeutic, diagnostic, or prophylactic nucleic acid agents, or combinations thereof in vivo, comprising administering to a subject or a cell in need thereof a polyplex or solid-core particle comprising the one or more therapeutic, prophylactic, or diagnostic nucleic acid agents and a polymer of Formula I:

wherein n is an integer from 1-30, m, o, and p are independently integers from 1-20, x, y, and q are independently integers from 1-1000, Rx is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy, Z and Z′ are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,

wherein R 1 and R 2 are chemical entities containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof.

2. The method of claim 1 comprising transfecting cells by contacting cells with the particles or polyplex.

3. The method of claim 1 , wherein R1 and/or R2 are not

4. The method of claim 1 , wherein polyplexes or particles formed from the polymer show improved loading, improved cellular transfection, improved intracellular endosomal release, or a combination thereof of a mRNA, relative to corresponding polyplexes or particles wherein R1 and/or R2 consist of

5. The method of claim 1 , wherein the polymer has a structure of Formula II:

wherein J 1 and J 2 are independently linking moieties or absent, wherein at least one of J 1 and J 2 is present,

R 3 and R 4 are substituted alkyl containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof.

6. The method of claim 5 , wherein the polymer has a structure of Formula III:

7. The method of claim 5 , wherein R 3 is the same as R4.

8. The method of claim 5 , wherein R3 and/or R4 are independently selected from the group consisting of

9. The method of claim 5 , wherein J1 is —O— or —NH, J 2 is —C(O)NH— or —C(O)O— or a combination thereof.

10. The method of claim 5 , wherein R 3 , R 4 , or both contain a primary amine group, and optionally one or more secondary or tertiary amine groups.

11. The method of claim 5 , wherein:

(i) R 3 , R 4 , or both contain a hydroxyl group, and optionally one or more amine groups,

(ii) R 3 , R 4 , or both contain a hydroxyl group and no amine group, or

(iii) at least one of R 3 and R 4 does not contain a hydroxyl group.

12. The method of claim 1 , wherein Z is the same as Z′.

13. The method of claim 1 , wherein n is 4, 10, 13, or 14.

14. The method of claim 1 , wherein m is 5, 6, or 7.

15. The method of claim 1 , wherein R x is substituted or unsubstituted alkyl.

16. The method of claim 1 , wherein the weight average molecular weight, as measured by gel permeation chromatography using narrow polydispersity polystyrene standards, is between about 2,000 Daltons and 20,000 Daltons.

17. A method of making a polymer of Formula I:

wherein n is an integer from 1-30, m, o, and p are independently integers from 1-20, x, y, and q are independently integers from 1-1000, Rx is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy, Z and Z′ are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,

wherein R 1 and R 2 are chemical entities containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof,

the method comprising modifying the end groups of the unmodified polymer of Formula VII,

wherein X′ is —OH or —NHR′.

18. A method of making a polymer of Formula III:

wherein n is an integer from 1-30, m, o, and p are independently integers from 1-20, x, y, and q are independently integers from 1-1000, Rx is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy, Z and Z′ are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,

R 3 and R 4 are substituted alkyl containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof,

the method comprising (1) reacting the polymer of Formula VII with 1,1′-carbonyldiimidazoleto obtain a polymer of Formula IV, and (2) reacting the polymer of Formula IV with R3-NH2 and R4-NH2, wherein the polymer of Formula IV has a structure:

and the polymer of Formula VII has a structure:

19. The method of claim 18 , wherein R3, R4, or both are selected from the group consisting of

20. A method of increasing the transfection efficiency of a nucleic acid agent delivered using a polymer of Formula I:

wherein n is an integer from 1-30, m, o, and p are independently integers from 1-20, x, y, and q are independently integers from 1-1000, Rx is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy, Z and Z′ are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,

wherein R 1 and R 2 are chemical entities containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof, comprising

producing the polymer with a weight average molecular weight, as measured by gel permeation chromatography using narrow polydispersity polystyrene standards, is between about 2,000 Daltons and 20,000 Daltons, preferably between about 2,000 Daltons and about 10,000 Daltons, most preferably between about 2000 Daltons and about 7,000 Daltons, and

exposing hydroxyl and carboxyl end groups on the polymer.