Anionic polymer, polyion complex and ternary polymer composite using anionic polymer, and pharmaceutical composition

1. An anionic polymer, comprising:

a main chain which comprises a repeating unit having a carboxyl group; and

a side chain which is bonded to the carboxyl group in the main chain and which is represented by the following formula:

-A-B—X

where: A represents a residue having one or more aminoethyl bonds; B represents an in vivo cleavable bond; and X represents a small RNA.

2. The anionic polymer of claim 1 , wherein the main chain comprises at least one selected from the group consisting of a polyamino acid having a carboxyl group, a polyvinyl having a carboxyl group, a polyester having a carboxyl group, a polysaccharide having a carboxyl group, and a dendrimer (cascade polymer) having a carboxyl group.

3. The anionic polymer of claim 1 , wherein the in vivo cleavable bond is a disulfide bond, an acetal bond, or a hydrazone bond.

4. The anionic polymer of claim 1 , which is represented by formula (I):

where: R 1 and R 2 each independently represent a hydrogen atom, an unsubstituted or substituted linear or branched C 1 -C 12 alkyl group, or a polyethylene glycol chain; A represents a residue having one or more aminoethyl bonds; B represents an in vivo cleavable bond; Q represents a hydroxyl group or a residue having one or more aminoethyl bonds in which an aminoethyl bond is substituted by a hydroxyl group; X represents a small RNA; l is an integer of 1 to 500; m is an integer of 1 to 499; and n is an integer of 1 to 5, wherein a sum of l and m is 10 to 500, and repeating units represented by l and m are arranged at random.

5. The anionic polymer of claim 4 , wherein A represents —NH—(CH 2 ) 2 — and Q represents —OH.

6. The anionic polymer of claim 4 , wherein l is an integer of 2 or more.

7. A polyion complex, comprising:

the anionic polymer of claim 1 ; and

a cationic polymer selected from the group consisting of polyethylene imine, polyarginine, polylysine, poly-[2-{(2-aminoethyl)amino}-ethyl-aspartamide] (pAsp(DET)), a block co-polymer of polyethylene glycol and polyarginine, a block co-polymer of polyethylene glycol and polylysine, and a block co-polymer of polyethylene glycol and poly-[2-{(2-aminoethyl)amino }-ethyl-aspartamide] (PEG-pAsp(DET)).

8. A ternary polymer composite, comprising:

the polyion complex of claim 7 ; and

a charge conversional polymer represented by formula (II):

where: R 11 and R 12 each independently represent a hydrogen atom, an unsubstituted or substituted linear or branched C 1 -C 12 alkyl group, or a polyethylene glycol chain; R 13 represents a conjugate of an amine compound residue having a primary amine, with a compound represented by formula (10):

where: R a and R b each independently represent a hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, heterocyclic ring, heterocyclic-alkyl, hydroxyl, alkoxyl, or aryloxy group, wherein R a and R b may be bonded together to form an aromatic or cycloalkyl ring with carbon atoms to which R a and R b are bonded, respectively, and a bond between the carbon atoms to which R a and R b are bonded is single or double;

m1 represents is an integer of 10 to 500; and m2 represents is an integer of 1 to 5.

9. The ternary polymer composite of claim 8 , wherein the amine compound residue having a primary amine is represented by formula (11) or (12):

—NH—(CH 2 ) r —NH 2   (11)

wherein r is an integer of 0 to 5;

—[NH—(CH 2 ) s1 ] t1 —NH 2   (12)

wherein in [NH—(CH 2 ) s1 ] units, s1's each independently are an integer of 1 to 5; and t1 is an integer of 2 to 5.

10. The ternary polymer composite of claim 8 , wherein the amine compound residue having a primary amine is —NH—(CH 2 ) 2 —NH 2 or —NH—(CH 2 ) 2 —NH—(CH 2 ) 2 —NH 2 .

11. The ternary polymer composite of claim 8 , wherein the compound represented by formula (10) is at least one selected from compounds represented by formulae (Ia) to (Ig):

12. A pharmaceutical composition, comprising:

the polyion complex of claim 7 ; and

a pharmaceutically acceptable carrier.

13. A pharmaceutical composition, comprising:

the ternary polymer composite of claim 8 ; and

a pharmaceutically acceptable carrier.

14. The anionic polymer of claim 1 , wherein the in vivo cleavable bond is a disulfide bond.

15. The anionic polymer of claim 1 , wherein the in vivo cleavable bond is an acetal bond.

16. The anionic polymer of claim 1 , wherein the in vivo cleavable bond is a hydrazone bond.

17. The anionic polymer of claim 4 , wherein l is an integer of 80 to 220, and a sum of l and m is 2 to 18.

18. A polyion complex, comprising:

the anionic polymer of claim 1 , and

polyethylene imine.

19. A polyion complex, comprising:

the anionic polymer of claim 1 , and

poly-[2-{(2-aminoethyl)amino}-ethyl-aspartamide] (pAsp(DET)).

20. A polyion complex, comprising:

the anionic polymer of claim 1 , and

a block co-polymer of polyethylene glycol and poly-[2-{(2-aminoethyl)amino}-ethyl-aspartamide] (PEG-pAsp(DET)).