Amphiphilic block copolymer and polymeric composition comprising the same for drug delivery

1. A polymeric composition for drug delivery, said composition comprising:

a block copolymer comprising hydrophilic A blocks and hydrophobic B blocks with a terminal hydroxyl group, said terminal hydroxyl group of the hydrophobic B block is substituted with tocopherol or cholesterol; and

a polylactic acid derivative, wherein at least one end of the polylactic acid derivative is covalently bound to at least one carboxyl group;

wherein the block copolymer and the polylactic acid derivative form a micelle or nanoparticle in aqueous solution.

2. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is represented by the following formula:

RO—CHZ-[A] n -[B] m —COOM  (I)

wherein A is —COO—CHZ—; B is —COO—CHY—, —COO—CH 2 CH 2 CH 2 CH 2 CH 2 — or —COO—CH 2 CH 2 OCH 2 ;

R is a hydrogen atom, or acetyl, benzoyl, decanoyl, palmitoyl, methyl, or ethyl group;

Z and Y each are hydrogen atoms, or methyl or phenyl groups;

M is H, Na, K, or Li;

n is an integer from 1 to 30; and

m is an integer from 0 to 20.

3. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is represented by the following formula:

RO—CHZ—[COO—CHX] p —[COO—CHY′] q —COO—CHZ—COOM  (II)

wherein X is a methyl group;

Y′ is a hydrogen atom or phenyl group;

p is an integer from 0 to 25;

q is an integer from 0 to 25, provided that p+q is an integer from 5 to 25;

R is a hydrogen atom, or acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl group;

Z is a hydrogen atom, or methyl or phenyl group; and

M is H, Na, K, or Li.

4. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is represented by the following formula:

RO—PAD-COO—W-M′  (III)

wherein W-M′ is

PAD is a member selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-Lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxan-2-one;

R is a hydrogen atom, or acetyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl group; and

M is H, Na, K, or Li.

5. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is represented by the following formula:

S—O—PAD-COO-Q  (IV)

wherein S is

L is —NR 1 — or —O—;

R 1 is a hydrogen atom or C 1-10 alkyl;

Q is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , or CH 2 C 6 H 5 ;

a is an integer from 0 to 4;

b is an integer from 1 to 10;

M is H, Na, K, or Li; and

PAD is a member selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-Lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxan-2-one.

6. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is represented by the following formula:

wherein R′ is —PAD-O—C(O)—CH 2 CH 2 —C(O)—OM and PAD is a member selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-Lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxan-2-one;

M is H, Na, K, or Li; and

a is an integer from 1 to 4.

7. The polymeric composition according to claim 1 , wherein:

the hydrophilic A block is a member selected from the group consisting of polyalkylene glycols, polyvinyl pyrrolidone, polyvinyl alcohols, polyacryl amides; and

the hydrophobic B block is a member selected from the group consisting of polylactides, polyglycolides, polydioxan-2-one, polycaprolactone, polylactic-co-glycolide, polylactic-co-caprolactone, and polylactic-co-dioxan-2-one.

8. The polymeric composition according to claim 1 , wherein the amphiphilic block copolymer is represented by the following formula:

R 1′ —O—[R 3′ ] 1′ —[R 4′ ] m′ —[R 5′ ] n′ —C(═O)—(CH 2 ) x′ —C(═O)—O—R 2′   (I′)

wherein R 1′ is CH 3 —, H—[R 5′ ] n′—[R 4′ ] m′ —, or R 2′ —O—C(═O)—(CH 2 ) x′ —C(═O)—[R 5′ ] n′ —[R 4′ ] m′ —;

R 2 ′ is tocopherol or cholesterol;

R 3′ is —CH 2 CH 2 —O—, —CH(OH)—CH 2 —, —CH(C(═O)—NH 2 )—CH 2 —, or

R 4′ is —C(═O)-CHZ′—O—, wherein Z′ is a hydrogen atom or methyl group;

R 5′ is —C(═O)—CHY″—O—, wherein Y″ is a hydrogen atom or methyl group, —C(═O)—CH 2 CH 2 CH 2 CH 2 CH 2 —O—, or —C(═O)—CH 2 OCH 2 CH 2 —O—;

l′ is an integer from 4-1150;

m′ is an integer from 1-300;

n′ is an integer from 0-300; and

X′ is an integer from 0-4.

9. The polymeric composition according to claim 1 , wherein the hydrophilic A blocks and the hydrophobic B blocks each have a number average molecular weight within the range of 200 to 50,000 Daltons and 50 to 50,000 Daltons, respectively.

10. The polymeric composition according to claim 1 , wherein the ratio of the hydrophilic A blocks to the hydrophobic B blocks in the block copolymer is 30:70 to 97:3by weight.

11. The polymeric composition according to claim 1 , comprising 0.1 to 99.9 wt % of the block copolymer and 0.1 to 99.9 wt % of the polylactic acid derivative, based on the total weight of the composition.

12. The polymeric composition according to claim 1 , wherein the polylactic acid derivative has a number average molecular weight of 50 to 50,000 Daltons.

13. The polymeric composition according to claim 1 , wherein the polylactic acid derivative is in the form of a sodium or potassium salt obtained by a condensation reaction in the absence of a catalyst followed by neutralization with sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, or potassium carbonate.

14. The polymeric composition according to claim 1 , further comprising 0.01 to 10 equivalents of a di- or tri-valent metal ion to 1 equivalent of the carboxyl terminal group of the polylactic acid derivative.

15. The polymeric composition according to claim 14 , wherein the di- or tri-valent metal ion is a member selected from the group consisting of Ca 2+ , Mg 2+ , Ba 2+ , Cr 3+ , Fe 3+ , Mn 2+ , Ni 2+ , Cu 2+ , Zn 2+ and Al 3+ .

16. A micelle or nanoparticle prepared from the polymeric composition according to claim 1 .

17. The micelle or nanoparticle according to claim 16 , wherein the particle size of the micelle or nanoparticle is within the range of 1 to 400 nm.

18. A pharmaceutical composition comprising 70 to 99.9 wt % of the polymeric composition according to claim 1 , and 0.1 to 30 wt % of a poorly water-soluble drug.

19. A pharmaceutical composition comprising 70 to 99.9 wt % of the polymeric composition according to claim 14 and 0.1 to 30 wt % of a poorly water-soluble drug.

20. A pharmaceutical composition useful as an anticancer agent, comprising:

an amphiphilic block copolymer of hydrophilic A blocks and hydrophobic B blocks with a terminal hydroxyl group, said terminal hydroxyl group of the hydrophobic B block is substituted with tocopherol or cholesterol;

a polylactic acid derivative, wherein at least one end of the polylactic acid derivative is covalently bound to at least one carboxyl group; and

an anticancer drug,

wherein the amphiphilic block copolymer and the polylactic acid derivative form a micelle or nanoparticle in aqueous solution.

21. The pharmaceutical composition to claim 20 , further comprising 0.01 to 10 equivalents of a di- or tri-valent metal ion to 1 equivalent of the carboxyl terminal group of the polylactic acid derivative.

22. A method for treating a drug-resistant cancer comprising administering an effective amount of the pharmaceutical composition according to claim 20 to a warm-blooded animal in need of said treatment.

23. A method for treating a drug-resistant cancer comprising administering an effective amount of the pharmaceutical composition according to claim 21 to a warm-blooded animal in need of said treatment.