Receptor-avid exogenous optical contrast and therapeutic agents

• US 6,706,254 B2
• Filed: 05/23/2001
• Issued: 03/16/2004
• Est. Priority Date: 01/18/2000
• Status: Expired due to Fees

• Current Assignee: MediBeacon Inc.
• Original Assignee: Mallinckrodt Incorporated (Mallinckrodt plc)
• Inventors: Achilefu, Samuel I., Rajagopalan, Raghavan, Dorshow, Richard B., Bugaj, Joseph E.
• Primary Examiner(s): JONES, DAMERON LEVEST
• Application Number:
  US09/864,011
• Publication Number:
  US 20020156117A1
• Time in Patent Office: 1,028 Days
• Field of Search: 424/1.11, 424/1.65, 424/1.49, 424/1.69, 424/9.1, 424/9.2, 424/9.3, 424/9.4, 424/9.5, 424/9.6, 424/9.7, 424/9.8, 514/411, 514/2, 514/359, 548/100, 548/146, 548/215, 548/300.1, 548/400
• US Class Current: 424/9.6
• 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: C09B 23/0066 the polymethine chain being part of a carbocyclic ring,(e.g. benzene, naphtalene, cyclohexene, cyclobutenene-quadratic acid)
• CPC Class Codes: C09B 23/08 more than three >CH- groups, e.g. polycarbocyanines

Abstract

Cyanine dye bioconjugates useful for diagnostic imaging and therapy are disclosed. The conjugates include several cyanine dyes with a variety of bis- and tetrakis (carboxylic acid) homologes. The compounds may be conjugated to bioactive peptides, carbohydrates, hormones, drugs, or other bioactive agents. The small size of the compounds allows more favorable delivery to tumor cells as compared to larger molecular weight imaging agents. The various dyes are useful over the range of 350 to 1,300 nm, the exact range being dependent upon the particular dye. The use of dimethylsulfoxide helps to maintain the fluorescence of the compounds. The inventive compounds are useful for diagnostic imaging and therapy, in endoscopic applications for the detection of tumors and other abnormalities, for localized therapy, for photoacoustic tumor imaging, detection and therapy, and for sonofluorescence tumor imaging, detection and therapy.

Claims

1. The compound of formula

wherein each W⁶ and X⁶ is C((CH₂)OH)₂;

Y⁶ is —

(CH₂)₂—

CONH-Bm;

Z⁶ is —

(CH₂)₂—

CONH-Dm;

A₄ is a single bond;

A₄, B₄, C₄, and D₄ together form a 6-membered carbocyclic ring wherein B₄, C₄, and D₄ are selected from the group consisting of —

CR¹R², —

CR¹, and —

C═

O;

R¹ and R² are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₂₀ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyalkoxyalkyl, C₁-C₂₀ polyhydroxyalkyl, C₅-C₂₀ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, cyano, nitro, halogen, saccharide, peptide, —

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;

a₆ is 1;

a is independently from 1 to 20;

b is independently from 1 to 100;

R⁶⁷ is galactose;

each R⁶⁸ to R⁷⁹ is hydrogen;

Bm is Octreotate; and

Dm is bombesin.

2. A method for performing a diagnostic or therapeutic procedure comprising administering to an individual an effective amount of the compound of formula

wherein each of W⁶ and X⁶ is C((CH₂)OH)₂;

Y⁶ is —

(CH₂)₂—

CONH-Bm;

Z⁶ is —

(CH₂)₂—

CONH-Dm;

A₄ is a single bond;

A₄, B₄, C₄, and D₄ together form a 6-membered carbocyclic ring wherein B₄, C₄, and D₄ are selected from the group consisting of —

CR¹R², —

CR¹, and —

C═

O;

R¹ and R² are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₂₀ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyalkoxyalkyl, C₁-C₂₀ polyhydroxyalkyl, C₅-C₂₀ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, cyano, nitro, halogen, saccharide, peptide, —

CH₂(CH₂OCH₂)_b—

(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—

OCH₂)_b—

CO₂H;

a₆ is 1;

a is independently from 1 to 20;

b is independently from 1 to 100;

R⁶⁷ is galactose;

each R⁶⁸ to R⁷⁹ is hydrogen;

Bm is Octreotate; and

Dm is bombesin;

activating the compound using light; and

performing the diagnostic or therapeutic procedure.

3. The method of claim 2 wherein said procedure utilizes light of wavelength in the region of 350-1300 nm.

4. The method of claim 2 wherein the diagnostic procedure is optical tomography.

5. The method of claim 2 wherein said diagnostic procedure is fluorescence endoscopy.

6. The method of claim 2 further comprising monitoring a blood clearance profile of said compound by a method selected from the group consisting of fluorescence, absorbance, and light scattering, wherein light of wavelength in the region of 350-1300 nm is used.

7. The method of claim 2 wherein said procedure further comprises imaging and therapy, wherein said imaging and therapy is selected from the group consisting of absorption, light scattering, photoacoustic and sonofluoresence technique.

8. The method of claim 2 wherein said procedure is capable of diagnosing atherosclerotic plaques and blood clots.

9. The method of claim 2 wherein said procedure comprises administering localized therapy.

10. The method of claim 2 wherein said therapeutic procedure comprises photodynamic therapy.

11. The method of claim 2 wherein said therapeutic procedure comprises laser assisted guided surgery for the detection of micrometastases.

12. The method of claim 2 further comprising adding a biocompatible organic solvent at a concentration of one to fifty percent to the compound to inhibit in vivo or in vitro fluorescence quenching.

13. The method of claim 12 wherein said compound is dissolved in a medium comprising one to fifty percent dimethyl sulfoxide.

14. A composition comprising a cyanine dye bioconjugate of formula

wherein each of W⁶ and X⁶ is C((CH₂)OH)₂;

Y⁶ is —

(CH₂)₂—

CONH-Bm;

Z⁶ is —

(CH₂)₂—

CONH-Dm;

A₄ is single bond;

A₄, B₄, C₄, and D₄ together form a 6-membered carbocyclic ring wherein B₄, C₄, and D₄ are selected from the group consisting of —

CR¹R², —

CR¹, and —

C═

O;

R¹ and R² are independently selected from the group consisting of hydrogen, C₁-C₁₀ alkyl, C₅-C₂₀ aryl, C₁-C₁₀ alkoxyl, C₁-C₁₀ polyalkoxyalkyl, C₁-C₂₀ polyhydroxyalkyl, C₅-C₂₀ polyhydroxyaryl, C₁-C₁₀ aminoalkyl, cyano, nitro, halogen, saccharide, peptide, —

CH₂(CH₂OCH₂)_b—

CH₂—

OH, —

(CH₂)_a)—

CO₂H, —

(CH₂)_a—

CONH-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

CONH-Bm, —

(CH₂—

NHCO-Bm, —

CH₂—

(CH₂OCH₂)_b—

CH₂—

NHCO-Bm, —

(CH₂)_a—

OH and —

CH₂—

(CH₂OCH₂)_b—

CO₂H;

a₆ is 1;

a is independently from 1 to 20;

b is independently from 1 to 100;

R⁶⁷ is galactose;

each R⁶⁸ to R⁷⁹ is hydrogen;

Bm is Octreatate; and

Dm is bombesin;

R⁶⁷ is galactose;

each of R⁶⁸ to R⁷⁹ is hydrogen;

Bm is Octreotate; and

Dm is bombesin (7-14), and a pharmaceutically acceptable carrier or excipient.