Magnetic resonance imaging with fluorocarbons encapsulated in a cross-linked polymeric shell

• US 5,362,478 A
• Filed: 03/26/1993
• Issued: 11/08/1994
• Est. Priority Date: 03/26/1993
• Status: Expired due to Term

• Current Assignee: Abraxis Bioscience LLC (Bristol-Myers Squibb Company)
• Original Assignee: Vivorx Pharmaceuticals Incorporated
• Inventors: Soon-Shiong, Patrick, Desai, Neil P., Grinstaff, Mark W., Suslick, Kenneth S., Sandford, Paul A.
• Primary Examiner(s): Hollinden, Gary E.
• Application Number:
  US08/035,150
• Time in Patent Office: 592 Days
• Field of Search: 424/9, 436/173, 436/806, 128/653.4, 128/654, 514/12, 514/54, 514/57, 514/59
• US Class Current: 424/9.322
• CPC Class Codes: A61K 47/6921 the form being a particulate, a powder, an adsorbate, a bead or a sphere
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/186 the organic macromolecular compound being polyethyleneglycol [PEG]
• CPC Class Codes: A61K 49/1863 the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
• CPC Class Codes: A61K 49/1869 coated or functionalised with a protein being an albumin, e.g. HSA, BSA, ovalbumin
• CPC Class Codes: A61K 49/222 characterised by a special physical form, e.g. emulsions, liposomes
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• 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

In accordance with the present invention, compositions comprising fluorine-containing magnetic resonance imaging agent(s) contained within polymeric shells are provided. Invention compositions are useful, for example, as contrast agents for magnetic resonance imaging (MRI). Fluorinated compounds in general are hydrophobic and as such have limited water solubility; thus the invention method permits preparation of such compounds in a biocompatible form suitable for ready delivery. The shell diameter is typically approximately 2 microns in diameter. Consequently, these materials have organ specificity due to rapid scavenging by the reticuloendothial system (RES) or the mononuclear phagocyte (MNP) system upon intravenous injection. Furthermore, fluorocarbon filled polymeric shells of the invention can be used to measure and monitor local oxygen and temperature.

Claims

1. A composition for obtaining in vivo fluorine magnetic resonance images, said composition comprising fluorine-containing magnetic resonance imaging agent(s) substantially completely contained within a polymeric shell;

wherein said polymeric shell comprises a biocompatible naturally occurring polymer which is substantially crosslinked by way of disulfide bonds,

wherein said biocompatible naturally occurring polymer, prior to crosslinking, has covalently attached thereto sulfhydryl groups or disulfide groups.

2. A composition according to claim 1 wherein said fluorine-containing magnetic resonance imaging agent is selected from:

(a) C_x F_2x+y-z A_z, wherein;

x=1-30,

y=2;

or 0 or -2, when x≧

2;

or -4 when x≧

4,

z=any whole number from 0 up to (2x+y-1), and

A is selected from H, halogens other than F, --CN, --OR, wherein R is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl, fluoroalkynyl, aryl, fluoroaryl, alkanoyl, fluoroalkanoyl, alkenoyl, fluoroalkenoyl, alkynoyl, fluoroalkynoyl,

(b) [C_x F_2x+y'"'"'-z A_z ]_a JR_b-a, wherein;

x, z, A and R are as defined above,

y'"'"'=+1;

or -1 or -3, when x≧

2;

or -5 when x≧

4,

J=O, S, N, P, Al or Si,

a=1, 2, 3, or 4, and

b=2 for a divalent J, or 3 for a trivalent J, or 4 for a tetravalent J,

(c) A'"'"'--[(CF₂)_x --O]_c --A", wherein;

x is as defined above,

A'"'"' is selected from H, halogens, --CN, --OR, wherein R is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl, fluoroalkynyl, aryl, fluoroaryl, alkanoyl, fluoroalkanoyl, alkenoyl, fluoroalkenoyl, alkynoyl, fluoroalkynoyl,

A" is selected from H or R, wherein R is as defined above,

c=1-300, or

(d) ##STR2## wherein;

x is as defined above, and

c'"'"'=2-20,

as well as mixtures of any two or more thereof.

3. A composition according to claim 1 wherein said composition is capable of undergoing a change in relaxation rate due to changes in the local oxygen concentration, and is therefore useful for the in vivo determination of local oxygen concentrations.

4. A composition according to claim 1 wherein said composition is capable of undergoing a solid to liquid phase transition in the temperature range of about 22 up to 55°

C., and is therefore useful for the in vivo determination of local temperature.

5. A composition according to claim 1 wherein said biocompatible naturally occurring polymer is selected from proteins containing sulfhydryl groups and/or disulfide groups, polypeptides containing sulfhydryl groups and/or disulfide groups, polynucleic acids containing sulfhydryl groups and/or disulfide groups, or polysaccharides containing sulfhydryl groups and/or disulfide groups.

6. A composition according to claim 1 wherein the disulfide bonds on the crosslinked polymer are formed by ultrasonic irradiation.

7. A composition according to claim 1 wherein said biocompatible naturally occurring polymer is albumin.

8. A composition according to claim 1 wherein said polymeric shell containing agent therein is suspended in a biocompatible aqueous liquid.

9. A composition according to claim 8 wherein said biocompatible aqueous liquid is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of sugars, solutions of vitamins, solutions of carbohydrates, or combinations of any two or more thereof.

10. A composition according to claim 1 wherein said agent is contained within said shell neat.

11. A composition according to claim 1 wherein said agent within said shell is dissolved or suspended in a biocompatible dispersing agent.

12. A composition according to claim 11 wherein said biocompatible dispersing agent is selected from soybean oil, mineral oil, corn oil, rapeseed oil, coconut oil, olive oil, safflower oil, cotton seed oil, aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms, aliphatic or aromatic alcohols having 2-30 carbon atoms, aliphatic or aromatic esters having 2-30 carbon atoms, alkyl, aryl, or cyclic ethers having 2-30 carbon atoms, alkyl or aryl halides having 1-30 carbon atoms, optionally having more than one halogen substituent, ketones having 3-30 carbon atoms, polyalkylene glycol, or combinations of any two or more thereof.

14. A method to obtain in vivo magnetic resonance images by administering to a subject a composition as described in claim 1.

15. A method for the delivery of fluorine-containing magnetic resonance imaging agents to a subject, said method comprising administering to said subject an effective amount of composition according to claim 1.

13. A composition for in vivo delivery of fluorine-containing magnetic resonance imaging agent,

wherein said agent is a solid or liquid, and is substantially completely contained within a polymeric shell,

wherein the largest cross-sectional dimension of said shell is no greater than about 10 microns,

wherein said polymeric shell comprises a biocompatible polymer which is substantially crosslinked by way of disulfide bonds, and

wherein said polymeric shell containing agent therein is suspended in a biocompatible aqueous liquid.

16. A composition for obtaining in vivo fluorine magnetic resonance images, said composition comprising fluorine-containing magnetic resonance imaging agent(s) substantially completely contained within a polymeric shell;

wherein said polymeric shell comprises lipid(s) containing sulfhydryl groups and/or disulfide groups which is substantially crosslinked by way of disulfide bonds,

wherein said lipid, prior to crosslinking, has covalently attached thereto sulfhydryl groups or disulfide groups.