Receptor mediated endocytosis type magnetic resonance imaging contrast agents

• US 5,342,607 A
• Filed: 08/03/1992
• Issued: 08/30/1994
• Est. Priority Date: 07/03/1986
• Status: Expired due to Term

• Current Assignee: AMAG Pharmaceuticals, Inc. (Apollo Global Management, Inc.)
• Original Assignee: Advanced Magnetics, Inc.
• Inventors: Josephson, Lee
• Primary Examiner(s): Hollinden, Gary E.
• Application Number:
  US07/924,121
• Time in Patent Office: 757 Days
• Field of Search: 424/9, 424/646, 424/648, 424/5, 436/173, 436/806, 514/8, 514/54, 514/57, 514/60, 128/654, 128/653.4, 423/633
• US Class Current: 424/9.45
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1866 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
• CPC Class Codes: A61K 49/1869 coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C08G 18/1808 having alkylene polyamine groups
• CPC Class Codes: C08G 18/1816 having carbocyclic groups
• CPC Class Codes: C08G 18/1825 having hydroxy or primary amino groups
• CPC Class Codes: C08G 18/2036 having at least three nitrogen atoms in the ring
• CPC Class Codes: C08G 18/246 containing also tin-carbon bonds
• CPC Class Codes: C08G 18/26 of lead
• CPC Class Codes: C08G 2101/00 Manufacture of cellular products
• CPC Class Codes: C08J 2375/04 Polyurethanes
• CPC Class Codes: C08J 9/144 containing carbon, halogen and hydrogen only
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
• CPC Class Codes: Y10S 436/806 Electrical property or magnetic property
• CPC Class Codes: Y10T 436/24 Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

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 hepatocytesurf 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.

Claims

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 selected cells of a tissue or organ 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 an affected organ or tissue to preadministration levels, within 30 days of administration; and

wherein such ligand

is a macromolecule selected from the group consisting of;

(i) a low density lipoprotein, (ii) a serum protein, (iii) transferrin, (iv) a hormone, (v) a monosaccharide, (vi) a polysaccharide, (vii) insulin and (viii) a macromolecule species conjugate, which macromolecular species conjugate comprises two macromolecular species conjugated together, a first macromolecular species which is selected from one of the foregoing macromolecules, (i) through (viii), and a second macromolecular species, such second macromolecular species being physically or chemically joined with the metal oxide particles,

is recognized by a receptor other than an asialoglycoprotein receptor, and

is internalized, thereby permitting said metal oxide particles to be internalized, by selected cells of said organ or tissue by receptor mediated endocytosis; and

(b) recording such MR image.

2. The method according to claim 1 in which said metal oxide particles have an overall mean diameter of about 2000 angstroms or less, as measured by light scattering.

3. The method according to claim 1 in which said metal oxide particles have an overall mean diameter of about 1000 angstroms or less, as measured by light scattering.

4. The method according to claim 1 in which the second macromolecular species of the macromolecular species conjugate is a carbohydrate.

5. The method according to claim 4 in which said carbohydrate is dextran.

6. The method according to claim 1 in which the second macromolecular species of the macromolecular species conjugate is an organosilane.

7. The method according to claim 6 in which said organosilane is selected from the group consisting of 3-aminopropyltrimethoxysilane, p-aminophenyltrimethoxysilane, n-2-aminoethyl-3-aminopropyltrimethoxysilane, n-dodecyltriethoxysilane, and nhexyltrimethoxysilane.

8. An MRI method for diagnosing the metabolic state of an organ or tissues of a human or animal subject, which method comprise:

(a) recording a series of MR images of the organ or tissue according to the method of claim 1; and

(b) comparing said images obtained in step (a) in order to determine the degree of internalization of said contrast agent by the cells of the organ or tissue, as well as the metabolic state of the organ or tissue.

9. The method according to claim 1 or 8 in which the metal of said metal oxide particles is iron.

10. The method of claim 1 in which said ligand is selected from the group consisting of a low density lipoprotein, a serum protein, transferrin, a hormone, a monosaccharide, a polysaccharide, and insulin.

11. A composition of matter comprising (1) colloidal 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 an affected organ or tissue to preadministration levels, within 30 days of administration; and

wherein such ligand;

is a macromolecule selected from the group consisting of;

(i) a low density lipoprotein, (ii) a serum protein, (iii) transferrin (iv) a hormone, (v) a monosaccharide, (vi) a polysaccharide, (vii) insulin and (viii) a macromolecule species conjugate, which macromolecular species conjugate comprises two macromolecular species conjugated together, a first macromolecular species which is selected from one of the foregoing macromolecules (i) through (viii), and a second macromolecular species, such second macromolecular species being physically or chemically joined with the metal oxide particles,

is capable of being recognized by a receptor other than the asialoglycoprotein receptor, and

is capable of being internalized, thereby making said metal oxide particles capable of being internalized, by selected cells of said organ or tissue by receptor mediated endocytosis.

12. The composition 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.

13. The composition 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.

14. The composition according to claim 11 in which the second macromolecular species of the macromolecular species conjugate is a carbohydrate.

15. The composition according to claim 14 in which said carbohydrate is dextran.

16. The composition according to claim 11 in which the second macromolecular species of the macromolecular species conjugate is an organosilane.

17. The composition according to claim 16 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.

18. The composition according to claim 11 in which the metal of said metal oxide particles is iron.

19. The composition of claim 11 in which said ligand is selected from the group consisting of a low density lipoprotein, a serum protein, transferrin, a hormone, a monosaccharide, a polysaccharide, and insulin.