Imageable polymers, methods of making and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11382990-B2
Application number	US-201716349458-A
Country	US
Kind code	B2
Filing date	Oct 31, 2017
Priority date	Nov 16, 2016
Publication date	Jul 12, 2022
Grant date	Jul 12, 2022

Abstract

Described herein are X-ray imageable polymers such as polymeric particles comprising bismuth as a radiopacifying agent, methods of making the polymers, and methods of using the polymers. The imageable particles may comprise a covalently bound compound which chelates the bismuth, for example, through a combination of nitrogen and oxygen atoms.

First claim

The invention claimed is:

1. An imageable bismuth particle comprising
a hydrophilic polymer particle having an average largest diameter of 40 to 700 μm, and comprising a covalently bound compound of Formula (1) or Formula (2),

wherein
A is a covalent bond or a functional group,
L is a C 1-12 linking group,
in Formula (1), G is —O—, —S—, —C(═O)—, —OC(═O)—, —C(═O)O—, —NH—, ═N—, —N═N—, or —S(═O) 2 —,
in Formula (2), G is a functional group,
provided that in Formula (1), when n is 1, then G is —O—, —S—, —C(═O)—, ═N—, —N═N—, or —S(═O) 2 —,
n is an integer corresponding to one less than the valence of L, and is 1 to 6, and
*is a point of covalent attachment to the polymer particle.

2. The imageable bismuth particle of claim 1 , wherein the hydrophilic polymer particle is spherical.

3. The imageable bismuth particle of claim 1 , wherein the hydrophilic polymer particle comprises polyvinyl alcohol, polyvinyl acetal, carboxymethylcellulose, hydroxyethylcellulose, polyacrylic acid, polyvinylpyrrolidone, polyacrylamide, poly(DL-lactide-co-glycolide), chitosan, alginate or a combination comprising at least one of the foregoing.

4. The imageable bismuth particle of claim 1 , wherein
A is a covalent bond, —C(═O)—, —N═, —N═N—, —N═N + ═N − , —(CH 2 ) p C(═O)NH—, â—(CH 2 ) p C(═O)NHC(═O)—, â—(CH 2 ) p OC(═O)—, â—(CH 2 ) p C(═O)O—, â—(CH 2 ) p NH—, â—(CH 2 ) p N═, â—(CH 2 ) p N═N—, or â—(CH 2 ) p NHC(═O)O—, wherein A indicates a bond to the nitrogen and p is 1 to 6,
L is a linking group having a valence of n+1, and is a C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-10 aryl, C 3-11 heteroaryl, C 7-12 arylalkyl, C 7-12 alkylaryl, C 5-10 cycloalkyl, or C 3-9 heterocycloalkyl,
G is —O—, —S—, —C(═O)—, —OC(═O)—, —C(═O)O—, —NH—, ═N—, —N═N—, or —S(═O) 2 —, and
n is 1-3.

5. The imageable bismuth particle of claim 1 , further comprising a reversibly bound active agent.

6. The imageable bismuth particle of claim 1 , wherein G is —O—, —OC(═O)—, or —C(═O)O—.

7. The imageable bismuth particle of claim 1 , wherein n is 2 to 6.

8. An imageable bismuth particle comprising
a hydrophilic polymer particle having an average largest diameter of 40 to 700 μm, and comprising a covalently bound compound of Formula (1) or Formula (2),

wherein
A is a covalent bond or a functional group,
L is a C 1-12 linking group,
in Formula (1), G is —O—, —S—, —C(═O)—, —OC(═O)—, —C(═O)O—, —NH—, ═N—, —N═N—, or —S(═O) 2 —,
in Formula (2), G is a functional group,
provided that in Formula (1), when n is 1, then G is —O—, —S—, —C(═O)—, —OC(═O)—, —C(═O)O—, ═N—, —N═N—, or —S(═O) 2 —,
n is an integer corresponding to one less than the valence of L, and is 1 to 6, and
*is a point of covalent attachment to the polymer particle,
wherein the ratio of the hydrophilic polymer particle to the compound of Formula (1) or Formula (2) is 0.1:1 to 1:1 (wt/wt).

9. An imageable bismuth particle comprising a hydrophilic polymer particle having an average largest diameter of 40 to 700 μm, and comprising a covalently bound compound of Formula (1a) or Formula (2a)

wherein
A is a covalent bond or a functional group,
R 1 is a bond or a C 1-11 divalent linking group, A is a covalent bond, —C(═O)—, —N═, —N═N—, — − N═N + ═N − , â—(CH 2 ) p C(═O)NH—, â—(CH 2 ) p C(═O)NHC(═O)—, â—(CH 2 ) p OC(═O)—, —(CH 2 ) p C(═O)O—, â—(CH 2 ) p NH—, â—(CH 2 ) p N═, â—(CH 2 ) p N═N—, or â—(CH 2 ) p NHC(═O)O—, wherein â indicates a bond to the nitrogen and p is 1 to 6, and is a point of covalent attachment to the polymer particle.

10. The imageable bismuth particle of claim 9 , wherein R 1 is a C 1-10 alkylene, C 2-10 alkenylene, C 6-10 arylene, C 3-11 heteroarylene, C 7-11 alkylenearylene, C 7-11 arylenealkylene, C 5-10 cycloalkylene, or C 3-9 heterocycloalkylene.

11. The imageable bismuth particle of claim 10 , wherein
A is a bond, —C(═O)—, or —CH 2 C(═O)O—, and
R 1 is a C 1-10 alkylene, C 6-10 arylene, or C 7-11 alkylenearylene.

12. The imageable bismuth particle of claim 11 , wherein the compound of Formula (1a) or Formula (2a) is

wherein n is 1 to 10,

13. A method of making the imageable bismuth particle of claim 1 , the method comprising
reacting a hydrophilic polymer precursor particle with a cyclen compound of Formula (3) or azanyl compound of Formula (4)

under conditions effective to covalently bind the compound of Formula (3) or Formula (4) to the particle to provide a modified particle, wherein FG is a functional group reactive with a functional group of the hydrophilic polymer precursor particle, and
adding a bismuth compound to the modified particle under conditions effective to chelate the bismuth compound to the covalently bound compound of Formula (3) or Formula (4) to provide the imageable bismuth particle.

14. A method of making the imageable bismuth particle of claim 1 , the method comprising
reacting a hydrophilic polymer precursor particle with a bismuth-cyclen complex of Formula (5) or a bismuth-azanyl complex of Formula (6)

under conditions effective to covalently bind the compound of Formula (5) or Formula (6) to the particle to provide the imageable bismuth particle, wherein FG is a functional group reactive with a functional group of the hydrophilic polymer precursor particle.

15. A method of imaging the imageable bismuth particles of claim 1 in a subject, comprising
intraarterially administering the imageable bismuth particles, and
imaging the imageable bismuth particles in the artery of the subject.

16. The method of claim 15 , wherein intraarterial administration is performed using a catheter and/or the imageable bismuth particles are administered in a contrast agent.

17. The method of claim 15 , wherein imaging comprises dual energy CT or photon counting CT.

18. The method of claim 15 , wherein the imageable bismuth particles further comprise a reversibly bound active agent.

19. A method of treating a subject having a tumor, comprising intraarterially administering to an artery of the subject the imageable bismuth particles of claim 5 , wherein the reversibly bound active agent is a chemotherapeutic agent, and
imaging the imageable bismuth particles in the artery of the subject, wherein the reversibly bound active agent is released from the particles into the artery.

20. The method of claim 19 , wherein tumor is in the pancreas, lung, kidney, prostate, stomach, colon, head or neck of the subject.

21. The method of claim 19 , wherein the subject has an intermediate stage hepatocellular carcinoma.

Assignees

• Us Health
• The Usa As Represented By The Secretary Dhhs

Inventors

• Negussie Ayele H
• Wood Bradford Johns

Classifications

• A61L29/18

  Materials at least partially X-ray or laser opaque · CPC title

• A61K9/1635 Primary

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

• A61K49/0419 Primary

  Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K49/0409

  Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound · CPC title