General Electric Company

Brian James Grimmond

Michael James Rishel

Rong Zhang

Michael Todd Luttrell

Jeannette Christine Roberts

Jeannette Christine DePuy

Patrick Joseph McCloskey

Slawomir Rubinsztajn

Bruce Allan Hay

Egidijus Edward Uzgiris

Brian Christopher Bales

Margaret Louise Blohm

Warren William Reilly

Mohan Mark Amaratunga

Bahram Moasser

Daniel Eugene Meyer

Mary Elizabeth Spilker

David Cheney deMoulpied

Zhebo Ding

Bruce Allen Hay

Jeannette Christine Depuy

A method of sterilizing a nanoparticle preparation at a high temperature is provided. A plurality of nanoparticles are purified to form the preparation, wherein the nanoparticles comprise at least a core and a shell and the shell comprises one or more ligand species attached to the core. The nanoparticle preparation is made by a purified nanoparticle composition, a carrier fluid and an excess of the one or more ligand species not attached to the core. The ligand species attached to the core and the excess ligand species added after purification are structurally identical. The nanoparticle preparation provided by the present invention may be used as contrast agents in medical imaging techniques such as X-ray and magnetic resonance imaging.

Heat stable nanoparticle preparations and associated methods thereof

A contrast agent composition and a method of diagnostic imaging are provided. The composition comprises a pharmaceutically acceptable carrier and a metal-complex comprising a ligand having structure (XXX): wherein R, R, R, R, R, R', R&#x2032;, R&#x2032;, R&#x2032; and R&#x2032; are selected form hydrogen, a protected C-Chydroxyalkyl group, or a C-Calkyl group; R, R&#x2032;are selected from a hydrogen, a hydroxyl, a protected hydroxyl group, a protected C-Chydroxyalkyl group, a C-Calkyl group; n is an integer between 0 and 4; R, R&#x2032;are selected from a hydrogen, a protecting group comprising C-Caliphatic radicals, C-Ccycloaliphatic radicals, C-Caromatic radicals, m is an integer between 1 and 10; at least one of Rand R&#x2032;is acidic groups or protected acidic groups; Y comprises a protein or peptide moiety, a particle, a micelle, a liposome, an organic molecule, oligomer, polymer or a hydrophilic moiety.

Contrast enhancement agents and method of use thereof

A method of diagnostic imaging is disclosed comprising administering a medical formulation to a subject, the formulation comprising a contrast enhancement agent having structure I and salts thereof wherein Ris independently at each occurrence a hydroxy group, a C-Chydroxyalkyl group, or a C-Calkyl group, and b is 0-4; R-Rare independently at each occurrence hydrogen, a C-Chydroxyalkyl group, or a C-Calkyl group, with the proviso that at least one of R-Ris a hydroxy group or a C-Chydroxyalkyl group; and wherein Q is one or more charge balancing counterions; and one or more pharmaceutically acceptable carriers and excipients. The subject is subjected to a diagnostic imaging technique such as magnetic resonance imaging. The technique may be used in a variety of diagnostic imaging regimes, such as imaging of circulatory systems, genitourinary systems, hepatobiliary systems, central nervous systems, tumors, and abscesses among others.

Hydroxylated contrast enhancement agents and imaging method

In one aspect, the present invention provides a contrast enhancement agent comprising an iron chelate having structure I and salts thereof wherein Ris independently at each occurrence a hydroxy group, a C-Chydroxyalkyl group, or a C-Calkyl group, and b is 0-4; R-Rare independently at each occurrence hydrogen, a C-Chydroxyalkyl group, or a C-Calkyl group, with the proviso that at least one of R-Ris a hydroxy group or a C-Chydroxyalkyl group; and wherein Q is one or more charge balancing counterions. Also provided are a metal chelating ligand having structure IX and medical formulations comprising the contrast enhancement agent I.

Hydroxylated contrast enhancement agents

In one aspect, the present invention provides a contrast enhancement agent comprising an iron chelate having structure I wherein Ris independently at each occurrence a hydroxy group, a C-Chydroxyalkyl group, or a C-Calkyl group, and b is 0-4; R-Rare independently at each occurrence hydrogen, a C-Chydroxyalkyl group, or a C-Calkyl group, with the proviso that at least one of R-Ris a hydroxy group or a C-Chydroxyalkyl group; and wherein Q is a charge balancing counterion. Also provided is a metal chelating ligand having structure IX and medical formulations comprising the contrast enhancement I.

In one aspect, the present invention provides a protected ligand precursor having structure XX wherein Ris independently at each occurrence a protected hydroxy group, a protected C-Chydroxyalkyl group, or a C-Calkyl group, and b is 0-4; R-Rare independently at each occurrence hydrogen, a protected C-Chydroxyalkyl group, or a C-Calkyl group, with the proviso that at least one of R-Ris a protected hydroxy group or a protected C-Chydroxyalkyl group; and Rand Rare independently at each occurrence a protecting group is selected from the group consisting of C-Caliphatic radicals, C-Ccycloaliphatic radicals, and C-Caromatic radicals.

Intermediates for hydroxylated contrast enhancement agents

Provided herein are chelator-functionalized nanoparticles comprising a passive core; and an active coating that demonstrate T1 magnetic resonance pattern upon exposure to a magnetic field. Also provided are methods of making such chelator-functionalized nanoparticles as well as imaging methods using the nanoparticles.

Chelator-functionalized nanoparticles

A method of conjugating a carboxylate-containing molecule to an amine-containing macromolecule to form a substituted macromolecule is provided. The method includes (a) forming a first solution by dissolving a substance comprising at least one macromolecule having free amine groups in an aqueous basic solution; (b) forming a second solution by combining at least one carboxylate-containing molecule with at least one acid acceptor in an aprotic solvent; (c) adding at least one carboxylate activating agent to the second solution to form an activated carboxylate-containing molecule; (d) combining the first solution and second solutions to form a multiphasic solution; and (e) isolating the resultant substituted macromolecule from the mixture. A substituted macromolecule produced by the aforementioned method is also provided. Further provided is a method of enhancing a magnetic resonance image of a subject including administering the carboxylate-containing molecule-substituted macromolecule produced by the aforementioned method.

Conjugated macromolecules

A method for synthesizing extended poly(amino acids) conjugated to imaging agents, such as DTPA, is disclosed. The amino acid is initially conjugated to the imaging agent at the monomer stage, followed by formation of the corresponding N-carboxyanhydride. The method utilizes catalyzed ring opening polymerization of the N-carboxyanhydride of the amino acid-imaging agent monomer allowing the formation of a poly(amino acid) backbone having 100% imaging agent conjugation if desired. However, the present method also permits the degree of conjugation to be controlled by copolymerizing the N-carboxyanhydride of the amino acid-imaging agent monomer with one or more unconjugated monomers, i.e. N-carboxyanhydrides of the same or of other amino acids. Various imaging agents may be employed, and new hybrid random, block, and mixed copolymers may be prepared.

Polymerization method for the synthesis of polypeptide imaging agents

Mixed alkali metal salts of phosphoric acid in combination with a co-catalyst such as tetramethylammonium hydroxide (TMAH) are excellent transesterification catalysts for use in the preparation of polycarbonate from bisphenol A and diphenyl carbonate. The mixed alkali metal phosphate salts were shown by kinetic measurements made on a model system composed of p-tert-octylphenol and bis(p-cumylphenyl) carbonate to be inherently more potent catalysts than salts of phosphoric acid comprising a single alkali metal ion. In addition to providing higher rates of polymerization, the new catalysts were shown to provide polycarbonates containing reduced levels of Fries rearrangement product relative to polymerization reactions catalyzed by conventional catalyst systems such as sodium hydroxide together with TMAH co-catalyst.

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Clifton Park, NY, United States of America

Brian James Grimmond