Polymeric shells for medical imaging prepared from synthetic polymers, and methods for the use thereof

• US 5,512,268 A
• Filed: 06/06/1995
• Issued: 04/30/1996
• 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 (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, Patrick, Desai, Neil P., Grinstaff, Mark W., Suslick, Kenneth S., Sandford, Paul A., Merideth, Noma R.
• Primary Examiner(s): Hollinden, Gary E.
• Application Number:
  US08/486,268
• Time in Patent Office: 329 Days
• Field of Search: 424/9.322, 424/9.42, 424/9.5, 424/9.52, 436/173, 128/653.4, 128/654, 128/662.02
• 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 imaging agent(s) contained within polymeric shells are provided. Invention compositions are useful, for example, as contrast agents for magnetic resonance imaging (MRI), ultrasonography, and X-ray computer tomography. The polymeric 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, polymeric shells of the invention can be used to measure and monitor local oxygen and temperature. Exemplary contrast agents contemplated for use in the practice of the present invention include fluorinated compounds. Fluorinated compounds in general are hydrophobic and as such have limited water solubility. The invention method permits preparation of such compounds in a biocompatible form suitable for ready delivery.

Claims

1. A composition for obtaining in vivo medical diagnostic images, said composition comprising imaging agent(s) substantially completely contained within a polymeric shell;

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

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

wherein said disulfide bonds are crosslinked directly, that is, without a crosslinking agent being used.

2. A composition according to claim 1 wherein said polymeric shell further comprises polyethylene glycol covalently linked thereto.

3. A composition according to claim 1 wherein said composition is 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 phase transition.

5. A composition according to claim 4 wherein said composition is useful for imaging as well as in vivo temperature determination.

6. A composition according to claim 1 wherein said synthetic polymers are selected from synthetic polypeptides containing sulfhydryl groups and/or disulfide groups, polyvinyl alcohol modified to contain free sulfhydryl groups and/or disulfide groups, polyhydroxyethyl methacrylate modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylic acid modified to contain free sulfhydryl groups and/or disulfide groups, polyethyloxazoline modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylamide modified to contain free sulfhydryl groups and/or disulfide groups, polyvinyl pyrrolidinone modified to contain free sulfhydryl groups and/or disulfide groups polyalkylene glycols modified to contain free sulfhydryl groups and/or disulfide groups, as well as mixtures of any two or more thereof.

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

8. A composition according to claim 1 wherein the disulfide bonds on the crosslinked polymer are formed by reaction with free radicals.

9. A composition according to claim 1 wherein said imaging agent is selected from superparamagnetic or paramagnetic metal particles suspended in a biocompatible medium.

10. A composition according to claim 9 wherein said metal particle is iron, iron oxide, manganese or manganese oxide.

11. A composition according to claim 9 wherein said particles are suspended in a biocompatible fluorocarbon medium 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, alkenyl, 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=0, 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 ##STR2## wherein;

x is as defined above, and

c'"'"'=2-20, or mixtures of any two or more thereof.

12. A composition according to claim 1 wherein said magnetic resonance imaging agent is selected from gadolinium, dysprosium, or manganese metal complexes that are encapsulated within the polymeric shell.

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

14. A composition according to claim 13 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.

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

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

17. A composition according to claim 16 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 carboatoms, 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.

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

19. A method for the delivery of imaging agents to a subject, said method comprising administering to said subject an effective amount of composition according to claim 1.

20. A composition according to claim 1, wherein said imaging agent is a fluorine-containing magnetic imaging agent 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=0, 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 ##STR3## wherein;

x is as defined above, and

c'"'"'=2-20,

as well as mixtures of any two or more thereof.

21. A composition according to claim 1, wherein said images are magnetic resonance images.

22. A composition according to claim 21, wherein said imaging agent(s) are selected from ferromagnetic or superparamagnetic metal particles.

23. A composition according to claim 22, wherein said particles are dispersed in a fluorocarbon.

24. A composition according to claim 21, further comprising a positron emission tomography (PET) contrast agent.

25. A composition according to claim 24, wherein said PET contrast agent contains ¹⁸ F.

26. A composition according to claim 21, wherein said biocompatible polymer comprises an iron containing protein.

27. A composition according to claim 1, wherein said images are ultrasonic images.

28. A composition according to claim 27, wherein said imaging agent is an ultrasonic contrast agent.

29. A composition according to claim 28, wherein said ultrasonic contrast agent is a perfluorohalocarbon.

30. A composition according to claim 28, wherein said perfluorohalocarbon is selected from perfluorooctylbromide, perfluorodecalin, perfluorotripropylamine, or perfluoropentane.

31. A composition according to claim 1, wherein said images are x-ray computer tomography images.

32. A composition according to claim 31, wherein said imaging agent is a perfluorohalocarbon.

33. A composition according to claim 31, wherein said imaging agent is a brominated or iodinated fluorocarbon.

34. A composition according to claim 1, wherein said polymeric shell further comprises a fluorocarbon.

35. A composition according to claim 1, wherein said polymeric shell further comprises a ligand.

36. A composition according to claim 35, wherein said ligand is natural or synthetic.

37. A composition according to claim 36, wherein said natural ligand is selected from a sugar, carbohydrate, steroid, protein, polypeptide, neurotransmitter, or antibody.