Compositions and methods for the treatment of metabolic bone disorders and bone metastases

• US 20030018371A1
• Filed: 07/13/2001
• Published: 01/23/2003
• Est. Priority Date: 01/15/1999
• Status: Abandoned Application

• Current Assignee: Light Sciences Corporation
• Original Assignee: Light Sciences Corporation
• Inventors: Chen, James
• Application Number:
  US09/905,405
• Publication Number:
  US 20030018371A1
• Time in Patent Office: Days
• US Class Current: 607/88
• CPC Class Codes: A61K 41/0033 Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds ultrasound therapy per se A61N7/00
• 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 41/0071 PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis

Abstract

Methods and compositions useful for targeting and treating target tissues affected by or involved in metabolic bone disorders and bone metastases with photodynamic therapy (PDT) in a mammalian subject are provided. The compositions are biphosphonates, pyrophosphates, or biphosphonate-like compounds conjugated to photosensitive agents which are optionally further conjugated to ligands which are target tissue specific antibodies, peptides, or polymers. The method of PDT treatment utilize these compositions to target the tissues or cells of a mammalian subject to be treated. The methods include irradiating at least a portion of the subject with light at a wavelength absorbed by said photosensitizing agent that under conditions of activation during photodynamic therapy using a relatively low fluence rate, but an overall high total fluence dose results in minimal collateral tissue damage.

Claims

1. A pharmaceutical composition comprising a photosensitizer agent conjugated to a compound selected from the group consisting of:

bisphosphonates;

pyrophosphonates;

thiobisphosphonates; and

nitrobisphosphonates.

2. The composition of claim 1 wherein the photosensitizer agent is selected from the group consisting of chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines, psoralens, benzoporphyrin derivatives (BPD), porfimer sodium, delta-aminolevulinic acid, protoporphyrin, indocyanine green (ICG), methylene blue, toluidine blue, texaphyrins and any other agent that absorbs light in a range of 500 nm-1100 nm.

3. The composition of claim 1 wherein the compound is a bisphosphonate of the formula

4. The composition of claim 3 wherein R¹ is hydroxyl or an amino group and R² is alkyl or aminoalkyl.

5. The composition of claim 3 wherein the compound is selected from the group consisting of etidronate, tiludronate, clodronate, pamidronate, alendronate, risedronate and ibandronate.

6. The composition of claim 1 further conjugated to a target tissue specific ligand.

7. The composition of claim 1 further conjugated to an imaging agent.

8. A method for destroying or impairing target cells involved in disease of bone tissue in a mammalian subject comprising:

administering to the subject a therapeutically effective amount of the composition of any one of claims 1 to 7, wherein said composition selectively binds the target cells or target tissues involved in the disease of bone tissue; and

irradiating at least a portion of the subject with light at a wavelength or waveband absorbed by said composition, wherein said light is provided by a light source, and wherein said irradiation is at a relatively low fluence rate that results in the activation of said composition; and

wherein said composition is cleared from non-target tissues of the subject prior to said irradiation.

9. The method of claim 8, wherein said disease of bone tissue is a metabolic bone disorder or bone metastases.

10. The method of claim 8 wherein said composition is conjugated to an imaging agent.

11. The method of claim 10 further comprising the steps of performing a nuclear medicine scan and imaging the target cells or target tissues to be destroyed or impaired.

12. The method of claim 8, wherein said composition is conjugated to a ligand that specifically binds to target cells or target tissues.

14. The method of claim 13, wherein said disease of bone is a metabolic bone disorder or bone metastases.

16. A method for destroying or impairing target cells involved in disease of bone tissue in a mammalian subject according to claim 13 or 15, wherein said compound is a bisphosphonate of the formula

17. The method according to claim 13 or 15, wherein R¹ is hydroxyl or an amino group and R² is alkyl or aminoalkyl.

18. A method according to claim 13 or 15, wherein the compound is selected from the group consisting of etidronate, tiludronate, clodronate, pamidronate, alendronate, risedronate and ibandronate.

19. A method according to claim 13 or 15, wherein the composition is conjugated to a target tissue specific ligand or an imaging agent.

22. The method of any one of claims 8-21, wherein said fluence rate results in the irradiating of said subject with a total fluence of irradiation delivered either internally or from an external light source at a range of about between 30 Joules/cm² to 25,000 Joules/cm².

23. The method of claim 22, wherein said range is between 100 Joules/cm² to 20,000 Joules/cm^2.

24. The method of claim 23, wherein said range is between 500 Joules/cm² to 10,000 Joules/cm².

13. A method for destroying or impairing target cells involved in disease of bone tissue in a mammalian subject comprising:

administering to the subject a therapeutically effective amount of a composition comprising a photosensitizer agent conjugated to a compound selected from the group consisting of;

bisphosphonates;

pyrophosphonates;

thiobisphosphonates; and

nitrobisphosphonates, wherein said composition selectively binds the target cells or target tissues involved in said disease of bone tissue; and

irradiating at least a portion of the subject with light at a wavelength absorbed by said composition, wherein said light is provided by a light source, and wherein said irradiation is at a relatively low fluence rate that results in the activation of said composition, wherein said composition is cleared from non-target tissues of the subject prior to said irradiation.

15. A method for treating a metabolic bone disorder or bone metastases in a mammalian subject comprising:

administering to the subject a therapeutically effective amount of a composition comprising

a photosensitizer agent selected from the group consisting of chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines, psoralens, benzoporphyrin derivatives (BPD), porfimer sodium, delta-aminolevulinic acid, protoporphyrin, indocyanine green (ICG), methylene blue, toluidine blue, texaphyrins and any other agent that absorbs light in a range of 500 nm-1100 nm

which is conjugated to a compound selected from the group consisting of;

bisphosphonates;

pyrophosphonates;

thiobisphosphonates; and

nitrobisphosphonates which selectively binds the target tissues or cells involved in the metabolic bone disorder or bone metastases and said composition is further conjugated to an imaging agent; and

performing a nuclear medicine scan;

imaging the target tissues or cells to be treated; and

irradiating at least a portion of the subject with light at a wavelength absorbed by said composition, wherein said light is provided by a light source, and wherein said irradiation is at a relatively low fluence rate that results in the activation of said composition, wherein said composition is cleared from non-target tissues of the subject prior to said irradiation.

20. A method for destroying or impairing target cells involved in disease of bone tissue in a mammalian subject comprising:

administering to the subject a therapeutically effective amount of a composition comprising a photosensitizer agent, wherein said agent is selected from the group consisting of chlorins, bacteriochlorins, phthalocyanines, porphyrins, purpurins, merocyanines, psoralens, benzoporphyrin derivatives (BPD), porfimer sodium, delta-aminolevulinic acid, protoporphyrin, indocyanine green (ICG), methylene blue, toluidine blue, texaphyrins and any other agent that absorbs light in a range of 600 nm-1100 nm, and wherein said agent is conjugated to a compound selected from the group consisting of;

bisphosphonates;

pyrophosphonates;

thiobisphosphonates; and

nitrobisphosphonates; and

wherein said composition selectively binds the target cells or target tissues involved in said disease of bone tissue; and

irradiating at least a portion of the subject with light at a wavelength absorbed by said composition, wherein said light is provided by a light source, and wherein said irradiation is at a relatively low fluence rate that results in the activation of said composition; and

wherein said composition is cleared from non-target cells or non-target tissues of the subject prior to said irradiation.

21. The method of claim 20, wherein said disease of bone tissue is a metabolic bone disorder or bone metastases.