US5679323A
Expired / Lapsed
US
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Hepatocyte-specific receptor-mediated endocytosis-type compositions
Assignee: Amag Pharmaceuticals Inc
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Filing: 1995-05-18
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Granted: 1997-10-21
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Expires: 2015-05-18
Abstract
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 of macromolecular species, including but not limited to, serum proteins, hormones, asialoglycoproteins, galactose-terminal species, polysaccharides, arabinogalactan, or conjugates of these molecules with other polymeric substances such as a poly(organosilane) and dextran. One of the advantages of 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.
Inventors
- 👤 Edward T. Menz
- 👤 Lee Josephson
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 21:36
CPC Classifications
G; G01; G01R; G01R33/00; G01R33/20; G01R33/44; G01R33/48; G01R33/54; G01R33/56; G01R33/5601; A; A61; A61K; A61K49/00; A61K49/06; A61K49/18; B; B82; B82Y; B82Y5/00; C; C08; C08G; C08G18/00; C08G18/06; C08G18/08; C08G18/16; C08G18/161; C08G18/163; C08G18/165; C08G18/18; C08G18/1808; C08G18/1816; C08G18/1825; C08G18/20; C08G18/2009; C08G18/2036; C08G18/22; C08G18/24; C08G18/244; C08G18/246; C08G18/26; C08G18/28; C08G18/40; C08G18/48; C08G18/4829; C08G18/50; C08G18/5021; C08G18/5024; C08J; C08J9/00; C08J9/04; C08J9/12; C08J9/14; C08J9/143; C08J9/144; C08G2101/00; C08J2375/00; C08J2375/04; Y; Y10; Y10S; Y10S436/00; Y10S436/806; Y10T; Y10T436/00; Y10T436/24
Claims Analysis
Total Claims: 35
Claim 1
Independent Claim
42 words
A composition of matter which comprises of arabinogalactan modified to incorporate a diagnostic label, which arabinogalactan is capable of being recognized and internalized by hepatocytes of the liver by receptor-mediated endocytosis, thereby making said composition capable of being internalized by such hepatocytes.
Claim 2
Dependent Claim
42 words
A composition of matter which comprises of arabinogalactan modified to incorporate a diagnostic label, which arabinogalactan is capable of being recognized and internalized by hepatocytes of the liver by receptor-mediated endocytosis, thereby making said composition capable of being internalized by such hepatocytes.
Claim 3
Dependent Claim
12 words
The composition of claim 1 in which said label comprises a radioisotope.
Claim 4
Dependent Claim
22 words
The composition of claim 1 in which said label comprises a metallic species selected from the group consisting of gallium-67 and technetium-99m.
Claim 5
Dependent Claim
11 words
The composition of claim 1 in which said label comprises iodine-123.
Claim 6
Dependent Claim
57 words
The composition of claim 1 in which said label comprises a biodegradable colloidal superparamagnetic metal oxide particle, which metal oxide particle is capable of being biodegraded in a subject, as evidenced by a return of proton relaxation rates to preadministration levels, within 30 days of administration and comprises one or more individual biodegradable superparamagnetic metal oxide crystals.
Claim 7
Dependent Claim
25 words
The composition of claim 5 in which said colloid has an overall mean diameter of about 3000 angstroms or less, as measured by light scattering.
Claim 8
Dependent Claim
25 words
The composition of claim 5 in which said colloid has an overall mean diameter of about 1000 angstroms or less, as measured by light scattering.
Claim 9
Dependent Claim
14 words
The composition of claim 1 in which said composition is an MRI contrast agent.
Claim 10
Dependent Claim
15 words
The composition of claim 1 in which said diagnostic label is a paramagnetic metal ion.
Claim 11
Dependent Claim
21 words
The composition of claim 9 in which said paramagnetic metal ion is selected from the group consisting of iron and gadolinium.
Claim 12
Independent Claim
217 words
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, 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: is capable of being recognized and internalized by hepatocytes of the liver by receptor mediated endocytosis, thereby permitting said metal oxide particles to be internalized by such hepatocytes, and is selected from the group consisting of (i) arabinogalactan, and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is arabinogalactan, 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.
Claim 13
Independent Claim
217 words
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, 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: is capable of being recognized and internalized by hepatocytes of the liver by receptor mediated endocytosis, thereby permitting said metal oxide particles to be internalized by such hepatocytes, and is selected from the group consisting of (i) arabinogalactan, and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is arabinogalactan, 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.
Claim 14
Dependent Claim
19 words
The method according to claim 11 in which said contrast agent is employed in combination with a receptor-blocking agent.
Claim 15
Dependent Claim
28 words
The method according to claim 11 in which said metal oxide particles have an overall mean diameter of about 2000 angstroms or less, as measured by light scattering.
Claim 16
Dependent Claim
28 words
The method according to claim 11 in which said metal oxide particles have an overall mean diameter of about 1000 angstroms or less, as measured by light scattering.
Claim 17
Dependent Claim
12 words
The method according to claim 11 in which said ligand is arabinogalactan.
Claim 18
Dependent Claim
20 words
The method according to claim 11 in which the second macromolecular species of the macromolecular species conjugate is a carbohydrate.
Claim 19
Dependent Claim
12 words
The method according to claim 16 in which said carbohydrate is dextran.
Claim 20
Dependent Claim
20 words
The method according to claim 11 in which the second macromolecular species of the macromolecular species conjugate is an organosilane.
Claim 21
Dependent Claim
23 words
The method according to claim 18 in which said organosilane is selected from the group consisting of 3-aminopropyltrimethoxysilane, p-aminophenyltrimethoxysilane, N-2-aminoethyl-3-aminopropyltrimethoxysilane, n-dodecyltriethoxysilane, and n-hexyltrimethoxysilane.
Claim 22
Dependent Claim
17 words
The method according to claim 11 in which the metal of said metal oxide particles is iron.
Claim 23
Dependent Claim
155 words
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 relaxation rates of the liver to preadministration levels, within 30 days of administration; and wherein such ligand: is capable of being recognized and internalized by hepatocytes of the liver by receptor mediated endocytosis, thereby making said metal oxide particles capable of being internalized by such hepatocytes, and is selected from the group consisting of (i) arabinogalactan, and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is arabinogalactan, and a second macromolecular species which is physically or chemically joined with the metal oxide particles and conjugated to the first macromolecular species.
Claim 24
Dependent Claim
155 words
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 relaxation rates of the liver to preadministration levels, within 30 days of administration; and wherein such ligand: is capable of being recognized and internalized by hepatocytes of the liver by receptor mediated endocytosis, thereby making said metal oxide particles capable of being internalized by such hepatocytes, and is selected from the group consisting of (i) arabinogalactan, and (ii) a macromolecular species conjugate, which macromolecular species conjugate comprises two macromolecular species, a first macromolecular species which is arabinogalactan, and a second macromolecular species which is physically or chemically joined with the metal oxide particles and conjugated to the first macromolecular species.
Claim 25
Dependent Claim
16 words
The composition of claim 21 in which the metal of said metal oxide particles is iron.
Claim 26
Dependent Claim
28 words
The composition of claim 22 in the molar ratio of galactose moieties of arabinogalactan to iron is not less than about 0.0001 and not greater than about 1.0.
Claim 27
Dependent Claim
32 words
The composition of claim 21 which is further characterized as having a distribution coefficient, D, favoring the hepatocytes of the liver over a reference organ or tissue of at least about 3.
Claim 28
Dependent Claim
32 words
The composition of claim 21 which is further characterized as having a distribution coefficient, D, favoring the hepatocytes of the liver over a reference organ or tissue of at least about 20.
Claim 29
Dependent Claim
25 words
The composition of claim 21 in which said particles have an overall mean diameter of about 2000 angstroms or less, as measured by light scattering.
Claim 30
Dependent Claim
25 words
The composition of claim 21 in which said particles have an overall mean diameter of about 1000 angstroms or less, as measured by light scattering.
Claim 31
Dependent Claim
12 words
The composition according to claim 21 in which said ligand is arabinogalactan.
Claim 32
Dependent Claim
20 words
The composition according to claim 21 in which the second macromolecular species of the macromolecular species conjugate is a carbohydrate.
Claim 33
Dependent Claim
12 words
The composition according to claim 29 in which said carbohydrate is dextran.
Claim 34
Dependent Claim
20 words
The composition according to claim 21 in which the second macromolecular species of the macromolecular species conjugate is an organosilane.
Claim 35
Dependent Claim
23 words
The composition according to claim 31 in which said organosilane is selected from the group consisting of 3-aminopropyltrimethoxysilane, p-aminophenyltrimethoxysilane N-2-aminoethyl-3-aminopropyltrimethoxysilane, n-dodecyltriethoxysilane, and n-hexyltrimethoxysilane.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-10-20 | 2001-04-21 | 2001-10-21 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-10-20 | 2005-04-21 | 2005-10-21 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-10-20 | 2009-04-21 | 2009-10-21 | $7700.00 | Window Closed / Lapsed |