WO2006079091A1 - Procedes pour conferer une stabilite a long terme a des colorants optiques biocompatibles et liquides organiques - Google Patents

Procedes pour conferer une stabilite a long terme a des colorants optiques biocompatibles et liquides organiques Download PDF

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Publication number
WO2006079091A1
WO2006079091A1 PCT/US2006/002581 US2006002581W WO2006079091A1 WO 2006079091 A1 WO2006079091 A1 WO 2006079091A1 US 2006002581 W US2006002581 W US 2006002581W WO 2006079091 A1 WO2006079091 A1 WO 2006079091A1
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WIPO (PCT)
Prior art keywords
dye
optical
blood
indocyanine
group
Prior art date
Application number
PCT/US2006/002581
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English (en)
Inventor
Richard B. Dorshow
Muthunadar P. Periasamy
Original Assignee
Mallinckrodt Inc.
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Application filed by Mallinckrodt Inc. filed Critical Mallinckrodt Inc.
Publication of WO2006079091A1 publication Critical patent/WO2006079091A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0056—Peptides, proteins, polyamino acids

Definitions

  • the present invention relates to the long-term stabilization and storage of optical dyes and their bioconjugates in bodily fluids such as blood, and the stabilization and storage of blood upon addition of such dyes and/or dye bioconjugates to the blood.
  • optical dyes for clinical disease monitoring, diagnosis, and therapy has been limited by their poor stability in solution.
  • the FDA-approved dye, indocyanine green (ICG) is an example of such an instable dye. Degradation of the dye in solution is dependent upon such factors as solvent composition, temperature, light exposure, and the like. 1 Indeed, quantum dot research has become a particular area of interest partly due to the goal of overcoming such stability problems of conventional dyes. 2
  • Page I of U invention to provide other and even longer term stability to optical dyes and optical dye-containing contrast agents.
  • a first aspect of the invention is directed to preserving optical stability of an optical dye, such as a biocompatible optical dye, by disposing the dye in contact with blood or a blood component of an animal.
  • the dye may be placed and/or stored in a container in an environment that includes blood or a blood component.
  • a blood component herein refers to any component of animal (e.g., a mammal) blood, such as, but not limited to plasma, red blood cells, white blood cells, platelets, and various blood proteins (e.g., albumin, fibrinogen, globulin).
  • Optical dyes appropriate for this first aspect of the invention include infrared dyes such as cyanine and indocyanine dyes, derivatives of such dyes, and bioconjugates of such dyes and derivatives.
  • an "infrared dye” herein refers to a dye that fluoresces upon exposure to at least one wavelength of light found in the infrared range of the light energy spectrum.
  • the optical dye is an indocyanine dye bioco ⁇ jugate (which includes bioconjugates of indocyanine dyes and indocyanine dye derivatives).
  • one embodiment utilizes cytate (bioconjugate including the peptide octreotate and the indocyanine dye derivative cypate) as the dye, while another embodiment utilizes cybesin (bioconjugate including cypate and the peptide bombesin) as the dye.
  • Other optical dyes such as visible dyes (e.g., fluorescein dye, derivatives and bioconjugates described herein), as well as various organic dyes and contrast agents known in the art, may also be utilized with this first aspect of the invention.
  • a "visible dye” herein refers to a dye that fluoresces upon exposure to at least one wavelength of light found in the visible range of the light energy spectrum.
  • the optical dye utilized with this first aspect of the invention be biocompatible (i.e., not having a significant injurious and/or toxic affect upon biological function when introduced into an animal (e.g., mammal, such as a human)).
  • the dye is placed and/or stored in a container that includes a biocompatible solvent and a blood component.
  • the biocompatible solvent utilized may be any appropriate solvent, such as one or more of DMSO, water, isopropyl alcohol, ethanol, and glycerol.
  • One particularly preferred embodiment of this first aspect is direct to placing/storing the dye in solution that includes both DMSO and a blood component (e.g., a blood protein such as albumin, fibrinogen, or globulin).
  • the optical dye that is stored in the blood or blood component may be said to maintain its ability to fluoresce for a significant amount of time due, at least in part, to the environment in which the dye is stored. For instance, as a result of storing the dye in the blood or blood component (and optionally, a biocompatible solvent), the dye may exhibit fluorescence excitation and emission capabilities months and even years after the dye was initially placed in contact with the blood or blood component.
  • this first aspect of the invention may be said to enable the dye to be stored without losing significant fluorescence ability for a duration of at least about 1 month in one embodiment, at least about 3 months in another embodiment, at least about 6 months in still another embodiment, at least about 9 months in yet another embodiment, at least about 12 months in another embodiment, at least about 18 months in still another embodiment, at least about 24 months in yet another embodiment, and at least about 30 months in still yet another embodiment.
  • a second aspect of the invention is also directed to a method of prolonging one or more optical properties (e.g., optical stability) of an optical dye.
  • the dye is stored in a solution that includes a biocompatible solvent.
  • biocompatible solvents include solvents such as DMSO, isopropyl alcohol, ethanol, and glycerol.
  • DMSO isopropyl alcohol
  • ethanol isopropyl alcohol
  • glycerol glycerol
  • One preferred biocompatible solvent for this second aspect of the invention is DMSO.
  • Optical dyes appropriate for this second aspect of the invention preferably include visible dyes (e.g., fluorescein dye, fluorescein dye derivatives, and fluorescein dye bioconjugates). For example, one embodiment utilizes flutate
  • This second aspect of the invention may be said to beneficially enable optical dyes to maintain their ability to fluoresce for significant durations of time due to the biocompatible solvents) in which the dyes are stored. For instance, as a result of storing a dye in a solution including DMSO, the dye may exhibit fluorescence excitation and emission capabilities months and even years after the dye was initially placed in contact with the solution.
  • this second aspect of the invention may be said to enable the dye to be stored without losing significant fluorescence ability for a duration of at least about 1 month in one embodiment, at least about 3 months in another embodiment, at least about 6 months in still another embodiment, at least about 9 months in yet another embodiment, at least about 12 months in another embodiment, at least about 18 months in still another embodiment, at least about 24 months in yet another embodiment, and at least about 30 months in still yet another embodiment.
  • Yet a third aspect of the present invention is directed to a method of storing biological fluid (i.e., bodily fluid).
  • the biological fluid is stored in an environment including at least one biocompatible optical dye. This method of storing biological fluid has been found to be useful for successfully preserving biological fluids for significant durations of time.
  • the biological fluid stored in accordance with this third aspect of the invention may be any appropriate biological fluid including, but not limited to, blood.
  • the biological fluid is blood or a biocompatible solution including at least one blood component.
  • the dye(s) used in this third aspect of the invention may be any appropriate dye(s) including, but not limited to one or both infrared and visible dyes such as, but not limited to, cyanine, indocyanine and fluorescein, as well as derivatives and bioconjugates thereof.
  • the dye is a dye bioconjugate (which includes bioconjugates of the dyes themselves as well as bioconjugates of the dye derivatives).
  • the dye is cytate, while cybesin is the dye in another embodiment.
  • “dye bioconjugate” or the like herein refers to a compound including a dye molecule and at least one biomolecule such as a peptide (e.g., hydrophilic peptide, bombesin, octreotate, cholecystokinin, neurotensin, and the like), a saccharide, or other known biomolecule.
  • the biological fluid/dye mixture of this third aspect of the invention may optionally include biocompatible solvents such as, but not limited to, DMSO, water, isopropyl alcohol, ethanol, and glycerol.
  • a fourth aspect of the invention is directed to a formulation that includes a blood component and an optical dye (which includes dye derivatives and conjugates).
  • Some embodiments of this fourth aspect also include a biocompatible solvent such as any of the biocompatible solvents mentioned above with regard to the first three aspects of the invention.
  • the formulations of this fourth aspect tend to beneficially exhibit prolonged stability.
  • the optical dye portion of the formulation may be stored for a significant duration of time (such as any of the durations described above with regard to the first three aspects) and may be capable of fluorescing (e.g., exhibiting optical stability) even after that storage period.
  • the blood component portion of the formulation may be stored for a significant duration of time (such as any of the durations described above with regard to the first three aspects) and remain substantially uniformly dispersed throughout the formulation (e.g., does not significantly separate or settle out in the formulation).
  • Figure Ia is a graph illustrating clearance time profiles of ICG and ICG-PASP measured on the day of formulation.
  • Figure Ib is a graph illustrating clearance time profiles of ICG and ICG-PASP two days after formulation.
  • Figure Ic is a graph illustrating a clearance time profile of ICG-PASP 24 days after formulation.
  • Figure 2 is a structural representation of the peptide-dye bioconjugate, cytate.
  • Figure 3 is a diagrammatic representation of a fluorescence imaging apparatus.
  • Figure 4 shows fluorescence images of four vials including various substances at initial formulation.
  • Figure 5 shows fluorescence images of three vials taken 48 months after initial formulation.
  • Figure 6 shows a fluorescence image of a vial containing cybesin and blood taken 30 months after initial formulation.
  • Figure 7 shows fluorescence images of four vials taken 30 months after initial formulation.
  • Biocompatible optical dyes in general, exhibit poor photostability in aqueous solution. This is especially true at the high concentrations needed for bolus administration in a clinical application.
  • Previously it has been shown that by using particular macromolecular additives, the stability of aqueous dye solutions may be enhanced from several hours to an order of several days.
  • the present invention provides procedures for enabling unexpected long-term stability on the order of months and even years for optical dyes such as infrared dyes and visible dyes (including derivatives and conjugates of those classes of dyes).
  • the dye-peptide conjugate known as cytate is an indocyanine-type dye attached to the peptide octreotate.
  • Cytate has been shown to exhibit excitation and emission in the near infrared (e.g., excitation at about 780 nm and emission at about 830 nm).
  • cytate has been shown to target somatostatin receptor rich tumors (e.g., tumors grown in rats from the CA20948 tumor line) and provide unambiguous contrast for optical imaging.
  • the preparation of cytate, as well as its tumor targeting and imaging capabilities with regard to rats, has been reported previously. 9 ' 10 In those previous reports, tumor to normal tissue ratios of greater than 20 were originally determined.
  • vial 3 a freshly prepared aqueous solution of cytate was mixed with blood (from a rat) in a small glass bottle (vial 3).
  • vial 1 included a dilute aqueous solution (i.e., much less than 1 mg/mL) of indocyanine green (ICG).
  • Vial 2 included cytate in a solution of DMSO/water with a 10/90 ratio by volume respectively.
  • Vial 4 included rat blood alone.
  • each of the small, glass vials 1-4 of ⁇ 10-mL volume were essentially filled with water or rat blood. Small aliquots of dye compounds were introduced into some of the vials (as described above), and the vials were then tightly sealed with screw caps.
  • the imaging assembly 10 utilized to conduct the above-described experiments is shown in Figure 3 and may be characterized as a noninvasive, continuous wave fluorescence imaging system.
  • a laser diode 12 (wavelength of 780 nm and nominal power of 40 mW) was utilized to emit light into a fiber optic bundle 14.
  • a defocusing lens 16 in position after the bundle 14 was utilized to expand a light beam emitted from the bundle 14 so as to span a sufficient area to project on a significant portion of an object to be imaged 30 (e.g., shown here as a rat).
  • the laser power at an output end of the bundle 14 was approximately one-half of the laser power at an input end of the bundle 14.
  • the imaging assembly 10 also included a detector 18 that included a 12 bit CCD camera 20 having a lens 22 attached.
  • An 830 nm interference filter 24 was mounted in front of the CCD input lens 22 such that only emitted fluorescent light from the contrast agent was imaged and displayed on the monitor 26. Images were acquired and processed using a processor 28 loaded with Win View software from Princeton Instruments.
  • Figure 5 after the over three year storage period, some of the vials were re-imaged using an imaging assembly similar to the one of Figure 3.
  • the imaging assembly utilized to provide the image of Figure 5 was different that the imaging assembly 10 in that it was equipped with a different CCD camera, a different fiber optic delivery system, and an upgraded version of the WinView software. Further, the imaging system utilized to generate Figure 5 performed a background subtraction to get rid of the underlying table in the displayed image.
  • Figure 5 shows fluorescent images of a plurality of vials (and the contents thereof) including the vial 3 from Figure 4.
  • Vial 7 contains a dilute aqueous solution of cypate, which is a derivative of indocyanine dye that is linked to the peptide octreotate to form the dye-peptide bioconjugate cytate.
  • the contents of the vial 7 were initially formulated around the same time as the contents of the vial 3 and serve as a control.
  • a vial of water W is disposed between vials 3 and 7 in Figure 5.
  • Figure 5 shows that, even after being stored for at least 36 months, the content of vial 3 (cytate of the cytate/blood mixture) still fluoresces when exposed to near infrared light.
  • any fluorescence from the aqueous cypate solution in the vial 7 is hardly, if at all, noticeable.
  • the results of the above-described experiments indicate that the dye-peptide conjugate cytate retains its fluorescence on the time scale of years when stored in rat blood.
  • cybesin bioconjugate including the indocyanine dye derivative cypate attached to the peptide octreotate
  • the vial was stored for about 30 months. After that time, a fluorescence image of the content of the vial was generated utilizing the imaging system described in regard to Figure 5.
  • FIG. 7 illustrates a fluorescence image from yet a third storage experiment.
  • each of four vials included different contents, and the vials (with the contents sealed therein) were stored for about 30 months.
  • One vial (labeled “water”) only had water disposed therein.
  • the second vial (labeled "flubesin”) included flubesin in a 25% DMSO aqueous solution at a concentration of about lmg/ml.
  • the third vial (labeled "Gsg-flubesin”) included gsg-flubesin ⁇ see S. Achilefu et al., Compounds 22-23 of Table 3, p.
  • the fourth vial included Bis-gsg flubesin ⁇ see S. Achilefu et al., Compound 24 of Table 3, p. 2006) in a 25% DMSO aqueous solution at a concentration of about lmg/ml.
  • gsg refers to "glycine-serine-glycine”.
  • the fluorescence images of Figure 7 show that the dyes in the "flubesin,” “Gsg-flubesin,” and “Bis-gsg fiubesin” vials all fluoresced even after being stored in DMSO solutions for about 30 months.
  • the control vial did not fluoresce
  • the contents of the "flubesin” vial fluoresced with greater intensity that the contents of the "Gsg-flubesin” vial, which fluoresced with greater intensity than the contents of the "Bis-gsg flubesin” vial.
  • the dye and the dye conjugates all fluoresced after about 30 months, it should be noted that the dye fluoresced with greater intensity than the dye conjugates. Regardless of which one of the vials fluoresced with the greatest intensity, the ability of the dyes to fluoresce after a duration of approximately 30 months was quite unexpected.
  • the blood in the vials that included the biocompatible optical dyes e.g., cytate and cybesin
  • the blood in the vial that contained only blood (vial 4) was solidified, separated, and petrified. Based on the results of those experiments, it may be said that optical dyes such as indocyanine dye-derived bioconjugates may be utilized to effectively preserve blood for durations of several years or more.

Abstract

Dans un mode de réalisation, l'invention concerne des procédés pour préserver la stabilité optique de colorants optiques et agents de contraste tels que des colorants visibles et infrarouges (par exemple des colorants de type cyanine, indocyanine et fluorescéine, ainsi que leurs dérivés et bioconjugués). Le colorant peut être placé dans un récipient comprenant un solvant biocompatible et/ou un composant sanguin, ce qui est avantageux, puisque dans ce cas le colorant peut émettre une fluorescence même après avoir été stocké pendant des mois et/ou des années. Dans un autre mode de réalisation, l'invention permet de conserver des liquides organiques, tels que le sang, pendant des mois, voire des années. A cet effet, le liquide organique est stocké dans un environnement comprenant au moins un colorant optique biocompatible. Dans un autre mode de réalisation, l'invention concerne une formulation comprenant un colorant optique, un composant sanguin, et éventuellement un solvant biocompatible. Ces formulations peuvent être caractérisées (au moins certaines d'entre elles) en ce qu'elles présentent une stabilité optique prolongée.
PCT/US2006/002581 2005-01-24 2006-01-23 Procedes pour conferer une stabilite a long terme a des colorants optiques biocompatibles et liquides organiques WO2006079091A1 (fr)

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US64646905P 2005-01-24 2005-01-24
US60/646,469 2005-01-24

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007030403A1 (de) 2007-06-29 2009-01-08 Universität Bielefeld Verfahren zur Verbesserung der Photostabilität von Fluoreszenzfarbstoffen
EP2277453A4 (fr) * 2008-05-15 2012-07-04 Osaka Prefectural Hospital Organization Procédé de collecte de données

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US3030273A (en) * 1959-09-02 1962-04-17 Abbott Lab Plastic tablet coating
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WO2004064751A2 (fr) * 2003-01-16 2004-08-05 St. Johns University New York Stabilisation a base de nanoparticules de colorants fluorescents infrarouges

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US3893447A (en) * 1973-06-04 1975-07-08 Univ Johns Hopkins Simultaneous angiography of the separate retinal and choroidal circulations
EP0602601A2 (fr) * 1992-12-17 1994-06-22 Dojin Iyaku-Kako Co., Ltd. Solution d'anticorps stable et stabilisation d'anticorps
WO2004064751A2 (fr) * 2003-01-16 2004-08-05 St. Johns University New York Stabilisation a base de nanoparticules de colorants fluorescents infrarouges

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102007030403A1 (de) 2007-06-29 2009-01-08 Universität Bielefeld Verfahren zur Verbesserung der Photostabilität von Fluoreszenzfarbstoffen
EP2277453A4 (fr) * 2008-05-15 2012-07-04 Osaka Prefectural Hospital Organization Procédé de collecte de données
US9717806B2 (en) 2008-05-15 2017-08-01 Osaka Prefectural Hospital Organization Method for detecting cancer using ICG fluorescence method

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