Optical diagnostic and therapeutic agents and compositions

• US 7,767,194 B2
• Filed: 06/06/2005
• Issued: 08/03/2010
• Est. Priority Date: 01/18/2000
• Status: Expired due to Fees

• Current Assignee: MediBeacon Inc.
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Bugaj, Joseph E., Achilefu, Samuel I., Periasamy, Muthunadar P., Rajagopalan, Raghavan, Dorshow, Richard B.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US11/146,377
• Publication Number:
  US 20050271592A1
• Time in Patent Office: 1,884 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.69, 424/1.49, 424/1.73, 424/1.37, 424/9.1, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 534/7, 534 10- 16, 548/146, 514/2, 514/359, 514/430, 435/1.11, 552/502
• US Class Current: 424/9.1
• 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 49/0032 Methine dyes, e.g. cyanine dyes
• CPC Class Codes: A61K 49/0056 Peptides, proteins, polyamino acids
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C09B 23/0066 the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
• CPC Class Codes: C09B 23/0075 the polymethine chain being part of an heterocyclic ring
• CPC Class Codes: C09B 23/08 more than three >CH- groups, e.g. polycarbocyanines
• CPC Class Codes: C09B 23/086 more than five >CH- groups

Abstract

Cyanine and indocyanine dye compounds and bioconjugates are disclosed. The present invention includes several cyanine and indocyanine dyes, including bioconjugates of the same, with a variety of bis- and tetrakis (carboxylic acid) homologues. The compounds of the invention may be conjugated to bioactive peptides, carbohydrates, hormones, drugs, or other bioactive agents. The small size of compounds of the invention allows favorable delivery to tumor cells as compared to larger molecular weight imaging agents. Further, use of a biocompatible organic solvent such as dimethylsulfoxide may be said to assist in maintaining the fluorescence of compounds of the invention. The compounds and bioconjugates herein disclosed are useful in a variety of medical applications including, but not limited to, diagnostic imaging and therapy, endoscopic applications for the detection of tumors and other abnormalities, localized therapy, photoacoustic tumor imaging, detection and therapy, and sonofluorescence tumor imaging, detection and therapy.

Claims

1. A compound having the formula, wherein:

2. The compound of claim 1 wherein:

Y³ is selected from the group consisting of —

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

NR³R⁴, and CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

Z³ is selected from the group consisting of —

(CH₂)_a—

CONH-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Dm, —

(CH₂)_a—

NHCO-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Dm, —

(CH₂)_a—

NR³R⁴, and —

CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

B₁, C₁, and D₁ are independently selected from the group consisting of —

O—

, —

S—

, NR³, (CH2)_a—

CR¹R², and —

CR;

A₁, B₁, C₁, and D₁ may together form a 6- to 10-membered carbocyclic ring or a 6- to 10-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₃ and b₃ independently vary from 0 to 3;

R¹ to R⁴, and R²⁹ to R³⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyhydroxyalkyl, C₅-C₁₂ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, mono- or oligosaccharide, peptide with 2 to 30 amino acid units, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, (CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

OH and —

CH₂—

(CH₂OCH₂)_b—

CO₂H;

Bm and Dm are independently selected from the group consisting of a bioactive peptide containing 2 to 30 amino acid units, an antibody, a mono- or oligosaccharide, a glycopeptide, a metal chelating agent, a radioactive or nonradioactive metal complex, a photosensitizer, and an echogenic agent;

a and c are independently from 1 to 10; and

b and d are independently from 1 to 30.

3. The compound of claim 2 wherein:

Y³ is —

(CH₂)₂—

CONH-Bm;

Z³ is —

(CH₂)₂—

CONH-Dm;

A₁ is a single bond;

A₁, B₁, C₁, and D₁ together form a 6-membered carbocyclic ring;

each of a₃ and b₃ is 1;

R²⁹ is galactose;

each R³⁰ to R³⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin.

4. The compound of claim 1, wherein at least one of Bm and Dm is a peptide.

5. The compound of claim 4, wherein at least one of Bm and Dm is Octreotide.

6. The compound of claim 4, wherein at least one of Bm and Dm is Octreotate.

7. The compound of claim 4, wherein at least one of Bm and Dm is Bombesin.

8. The compound of claim 4, wherein at least one of Bm and Dm is Cholecystokinin.

9. The compound of claim 4, wherein at least one of Bm and Dm is Neurotensin.

10. The compound of claim 1, wherein at least one of Y³, Z³, R¹, R², R³, R⁴, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶ and R³⁷ is a constituent including Bm or Dm, wherein said Bm or Dm is selected from the group consisting of a peptide, a protein, a cell, a metal chelating agent, a radioactive or nonradioactive metal complex, a photosensitizer, and an echogenic agent.

11. The compound of claim 10 wherein at least one of Bm and Dm is a peptide.

12. The compound of claim 11 wherein at least one of Bm and Dm is Octreotide, Octreotate, Bombesin, Cholecystokinin or Neurotensin.

13. The compound of claim 11 wherein at least one of Bm and Dm is a photosensitizer.

14. The compound of claim 1 wherein at least one of Y³, Z³, R¹, R², R³, R⁴, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, R³⁵, R³⁶ and R³⁷ is a constituent including Bm, Z² is a constituent including Dm, one of Bm and Dm is a peptide, and another of Bm and Dm is a photosensitizer.

15. A diagnostic and/or therapeutic composition comprising a compound of the following general formula and at least one of a pharmaceutical carrier, excipient, and buffer, wherein:

16. The composition of claim 15 wherein:

Y³ is selected from the group consisting of —

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

NR³R⁴, and CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

Z³ is selected from the group consisting of —

(CH₂)_a—

CONH-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Dm, —

(CH₂)_a—

NHCO-Dm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Dm, —

(CH₂)_a—

NR³R⁴, and —

CH₂(CH₂OCH₂)_b—

CH₂NR³R⁴;

B₁, C₁, and D₁ are independently selected from the group consisting of —

O—

, —

S—

, NR³, (CH2)_a—

CR¹R², and —

CR₁;

A₁, B₁, C₁, and D₁ may together form a 6- to 10-membered carbocyclic ring or a 6- to 10-membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or sulfur atom;

a₃ and b₃ independently vary from 0 to 3;

R¹ to R⁴, and R²⁹ to R³⁷ are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₁₂ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyhydroxyalkyl, C₅-C₁₂ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, mono- or oligosaccharide, peptide with 2 to 30 amino acid units, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a—

CO₂H, (CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂)_a—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

OH and —

CH₂—

(CH₂OCH₂)_b—

CO₂H;

Bm and Dm are independently selected from the group consisting of a bioactive peptide containing 2 to 30 amino acid units, an antibody, a mono- or oligosaccharide, a glycopeptide, a metal chelating agent, a radioactive or nonradioactive metal complex, a photosensitizer, and an echogenic agent;

a and c are independently from 1 to 10; and

b and d are independently from 1 to 30.

17. The composition of claim 16 wherein:

Y³ is —

(CH₂)₂—

CONH-Bm;

Z³ is —

(CH₂)₂—

CONH-Dm;

A₁ is a single bond;

A₁, B₁, C₁, and D₁ together form a 6-membered carbocyclic ring;

each of a₃ and b₃ is 1;

R²⁹ is galactose;

each R³⁰ to R³⁷ is hydrogen;

Bm is Octreotate; and

Dm is bombesin.

18. The composition of claim 15, wherein at least one of Bm and Dm is a peptide.

19. The composition of claim 18, wherein the peptide is selected from the group consisting of octreotate, bombesin, cholecystokinin, and neurotensin.

20. A method of performing a diagnostic or therapeutic procedure comprising:

administering to an individual an effective amount of a composition including an compound of the following general formula, wherein;

21. The method according to claim 20, wherein the procedure comprises optical tomography.

22. The method according to claim 20, wherein the procedure comprises fluorescence endoscopy.

23. The method according to claim 20, further comprising monitoring a blood clearance profile of the bioconjugate invasively or non-invasively by fluorescence, absorbance, or light scattering.

24. The method according to claim 20 further comprising imaging or therapy, wherein the imaging or therapy includes at least one of absorption, light scattering, photoacoustic, fluorescence, and sonofluorescence techniques.

25. The method according to claim 20 wherein the procedure comprises diagnosing atherosclerotic plaques or blood clots.

26. The method according to claim 20 wherein the procedure comprises administering localized therapy.

27. The method according to claim 20 wherein the procedure comprises phototherapy.

28. The method according to claim 20 wherein the procedure comprises laser assisted guided surgery (LAGS) for detection of small micrometastases.

29. The method according to claim 20 wherein:

the composition is administered in a formulation selected from at least one of a liposome, micelle, microcapsule and microparticle.