Brush amphiphilic block copolymers, and self-assembled nanoparticles therefrom

Patent metadata

Field	Value
Publication number	US-10774169-B2
Application number	US-201715646630-A
Country	US
Kind code	B2
Filing date	Jul 11, 2017
Priority date	Jul 11, 2016
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

The present application relates to brush amphiphilic block copolymers comprising at least one block which is hydrophilic and at least another block which is hydrophobic. The block copolymers can be used to prepare nanoparticles for biomedical applications including delivery of pharmaceuticals and other bioactive agents

First claim

The invention claimed is:

1. A brush amphiphilic block copolymer, comprising
a) at least one hydrophilic block comprising between 2 and 1000 monomeric units of:

wherein
R 1 is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl;
R 2 is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
(i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycles, or triazoles;

Z is O, NR′ or S;
R′ is H or (C 1 -C 6 )-alkyl; and
n is 0 or at least 2;
b) at least one hydrophobic block comprising between 2 and 1000 monomeric units of

wherein
R 3 is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl;
L is a linker;
Q is a hydrophobic polymer or copolymer; and
R 5 is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
(i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycles or triazoles.

2. The brush amphiphilic block copolymer of claim 1 , wherein R 1 is H or (C 1 -C 3 )-alkyl, optionally substituted with —COOH.

3. The brush amphiphilic block copolymer of claim 1 , wherein R 2 is H, (C 1 -C 6 )-alkyl, (C 6 )-aryl, (C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkylene-(C 6 )-aryl, the latter four groups are
(i) are optionally substituted with (C 1 -C 3 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle.

4. The brush amphiphilic block copolymer of claim 1 , wherein n is an integer between 2 and 50.

5. The brush amphiphilic block copolymer of claim 1 , wherein the monomeric units of the hydrophilic block has the structure

wherein R 1 is H or (C 1 -C 6 )-alkyl.

6. The brush amphiphilic block copolymer of claim 1 , wherein the hydrophobic polymer or copolymer is a polyurethane, polythiourethane, polyether, polyamide, polyester, polyphosphazine, polyphosphamide, polyphosphodiester, polyureas, polythiourea, polyfumurates, or polyanhydride.

7. The brush amphiphilic block copolymer of claim 1 , wherein the linker L is (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups
(i) are optionally substituted with halo, OH, COOH, or (C 1 -C 6 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer, heterocycle or triazoles.

8. The brush amphiphilic block copolymer of claim 1 , wherein the at least one hydrophobic block comprises monomeric units of

wherein
R 3 is H or (C 1 -C 6 )-alkyl, optionally substituted with —COOR or —CON(R) 2 , wherein R is independently or simultaneously H or (C 1 -C 6 )-alkyl;
each R 4 is independently or simultaneously H, OH, COOH, (C 1 -C 10 )-alkyl, or aryl, wherein the latter two groups may optionally contain functional groups which are esters, acids, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfonamides, sulfones, sulfonates, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle;
R 5 is H, (C 1 -C 20 )-alkyl, (C 2 -C 24 )-alkenyl, (C 2 -C 24 )-alkynyl, (C 6 -C 14 )-aryl, (C 5 -C 14 )-heteroaryl, or (C 1 -C 10 )-alkylene-(C 6 -C 14 )-aryl, wherein the latter 6 groups:
(i) are optionally substituted with halo, OH, or (C 1 -C 6 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with O, NR′, or C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or triazoles;

L is a linker;
X and Y are independently or simultaneously O, NR′ or S;
W is O or NR′;
R′ is H or (C 1 -C 6 )-alkyl;
each p is independently or simultaneously 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and
m is at least 2.

9. The brush amphiphilic block copolymer of claim 1 , wherein R 3 is H or (C 1 -C 3 )-alkyl, optionally substituted with —COOH.

10. The brush amphiphilic block copolymer of claim 1 , wherein R 5 is H, (C 1 -C 6 )-alkyl, (C 6 )-aryl, (C 5 -C 6 )-heteroaryl, or (C 1 -C 3 )-alkylene-(C 6 )-aryl, the latter four groups are
(i) are optionally substituted with (C 1 -C 3 )-alkyl;
(ii) 1-3 carbon atoms are optionally replaced with C(═O); and/or
(iii) optionally contain one or more functional groups comprising esters, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amines, disulfides, sulfone, sulfonate, phosphoesters, phosphoramidates, phosphazenes, a hydrophilic or hydrophobic polymer and/or a heterocycle.

11. The brush amphiphilic block copolymer of claim 8 , wherein each R 4 is independently or simultaneously H, (C 1 -C 6 )-alkyl, or (C 6 -C 14 )-aryl, wherein the latter two groups may optionally contain esters, acids, thioesters, amides, ureas, thioureas, carbonates, carbamates, thiocarbamates, ethers, thioethers, primary, secondary, tertiary and/or quaternary amin

Assignees

• Univ Mcmaster

Inventors

• Sadowski Lukas
• Hoare Todd
• Luo Haiming (Daniel)
• Badv Maryam

Classifications

• A61K9/5138 Primary

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K31/704

  attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} · 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

• C08F293/005

  using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent · CPC title