# US 7,745,590 B1 · Degradable macromolecular magnetic resonance imaging contrast agents and methods thereof

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- Number: US 7,745,590 B1
- Document ID: US7745590B1
- Status: Granted
- Kind: B1
- Application number: 11/203,799
- Filed: 2005-08-15
- Granted: 2010-06-29
- Earliest claimed: 2001-11-13
- Assignees: University of Utah Research Foundation
- Inventors: Zheng-Rong Lu; Jindrich Kopecek; Dennis L. Parker
- Web page: https://patentgrep.com/patent/US7745590B1

## CPC

- A61K 49/14: Peptides, e.g. proteins
- A61K 49/128: {comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone}
- A61K 49/146: {the peptide being a polyamino acid, e.g. poly-lysine}
- A61K 49/16: Antibodies; Immunoglobulins; Fragments thereof
- C07C 323/41: Y being a hydrogen or an acyclic carbon atom
- C08G 73/0206: {Polyalkylene(poly)amines}
- C08G 73/0233: {Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups}
- C08L 79/02: Polyamines
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08L: COMPOSITIONS OF MACROMOLECULAR COMPOUNDS (compositions based on polymerisable monomers C08F, C08G; artificial filaments or fibres D01F; textile treating compositions D06)

## Abstract

Degradable macromolecular magnetic resonance imaging contrast agents for use in various diagnostic procedures, and methods for synthesizing, using and degrading these agents, are described. The macromolecule contrast agents disclosed in various aspects of this invention are degradable gadolinium compounds which show prolonged plasma retention, and enhanced permeability and retention in solid tumors, but are still capable of being rapidly cleared from the body.

## Claims

### Claim 1

A macromolecule contrast agent comprising a compound according to the following formula:
wherein R and R′ are independently selected from the group consisting of C1 to C18 alkyls, substituted alkyls, aryls, polyethylene glycol, saccharides, amino acids, peptides, proteins, peptide conjugates and protein conjugates, and combinations of at least two of alkyl, aryl, and polyethylene glycol groups;
wherein X and Y are independently selected from the group consisting of amide groups, ester groups, urea groups, thiourea groups, carbonate groups, carbamate groups, ether bonds and thioether bonds;
wherein P is selected from the group consisting of water soluble polymer chains, dendrimers, polysaccharides, peptides, proteins, polymer-peptide conjugates and polymer-protein conjugates;
wherein n is an integer between 2 and 10,000; and
wherein L is selected from the group consisting of diethylenetriaminepentaacetate (DTPA), 1,4,7,10-tetraazadodecanetetraacetate (DOTA), 1,4,7,10-tetraazadodecane-1,4,7-triacetate (DO3A), ethylenediaminetetraacetate (EDTA), 1,4,7,10-tetraazacyclotridecanetetraacetic acid (TRITA), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 1,4,7,10-tetraazadodecanetetramethylacetate (DOTMA), 1,4,7,10-tetraazadodecane-1,4,7-trimethylacetate (DO3MA), N,N′,N″,N′″-tetraphosphonatomethyl-1,4,7,10-tetraazacyclododecane (DOTP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis (methylene methylphosphonic acid) (DOTMP), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phenylphosphonic acid) (DOTPP).

### Claim 2 (depends on 1)

The macromolecule contrast agent of claim 1, wherein at least one of R and R′ comprises polyethylene glycol with a molecular weight of from about 50 Daltons to about 50,000 Daltons.

### Claim 3

A macromolecule contrast agent comprising a compound according to the following formula:
wherein R and R′ are independently selected from the group consisting of C1 to C18 alkyls, substituted alkyls, aryls, polyethylene glycol, saccharides, amino acids, peptides, proteins, peptide conjugates and protein conjugates, and combinations of at least two of alkyl, aryl, and polyethylene glycol groups;
wherein X is selected from the group consisting of amide groups, ester groups, and ether bonds;
wherein Y is selected from the group consisting of O and NH;
wherein n is an integer between 2 and 10,000; and
wherein P is selected from the group consisting of water soluble polymer chains, dendrimers, polysaccharides, peptides, proteins, polymer-peptide conjugates and polymer-protein conjugates.

### Claim 4 (depends on 3)

The macromolecule contrast agent of claim 3, wherein at least one of R and R′ comprises polyethylene glycol with a molecular weight of from about 50 Daltons to about 50,000 Daltons.

### Claim 5

A macromolecule contrast agent comprising a compound according to the following formula:
wherein R and R′ are independently selected from the group consisting of C1 to C18 alkyls, substituted alkyls, aryls, polyethylene glycol, saccharides, amino acids, peptides, proteins, peptide conjugates and protein conjugates, and combinations of at least two of alkyl, aryl, and polyethylene glycol groups;
wherein X is selected from the group consisting of amide groups, ester groups, and ether bonds;
wherein Y is selected from the group consisting of O and NH;
wherein n is an integer between 2 and 10,000; and
wherein P is selected from the group consisting of water soluble polymer chains, dendrimers, polysaccharides, peptides, proteins, polymer-peptide conjugates and polymer-protein conjugates.

### Claim 6 (depends on 5)

The macromolecule contrast agent of claim 5, wherein at least one of R and R′ comprises polyethylene glycol with a molecular weight of from about 50 Daltons to about 50,000 Daltons.

### Claim 7

A macromolecule contrast agent comprising a compound according to the following formula:
wherein R and R′ are independently selected from the group consisting of C1 to C18 alkyls, substituted alkyls, aryls, polyethylene glycol, saccharides, amino acids, peptides, proteins, peptide conjugates and protein conjugates, and combinations of at least two of alkyl, aryl, and polyethylene glycol;
wherein X is selected from the group consisting of amide groups, ester groups, and ether bonds;
wherein Y is selected from the group consisting of O and NH;
wherein n is an integer between 2 and 10,000; and
wherein P is selected from the group consisting of water soluble polymer chains, dendrimers, polysaccharides, peptides, proteins, polymer-peptide conjugates and polymer-protein conjugates.

### Claim 8 (depends on 7)

The macromolecule contrast agent of claim 7, wherein at least one of R and R′ comprises polyethylene glycol with a molecular weight of from about 50 Daltons to about 50,000 Daltons.

### Claim 9

A macromolecule contrast agent comprising a compound selected from the group consisting of compounds according to the following formulae:
wherein n is an integer between 2 and 10,000; and
wherein x is an integer between 1 and 20; and
wherein m is an integer between 0 and 10,000.

### Claim 10 (depends on 1)

A method for obtaining a magnetic resonance image of a tissue or organ of a mammal comprising administering an effective amount of one or more macromolecule contrast agents of claim 1 to the mammal and obtaining a magnetic resonance image of the tissue or organ.

### Claim 11 (depends on 10)

The method of claim 10, wherein the tissue or organ comprises the liver, spleen, lung, esophagus, bone marrow, lymph node, lymph vessels, nervous system, brain, spinal cord, blood capillaries, stomach, small intestine, or large intestine.

### Claim 12 (depends on 10)

The method of claim 10, wherein the method is performed during a medical procedure selected from the group consisting of angiography, plethysmography, lymphography, mammography, cancer diagnosis, functional MRI and dynamic MRI.

### Claim 13 (depends on 10)

The method of claim 10, wherein one or more disulfide bond reducing compounds are administered with the contrast agent.

### Claim 14 (depends on 10)

The method of claim 10, wherein the disulfide bond reducing compound is selected from the group consisting of one or more mercaptans, NADH, NADPH, hydrazines, phosphines, zinc, tin(II), sodium sulfide, performic acid, and hydrogen peroxide.

### Claim 15 (depends on 14)

The method of claim 14, wherein the mercaptan is selected from the group consisting of cysteine, glutathione, cysteinylglycine and its derivatives, 2,3-dimercaptosuccinic acid, 2,3-dimercapto-1-propanesulfonic acid and its derivatives, 2-mercaptoethanol, penicillamine and its derivatives, mercaptoacetic acid, mercaptoanisole, 2-mercaptobenzoic acid, 4-mercaptobenzoic acid, 2-mercapto-5-benzimidazolesulfonic acid, 2-mercaptobenzothiazole, 3-mercapto-iso-butyric acid, mercaptocyclohexane, 2-mercaptoethanesulfonic acid, 2-mercaptoethylamine, 2-mercaptoethylamine hydrochloride, 3-mercapto-1,2-propanediol, 3-mercapto-1-propanesulfonic acid, 3-mercapto-1-propanol, 2-mercaptopropionic acid, 3-mercaptopropionic acid, diethyldithiocarbamate, dithioerythritol, and dithioglycol.

### Claim 16 (depends on 10)

The method of claim 10, wherein the contrast agent comprises a targeting molecule.

### Claim 17 (depends on 16)

The method of claim 16, wherein the targeting molecule comprises an antibody, an antibody fragment, a peptide, or a protein.

### Claim 18 (depends on 10)

The method of claim 10, wherein two or more of macromolecule contrast agents are administered simultaneously.

### Claim 19 (depends on 10)

The method of claim 10, wherein the macromolecule contrast agent comprises a first macromolecule contrast agent and a second macromolecule contrast agent, wherein the second macromolecule contrast agent is administered after the administration of said first macromolecule contrast agent.

### Claim 20 (depends on 10)

The method of claim 10, wherein one or more contrast agents selected from the group consisting of paramagnetic metal complexes, radioactive metal complexes, proteins, DNA, and RNA, is administered in conjunction with the macromolecule contrast agent.