Block copolymer having phenylboronic acid group introduced therein, and use thereof

• US 9,114,177 B2
• Filed: 11/19/2012
• Issued: 08/25/2015
• Est. Priority Date: 11/17/2011
• Status: Active Grant

• Current Assignee: NanoCarrier Co., Ltd., Tokyo Medical and Dental University, University of Tokyo
• Original Assignee: NanoCarrier Co., Ltd., Tokyo Medical and Dental University, University of Tokyo
• Inventors: Kataoka, Kazunori, Ishii, Takehiko, Naito, Mitsuru, Matsumoto, Akira, Kato, Yasuki
• Primary Examiner(s): JONES JR., ROBERT STOCKTON
• Application Number:
  US14/358,816
• Publication Number:
  US 20150051347A1
• Time in Patent Office: 1,009 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: C08G 2650/28 characterised by the polymer type
• CPC Class Codes: C08G 69/40 Polyamides containing oxygen in the form of ether groups C08G69/12, C08G69/32 take precedence
• CPC Class Codes: C08G 69/42 Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen C08G69/12, C08G69/32 take precedence
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42

Abstract

A block copolymer includes a polyamino acid chain segment and a hydrophilic polymer chain segment. The polyamino acid chain segment includes at least one amino acid residue having a side chain that contains a cationic group and at least one amino acid residue having a side chain that contains a substituted phenylboronic acid group. In the substituted phenylboronic acid group, at least one hydrogen of the phenyl ring is substituted so that the phenylboronic acid group has a pKa of less than 8. Such a block copolymer serves as a carrier that simultaneously imparts stability to a biotechnology-based drug in blood and provides suitable drug-releasing properties of the drug at an affected area.

Claims

1. A pharmaceutical composition, comprising a complex of:

a block copolymer having a polyamino acid chain segment and a hydrophilic polymer chain segment, and

a nucleic acid,

wherein the polyamino acid chain segment includes at least one amino acid residue having a side chain that contains a cationic group and at least one amino acid residue having a side chain that contains a substituted phenylboronic acid group,

at least one hydrogen atom of the phenyl ring of the substituted phenylboronic acid group has been substituted so that the substituted phenylboronic acid group has a pKa of less than 8, and

the nucleic acid is reversibly covalently bound to the substituted phenylboronic acid group.

2. The pharmaceutical composition according to claim 1, wherein the substituted phenylboronic acid group of the at least one amino acid residue has a pKa of less than 7.5.

3. The pharmaceutical composition according to claim 1, wherein the substituted phenylboronic acid group of the at least one amino acid residue comprises a fluorinated phenylboronic acid group having the following formula (I):

4. The pharmaceutical composition according to claim 1, wherein the cationic group of the at least one amino acid residue is an amino group.

5. The pharmaceutical composition according to claim 1, wherein the cationic group of the at least one amino acid residue is a lysine residue or an amino acid residue, in which an —

OH moiety of a carboxyl group (—

C(═

O)OH) of an acidic amino acid has been substituted with a group selected from any one the following formulas (i) to (iv);

—

NH—

(CH₂)_p1—

[NH—

(CH₂)_q1—

]_r1NH₂ 

 

(i);

—

NH—

(CH₂)_p2—

N[—

(CH₂)_q2—

NH₂]₂ 

 

(ii);

—

NH—

(CH₂)_p3—

N{[—

(CH₂)_q3—

NH₂][—

(CH₂)_q4—

NH-]_r2H} 

 

(iii); and

—

NH—

(CH₂)_p4—

N{—

(CH₂)_q5—

N[—

(CH₂)_q6—

NH₂]₂}₂ 

 

(iv); and

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5.

6. The pharmaceutical composition according to claim 1, wherein the following relationship is satisfied:

√

A+2·

√

B≧

C,

wherein A is the number of cationic amino acid residue(s) in the polyamino acid chain segment that contain no substituted phenylboronic acid group,

B is the number of substituted phenylboronic acid group(s) in the polyamino acid chain segment and

C is 12.0.

7. The pharmaceutical composition according to claim 1, wherein the polyamino acid chain segment further includes at least one amino acid residue having a side chain containing a hydrophobic group.

8. The pharmaceutical composition according to claim 2, wherein the substituted phenylboronic acid group of the at least one amino acid residue comprises a fluorinated phenylboronic acid group having the following formula (I):

9. The pharmaceutical composition according to claim 8, wherein the cationic group of the at least one amino acid residue is an amino group.

10. The pharmaceutical composition according to claim 9, wherein the amino group is a lysine residue or an amino acid residue, in which an —

OH moiety of a carboxyl group (—

C(═

O)OH) of an acidic amino acid has been substituted with a group selected from any one the following formulas (i) to (iv);

—

NH—

(CH₂)_p1—

[NH—

(CH₂)_q1—

]_r1NH₂ 

 

(i);

—

NH—

(CH₂)_p2—

N[—

(CH₂)_q2—

NH₂]₂ 

 

(ii);

—

NH—

(CH₂)_p3—

N{[—

(CH₂)_q3—

NH₂][—

(CH₂)_q4—

NH-]_r2H} 

 

(iii); and

—

NH—

(CH₂)_p4—

N{—

(CH₂)_q5—

N[—

(CH₂)_q6—

NH₂]₂}₂ 

 

(iv); and

wherein p1 to p4, q1 to q6, and r1 and r2 are each independently an integer of 1 to 5.

11. The pharmaceutical composition according to claim 10, wherein the following relationship is satisfied:

√

A+2·

√

B≧

C,

wherein A is the number of cationic amino acid residue(s) in the polyamino acid chain segment that contain no substituted phenylboronic acid group,

B is the number of substituted phenylboronic acid group(s) in the polyamino acid chain segment and

C is 12.0.

12. The pharmaceutical composition according to claim 11, wherein the polyamino acid chain segment further includes at least one amino acid residue having a side chain containing a hydrophobic group.

13. The pharmaceutical composition according to claim 11, wherein the block copolymer is selected from the group consisting of the following formulas (1)-(4):

14. The pharmaceutical composition according to claim 13, wherein k is 50-1500.

15. The pharmaceutical composition according to claim 14, wherein R¹ is a linear or branched alkyl group having 1 to 12 carbon atoms substituted with a target binding site.

16. The pharmaceutical composition according to claim 15, wherein the target binding site comprises a peptide having 1-100 amino acid residues.

17. The pharmaceutical composition according to claim 16, wherein z is 40-150.

18. The pharmaceutical composition according to claim 1, wherein the block copolymer is selected from the group consisting of the following formulas (1)-(4):

19. A block copolymer comprising:

a polyamino acid chain segment and a hydrophilic polymer chain segment,

wherein the polyamino acid chain segment includes at least one amino acid residue having a side chain that contains a cationic group and at least one amino acid residue having a side chain that contains a substituted phenylboronic acid group,

at least one hydrogen atom of the phenyl ring of the substituted phenylboronic acid group has been substituted so that the substituted phenylboronic acid group has a pKa of less than 8, and

the following relationship is satisfied;

√

A+2·

√

B≧

12.0

wherein A is the number of cationic amino acid residue(s) in the polyamino acid chain segment that contain no substituted phenylboronic acid group,

B is the number of substituted phenylboronic acid group(s) in the polyamino acid chain segment and

C is 12.0.

20. The block copolymer according to claim 19, wherein the block copolymer is selected from the group consisting of the following formulas (1)-(4):