WO1998048846A1 - Agents de contraste utilises dans des techniques d'imagerie basees sur la lumiere - Google Patents

Agents de contraste utilises dans des techniques d'imagerie basees sur la lumiere Download PDF

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WO1998048846A1
WO1998048846A1 PCT/GB1998/001248 GB9801248W WO9848846A1 WO 1998048846 A1 WO1998048846 A1 WO 1998048846A1 GB 9801248 W GB9801248 W GB 9801248W WO 9848846 A1 WO9848846 A1 WO 9848846A1
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Prior art keywords
particles
image
light
particulate
agent
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PCT/GB1998/001248
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English (en)
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Eric Hohenschuh
Paul Mark Henrichs
Edward Bacon
Vinay Chandrakant Desai
Gregory Lynn Mcintire
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Nycomed Imaging As
Cockbain, Julian, Roderick, Michaelson
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Priority claimed from US08/984,771 external-priority patent/US6159445A/en
Priority claimed from GBGB9727124.1A external-priority patent/GB9727124D0/en
Application filed by Nycomed Imaging As, Cockbain, Julian, Roderick, Michaelson filed Critical Nycomed Imaging As
Priority to EP98919339A priority Critical patent/EP0979107A1/fr
Priority to AU72216/98A priority patent/AU7221698A/en
Priority to JP54675198A priority patent/JP2001526650A/ja
Publication of WO1998048846A1 publication Critical patent/WO1998048846A1/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
    • A61K49/001—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
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • A61K41/0033—Sonodynamic cancer therapy with sonochemically active agents or sonosensitizers, having their cytotoxic effects enhanced through application of ultrasounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—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
    • 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
    • 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
    • A61K49/0052—Small organic molecules
    • 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
    • A61K49/006—Biological staining of tissues in vivo, e.g. methylene blue or toluidine blue O administered in the buccal area to detect epithelial cancer cells, dyes used for delineating tissues during surgery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions
    • A61K49/0466—Liposomes, lipoprotein vesicles, e.g. HDL or LDL lipoproteins, phospholipidic or polymeric micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0476—Particles, beads, capsules, spheres
    • A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to the use of contrast agents, more particularly particulate contrast agents, in various diagnostic imaging techniques based on light, more particularly to particulate light imaging contrast agents .
  • Contrast agents are employed to effect image enhancement in a variety of fields of diagnostic imaging, the most important of these being X-ray, magnetic resonance imaging (MRI) , ultrasound imaging and nuclear medicine.
  • Other medical imaging modalities in development or in clinical use today include magnetic source imaging and applied potential tomography.
  • the history of development of X-ray contrast agents is almost 100 years old.
  • the X-ray contrast agents in clinical use today include various water-soluble iodinated aromatic compounds comprising three or six iodine atoms per molecule.
  • the compounds can be charged (in the form of a physiologically acceptable salt) or non-ionic.
  • the most popular agents today are non-ionic substances because extensive studies have proven that non-ionic agents are much safer than ionics. This has to do with the osmotic loading of the patient.
  • barium sulphate is still frequently used for X-ray examination of the gastrointestinal system.
  • Typical particulate X-ray contrast agents for parenteral administration include for example suspensions of solid iodinated particles, suspensions of liposomes containing water-soluble iodinated agents or emulsions of iodinated oils .
  • the current MRI contrast agents generally comprise paramagnetic substances or substances containing particles (hereinafter “magnetic particles”) exhibiting ferromagnetic, ferrimagnetic or superparamagnetic behaviour.
  • Paramagnetic MRI contrast agents can for example be transition metal chelates and lanthanide chelates like Mn EDTA and Gd DTPA.
  • gadolinium based agents are in clinical use; including for example Gd DTPA (Magnevist ® ) , Gd DTPA-BMA (Omniscan ® ) , Gd DOTA (Dotarem ® ) and Gd HPD03A (Prohance ® ) .
  • Magnetic particles proposed for use as MR contrast agents are water-insoluble substances such as Fe 3 0 4 or ⁇ - Fe 2 0 3 optionally provided with a coating or carrier matrix. Such substances are very active MR contrast agents and are administered in the form of a physiologically acceptable suspension.
  • Contrast agents for ultrasound contrast media generally comprise suspensions of free or encapsulated gas bubbles .
  • the gas can be any acceptable gas for example air, nitrogen or a perfluorocarbon.
  • Typical encapsulation materials are carbohydrate matrices (e.g. Echovist ® and Levovist ® ) , proteins (e.g. Albunex ® ) , lipid matrials like phospholipids (gas-containing liposomes) and synthetic polymers.
  • Markers for diagnostic nuclear medicine like scintigraphy generally comprise radioactive elements like for example technetium (99m) and indium (III) , presented in the form of a chelate complex, whilst lymphoscintigraphy is carried out with radiolabelled technetium sulphur colloids and technetium oxide colloids .
  • light imaging used here includes a wide area of applications, all of which utilize an illumination source in the UV, visible or IR regions of the electromagnetic spectrum.
  • the light which is transmitted through, scattered by or reflected (or re-emitted in the case of fluorescence) from the body, is detected and an image is directly or indirectly generated.
  • Light may interact with matter to change its direction of propagation without significantly altering its energy. This process is called elastic scattering.
  • Elastic scattering of light by soft tissues is associated with microscopic variations in the tissue dielectric constant.
  • the probability that light of a given wavelength ( ⁇ ) will be scattered per unit length of travel in tissue is termed the (linear) scattering coefficient ⁇ s .
  • the scattering coefficient of soft tissue in an optical window of approx.
  • 600-1300 nm ranges from 10 1 - 10 3 cm “1 and decreases as 1/ ⁇ .
  • ⁇ s >> ⁇ a (the absorption coefficient) and although ⁇ s (and the total attenuation) is very large, forward scattering gives rise to substantial penetration of light into tissue.
  • Ballistic light is light that has travelled through a region of tissue without being scattered.
  • Quasi-ballistic light (“snake” light) is scattered light that has maintained approximately the same direction of travel .
  • the effective penetration depth shows a slow increase or is essentially constant with increasing wavelengths above 630 nm (although a slight dip is observed at the water absorption peak at 975 nm) .
  • the scattering coefficient shows only a gradual decrease with increasing wavelength.
  • Light that is scattered can either be randomly dispersed (isotropic) or can scatter in a particular direction with minimum dispersion (anisotropic) away from the site of scattering.
  • scattering in tissue is assumed to occur at discrete, independent scattering centers ("particles").
  • the scattering coefficient and the mean cosine of scatter (phase function) depend on the difference in refractive index between the particle and its surrounding medium and on the ratio of particle size to wavelength. Scattering of light by particles that are smaller than the wavelength of the incident light is called Rayleigh scattering. This scattering varies as 1/ ⁇ 4 and the scattering is roughly isotropic.
  • Mie scattering Scattering of light by particles comparable to or larger than the wavelength of light. This scattering varies as l/ ⁇ and the scattering is anisotropic (forward peaked) . In the visible/near-IR where most measurements have been made, the observed scattering in tissue is consistent with Mie-like scattering by particles of micron scale: e.g. cells and major organelles.
  • the scattering coefficient is so large for light wavelengths in the optical window (600-1300 nm) , the average distance travelled by a photon before a scattering event occurs is only 10-100 ⁇ m. This suggests that photons that penetrate any significant distance into tissue encounter multiple scattering events. The ballistic component of light that has travelled several centimeters through tissue is exceedingly small. Multiple scattering in tissue means that the true optical path length is much greater than the physical distance between the light input and output sites. The scattering acts, therefore, to diffuse light in tissue (diffuse-transmission and -reflection) .
  • the difficulty that multiple scattering presents to imaging is three-fold: (i) light that has been randomized due to multiple scattering has lost signal information and contributes noise to the image (scattering increases noise) ; (ii) scattering keeps light within tissue for a greater period of time, increasing the probability for absorption, so less light transmits through tissue for detection (scattering decreases signal) ; and (iii) the determination of physical properties of tissue (or contrast media) such as concentration that could be obtained from the Beer-Lambert law is complicated since the true optical path length due to scattering is difficult to determine (scattering complicates the quantification of light interactions in tissue) .
  • the large value of the mean cosine of scattering indicates that a significant fraction of photons in an incident beam may undergo a large number of scatters without being deviated far from the original optical axis, and as such can contribute in creating an image.
  • UV light and visible light below 600 nm wavelength can also be used.
  • Light can also be used in therapy; thus for example in Photodynamic Therapy (PDT) photons are absorbed and the energy is transformed into heat and/or photochemical reactions which can be used in cancer therapy.
  • PDT Photodynamic Therapy
  • the main methods of light imaging today include simple transillumination, various tomographic techniques, fluorescence imaging, and hybrid methods that involve irradiation with or detection of other forms of radiation or energy in conjunction with irradiation with or detection of light (such as photoacoustic or acousto- optical) . These methods take advantage of either transmitted, scattered or emitted (fluorescence) photons or a combination of these effects.
  • the present invention relates to contrast agents for any of these and further imaging methods based on any form of ligh .
  • particle is used to refer to any physiologically acceptable particulate materials.
  • Such particles may be solid (e.g. coated or uncoated crystalline materials) or fluid (e.g. liquid particles in an emulsion) or may be aggregates (e.g. fluid containing liposomes) .
  • Particulate material with a particle size smaller than or similar to the incident light wavelength are preferred.
  • the invention provides the use of a physiologically tolerable material, preferably a physiologically tolerable particulate material, for the manufacture of a contrast-agent containing contrast medium, particurly a particulate contrast-agent containing contrast medium for use in in vivo dignostic optical microscopy.
  • the invention also provides a method of generating an image of the human or non- human (preferably mammalian, avian or reptilian) animal body by optical microscopy, characterised in that a contrast effective amount of a physiologically tolerable contrast agent, preferably a physiologically tolerable particulate contrast agent, is administered to said body, and an image of at least part of said body is generated.
  • a contrast effective amount of the agent, particularly particulate agent is administered, e.g. parenterally or into an externally voiding body organ or duct, light emitted, transmitted or scattered by the body is detected and an image is generated of at least part of the body in which the contrast agent is present.
  • the other form of radiation may be ultrasound.
  • the particles used according to the invention are preferably water-insoluble or at least sufficiently poorly soluble as to retain their desired particle size (e.g. 15-1500 nm) for at least 2 hours following administration into the body under investigation.
  • the images generated may be spatial or temporal and mono- or multi-dimensional .
  • the imaging technique may be used to determine a value for a parameter characteristic of the body or the part of the body under study, e.g. blood flow rate.
  • the parameter determination should be based on light detected from particles studied through the skin or through an endoscopically or surgically exposed surface .
  • the light imaging procedure used is selected from confocal scanning laser microscopy (CSLM) , optical coherence tomography (OCT) , laser doppler, laser speckle, and multi-photon microscopy techniques (for a description of the latter see for - 16 - example Denk, W. in Photonics Spectra (1997) July 125- 130, Denk, W. et al . in Science (1990) April 248 73-76, Denk, W. et al . in J.Neurosci . Meth. (1994) 54:2:151-162, Denk, W. et al . in Neuron (1997) January 18:351-357, Maiti, S. et al . in Science (1997) January 275 530-532 and Denk, W. et al . in Proc.Natl .Acad. (1995) August 92:18:8279-8282, and below) .
  • microscopy is defined as an optical method with a resolution between 1 mm and 0.1 micron.
  • Multiphoton microscopy is an imaging method that relies on irradiation intensity for optical sectioning.
  • Two photons of light in the near infrared region reaching a molecule essentially simultaneously can induce an electronic transition that normally requires a photon of light in the ultraviolet.
  • the sum of the energies of the two infrared photons should approximate that of the single ultraviolet photon.
  • the requirement that two photons interact with the molecule almost simultaneously means that the light intensity must be high.
  • the number of electronic transitions produced by two-photon processes is proportional to the square of the instantaneous intensity. Even more stringent restrictions on the intensity of light are required for multiphoton excitation with more than two photons.
  • the principle behind multiphoton microscopy is that diffraction-limited focusing of a laser beam limits two- photon transitions to a narrow plane within the region of focus. Outside of the focus region there is insufficient intensity to result in two-photon transitions. Temporal concentration of the required intensity within 100-fsec pulses minimizes thermal and optical damage to the skin.
  • Suitable contrast agents for multiphoton microscopy are fluorescing substances whose wavelengths of maximum absorption are in the range 300 to 650 nm. These will be suitable for two-photon microscopy with light in the wavelength range 600 to 1300 nm. More preferably the contrast agents will absorb in the range from 325 to 500 nm with excitation in the range 650 to 1000 nm.
  • Confocal scanning laser microscopy is an imaging modality that selectively detects a single point within a test object by focusing light from a pinhole source onto that point. The light transmitting past or reflecting from that point is refocused onto a second pinhole or back into the same pinhole that filters out light coming from any other site in the object except the focal point. Raster scanning of the focus point through a plane passing through the sample generates a full image of that plane of points. Moving the pinholes and focusing apparatus back and forth from the sample selects out different sample planes.
  • CSLM is a means for "optically" sectioning a test sample. It pulls out images of individual sections of the sample, but without the necessity that those sections be physically separated from the rest of the sample.
  • OCT optical coherence tomography
  • a collimated beam of light is reflected from the sample, then is compared with a reference beam that has travelled a precisely known distance. Only the light travelling exactly the same distance to the sample and back as the distance the reference beam travels from the source to the detector constructively interferes with the reference beam and is detected. Thus the light from a single plane within the sample is again selected. Varying the distance that the reference beam travels before it is compared with the sampling beam selects out different sample planes.
  • CSLM, OCT, laser doppler and laser speckle are discussed for example by: Rajadhyaksha et al . in Laser Focus World, February 1997, pages 119 to 127; Sabel et al . in Nature Medicine 2(2): 244-247 (1997); Tearney et al . in SPIE 2389: 29-34 (1995); Bonner et al . in "Scattering techniques applied to supramolecular and non-equilibrium systems", pages 685-701, Ed. Chen et al . , Plenum; Ruth in J. Microcirc: Clin Exp 9_: 21-45 (1990); Pierard in Dermatology 186 : 4-5 (1993); and Bonner et al . in "Laser-doppler blood flowmetry" pages 17 to 46, Ed. Shepherd et al . , Kluwer, 1990.
  • CSLM, OCT or other forms of in-vivo microscopy may be used particularly effectively to study structures and events occurring in the skin or within about a millimeter of an accessible surface of the body under study, e.g. a surface exposed during surgical operation or exposed endoscopically.
  • CSLM, OCT or other forms of in-vivo microscopy can be useful in optically guided tumor resection.
  • either device attached to a colonoscope may facilitate determination that no residual malignant tissue remains after removal of a cancerous colon polyp.
  • Additional applications include, but are not limited to, diagnosis and treatment of disease in the rest of the digestive tract, surgical treatment of ulcerative colitis, and diagnosis and treatment of endometriosis .
  • CSLM, OCT or other forms of in-vivo microscopy can be used to follow the movement of blood cells through the capillaries of the skin and other vascularized tissue lying within about a millimeter of an exposed surface. Potentially they can also be used in conjunction with laser Doppler or speckle inferferometry for the measure of blood flow.
  • Laser Doppler and speckle interferometry are related, each relying upon the fact that the intensity of light detected after a beam of laser light that interacts with a collection of moving particles changes with time. Mathematical analysis of the changes provides a basis for calculating the rate at which the particles are moving .
  • Blood flow within the skin of the breast may be an indicator of internal disease. Blood flow in the skin can be detected by laser Doppler blood-flow measurement or laser speckle interferometry, either by itself or in conjunction with CSLM, OCT or other forms of in-vivo microscopy.
  • synthetic particles capable of scattering light of the wavelength used for the imaging procedure, may be administered as contrast agents in an in vivo light imaging procedure.
  • scattering particles will be administered in suspension in a physiologically tolerable fluid (e.g. water for injections, physiological saline, Ringer's solution etc.) into the vasculature or musculature or into the tissue or organ of interest.
  • a physiologically tolerable fluid e.g. water for injections, physiological saline, Ringer's solution etc.
  • a preferred contrast agent for intraoperative CSLM, OCT or other forms of in-vivo microscopy will have the following properties: it will consist of stabilized particles in an aqueous or buffered liquid medium.
  • the particle size will preferably be around 5 to 10000 nm, preferably 600 to 1300 nm, more preferably 700 to 1100 nm (i.e. roughly equal to the wavelength of the light source) .
  • the refractive index of the particles will preferably differ from that of body fluids, such as blood and lymph, by at least 0.01.
  • the particles may have fluorescent dyes attached to their surfaces or contained within them or the particles themselves may be composed of fluorescent dyes .
  • the particles may have suitable surface modifying agents, such as poly (ethylene glycol), to slow their uptake by macrophages in the body and to prolong their blood circulation lifetimes.
  • the particles may be of a material which is transparent or translucent or more preferably opaque to light of the wavelength of the light source.
  • the particles are substantially monodisperse polymer particles (with a coefficient of variation of the particle size (i.e. 100 x standard deviation ⁇ mean particle size by volume of the major mode of the detectable particles) as measured by a Coulter LS 130 particle size analyzer of less than 10%, preferably less than 5%) .
  • Such particles may be prepared by the SINTEF technique disclosed in US-A-4336173 and US-A-4459378.
  • Such polymer particles may be simple scatterers or may be modified to carry a chromophore (or fluorophore) , preferably having characteristic absorption and/or emission maxima in the 300 to 1300 nm range.
  • a targetting vector e.g.
  • a species serving to cause the particles to accumulate at a desired target site for example superparamagnetic crystals which allow the particle to be accumulated at a target site by application of an external magnetic field, or a drug, antibody, antibody fragment or peptide (e.g. an oligopeptide or polypeptide) which has a binding affinity for sites within the target zone, e.g. cell surface receptors.
  • a drug, antibody, antibody fragment or peptide e.g. an oligopeptide or polypeptide which has a binding affinity for sites within the target zone, e.g. cell surface receptors.
  • the particulate contrast agent can be applied through simple topical application or other pharmaceutically acceptable routes.
  • the contrast agents may be modified to be delivered through transdermal patches or by iontophoretesis. Iontophoretic delivery is preferred, as one can control the amount of the agent that is delivered.
  • the contrast agent can be injected into the vasculature or into the lesion to be removed prior to or during the surgery.
  • the contrast agent can be injected into a lymph duct or intramucosally into the tissue draining into the surgical area. Alternatively it may be applied during surgery as a topical ointment, a liquid, or a spray.
  • the agent can be injected intravascularly prior to the measurement.
  • the particulate agents used according to the invention may comprise a chromophore or fluorophore, i.e. may absorb or emit light in the wavelength range detected in the imaging procedure or alternatively may rely primarily upon light scattering effects.
  • physiologically tolerable non photo-labelled particles e.g. particles of an inert organic or inorganic material, e.g. an insoluble triiodophenyl compound or titanium dioxide, which appears white or colourless to the eye.
  • the particles comprise a fluorophore or chromophore, i.e. are photo-labelled, this may be in a material carried by (e.g.
  • a particulate carrier e.g. a solid particulate or a liposome
  • the carrier itself may have chromophoric or fluorophoric properties.
  • the photolabel may be a black photolabel (i.e. one which absorbs across the visible spectrum and thus appears black to the eye) non-black photolabels are preferred.
  • Scattering contrast agents can have several mechanisms in image enhancement for light imaging applications.
  • the first mechanism is a direct image enhancing role similar to the effect that x-ray contrast media have in x-ray imaging.
  • direct image enhancement the contrast medium contributes directly to an improvement in image contrast by affecting the signal intensity emanating from the tissue containing the contrast medium.
  • scattering (and absorbing) agents localized in a tissue can attenuate light differently than the surrounding tissue, leading to contrast enhancement .
  • scattering agents For near surface methods such as confocal microscopy and optical coherence tomography, scattering agents generate contrast primarily by serving as reflection centres that selectively direct the incident light to the detector.
  • a moving fluid such as blood
  • the "speckle" phenomenon results from the interaction of coherent radiation (such as that from a laser) with scattering sites.
  • coherent radiation such as that from a laser
  • the speckle pattern changes with time, and the rate of change of the speckle pattern can be used to determine the rate of movement of the scattering sites. If the movement of the scattering sites is non-random, for example when they are entrained in a moving fluid, the rate of fluid flow can be determined by the changes in the speckle pattern over time.
  • a second mechanism by which a scattering (or absorbing) agent could be used is as a noise rejection agent.
  • the contrast agent in this case is not directly imaged as described above, but functions to displace a noise signal from an imaging signal so that the desired signal is more readily detected. Noise in light imaging applications results from multiple scattering and results in a degradation of image quality. The origin of this noise is as follows:
  • the introduction of a small isotropic scattering agent greatly increases the residence time of the highly scattered signal component while having a lesser effect on the ballistic and quasi-ballistic components. This effectively provides a longer separation between the ballistic and quasi-ballistic signals and the highly scattered component, providing improved rejection of the scattered (noise) component and better image quality.
  • particulate scattering-based contrast agents Very little is disclosed in prior art regarding particulate scattering-based contrast agents.
  • US 5,140,463 (Yoo, K.M. et al . ) which discloses a method and apparatus for improving the signal to noise ratio of an image formed of an object hidden in or behind a semi -opaque medium.
  • the patent in general terms suggests to make the random medium less random (so that there will be less scattered light) and it is also suggested to increase the time separation between ballistic and quasi-ballistic light and the highly scattered light.
  • One of many ways to obtain this will, according to the patent, be to introduce small scatterers into the random medium. There are no further suggestions regarding these small scatterers and no suggestion of in vivo use.
  • Particulate materials in the form of liposomes have been suggested; liposome or LDL-administered Zn(II)- phthalocyanine has been suggested as photodynamic agent for tumors by Reddi, E. et al . in Lasers in Medical Science 5 (1990) 339, parenterally administered zinc phtalocyanine compositions in form of liposome dispersion containing synthetic phopholipid in EP 451 103 (CIBA Geigy) and liposome compositions containing benzoporphyrin derivatives used in photodynamic cancer therapy or an antiviral agents in CA 2,047,969 (Liposome Company) . These particulate materials have been suggested as therapeutic agents and have nothing to do with scattering light imaging contrast agents.
  • the contrast medium for imaging modalities based on light will comprise physiologically tolerable gas containing particles.
  • physiologically tolerable gas containing particles Preferred are e.g. biodegradable gas-containing polymer particles, gas-containing liposomes or aerogel particles .
  • This embodiment of the invention includes, for example, the use in light imaging of particles with gas filled voids (US 4,442,843), galactose particles with gas (US 4,681,119), microparticles for generation of microbubbles (US 4,657756 and DE 3313947), protein microbubbles (EP 224934) , clay particles containing gas (US 5,179,955), solid surfactant microparticles and gas bubbles (DE 3313946) , gas-containing microparticles of amylose or polymer (EP 327490) , gas-containing polymer particles (EP 458079), aerogel particles (US 5,086,085), biodegradable polyaldehyde microparticles (EP 441468) , gas associated with liposomes (WO 9115244) , gas- containing liposomes (WO 9222247) , and other gas containing particles (WO 9317718, EP 0398935, EP 0458745, WO 9218164, EP 0554213, WO 95038
  • the surface or coating of the particle can be any physiologically acceptable material and the gas can be any acceptable gas or gas mixture.
  • Specially preferred gases are the gases used in ultrasound contrast agents like for example air, nitrogen, lower alkanes and lower fluoro or perfluoro alkanes (e.g. containing up to 7, especially 4, 5 or 6 carbons) .
  • gas microbubbles with or without a liposomal encapsulating membrane
  • advantage may be taken of the known ability of relatively high intensity bursts of ultrasound to destroy such microbubbles.
  • the detected light signal or image
  • the distribution of the contrast agent may be facilitated.
  • the contrast medium for imaging modalities based on light will comprise physiologically tolerable particles of lipid materials, e.g. emulsions, especially aqueous emulsions.
  • physiologically tolerable particles of lipid materials e.g. emulsions, especially aqueous emulsions.
  • This embodiment of the invention includes, for example, the use in light imaging of fat emulsions (JP 5186372) , emulsions of fluorocarbons (JP 2196730, JP 59067229, JP 90035727, JP 92042370, WO 930798, WO 910010, EP 415263, WO 8910118, US 5,077,036, EP 307087, DE 4127442, US 5,114,703), emulsions of brominated perfluorocarbons (JP 60166626, JP 92061854, JP 5904630, JP 93001245, EP 231070) , perfluorochloro emulsions (WO 9311868) or other emulsions (EP 321429) .
  • the contrast medium for imaging modalities based on light will comprise physiologically tolerable liposomes.
  • Preferred groups of liposomes are phospholipid liposomes and multilamelar liposomes.
  • This embodiment of the invention includes, for example, the use in light imaging of phospholipid liposomes containing cholesterol derivatives (US-A-4544545) ; liposomes associated with compounds containing aldehydes (US-A-4590060) ; lipid matrix carriers (US-4610868) ; liposomes containing triiodobenzoic acid derivatives of the type also suitable for X-ray examination of liver and spleen (DE-2935195) ; X-ray contrast liposomes of the type also suitable for ly ⁇ nphography (US-4192859) ; receptor-targeted liposomes (WO-8707150) ; immunoactive liposomes (EP-307175) ; liposomes containing antibody specific for antitumor antibody (US-4865835) ; liposomes containing oxidants able to restore MRI contrast agents (spin labels) which have been reduced (US-4863717) ; liposomes containing macromolecular bound paramagne
  • iodixanol and other soluble iodinated X-ray contrast agents that are commercially available
  • iodixanol provides a clear solution on dissolution in water.
  • iodixanol is encapsulated in liposomes the resulting particulate product is off-white indicating a significant light scattering capability.
  • liposomes as carriers for light imaging contrast agents, it is possible to use simple micelles, formed for example from surfactant molecules, such as sodium dodecyl sulphate, cetyltrimethylammonium halides, pluronics, tetronics etc., as carriers for photolabels which are moderately or substantially water insoluble but are solubilised by the amphiphilic micelle forming agent, e.g. photolabels such as indocyanine green.
  • peptides such as PEG modified polyaspartic acid (see Kwon et al . Pharm. Res. 10 . : 970 (1993)) which spontaneously aggregate into polymeric micelles may be used to carry such photolabels.
  • photolabel carrier aggregate particles can be produced by treatment of polycyclic aromatic hydrocarbons with anionic surfactants (e.g. sodium dodecyl sulphate or sulphated pluronic F108) and subsequent addition of heavy metal ions (e.g. thorium or silver) .
  • anionic surfactants e.g. sodium dodecyl sulphate or sulphated pluronic F108
  • heavy metal ions e.g. thorium or silver
  • the contrast medium for imaging modalities based on light will comprise physiologically tolerable particles containing iodine.
  • These particles may for example be particles of a substantially water insoluble solid or liquid iodine-containing compound, e.g. an inorganic or organic compound, in the latter case preferably a triiodophenyl group containing compound, or alternatively they may be aggregate particles (such as liposomes) in which at least one of the components is an iodinated compound.
  • the iodinated compound may be a membrane forming compound or may be encapsulated by the membrane.
  • emulsified iodinated oils US 4,404,182
  • particulate X- ray contrast agents JP 67025412, SU 227529, DE 1283439, US 3,368,944, AU 9210145, EP 498482, DE 4111939, Us 5,318,767
  • iodinated esters WO 9007491, EP 300828, EP 543454, BE 8161143
  • iodinated lipids EP 294534
  • the contrast medium for imaging modalities based on light will comprise physiologically tolerable magnetic particles.
  • the term "magnetic particle” as used here means any particle displaying ferromagnetic, ferrimagnetic or superparamagnetic properties and preferred are composite particles comprising magnetic particles and a physiologically tolerable polymer matrix or coating material, e.g. a carbohydrate and/or a blood residue prolonging polymer such as a polyalkyleneoxide (e.g. PEG) as described for example by Pilgrimm or Ilium in US-A-5160725 and US-A-4904479 e.g. biodegradable matrix/polymer particles containing magnetic materials.
  • a physiologically tolerable polymer matrix or coating material e.g. a carbohydrate and/or a blood residue prolonging polymer such as a polyalkyleneoxide (e.g. PEG) as described for example by Pilgrimm or Ilium in US-A-5160725 and US-A-4904479 e.g. bio
  • This embodiment of the invention includes, for example, the use in light imaging of magnetic liquid (SU 1187221) , ferrite particles coated with a negatively charged colloid (DE 2065532) , ferrite particles (US 3832457) , liquid microspheres containing magnetically responsive substance (EP 42249) , magnetic particles with metal oxide core coated with silane (EP 125995) , magnetic particles based on protein matrix (DE 3444939) , magnetic vesicles (JP 60255728) , magnetic particles (SU 106121) , magnetic particles embedded in inert carrier (JP 62167730) , ferromagnetic particles loaded with specific antibodies (DE 3744518) , superparamagnetic particles coated with biologically acceptable carbohydrate polymers (WO 8903675) , polymerized lipid vesicles containing magnetic material (US 4,652,257), superparamagnetic materials in biodegradable matrices (US 4,849,210), biodegradable matrix particles containing paramagnetic or fer
  • the particulate contrast agent used according to the invention may, as mentioned above, be non-photo-labelled or photolabelled. In the latter case this means that the particle either is an effective photoabsorber at the wavelength of the incident light (i.e. carries a chromophore) or is a fluorescent material absorbing light of the incident wavelength and emitting light at a different wavelength (i.e. carries a fluorophore) .
  • fluorophores examples include fluorescein and fluorescein derivatives and analogues, indocyanine green, rhodamine, triphenylmethines, polymethines, cyanines, phalocyanines, naphthocyanines, merocyanines , lanthanide complexes (e.g. as in US-A-4859777) or cryptates, etc. including in particular fluorophores having an emission maximum at a wavelength above 600 nm (e.g. fluorophores as described in WO-A-92/08722) .
  • Other labels include fullerenes, oxatellurazoles (e.g.
  • porphyrins and porphyrin analogues e.g. verdins, purpurins, rhodins, perphycenes, texaphyrins, sapphyrins, rubyrins, benzoporphyrins, photofrin, metalloporphyrins, etc.
  • natural chromophores/fluorophores such as chlorophyll, carotenoids, flavonoids, bilins, phytochrome, phycobilins, phycoerythrin, phycocyanins , retinoic acid and analogues such as retinoins and retinates.
  • photolabels which contain chromophores should exhibit a large molar absorptivity, e.g. >10 5 cra ⁇ M "1 and an absorption maximum in the optical window 600 to 1300 nm.
  • an appropriate integer multiple of the absorption maximum should fall in the optical window of 600-1300.
  • Particulates for use as noise rejection agents by virtue of their absorption properties should similarly preferably have molar absorptivities in excess of 10 5 cm “ 1 M ⁇ 1 and an absorption maximum in the range 600 to 1300 nm "1 .
  • the quantum yield for fluorescence is one of the most important characteristics. This should be as high as possible.
  • the molar absorptivity should also desirably be above 10 5 cra ⁇ M "1 for the fluorophore and the absorption maximum should desirably be in the range 600 to 1300 nm for diffuse reflectance studies or 300 to 1300 nm for surface or near-surface studies.
  • photo-labelled materials may be used as such if substantially water-insoluble and physiologically tolerable, e.g. as solid or liquid particles, or alternatively may be conjugated to or entrapped within a particulate carrier (e.g. an inorganic or organic particle or a liposome) .
  • a particulate carrier e.g. an inorganic or organic particle or a liposome
  • conjugates of formula I are particularly preferred.
  • I 3 Ph is a triiodophenyl moiety
  • L is a linker moiety
  • C* is a chromophore or fluorophore (e.g. as described above) .
  • Such compounds form a further aspect of the invention.
  • the I 3 Ph moiety is preferably a 2, 4, 6 triiodo moiety having carboxyl or amine moieties (or substituted such moieties, e.g. alkoxycarbonyl , aminocarbonyl , alkylaminocarbonyl , alkoxycarbonylalkoxycarbonyl , or alkylcarbonylamino groups where the alkyl or alkylene moieties are optionally hydroxy substituted and preferably contain up to 20, particularly 1 to 6, especially 1 to 3 carbons) at the 3 and 5 positions.
  • the linker group L may be any group capable of linking the group C* to the I 3 Ph moiety, e.g.
  • group L include -NHS0 2 - and -C0 2 (CH 2 ) 2 0-CS-NH- .
  • Such compounds may be prepared by conjugating a chromophoric or fluorophoric molecule to a triiodophenyl compound of the type proposed as X-ray contrast agents by Nycomed, Sterling Winthrop, or Bracco in their numerous patent publications (by way of example US-A- 5264610, US-A-5328404, US-A-5318767 and US-A-5145684) .
  • non- photolabelled particles e.g. solid particles of a polymer or an iodinated X-ray contrast agent
  • a coating or shell of a photolabel e.g. a fluorescent agent, for example by chemically or physiochemically binding the photolabel to the particles (e.g. by using oppositely charged photolabel and particles) .
  • the resulting coated particles preferably of nano particle size (e.g. 5 to 10000 nm, especially 10 to 1000 nm, more preferably 10-500 nm) if labelled with a fluorophore would allow light energy trapped by the core to be transferred to the luminescing surface and so enhance light emission by the fluorophore.
  • Compositions containing such particles form a further aspect of the invention.
  • the photo-label may be entrapped within a solid polymer matrix, e.g. by co-precipitation of polymer and photolabel or by precipitation of photo- label within the pores of a porous inorganic or organic matrix.
  • Suitable organic polymer matrices for use as carriers or cores for photolabels are substantially water insoluble physiologically tolerable polymers, e.g. polystyrene latex, polylactide coglycolide, polyhydroxybutyrate co- valerate etc.
  • physiologically acceptable particles may be used in contrast media for imaging methods based on light in accordance with of the present invention.
  • Preferred groups of materials are e.g. biodegradable polymer particles, polymer or copolymer particles and particles containing paramagnetic materials.
  • the particles can for example be crosslinked gelatin particles (JP 60222046) , particles coated with hydrophilic substances (JP 48019720) , brominated perfluorocarbon emulsions (JP 58110522), perfluorocarbon emulsions (JP 63060943), particles and emulsions for oral use (DE 3246386) , polymer particles (WO 8601524, DE 3448010), lipid vesicles (EP 28917) , metal oxide particles (JP 1274768) , metal transferrin dextran particles (US 4735796) , monodisperse magnetic polymer particles (WO 8303920) , polymer particles (DE 2751867) , microparticles containing paramagnetic metal compounds (US 4,615,879), porous particles containing paramagnetic materials (WO 8911874) , hydrophilic polymer particles (CA 1109792) , water-swellable polymer particles (DE 2510221) , polymer particles (WO
  • the particulate agent is intended for parenteral administration (e.g. into the vasculature)
  • it may be desirable to prolong the blood residence time for the particles by attaching to these a blood residence time prolonging polymer as described for example by Pilgrimm in US-A-5160725 or Ilium in US-A- 4904479.
  • imaging of the vascular system may be facilitated by delaying the uptake of the particle by the reticuloendothelial system.
  • the blood residence prolonging polymer may be bound to preformed liposomes or, conjugated to liposomal membrane forming molecules, may be used as an amphiphilic membrane forming component so resulting in liposomes carrying the hydrophilic blood residence polymer component on their surfaces.
  • the particles may be conjugated to a biotargetting moiety (e.g. as described in WO-A-94/21240) so as to cause the particles to distribute preferentially to a desired tissue or organ, e.g. to tumor tissue.
  • the particle size utilized according to the invention will depend upon whether particle administration is parenteral or into an externally voiding body cavity and on whether or not the particles are photo-labelled.
  • particle sizes will be in the range 5 to 10000 nm, especially 15 to 1500 nm, particularly 50 to 400 nm and for particles which are being used for their scattering effect particle size will preferably be in the range 1/15 ⁇ to 2 ⁇ , or more preferably 1/10 ⁇ to ⁇ , especially ⁇ /4 ⁇ to ⁇ / ⁇ , more especially about ⁇ /2 ⁇ (where ⁇ is the wavelength of the incident light in the imaging technique) .
  • the particles may conveniently be formulated together with conventional pharmaceutical or veterinary carriers or excipients .
  • the contrast media used according to the invention may conveniently contain pharmaceutical or veterinary formulation aids, for example stabilizers, antioxidants, osmolality adjusting agents, buffers, pH adjusting agents, colorants, flavours, viscosity adjusting agents and the like. They may be in forms suitable for parenteral or enteral administration, for example, injection or infusion or administration directly into a body cavity having an external voidance duct, for example the gastrointestinal tract, the bladder and the uterus.
  • the media of the invention may be in conventional pharmaceutical administration forms such as tablets, coated tablets, capsules, powders, solutions, suspensions, dispersions, syrups, suppositories, emulsions, liposomes, etc; solutions, suspensions and dispersions in physiologically acceptable carrier media, e.g. water for injections, will however generally be preferred.
  • physiologically acceptable carrier media e.g. water for injections
  • the carrier medium incorporating the particles is preferably isotonic or somewhat hypertonic.
  • the contrast agents can be used for light imaging in vivo, in particular of organs or ducts having external voidance (e.g. Gl tract, uterus, bladder, etc.), of the vasculature, of phagocytosing organs (e.g. liver, spleen, lymph nodes, etc.) or of tumors.
  • the imaging technique may involve endoscopic procedures, e.g. inserting light emitter and detector into the abdominal cavity, the Gl tract etc. and detecting transmitted, scattered or reflected light, e.g. from an organ or duct surface. Where appropriate monochromatic incident light may be utilized with detection being of temporally delayed light emission (e.g.
  • images may be temporal images of a selected target demonstrating build up or passage of contrast agent at the target site.
  • the light used may be monochromatic or polychromatic and continuous or pulsed; however monochromatic light will generally be preferred, e.g. laser light.
  • the light may be ultraviolet to near infra-red, e.g. 100 to 1300 nm wavelength however wavelengths above 300 nm and especially 600 to 1300 nm are preferred.
  • the contrast media of the invention should generally have a particle concentration of l- 10 "6 g/ml to 50 ' 10 "3 g/ml, preferably 5 • 10 "6 g/ml to 10 • 10 "3 g/ml. Dosages of from I- 10 "7 g/kg to 5 ' 10 "1 g/kg, preferably r 10 "6 g/kg to 5' 10 "2 g/kg will generally be sufficient to provide adequate contrast although dosages of 1' 10 "4 g/kg to 1' 10 "2 g/kg will normally be preferred.
  • Liposomes of average diameter 300 to 600 nm are prepared by a modification of the "Thin film hydration method" described by A.D. Bangham et al . "Methods in Membrane Biology (E.D. Korn, ed) , Plenum Press, NY, pp 1-68 (1974) .
  • the maximum batch size produced by the process is 2.0 L.
  • the hydrogenated phosphatidylcholine (lOg H- PC) and hydrogenated phosphatidyl serine (lg H-PS) are dissolved in chloroform/methanol/water (4:1:0.025, volume ratios) by shaking in a water bath at 70°C. The solvents are removed by rotary evaporation until a dry mixture of the PLs appear.
  • the phospholipid mixture is added to an aqueous, isotonic solution of iodixanol and tonicity agent at a temperature of 60-70°C, and the mixture is homogenised with a homomixer, (6000 rpm for 10 minutes at a temperature of 65-70°C) .
  • the liposomes formed are extruded once through three polycarbonate filters. 5.0 mL of the liposome suspension are filled in 20 mL glass bottles, closed with grey rubber stoppers and sealed with aluminium capsules. The liposomes are sterilised by autoclaving (at 121°C for 20 minutes) .
  • An oil-in-water emulsion is prepared from soybean oil lOg safflower oil lOg egg phosphatides 1.2g glycerin 2.5g water to osmolarity of 258 mOsm/L and pH of 8.3 to 9.0
  • a gas-filled (e.g. air filled) microbubble suspension with particle size 1 to 12 ⁇ m may be prepared with oleic acid and human serum albumin as the microbubble shell material .
  • a 216 ml sample of a 0.5% aqueous solution of sodium oleate was titrated with 0.1 N HCl so that the final pH was in the range 3.9-4.0.
  • the solution had become very turbid due to the formation of an oleic acid suspension.
  • the particle size as measured by optical microscopy was in the 0.1 micron range .
  • the suspension was pressurized to increase the solubility of the gas in the oleic acid suspension.
  • the suspension was placed in a 500 ml stirred autoclave (Zipperclave manufactured by Autoclave Engineers, Inc.) fitted with a 6 blade turbine-type impeller (from Dispersimax) .
  • the vessel was sealed and charged to 1000 psig air (typical pressure ranges were 900-1100 psig) .
  • the suspension was agitated at 1000 rpm (agitation ranged from 750-1500 rpm) for one hour at room temperature (23-25°C) . Typically the temperature rose 2-3°C during the run. Agitation was stopped, the vessel vented and the suspension was held for 30 minutes before use.
  • the particle size as measured by optical microscopy was in the 0.1 micron range.
  • HSA human serum albumin
  • 2g of a 25% aqueous solution of human serum albumin (HSA) was added to 28g of water and 20g of the emulsion described above.
  • the turbid solution was heated to 65°C while oxygen gas was bubbled in.
  • the solution was then stirred using an Omni-Stirrer (homogenizer) for 5 minutes at the mid-range setting.
  • the foamy mixture was poured into a separatory funnel and left to stand for 30 minutes.
  • the liquid was removed from the bottom and 10 ml of fresh 1% HSA solution was added to the foam. After 30 minutes the liquid was removed and 10 ml fresh 5% HSA solution was added so that the foam was resuspended in solution.
  • the liquid was quickly collected from the bottom.
  • the particles (microbubbles) had a diameter range of 1-12 microns with a wall thickness of 1-2 microns.
  • Encapsulated gas micropheres may be prepared according to WO-A- 95/01187 by mixing an aqueous solution of human serum albumin with a water insoluble gas such as a perfluoroalkane (e.g. dodecafluoropentane) .
  • a perfluoroalkane e.g. dodecafluoropentane
  • a polymer particle suspension may be prepared by dissolving the biodegradable polymer polyhydroxybutyrate-co-valerate in a suitable organic solvent such as acetone, methylene chloride and the like, precipitation in water and removal of the organic solvent by vacuum distillation or diafiltration.
  • Particle size may be selected to be within the range 0.05 ⁇ m to 10 ⁇ m by choice of surfactant stabilizers, rate of solvent evaporation, agitations as is well known in the art .
  • a solution of WIN 70177 (an iodinated contrast agent prepared according to Example 24 below) and, optionally fluoroscein in the molar ratio 100:1, optimally 50:1, most optimally 25:1, in DMSO (or DMF) is precipitated in water.
  • the resulting precipitate is milled as described in US-A-5145684 together with a surfactant stabilizer (eg. Pluronic F108 or Tetronic T-908 or 1508) to a particle size of 0.2 ⁇ m and dispersed in an aqueous medium to a contrast agent concentration of 0.5 to 25% by weight and a surfactant content of 0.1 to 30% by weight .
  • a cloud point modifier such as polyethylene glycol 400 (PEG 400) or propylene glycol as disclosed in US-A-5352459 may also be included to ensure stability on autoclave stabilization.
  • Phytochrome is added to an aqueous solution of sodium dodecyl sulphate (pH >10) .
  • the resulting solution is added to a stirred solution of acetic acid containing a surfactant (selected from PVP, pluronics and tetronics) and the mixture is diafiltered to remove soluble salts, excess acid etc. from the suspension yielding a dispersion of 10-100 nm particles.
  • a surfactant selected from PVP, pluronics and tetronics
  • ICG Indocyanine green
  • the ICG content used may be high (>0.5%) to produce mixed micelles or low ( ⁇ 0.5%) to produce micellar solutions of ICG.
  • ICG-concentrations of 0.2 to 0.5% are preferred.
  • a liposome suspension is prepared using a 0.01 M solution of indocyanine green and 5 to 10% of a phospholipid (10:1 ratio of lecithin to dipalmitoylphosphatidyl serine) . Preparation is effected by conventional techniques (eg. ultrasound) followed by extrusion through controlled pore size filters and diafiltration or microfluidisation. The resulting liposomes are steam sterilizable and are sterile filterable and have demonstrated physical stability under nitrogen for over six months.
  • An oil in water emulsion is prepared from lOg safflower oil, lOg sesame oil, 1.2g egg phosphatides, 2.5g glycerin, 0.5 to lOg photo-label (eg. fluorescein or indocyanine green) and water to lOOg total.
  • Emulsification is effected by conventional means and the resultant emulsion is sterile filtered through 0.2 ⁇ m sterile filters or steam sterilized using conventional means .
  • WIN 70146 an iodinated X-ray contrast agent prepared according to Example 23 below was added to each of 3 x 1.5 oz brown glass bottles containing approximately 12 ml of zirconium silicate, 1.1 mm diameter beads in an amount sufficient to be 15% (wt/vol %) of the final suspension.
  • Bottle A was also made 3% (wt/vol %) Pluronic F-68 while bottle B was made 3% (wt/vol%) ) Pluronic F-108 and bottle C was made 3% (wt/vol%) Tetronic T-908.
  • the resulting suspensions were milled at approx 150 rpm for a total of 9 days with estimates of particle size determined at various intervals as detailed below.
  • DOSS Dioctylsulfosuccinate sodium
  • WIN 70146 was prepared as in Example 10 and injected into the tail vein of mice at doses of 3 ml/kg, 15 ml/kg, and 30 ml/kg (ie. 0.45 g /kg, 2.25 gm/kg and 4.5 gm/kg) . No untoward effects were noted in any of the mice at any dose for a period of 7 days after which time the animals were sacrificed. Gross observation of these animals did not reveal any obvious lesions or disfigurations .
  • WIN 70146 was milled with 1.1 mm diameter zirconium silicate beads for 3 days under aseptic conditions. The concentration of this agent was 15% WIN 70146 in the presence of 4% Pluronic F-108. No additional salts or surfactants were added. The average particle size of the resulting nanoparticle suspension was 162 nm as determined by light scattering.
  • WIN 70146 was milled with 1.1 mm diameter zirconium silicate beads in the presence of Pluronic F-108 for 3 days. The final particle size was determined to be 235 nm. At this point, sterile PEG 400 was added to the suspension such that at completion, the formulation contained 15% (wt/vol%) WIN 70146, 3% (wt/vol%) Pluronic F-108 and 10% PEG 400. This formulation was then autoclaved under standard conditions (ie. 121 degrees C for 20 min.) resulting in a final particle size of 248 nm.
  • a nanoparticle suspension of WIN 70146 was prepared as in Example 10 using 4.25% F108/ 10% PEG 400 which after autoclaving resulted in particles with an average diameter of 228 nm. This suspension was then diluted in water to various levels listed below. The per cent of incident light transmitted was then determined for each suspension at several wavelengths (see below) . The suspensions were then dissolved by addition of methanol and examined for per cent transmitted light against an equivalent solvent blank. The results are given below. Per Cent Transmission at 632nm, 700nm and 820 nm of Both NanoParticulate WIN 70146 and Dissolved WIN 70146
  • suspensions are efficient light scattering agents which do not absorb significant amounts of incident light in these wavelength regions (ie., dissolved WIN 70146 does not absorb light above 600 nm) . Additional examination of the absorbance vs wavelength for the dissolved agent does not show any evidence of light absorbance from 600 to 800 nm while the nanoparticle agent shows a classic absorbance decay due to scattering of the incident light.
  • a formulation of WIN 70177 (an iodinated X-ray contrast agent prepared according to Example 24) was prepared as 15 gm of WIN 70177/100 ml of suspension and 4.25 gm of Pluronic F108/100 ml of suspension and 10 gm of PEG 400/100 ml of suspension. The suspension was milled for 5 days after which the average particle size was determined by light scattering to be about 235 nm. Stability testing in fresh rat plasma and simulated gastric fluid did not show any aggregation.
  • a nanoparticle suspension of WIN 70177 was prepared as in Example 15 using 4.25% F108/10% PEG 400 which after autoclaving resulted in particles with an average diameter of 236 nm. This suspension was then diluted in water to various levels listed below. The per cent of incident light transmitted was then determined for each suspension at several wavelengths (see below) . The suspensions were then dissolved by addition of methanol and examined for per cent transmitted light against an equivalent solvent blank. The results are given below.
  • a formulation of WIN 67722 (an iodinated X-ray contrast agent as described in US-A-5322679) was prepared as in Example 1 using 3% Pluronic F108 and 15% PEG 1450. The suspension was milled for 3 days and achieved a particle size of 213 nm (small fraction at 537 nm) as determined by light scattering with a Coulter N4MD particle sizer.
  • a nanoparticle suspension of WIN 67722 was prepared as in Example 17 using 3% Pluronic F108 and 15% PEG 1450 which after autoclaving gave particles with an average diameter of 214 nm. This suspension was then diluted in water to various levels listed below. The per cent of incident light transmitted was then determined for each suspension at several wavelengths (see below) . The suspensions were then dissolved by addition of methanol and examined for per cent transmitted light against an equivalent solvent blank. The results are given below.
  • Nanoparticle WIN 72115 (a fluorescent iodinated contrast agent as described in Example 21 below) was prepared by combining WIN 72115 and Pluronic F108 (BASF, Parsippany, NJ) in a glass jar at concentrations of 15 gm/lOO ml suspension and 3 gm/100 ml suspension. The jar was then half filled with 1.0 mm diameter zirconium silicate beads and sufficient water added to complete the required concentrations of agent/surfactant as noted above. Alternatively, the surfactant can be dissolved in the water before addition to the jar (with or without sterile filtration through 0.2 micron filters).
  • Pluronic F108 BASF, Parsippany, NJ
  • the jar is then rolled on its side for not less than 24 hours or more than 14 days at a rate of rotation sufficient to cause the beads within the jar to "cascade" down the walls of the jar as it turns (see US- A-5145684) .
  • the material is harvested from the jar and separated from the milling beads.
  • Nanoparticles of WIN 72115 prepared in this manner have an average particle size of 225 nm by light scattering.
  • WIN 72115 was designed to be excited with incident radiation from an Argon Ion laser (in the green, near 514 nm) and emit light at wavelengths above that value.
  • Argon Ion laser in the green, near 514 nm
  • illumination of the patient with green light would stimulate emission of light of a slightly different wavelength that could be used for diagnostic purposes.
  • the key features of this agent are that it can be prepared as nanoparticles, remain within the vasculature for greater than 15 minutes, provide both scattering and fluorescence contrast for light imaging .
  • a suspension of multilamellar liposomes formed in a solution of 40% (wt/vol%) iodixanol were injected into white rats which had been implanted with a hepatoma 9L tumor on their rear flank.
  • the injection was imaged using a time gated diode laser incident at 780 nm with detection of the scattering component at 180 degrees to the incident light using fiber optic cables and a phase sensitive detection device in the laboratory of Dr. Britton Chance at the University of Pennsylvania.
  • the liposome particles enhanced scattering in the tumor over the background signal by more than 4X at the dose administered (i.e. 3 ml/kg) . While not optimized, these data indicate the feasibility of contrast by scattering agents for light imaging.
  • a suspension of liposomes were prepared in the presence of 0.7 micrograms/ml of indocyanine green (ICG) and sterilized using steam and pressure.
  • the resulting particles had an average diameter of approximately 120 nm as determined by light scattering using a Horiba 910 particle sizing instrument.
  • these liposomes afforded significantly longer residence in the tumor of the fluorescent agent (i.e. the ICG) than observed with a homogeneous solution of ICG alone. This is useful for imaging in that signal averaging techniques can be applied to enhance the image as well as to mark sites of leaky vasculature .
  • contrast media for enhancement of laser Doppler measurement of blood flow in the skin
  • a sterile aqueous suspension containing 5- 20 mg of suspended particles of a dye e.g. 3,3'- diethylthiatricarbocyanine iodide
  • a dye e.g. 3,3'- diethylthiatricarbocyanine iodide
  • the mean particle size is preferably about 800 nm and as suspension medium is preferably used physiological saline.
  • the measurement of blood flow is made after the concentration of contrast agent particles in the blood has stabilized. Measurement may be made with a standard laser Doppler instrument, for example that from Lisca Development AB, Kinkoping, Sweden, that optionally may be modified to incorporate a laser source operating at 830 or 780 nm (see Abbot et al . , J. Invest. Dermatol., 107: 882-886 (1996)).
  • a standard laser Doppler instrument for example that from Lisca Development AB, Kinkoping, Sweden, that optionally may be modified to incorporate a laser source operating at 830 or 780 nm (see Abbot et al . , J. Invest. Dermatol., 107: 882-886 (1996)).
  • contrast media for enhancement of measurement of blood flow through the skin with confocal microscopy
  • a sterile aqueous suspension containing 5- 20 mg of dye e.g. 3 , 3 ' -diethylthiatricarbocyanine iodide
  • the mean particle size is preferably about 800 nm and as suspension medium is preferably used physiological saline .
  • the measurement of blood flow is made by following the movement of the particles through the capillaries with the confocal microscope.
  • Solution A was prepared by dissolving 216 g sorbitol and 5084.4 g Iodixanol to 12 1 water-for-injection (WFI) under continuous stirring at approximately 90°C. The cooled solution was filtered through an 0.2 ⁇ m sterile filter.
  • Solution B was prepared by dissolving 121 g TRIS and 14.05 g sodium calcium edetate (89%) in about 200 ml WFI at 40°C. The pH was adjusted to between 7.2 and 7.4 with 5M hydrochloric acid, then water was added to 500 ml. The cooled solution was filtered through an 0.2 ⁇ m sterile filter.
  • the collected liposomal concentrate was mixed with solution A in a proportion of 4:1.
  • Solution B was then added such that the final concentration of TRIS was 1 mg/ml .
  • the final product contained 400 mg/ml Iodixanol, 17 mg/ml sorbitol, 56.3 mg/ml phospholipid mixture (PC: PS at 10:1), 1 mg/ml TRIS, 0.1 mg/ml sodium calcium edetate, hydrochloric acid for pH adjustment and WFI.
  • the particle-size distribution of the liposomes ranged from 259 to 1900 nm with a maximum at 738 ⁇ 216 nm. There was about 80 mg encapsulated iodine per milliliter.
  • the imaging device was an in vivo confocal microscope at the Wellman Laboratories of Photomedicine that operates at a wavelength of 1064 nm through a 0.9 aperture pasted on the ear of an anesthesized 400 g albino rat .
  • the aperture was covered by water to reduce scattering from the stratum corneum.
  • Prior to the injection of the contrast agent blood flow through a single capillary was detected by scanning across the imaging field and by variation of the depth of view.
  • the contrast agent (0.175 ml) was injected under a low- power microscope through a femoral vein that was exposed by a skin incision. Imaging began again within 5 minutes . The same blood vessel seen before was again detected, but in addition many more vessels were visible, some at depths as great as 150 ⁇ m. Vessels were still clearly apparent after 25 minutes. After 45 minutes blood vessels could still be found, but with diminished intensity.
  • blood vessels resemble other features of the tissue.
  • a blood vessel is differentiated from surrounding tissue by clear movement of plasma and cells within the capillary.
  • the contrast agent serves to make this movement more obvious .
  • Figure 1 shows four images recorded with confocal microscopy from the ear of an albino rat after injection in a femoral vein with 0.175 ml of CTP-10 formulation, as described above.
  • blood flow in the pathways indicated by arrows was visible up to 45 minutes following injection. Without contrast agent blood flow was visible in only a few isolated pathways (not shown) .
  • Intralipid is a commercially available emulsion of egg phosphatidylcholine and glycerin.
  • the average particle size in the product used was 310 nm.
  • Imaging after injection of Intralipid was done 2 hours and 45 minutes after the albino rat had been injected with CTP-10. Capillaries in the confocal image were once again rare and difficult to find. Injection with 0.45 ml of the Intralipid was done 45 minutes later, and imaging was begun within 3 minutes. Once again, capillaries had become readily apparent as a result of the presence of the contrast agent in the blood.
  • the imaging device is an in vivo confocal microscope operating at a wavelength of 1064 nm through an 0.9 aperture pasted on the ear of an anesthesized albino rat .
  • the contrast agent is a suspension of gas-filled bubbles similar to those sold commercially for use as contrast agents for untrasound imaging.
  • the particle size is 2 to 4 microns.
  • the bubbles are resuspended in sterile water at a concentration of 10 mg/ml with agitation for 3 hours at a rate of 300 revolutions/min before use.
  • the solution is injected in a femoral vein exposed by skin incision at a dose of 50 microliter per kilogram body weight prior to imaging. Blood flow through the capilaries appears as a bright stream of fluid following injection.

Abstract

L'invention concerne l'utilisation de matériaux en tant qu'agents de contraste dans des techniques d'imagerie in vivo basées sur la lumière et mettant en application la microscopie optique.
PCT/GB1998/001248 1997-04-29 1998-04-29 Agents de contraste utilises dans des techniques d'imagerie basees sur la lumiere WO1998048846A1 (fr)

Priority Applications (3)

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EP98919339A EP0979107A1 (fr) 1997-04-29 1998-04-29 Agents de contraste utilises dans des techniques d'imagerie basees sur la lumiere
AU72216/98A AU7221698A (en) 1997-04-29 1998-04-29 Light imaging contrast agents
JP54675198A JP2001526650A (ja) 1997-04-29 1998-04-29 光画像造影剤

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US84858697A 1997-04-29 1997-04-29
US08/984,771 US6159445A (en) 1994-07-20 1997-12-04 Light imaging contrast agents
GB9727124.1 1997-12-22
GBGB9727124.1A GB9727124D0 (en) 1997-12-22 1997-12-22 Compounds
US3528598A 1998-03-05 1998-03-05
US08/848,586 1998-03-05
US08/984,771 1998-03-05
US09/035,285 1998-03-05

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