Hepatocyte specific composition and their use as diagnostic imaging agents
First Claim
1. A method for obtaining an enhanced MR image of an organ or tissue of an animal or human subject which comprises:
- (a) administering to such a subject an effective amount of a colloidal biodegradable superparamagnetic contrast agent in a physiologically acceptable medium such that an image-enhancing amount of such contrast agent can be internalized by hepatocytes of the liver by receptor mediated endocytosis, said contrast agent comprising (1) biodegradable superparamagnetic metal oxide particles, physically or chemically joined with (2) a ligand,wherein such metal oxide particles;
comprise one or more individual biodegradable superparamagnetic metal oxide crystals, andare capable of being biodegraded in such subject, as evidenced by a return of proton relaxation rates of the liver to preadministration levels, within 30 days of administration; and
wherein such ligand;
comprises a terminal galactose moiety,is recognized and internalized, thereby permitting said metal oxide particles to be internalized, by hepatocytes of the liver by receptor mediated endocytosis, and is selected from the group consisting of (i) a polysaccharide and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is a polysaccharide and a second macromolecular species which is physically or chemically joined with the metal oxide particles and conjugated to the first macromolecular species; and
(b) recording such MR image.
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Abstract
A new class of magnetic resonance (MR) contrast agents are described whose in vivo biodistribution is based upon the ability of certain cells to recognize and internalize macromolecules, including the MR contrast agents of the present invention, via a process which substantially involves receptor mediated endocytosis. The RME-type MR contrast agents described herein comprised of biodegradable superparamagnetic metal oxides associated with a variety macromolecular species, including but not limited to, serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates these molecules with other polymeric substances such as a poly(organosilane) and dextran. One of the advantages or these MR contrast agents is that they may be selectively directed to those cells which bear receptors for a particular macromolecule or ligand and are capable of undergoing receptor mediated endocytosis. An MR contrast agent prepared from biodegradable superparamagnetic iron oxide and asialofetuin, or more preferably arabinogalactan, for example, is selectively localized in the hepatocytes the liver with no significant accumulation in the spleen. An MR experiment which can be carried out shortly after administration to the subject of the contrast agents of the invention can thus provide a method for obtaining an enhanced MR image, as well as valuable information regarding the functional or metabolic state of the organ or tissue under examination. Preparative methods, biodistribution data, and time function MR images are further provided.
44 Citations
24 Claims
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1. A method for obtaining an enhanced MR image of an organ or tissue of an animal or human subject which comprises:
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(a) administering to such a subject an effective amount of a colloidal biodegradable superparamagnetic contrast agent in a physiologically acceptable medium such that an image-enhancing amount of such contrast agent can be internalized by hepatocytes of the liver by receptor mediated endocytosis, said contrast agent comprising (1) biodegradable superparamagnetic metal oxide particles, physically or chemically joined with (2) a ligand, wherein such metal oxide particles; comprise one or more individual biodegradable superparamagnetic metal oxide crystals, and are capable of being biodegraded in such subject, as evidenced by a return of proton relaxation rates of the liver to preadministration levels, within 30 days of administration; and wherein such ligand; comprises a terminal galactose moiety, is recognized and internalized, thereby permitting said metal oxide particles to be internalized, by hepatocytes of the liver by receptor mediated endocytosis, and is selected from the group consisting of (i) a polysaccharide and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is a polysaccharide and a second macromolecular species which is physically or chemically joined with the metal oxide particles and conjugated to the first macromolecular species; and (b) recording such MR image. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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13. A colloidal biodegradable superparamagnetic contrast agent, said contrast agent comprising (1) biodegradable superparamagnetic metal oxide particles, physically or chemically joined with (2) a ligand,
wherein such metal oxide particles: -
comprise one or more individual biodegradable superparamagnetic metal oxide crystals, and are capable of being biodegraded in such subject, as evidenced by a return of proton relation rates of the liver to preadministration levels within 30 days of administration; and wherein such ligand; comprises a terminal galactose moiety, where such ligand; is capable of being recognized and internalized, thereby making said metal oxide particles capable of being internalized, by hepatocytes of the liver by receptor mediated endocytosis, and is selected from the group consisting of (i) a polysaccharide, and (i) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is a polysaccharide and a second macromolecular species which is physically or chemically joined with the metal oxide particles and conjugated to the first macromolecular species. - View Dependent Claims (14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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Specification