Block copolymer and micelle compositions and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10017598-B2
Application number	US-201715662184-A
Country	US
Kind code	B2
Filing date	Jul 27, 2017
Priority date	Sep 22, 2010
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

Provided herein are block copolymers comprising a hydrophilic polymer segment and a hydrophobic polymer segment, wherein the hydrophilic polymer segment comprises a polymer selected from the group consisting of: poly(ethylene oxide) (PEO), poly(methacrylate phosphatidyl choline) (MPC), and polyvinylpyrrolidone (PVP), wherein the hydrophobic polymer segment comprises

wherein R′ is —H or —CH 3 , wherein R is —NR 1 R 2 , wherein R 1 and R 2 are alkyl groups, wherein R 1 and R 2 are the same or different, wherein R 1 and R 2 together have from 5 to 16 carbons, wherein R 1 and R 2 may optionally join to form a ring, wherein n is 1 to about 10, and wherein x is about 20 to about 200 in total. Also provided are pH-sensitive micelle compositions for therapeutic and diagnostic applications.

First claim

The invention claimed is:

1. A block copolymer comprising a compound of Formula I:

wherein the following portion of the structure

is a poly(ethylene oxide) (PEO), wherein z is an integer such that the PEO is about 2 kD to about 10 kD in size;
wherein R′ and R″ are each CH 3 ;
wherein R′″ is an endgroup resulting from a polymerization reaction;
wherein R is NR 1 R 2 , wherein R 1 and R 2 are each independently an alkyl group and R 1 and R 2 together have 5 to 10 carbons, or wherein R 1 and R 2 join to form a ring having 5 to 10 carbons;
wherein L is a fluorescent label or a near-infrared label;
wherein x is about 20 to about 200;
wherein y is about 1 to about 6;
wherein n is about 1 to about 4;
wherein m is about 1 to about 4; and
wherein the following portion of the structure:

may be arranged in any order; wherein the block copolymer provides a micelle that has a pH transition range of less than about 0.3 pH unit and a signal response of at least about 10.

2. The block copolymer of claim 1 , wherein the poly(ethylene oxide) (PEO) is about 4 kD to about 6 kD in size.

3. The block copolymer of claim 1 , wherein the poly(ethylene oxide) (PEO) is about 5 kD in size.

4. The block copolymer of claim 1 , wherein R 1 and R 2 are each independently a straight or a branched alkyl.

5. The block copolymer of claim 1 , wherein R 1 and R 2 are each independently propyl or butyl.

6. The block copolymer of claim 1 , wherein R 1 and R 2 join to form a ring having —(CH 2 ) 5 — or —(CH 2 ) 6 —.

7. The block copolymer of claim 1 , wherein the fluorescent label is tetramethyl rhodamine (TMR).

8. The block copolymer of claim 1 , wherein the near-infrared (NIR) label is a cypate or a cypate analog.

9. The block copolymer of claim 1 , wherein x is about 40 to about 100 in total.

10. The block copolymer of claim 1 , wherein y is about 3.

11. The block copolymer of claim 1 , wherein n is about 2.

12. The block copolymer of claim 1 , wherein m is about 2.

13. The block copolymer of claim 1 , wherein the block copolymer is

14. The block copolymer of claim 1 , wherein R′″ is Br, thiolate, or thioester.

15. A composition comprising a pH-sensitive micelle formed from a block copolymer comprising the structure of Formula I:

wherein the following portion of the structure

is a poly(ethylene oxide) (PEO), wherein z is an integer such that the PEO is about 2 kD to about 10 kD in size;
wherein R′ and R″ are each —CH 3 ;
wherein R′″ is an endgroup resulting from a polymerization reaction;
wherein R is —NR 1 R 2 , wherein R 1 and R 2 are each independently an alkyl group and R 1 and R 2 together have 5 to 10 carbons, or wherein R 1 and R 2 join to form a ring having 5 to 10 carbons;
wherein L is a fluorescent label or a near-infrared label;
wherein x is about 20 to about 200;
wherein y is about 1 to about 6;
wherein n is about 1 to about 4;
wherein m is about 1 to about 4;
wherein the following portion of the structure:

may be arranged in any order; and
a carrier; wherein the micelle has a pH transition range of less than about 0.3 pH unit and a signal response of at least about 10.

16. A method of imaging a tumor in an individual in need thereof, comprising (a) administering to the individual a composition comprising a pH-sensitive micelle formed from a block copolymer comprising the structure of Formula I:

wherein the following portion of the structure

is a poly(ethylene oxide) (PEO), wherein z is an integer such that the PEO is about 2 kD to about 10 kD in size;
wherein R′ and R″ are each —CH 3 ;
wherein R′″ is an endgroup resulting from a polymerization reaction;
wherein R is —NR 1 R 2 , wherein R 1 and R 2 are each independently an alkyl group and R 1
and R 2 together have 5 to 10 carbons, or wherein R 1 and R 2 join to form a ring having 5 to 10 carbons;
wherein L is a fluorescent label or a near-infrared label;
wherein x is about 20 to about 200;
wherein y is about 1 to about 6;
wherein n is about 1 to about 4;
wherein m is about 1 to about 4;
wherein the following portion of the structure:

may be arranged in any order; wherein the micelle has a pH transition range of less than about 0.3 pH unit and a signal response of at least about 10; and
(b) measuring emission level of the fluorescent label or a near-infrared label.

Assignees

• Univ Texas

Inventors

• Gao Jinming
• Boothman David
• Zhou Kejin
• Huang Xiaonan
• Wang Yiguang

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title

• A61K31/337

  having four-membered rings, e.g. taxol · CPC title

• C08F2438/01

  Atom Transfer Radical Polymerization [ATRP] or reverse ATRP · CPC title