Method of magnetic resonance image enhancement

• US 5,580,543 A
• Filed: 06/02/1995
• Issued: 12/03/1996
• Est. Priority Date: 01/21/1992
• Status: Expired due to Term

• Current Assignee: Pharmacyclics LLC (Abbvie Incorporated)
• Original Assignee: Pharmacyclics Incorporated (Abbvie Incorporated), Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Sessler, Jonathan L., Magda, Darren, Mody, Tarak D., Hemmi, Gregory W., Kr al, Vladimir A.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/458,267
• Time in Patent Office: 550 Days
• Field of Search: 424/9.34, 424/9.341, 424/9.35, 424/9.351, 424/9.361, 424/9.362, 424/9.363
• US Class Current: 424/9.34
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: A61K 41/0076 PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
• CPC Class Codes: A61K 47/546 Porphyrines; Porphyrine with an expanded ring system, e.g. texaphyrine
• CPC Class Codes: A61K 49/0021 the fluorescent group being a small organic molecule
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/085 conjugated systems
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 51/0485 Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
• CPC Class Codes: A61L 2/0011 using physical methods
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 2531/025 Ligands with a porphyrin ring system or analogues thereof, e.g. phthalocyanines, corroles
• CPC Class Codes: B01J 2531/23 Calcium
• CPC Class Codes: B01J 2531/26 Zinc
• CPC Class Codes: B01J 2531/27 Cadmium
• CPC Class Codes: B01J 2531/28 Mercury
• CPC Class Codes: B01J 2531/36 : Yttrium
• CPC Class Codes: B01J 2531/37 : Lanthanum
• CPC Class Codes: B01J 2531/38 : Lanthanides other than lanthanum
• CPC Class Codes: B01J 2531/72 : Manganese
• CPC Class Codes: B01J 2531/842 : Iron
• CPC Class Codes: B01J 2531/845 : Cobalt
• CPC Class Codes: B01J 2531/847 : Nickel
• CPC Class Codes: B01J 2531/96 : Water
• CPC Class Codes: B01J 31/061 : Chiral polymers
• CPC Class Codes: B01J 31/1658 : immobilised by covalent linkages, i.e. pendant complexes with optional linking groups, e.g. on Wang or Merrifield resins
• CPC Class Codes: B01J 31/1805 : the ligands containing nitrogen
• CPC Class Codes: B01J 31/1815 : with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
• CPC Class Codes: C07D 487/22 : in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Texaphyrins are provided for use as radiation sensitizers. Advantageous properties of texaphyrins for use as a radiation sensitizer include: i) a low redox potential which allows radiation-induced hydrated electrons to flow to texaphyrin rather than neutralizing hydroxyl radicals, allowing hydroxyl radicals to cause cellular damage, ii) a relatively stable texaphyrin radical that reacts readily to covalently modify neighboring molecules causing further cellular damage, iii) intrinsic biolocalization, and iv) indifference to the presence or absence of O₂. These properties allow texaphyrins to be particularly effective for treating the hypoxic areas of solid neoplasms. Methods of treatment for an individual having a neoplasm or atheroma include the use of a texaphyrin as a radiation sensitizer and as an agent for photodynamic tumor therapy, or the use of a texaphyrin for internal and for external ionizing radiation. Novel texaphyrins are provided.

Claims

1. A method of magnetic resonance image enhancement in a subject, the method comprising:

administering to the subject an effective amount of a paramagnetic texaphyrin complex-oligonucleotide conjugate; and

imaging the subject using a magnetic resonance device;

wherein the texaphyrin has structure A or B;

##STR5## wherein, M is a paramagnetic metal cation;

R₁ -R₄ and R₆ -R₉ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, aminoalkyl, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, aminoalkyl, oxyaminoalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a site-directing molecule;

where, at least one of R₁ -R₁₀ is an oligonucleotide or a couple to an oligonucleotide;

R₁₁ is alkyl, alkenyl, oxyalkyl or hydroxyalkyl having up to about 3 carbon atoms and having rotational flexibility around a first-bound carbon atom;

where R₆ and R₉ are other than hydrogen, then R₅ and R₁₀ are hydrogen or methyl;

where R₅ and R₁₀ are other than hydrogen, then R₆ and R₉ are hydrogen, hydroxyl, or halide other than iodide; and

N is zero, 1 or 2.

4. The method of claim 1 where the paramagnetic metal cation is selected from the group consisting of Mn(II), Mn(III), Fe(III) and all trivalent lanthanide metals other than La(III), Lu(III) and Pm(III).

5. The method of claim 1 where M is Gd(III).

6. The method of claim 1 where the oligonucleotide is a derivatized oligonucleotide or an oligonucleotide analog.

7. The method of claim 6 where the derivatized oligonucleotide is selected from the group consisting of methylphosphonates, phosphotriesters, phosphorothioates, and phosphoramidates.

8. The method of claim 6 where the derivatized oligonucleotide is 2'"'"'-O-substituted oligoribonucleotide.

9. The method of claim 1 where the oligonucleotide has binding specificity for localization to a treatment site.

10. The method of claim 1 where the oligonucleotide has complementary binding affinity for oncogenes.

11. The method of claim 1 where the oligonucleotide has complementary binding affinity for DNA.

12. The method of claim 1 where the oligonucleotide has complementary binding affinity for RNA.

13. The method of claim 1 where the oligonucleotide is an antisense oligonucleotide.

14. The method of claim 1 where R₁ is hydroxyalkyl, and each of R₂, R₃ and R₄ is alkyl.

15. The method of claim 1 where one of R₃, R₇ and R₈ is an oligonucleotide or a couple to an oligonucleotide.

16. The method of claim 1 where the oligonucleotide or couple to oligonucleotide is O(CH₂)_n CO-oligonucleotide where n is 1 to 7.

17. The method of claim 1 where the texaphyrin is attached to the 5'"'"' end of the oligonucleotide.

18. The method of claim 1 where the texaphyrin is attached to the 3'"'"' end of the olignucleotide.

19. The method of claim 1 where the texaphyrin is attached to the oligonucleotide at an internal position.

20. The method of claim 1 wherein R₁ is CH₂ CH₃ or CH₂ CH₂ OH;

R₂ and R₃ are CH₂ CH₃ ;

R₄ is CH₃ ;

R₅, R₆, R₉ and R₁₀ are H; and

one of R₇ and R₈ is an oligonucleotide or a couple to an oligonucleotide.

21. The method of claim 20 wherein M is Gd(III).

2. A method of detection of neoplastic tissue or atheroma in a subject, the method comprising:

administering to the subject a paramagnetic texaphyrin complex-oligonucleotide conjugate in an amount effective to enhance a magnetic resonance image of neoplastic tissue or atheroma; and

detecting neoplastic tissue or atheroma by magnetic resonance imaging of the subject;

wherein the texaphyrin has structure A or B;

##STR6## wherein, M is a paramagnetic metal cation;

R₁ -R₄ and R₆ -R₉ are independently hydrogen, halide other than iodide, hydroxyl, alkyl, aryl, haloalkyl other than iodoalkyl, nitro, formyl, acyl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, saccharide, aminoalkyl, oxyaminoalkyl, carboxy, carboxyalkyl, carboxyamidealkyl, a site-directing molecule or a couple to a site-directing molecule;

R₅ and R₁₀ are independently hydrogen, alkyl, aryl, hydroxyalkyl, oxyalkyl, oxyhydroxyalkyl, aminoalkyl, oxyaminoalkyl, carboxyalkyl, carboxyamidealkyl or a couple to a site-directing molecule;

where, at least one of R₁ -R₁₀ is an oligonucleotide or a couple to an oligonucleotide;

R₁₁ is alkyl, alkenyl, oxyalkyl or hydroxyalkyl having up to about 3 carbon atoms and having rotational flexibility around a first-bound carbon atom;

where R₆ and R₉ are other than hydrogen, then R₅ and R₁₀ are hydrogen or methyl;

where R₅ and R₁₀ are other than hydrogen, then R₆ and R₉ are hydrogen, hydroxyl, or halide other than iodide; and

N is zero, 1 or 2.

3. The method of claim 2 where the neoplastic tissue is a tumor.