WO2013186735A2 - Détection photothermique - Google Patents

Détection photothermique Download PDF

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Publication number
WO2013186735A2
WO2013186735A2 PCT/IB2013/054849 IB2013054849W WO2013186735A2 WO 2013186735 A2 WO2013186735 A2 WO 2013186735A2 IB 2013054849 W IB2013054849 W IB 2013054849W WO 2013186735 A2 WO2013186735 A2 WO 2013186735A2
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Prior art keywords
another embodiment
tissue
nanoparticles
irradiating
laser
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PCT/IB2013/054849
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English (en)
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WO2013186735A3 (fr
Inventor
Moshe Prof. SINVANI
Zeev Prof. ZALEVSKY
Rachela Dr. POPOVTZER
Kobi JAKOBSOHN
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Bar-Ilan Research And Development Company Ltd.
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Publication of WO2013186735A2 publication Critical patent/WO2013186735A2/fr
Publication of WO2013186735A3 publication Critical patent/WO2013186735A3/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
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04N—PICTORIAL COMMUNICATION, e.g. TELEVISION
    • H04N23/00—Cameras or camera modules comprising electronic image sensors; Control thereof
    • H04N23/20—Cameras or camera modules comprising electronic image sensors; Control thereof for generating image signals from infrared radiation only
    • H04N23/23—Cameras or camera modules comprising electronic image sensors; Control thereof for generating image signals from infrared radiation only from thermal infrared radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • 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 invention relates to photothermal detection of cell clusters utilizing gold nanoparticles and to a system which includes a thermal imaging camera, laser irradiating device, and gold nanoparticles.
  • Histopathologic evaluation of surgical specimens is a well established technique for disease identification, and has remained relatively unchanged since its clinical introduction. Although it is essential for clinical investigation, histopathologic identification of tissues remains a time consuming and subjective technique, with unsatisfactory levels of inter- and intra-observer discrepancy.
  • Cancer is a leading cause of death worldwide.
  • One of the critical problems in cancer management is local cancer recurrence. Between 20-30 percent of patients who undergo tumor resection surgery require re-operation because of incomplete excision.
  • tumor margins are examined using conventional histological tests which are being mostly performed as a post-surgical procedure.
  • few methods for real time intra- operative tumor margin detection were developed with relative success, such as diffusive reflectance methods radiofrequency based detection and targeted fluorescent imaging.
  • NIR near infrared
  • Particles such as fluorescent dyes, gold nanoshells and gold nanoparticles (GNP) were utilized either as diagnostic tool or as photothermal therapy mediated agents.
  • GNP As a diagnostic tool, GNP gained much attention due to their biocompatibility, their relatively easy fabrication and bioconjugation with biomolecules for targeting, and their unique optical properties; they have an enhanced optical extinction coefficient as compared to conventional fluorescent dyes, and by changing their size and aspect ratio, their surface plasmon resonance (SPR) wavelength and absorption to scattering coefficient ratio can be tuned and controlled. Therefore, nanoparticles have been vastly utilized as NIR, photoacoustic, Raman scattering and diffusion reflection imaging contrast agents.
  • SPR surface plasmon resonance
  • GNP were utilized as phototheraial therapy mediated agents.
  • the absorption properties of GNP in the SPR wavelength are used to elevate temperature to 50°C and above, usually by using lasers with high optical outputs (above 10W/cm 2 ) for about 10 minutes, in order to achieve effective denaturation and coagulation of cellular proteins and cell death.
  • the present invention provides a method for in- vivo imaging a tissue, comprising the steps of: (a) introducing a composition comprising gold nanoparticles into the tissue; (b) selectively increasing the temperature of the nanoparticles by up to 5°C comprising irradiating the tissue by laser; and (c) in-vivo imaging the tissue comprising the nanoparticles by a thermal imaging camera, thereby imaging a tissue.
  • irradiating the tissue by laser is irradiating at 500 to 900nm wavelength.
  • irradiating is irradiating at 10 to 100 joules per square cm (J/cm 2 ).
  • irradiating is irradiating at 1 to 10 Watts per square cm (W/ cm 2 ) for about 1-10 seconds.
  • the laser operates in pulsed beam having temporal width less than or equal to 0.8 psec.
  • the method further includes interfering the back scattered light with a reference, wherein the reference is the reference used for irradiating the tissue.
  • the present invention further provides that the gold nanoparticles comprise a gold nucleus coated with thiol-polyethylene-glycol (SH- PEG-COOH) and a heterofunctional polyethylene-glycol.
  • thermal imaging camera comprises temperature sensitivity of at least 0.1 degree Celsius, spatial resolution of 0.9 mm to 0.1 mm, thermal radiation sensitivity at a wavelength range of 8 to 14 ⁇ m, or any combination thereof.
  • the present invention further provides that the tissue comprises cancerous cells.
  • the present invention further provides a system for in- vivo imaging a tissue comprising gold nanoparticles, comprising: (a) a composition comprising cellular gold nanoparticles; (b) an irradiation device configured to irradiate at 10 to 100 joules per square cm (J/cm 2 ); and (c) a thermal imaging camera configured to in-vivo image the tissue comprising the nanoparticles.
  • Figure 1 Optical setup scheme.
  • the laser radiation raises the temperature by ⁇ and the thermal camera read the temperature field by sensing the thermal radiation in the long IR region.
  • Figure 2 A graph showing the absorbance spectra of GNS (line) and GNR (dashed line) (2A). Micrographs showing TEM image of 30 nm GNS (2B) and 25 nm X 65 nm GNR (2C, scale bar 100nm).
  • Figure 3 Is a graph showing the temperature elevation as a function of the irradiation time with 663nm laser, for different concentration of GNR in aqueous solution. The graph reaches a plateau after approximately 5 seconds.
  • Figure 4 Are graphs showing temperature difference as a function of the concentration of GNS (4A) and GNR (4B), for the two lasers. The temperature is defined after 5 seconds of laser irradiation, when the temperature curves have reached a plateau. The laser optical intensity on the sample was 10W/cm 2 for both lasers.
  • Figure 5 Are thermal images of a sample made of two halves of cylindrical solid phantoms joint together, one with GNR and the other without. Image (5 A) was taken before the laser incitation. The border in-between the phantoms are shown by a dashed strait line. The elliptical contour shows the place where the laser beam aims to be on the sample. Images (5B) and (5C) were taken after 10 seconds and five minutes of laser irradiance, respectively. It can be seen that the temperature of the part of the sample with the GNR, rise up compare to that of the part without GNR.
  • Figure 6 Is a graph showing temperature elevation of GNR bioconjugated to A431 cancer cell line (GNR-A431) compared to A431 cells without GNR, in solution. It can be seen that the bioconjugated GNR-A431 has a distinct heating profile compared to the A431 cells.
  • Figure 7 Is a schematic sketch of a proposed configuration.
  • the present invention provides a method for in- vivo imaging a tissue in a subject in need thereof, comprising the steps of: (a) introducing gold nanoparticles to the tissue; (b) selectively increasing the temperature of the nanoparticles by 1-7°C comprising irradiating the tissue by laser; and (c) in-vivo imaging the tissue comprising the nanoparticles by a thermal imaging camera, thereby imaging a tissue.
  • nanoparticles as described herein can be of any shape known to one of skill in the art.
  • nanoparticles are nanorods.
  • nanoparticles are nanospheres.
  • nanoparticles of the present invention are gold nanospheres (GNS).
  • nanoparticles of the present invention comprise a diameter of up to 90 nm.
  • nanoparticles of the present invention comprise a diameter of up to 80 nm.
  • nanoparticles of the present invention comprise a diameter of up to 70 nm.
  • nanoparticles of the present invention comprise a diameter of up to 60 nm.
  • nanoparticles of the present invention comprise a diameter of up to 50 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of up to 40 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of up to 30 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of 15-100 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of 15-90 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of 20-80 nm. In another embodiment, nanoparticles of the present invention comprise a diameter of 20-60 nm.
  • the method of the present invention provides in-vivo tissue or tumor targeting using a passive targeting mechanism known as enhanced permeability and retention (EPR).
  • EPR enhanced permeability and retention
  • the present invention provides that a pathological tissue such as a tumor or a degenerative tissue, comprise leaky vasculature which enables systemically circulating nanoparticles to extravasate and accumulate.
  • the method of the present invention provides in-vivo tissue or tumor active targeting which exploits, for example, the over- expression of surface receptors on cancer cells by providing targeting ligands that can engage these receptors.
  • the targeting ligand or molecule is an antibody.
  • the targeting ligand or molecule is anti-VEGF antibody.
  • the targeting ligand or molecule is anti-EGFR antibody.
  • the targeting ligand is any protein targeting a cancer cell.
  • gold nanoparticles comprise a gold nucleus. In another embodiment, gold nanoparticles comprise a gold nucleus coated with a biocompatible polymer. In another embodiment, gold nanoparticles comprise a gold nucleus coated with a non-toxic polymer. In another embodiment, gold nanoparticles comprise a gold nucleus coated with a non-toxic polymer that prevents agglomeration. In another embodiment, gold nanoparticles comprise a gold nucleus coated with a non-toxic polymer utilized as anchoring means for selective targeting molecules such as but not limited to antibodies. In another embodiment, gold nanoparticles comprise a gold nucleus coated with a biopolymer. In another embodiment, gold nanoparticles are pegylated gold nanoparticles. In another embodiment, the selective targeting molecules are covalently conjugated to the coating.
  • gold nanoparticles comprise a coating aimed at increasing the in vivo tumor targeting competence.
  • gold nanoparticles of the present invention comprise optical and thermal properties that make them effective contrast and photo-thermal agents.
  • gold nanoparticles of the present invention are neutral or slightly negatively charged.
  • gold nanoparticles of the present invention are slightly positively charged.
  • the coating layer of the gold nanoparticles comprises thiol-polyethylene-glycol, a heterofunctional polyethylene-glycol, or a combination thereof. In another embodiment, thiol-polyethylene-glycol is about 5 kDa. In another embodiment, the coating layer of the gold nanoparticles comprises at least 65% thiol- polyethylene-glycol. In another embodiment, the coating layer of the gold nanoparticles comprises at least 70% thiol-polyethylene-glycol. In another embodiment, the coating layer of the gold nanoparticles comprises at least 75% thiol- polyethylene-glycol.
  • the coating layer of the gold nanoparticles comprises at least 80% thiol-polyethylene-glycol. In another embodiment, the coating layer of the gold nanoparticles comprises at least 85% thiol- polyethylene-glycol. In another embodiment, the coating layer of the gold nanoparticles comprises at least 90% thiol-polyethylene-glycol.
  • heterofunctional polyethylene-glycol is about 3.4 kDa.
  • the coating layer of the gold nanoparticles comprises up to 35% heterofunctional polyethylene-glycol.
  • the coating layer of the gold nanoparticles comprises up to 30% heterofunctional polyethylene-glycol.
  • the coating layer of the gold nanoparticles comprises up to 25% heterofunctional polyethylene-glycol.
  • the coating layer of the gold nanoparticles comprises up to 20% heterofunctional polyethylene-glycol.
  • the coating layer of the gold nanoparticles comprises up to 15% heterofunctional polyethylene-glycol.
  • gold nanoparticles of the invention are functionalized with hybrid biomolecules.
  • gold nanoparticles are conjugated with tumor-avid peptides or other biomolecules.
  • gold nanoparticles are labeled.
  • labeling is intended to be broadly interpreted, and may include attachment or conjugation.
  • gold nanoparticles have high reactivity with sulfhydryl (SH) groups; example methods of the invention utilize a biomolecule having a sulfhydryl group.
  • cysteine is used to label gold nanoparticles according to methods known to one of skill in the art.
  • the invention includes conjugating of the gold nanoparticles with a biomolecule such as a protein to develop a viable gold nanoparticle labeling approach for potential applications such as labeling target specific biological proteins or peptides with gold nanoparticles.
  • gold nanoparticles are directed to tumor sites for potential applications in the development of cancer diagnostic/therapeutic agents.
  • methods of the invention include steps of conjugating gold nanoparticles with a peptide.
  • conjugating to link gold nanoparticles with a tumor- avid peptide are beneficial and advantageous for the design and development of cancer specific diagnostic agent.
  • conjugation protocols for labeling nanoparticles of gold are known in the art.
  • methods of the invention include introduction of additional spacer functions (for example, in the form of 5- aminopentanoic acid) to the N-terminal region of a peptide to avoid interference of the chelating moiety with the receptor binding C-terminus of the peptide.
  • steps that maximize binding of gold nanoparticle labeled with a peptide with receptors over expressed on cancer cells are used.
  • tissue includes a cluster of cells.
  • tissue includes an aggregate of cells in an organism that have similar structure and function.
  • tissue is an epithelial tissue, a nerve tissue, a connective tissue, a muscle, a vascular tissue, a cancerous tissue, a diseased tissue, or a pathological tissue.
  • tissue includes a cluster of cells of at least 2 mm in size.
  • tissue includes a cluster of cells of at least 5 mm in size.
  • tissue includes a cluster of cells of at least 8 mm in size.
  • tissue includes a cluster of cells of at least 10 mm in size.
  • tissue includes a cluster of cells of at least 15 mm in size.
  • a diseased tissue or a pathological tissue includes cellular abnormalities used as disease indicators.
  • a diseased tissue or a pathological tissue is a disorganized tissue such as but not limited to a neoplastic tissue, degenerative tissue, or a hypoxic tissue.
  • a diseased tissue or a pathological tissue is characterized by elevated cell death or apoptosis.
  • a diseased tissue or a pathological tissue is an injured tissue.
  • a diseased tissue or a pathological tissue is a damaged tissue.
  • a diseased tissue or a pathological tissue is an inflamed tissue.
  • a diseased tissue or a pathological tissue is a tissue undergoing degeneration.
  • the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging a tissue or a portion thereof. In another embodiment, the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging a tissue or a portion thereof during a medical procedure. In another embodiment, the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging a tissue or a portion thereof during surgery. In another embodiment, the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging a tumor or tumor margins. In another embodiment, the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging metastasis.
  • the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging clusters of inflammatory and/or immune cells.
  • the method and system of the present invention provide a long desired, non-invasive, fast solution for imaging disorganized, pathological cellular structures such as but not limited to the CNS in Alzheimer's disease or muscle atrophy.
  • the term “introducing” is injecting the nanoparticles to the tissue. In another embodiment, the term “introducing” is injecting the nanoparticles to the tissue's surrounding. In another embodiment, the term “introducing” is systemically introducing the nanoparticles. In another embodiment, the term “introducing” is administering the nanoparticles according to the desired medical procedure.
  • selectively increasing the temperature of the nanoparticles is selectively increasing the temperature of the nanoparticles present within the target tissue. In another embodiment, selectively increasing the temperature of the nanoparticles is selectively increasing the temperature of the nanoparticles present within the cells or bound to the cells or to the target tissue. In another embodiment, selectively increasing the temperature of the nanoparticles is by 1-7°C. In another embodiment, selectively increasing the temperature of the nanoparticles is by 1-5°C. In another embodiment, selectively increasing the temperature of the nanoparticles is by 1-4°C. In another embodiment, selectively increasing the temperature of the nanoparticles is by 2-5°C. In another embodiment, selectively increasing the temperature of the nanoparticles is by 2-4°C.
  • selectively increasing the temperature lasts 1-40 seconds. In another embodiment, selectively increasing the temperature lasts 10-35 seconds. In another embodiment, selectively increasing the temperature lasts 1-20 seconds. In another embodiment, selectively increasing the temperature lasts 1-15 seconds. In another embodiment, selectively increasing the temperature lasts 2-12 seconds. In another embodiment, selectively increasing the temperature lasts 2-10 seconds. In another embodiment, selectively increasing the temperature lasts 2-8 seconds. In another embodiment, selectively increasing the temperature lasts 3-6 seconds.
  • selectively increasing the temperature is irradiating at a wavelength of 500 to 900nm. In another embodiment, selectively increasing the temperature is irradiating at a wavelength of 530 to 900nm. In another embodiment, selectively increasing the temperature is irradiating at a wavelength of 650 to 900nm. In another embodiment, selectively increasing the temperature is irradiating at a wavelength of 650 to 850nm. In another embodiment, selectively increasing the temperature is irradiating at a wavelength of 650 to 750nm. In another embodiment, selectively increasing the temperature is irradiating at a wavelength of 700 to 850nm.
  • irradiating is irradiating for 1-15 seconds. In another embodiment, irradiating is irradiating for 2-12 seconds. In another embodiment, irradiating is irradiating for 2-10 seconds. In another embodiment, irradiating is irradiating for 2-8 seconds. In another embodiment, irradiating is irradiating for 3-6 seconds.
  • irradiating is irradiating at 1 to 100 joules per square cm
  • irradiating is irradiating at 10 to 50 J/cm 2 . In another embodiment, irradiating is irradiating at 20 to 70 J/cm 2 . In another embodiment, irradiating is irradiating at 30 to 80 J/cm 2 . In another embodiment, irradiating is irradiating at 20 to 40 J/cm 2 . In another embodiment, irradiating is irradiating at 1 to 20 Watts per square cm
  • irradiating is irradiating at 1 to 10 W/ cm 2 . In another embodiment, irradiating is irradiating at 1 to 5 W/ cm 2 . In another embodiment, irradiating is irradiating at 2 to 8 W/ cm 2 . In another embodiment, irradiating is irradiating at 3 to 6 W/ cm 2 .
  • irradiating is laser irradiating.
  • the laser irradiation is two-photon laser irradiation.
  • the laser is a swept laser source.
  • the laser source comprises a polygon- based tunable filter.
  • the laser source has a sweeping range of at least 100 nm centered at about 1300 nm. In another embodiment, the sweeping range is of at least 70 nm centered at 1000 to 1500 nm. In another embodiment, the laser is pulsed laser.
  • laser is a a red diode laser. In another embodiment, laser is a green Nd:YAG diode.
  • the laser source has an axial resolution of 3-25 ⁇ m in a tissue. In another embodiment, the laser source has an axial resolution of 3-10 ⁇ m in a tissue. In another embodiment, the laser source has an axial resolution of 6-12 ⁇ m in a tissue. In another embodiment, the laser source has an axial resolution of 7-9 ⁇ m in a tissue.
  • the laser source has an average output power of 30-80 mW. In another embodiment, the laser source has an average output power of 30-50 mW. In another embodiment, the laser source has an average output power of 45-55 mW.
  • the laser source is a Cladding-pumped Fiber Laser. In another embodiment, the laser source is a diode-laser-based.
  • the imaging scan area is 1x1 mm 2 to 20x20 mm 2. In another embodiment, the imaging scan area is 3x3 mm 2 to 10x10 mm 2. In another embodiment, the imaging scan area is 6x6 mm 2 to 10x10 mm 2.
  • the imaging depth in tissue is 0.2 to 5 mm. In another embodiment, the imaging depth in tissue is 0.5 to 5 mm. In another embodiment, the imaging depth in tissue is 0.5 to 3 mm. In another embodiment, the imaging depth in tissue is 1 to 3 mm. In another embodiment, the imaging depth in tissue is 0.5 to 5 mm. In another embodiment, in-vivo imaging a tissue is non-invasive imaging. In another embodiment, in-vivo imaging is performed utilizing a thermal imaging device. In another embodiment, a thermal imaging device is a thermal imaging camera.
  • the present invention utilizes the absorption properties of GNPs and not their scattering properties.
  • the present invention provides an imaging technique utilizing the absorption properties of GNPs rather than their scattering properties, leading to high contrast between labeled structures (such as targeted cancer cells) and normal background tissue.
  • a thermal imaging device comprises temperature sensitivity of at least 0.8 degree Celsius. In another embodiment, a thermal imaging device comprises temperature sensitivity of at least 0.6 degree Celsius. In another embodiment, a thermal imaging device comprises temperature sensitivity of at least 0.5 degree Celsius. In another embodiment, a thermal imaging device comprises temperature sensitivity of at least 0.3 degree Celsius. In another embodiment, a thermal imaging device comprises temperature sensitivity of at least 0.1 degree Celsius.
  • a thermal imaging device comprises spatial resolution of at least 2 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 1.5 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 1 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 0.8mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 0.6 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 0.5 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 0.3 mm. In another embodiment, a thermal imaging device comprises spatial resolution of at least 0.2 mm. In another embodiment, a thermal imaging device comprises spatial resolution of 1 to 0.1 mm.
  • a thermal imaging device comprises radiation sensitivity at a wavelength range of 1 to 20 ⁇ m. In another embodiment, a thermal imaging device comprises radiation sensitivity at a wavelength range of 2 to 16 ⁇ m. In another embodiment, a thermal imaging device comprises radiation sensitivity at a wavelength range of 4 to 12 ⁇ m. In another embodiment, a thermal imaging device comprises radiation sensitivity at a wavelength range of 5 to 10 ⁇ m.
  • a thermal imaging device comprises magnification of up to x2 to x100. In another embodiment, a thermal imaging device comprises magnification of x2 to x50. In another embodiment, a thermal imaging device comprises magnification of x10 to x50. In another embodiment, a thermal imaging device comprises magnification of up to x100. In another embodiment, a thermal imaging device comprises magnification of up to x80. In another embodiment, a thermal imaging device comprises magnification of up to x50. In another embodiment, a thermal imaging device comprises magnification of up to x40. In another embodiment, a thermal imaging device comprises magnification of up to x25.
  • the invention further provides analysis of data including the extraction of the non scattered data via interference.
  • the invention further provides analysis of data in scattering resonance of the nanoparticles rather than only in absorption resonance.
  • image analysis programs that reduce interference are utilized according to the method and system of the invention.
  • the present invention further provides a system for in- vivo imaging a tissue comprising gold nanoparticles, comprising (a) a composition comprising cellular gold nanoparticles; (b) an irradiation device configured to irradiate at 10 to 100 joules per square cm (J/cm 2 ); and (c) a thermal imaging camera configured to in-vivo image the tissue comprising the nanoparticles.
  • cellular gold nanoparticles are nanoparticles that can be engulfed by a cell.
  • cellular gold nanoparticles are nanoparticles that can be internalized by a cell.
  • cellular gold nanoparticles are intracellular gold nanoparticles.
  • cellular gold nanoparticles are nanoparticles that are capable of binding a cell. In another embodiment, cellular gold nanoparticles are nanoparticles that are capable of binding an extra-cellular matrix component. In another embodiment, cellular gold nanoparticles are cellular nanoparticles. In another embodiment, cellular gold nanoparticles are attached to a cell. In another embodiment, cellular gold nanoparticles are attached to a specific molecule present on the cell's surface cell. In another embodiment, cellular gold nanoparticles are intracellular particles present within the cell's cytoplasm.
  • the present invention further provides a kit for in-vivo imaging a tissue
  • the kit comprises (a) a composition comprising cellular gold nanoparticles; (b) an irradiation device configured to irradiate at 10 to 100 joules per square cm (J/cm 2 ); (c) a thermal imaging device configured to in-vivo image the tissue comprising the nanoparticles (d) an instruction manual for: (1) administering the nanoparticles to a subject; (2) operating the irradiating device and the thermal imaging device.
  • methods of the present invention enable an accurate photo-thermal detection of cancerous tumor margins.
  • this detection allows to in-vivo distinguish between cancerous and non-cancerous cells within a target tissue, for example during, before, or after a surgical tumor excision procedure. Then, advantageously, the cancerous cells are excised in a relatively accurate manner.
  • nano-particles such as gold nano-particles (GNPs) are introduced into the target tissue.
  • the nanoparticles are free of specific targeting molecules.
  • nanoparticles free of specific targeting molecules are primarily internalized by cancerous cells.
  • the nanoparticles comprise a targeting molecule which facilitates the specific association between the nanoparticle and a cell comprising the specific ligand recognizing the targeting molecule.
  • the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings will be relatively high. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x2. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x3. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x4. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x5.
  • the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings will be at least x7. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x10. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x25. In some embodiments, the concentration of the nanoparticles within the tumor, as opposed to its non-cancerous surroundings, will be at least x50.
  • the difference in nanoparticles concentrations between a cluster of diseased cells and healthy cells is readily visible according to the methods disclosed herein.
  • the target tissue is then irradiated for few seconds, for example using laser, so as to selectively raise the temperature of the nano-particles.
  • An infrared and/or near-infrared imaging device may be used to receive photons emitted from the nanoparticles, thereby precisely detecting the margins of the cancerous tumor.
  • the detection is conducted whilst the temperature of the target tissue is slightly elevated (1-5°C). This feature prevents or at least mitigates damage to the irradiated non-cancerous tissue or to the surrounding tissue.
  • the target tissue is heated to a temperature of approximately (namely, +5%) 40°C or less, such that cell viability of non-diseased (such as cancerous) cells is not affected or is minimally affected.
  • Some embodiments utilize a photothermal imaging technique which overcomes the inevitable background signal caused by light scattering from the target tissue.
  • This imaging technique optionally uses the absorption properties of the nano-particles rather than their scattering properties, which scattering properties are known to suffer from relatively high background noise and low contrast.
  • the photothermal imaging is combined with photothermal therapy, instead of or in addition to surgical excision of the tumor or parts thereof. Irradiation of the target tissue, for example using laser, may selectively destruct the cancer cells that were targeted with GNPs.
  • this photothermal therapy may be conducted within the same clinical setting as the photothermal imaging, namely - in the same surgical procedure.
  • the method and system of the invention include a new optical configuration allowing to image in high resolution clusters of cells and or borders of a tumor, in-vivo, in a non-invasive manner.
  • the method and system of the invention include heating the nanoparticles of the invention with pulsed laser.
  • imaging is performed with infra-red camera.
  • the invention further provides means for avoiding blurring the tissue structure or the border of a tumor due to the scattering of the tissue.
  • the invention further provides extracting the first arriving photons scattered from the inspected tissue.
  • scattering of light in a tissue is provided in example 4.
  • a femto second laser is used such that the temporal width of its pulses is less than 0.8 [psec] thus even the first scattering photons are filtered out and only the first arriving light i.e. the photons that passed the tissue without being scattered at all arrive the camera/detector.
  • a femto second laser is used such that the temporal width of its pulses is less than 0.6 [psec] thus even the first scattering photons are filtered out and only the first arriving light i.e. the photons that passed the tissue without being scattered at all arrive the camera/detector.
  • a femto second laser is used such that the temporal width of its pulses is less than 0.5 [psec] thus even the first scattering photons are filtered out and only the first arriving light i.e. the photons that passed the tissue without being scattered at all arrive the camera/detector.
  • a femto second laser is used such that the temporal width of its pulses is less than 0.44 [psec] thus even the first scattering photons are filtered out and only the first arriving light i.e. the photons that passed the tissue without being scattered at all arrive the camera/detector.
  • the first arriving light photons are the one that have the high spatial resolution and they are separated from the photons that are spatially blurred due to multiple scattering effects.
  • the nanoparticles illuminating the tissue or the tumor from a distance and through other body tissues (such as the skin) using the pulsed laser configuration at the absorption resonance of the nanoparticles results in controlled heating of the nanoparticles.
  • 0.5-7°C degrees heating and inspecting the nanoparticles with infra red (IR) camera allows high quality detection of the boundaries of the tissue/tumor.
  • the IR photons are scattered on their way back to the detector/camera and thus although the heating process of the nanoparticles is used to detect the boundaries, at reality the boundaries are blurred due to this scattering process.
  • proper adaptation of the irradiation/illumination and detection scheme is performed to overcome this drawback.
  • a pulsed beam having temporal width less than 0.4 psec is generated and then interfering the back scattered light with the reference that was also used for the illumination/irradiation of the tissue (see Fig. 7).
  • the first detection (arriving light information) is extracted not only via pulsed laser and holography/interference but also by sending non-pulsed light having very short coherence length corresponding to the temporal length mentioned above (less than 0.4 psec).
  • a non pulsed broad band source to have sufficiently short coherence length is used and the extracted energy is very low and the SNR of the captured image is not sufficient.
  • nanoparticles are intravenously injected in doses of 1-50 ⁇ L/g of nanoparticles (nanoparticles: 2.5 x 10 8 -2.5 x 1012 particles/ ⁇ L).
  • nanoparticles are administered in a single dose.
  • nanoparticles are administered in multiple-doses.
  • nanoparticles are administered in 1-10 doses.
  • nanoparticles are administered in 3-6 doses.
  • nanoparticles are administered once a day.
  • nanoparticles are administered once every 2 days.
  • nanoparticles are administered twice a day.
  • a composition comprising nanoparticles is a "pharmaceutical composition” and includes chemical components such as physiologically suitable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of the nanoparticles to an organism.
  • physiologically acceptable carrier and “pharmaceutically acceptable carrier” which be interchangeably used refer to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An adjuvant is included under these phrases.
  • one of the ingredients included in the pharmaceutically acceptable carrier can be for example polyethylene glycol (PEG), a biocompatible polymer with a wide range of solubility in both organic and aqueous media (Mutter et al. (1979).
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of the nanoparticles.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • suitable routes of administration include oral, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • Peroral compositions in some embodiments, comprise liquid solutions, emulsions, suspensions, and the like.
  • pharmaceutically- acceptable carriers suitable for preparation of such compositions are well known in the art.
  • liquid oral compositions comprise from about 0.0012% to about 0.933% of the nanoparticles, or in another embodiment, from about 0.033% to about 0.7%.
  • compositions for use in the methods of this invention comprise solutions or emulsions, which in some embodiments are aqueous solutions or emulsions comprising a safe and effective amount of the nanoparticles of the present invention.
  • the pharmaceutical compositions are administered by intravenous, intra-arterial, or intramuscular injection of a liquid preparation.
  • liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
  • the pharmaceutical compositions are administered intravenously, and are thus formulated in a form suitable for intravenous administration.
  • the pharmaceutical compositions are administered intra-arterially, and are thus formulated in a form suitable for intraarterial administration.
  • the pharmaceutical compositions are administered intramuscularly, and are thus formulated in a form suitable for intramuscular administration.
  • compositions of the present invention are manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention is formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically.
  • formulation is dependent upon the route of administration chosen.
  • injectables, of the invention are formulated in aqueous solutions.
  • injectables, of the invention are formulated in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the preparations described herein are formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • formulations for injection are presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • compositions are suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • polymers e.g. poloxamers or poloxamines
  • preparation of effective amount or dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models and such information can be used to more accurately determine useful doses in humans.
  • the dosages vary depending upon the dosage form employed and the route of administration utilized.
  • compositions of the present invention are presented in a pack or dispenser device, such as an FDA approved kit, which contain one or more unit dosage forms containing the nanoparticles.
  • the pack for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device is accompanied by instructions for administration.
  • the pack or dispenser is accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
  • a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration.
  • Such notice is labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • the terms “comprises,” “comprising,” “containing,” “having” and the like can have the meaning ascribed to them in U.S. patent law and can mean “includes,” “including,” and the like; “consisting essentially of or “consists essentially” likewise has the meaning ascribed in U.S. patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.
  • the term “comprise” includes the term “consist”.
  • the term "about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • GNS Gold nanospheres
  • TEM transmission electron microscopy
  • the PEG layer consisted of a mixture of thiol-polyethylene-glycol (SH-PEG-COOH) ( ⁇ 85%, MW ⁇ 5 kDa) and a heterofunctional polyethylene-glycol (SH-PEG-COOH) ( ⁇ 15%, MW ⁇ 3.4 kDa) (creative PEGWorks, Winston Salem, USA).
  • the heterofunctional PEG was covalently conjugated to an anti-EGFR monoclonal antibody (Erbitux®, Merck KGaA), using l-ethyl-3-(3'- (dimethylamino)propyl)carbodiimide (EDC) and Sulfo-NHS (Thermo Scientific).
  • the bioconjugation of the GNR to the anti-EGFR antibody was achieved according to the method described (Ai H, Fang M, Jones SA, Lvov YM. Electrostatic layer-by-layer nanoassembly on biological micro templates: Platelets. Biomacromolecules. May-Jun 2002;3(3):560-564) using polystyrene sulfonate (PSS).
  • PSS polystyrene sulfonate
  • Phantoms were prepared in order to simulate the optical properties of skin tissue. Phantoms were prepared using 3x10 -3 % of India Ink as an absorbing component and 2% of Intralipid (Lipofundin MCT/LCT 20%, B.Braun Melsungen AG, Germany) as a scattering component. GNS (30 mg/mL) or GNR (5 mg/mL) were added to the phantom solutions and achieved final concentrations of 0.002, 0.02, 0.022, 0.03, 0.04, and 0.1 mg/ml of gold.
  • Intralipid Lipofundin MCT/LCT 20%, B.Braun Mels Institute AG, Germany
  • the solutions were heated and mixed at a temperature of approximately 90 C while the 1% Agarose powder (SeaKem LE Agarose, Lonza, USA) was slowly added.
  • the heated phantom solutions were cooled under vacuum conditions (to avoid bubbles). All phantoms were poured into a 24- well plate (16 mm diameter wells), each well containing different concentrations of gold.
  • A431 human head and neck cancer cells (2.5x10 6 ), which are known to express an extremely high level of EGFR, 30 were cultured in 5 ml DMEM medium containing 5% FCS, 0.5% Penicillin and 0.5% Glutamine at 37 °C under 5% CO 2 .
  • Cell-GNP conjugation 1 mL of cell suspension (2.5x10 6 /mL) was mixed with 1 mL of antibody-coated GNR solution (5 mg/mL), and allowed to interact for 30 min at room temperature. Then, the solution was centrifuged 3 times at 1000 rpm for 5 min, to wash out unbound GNR; after each centrifugation the mixture was redispersed in PBS solution (1 mL total volume).
  • This experiment was designed to image the distribution of temperature over the sample area under laser illumination.
  • the laser beam was directed at the sample from above as shown in Figure 1.
  • Two different lasers were used: one, a red diode laser at wavelength of 663nm (custom built), and the other, a green Nd:YAG diode pumped solid state laser at 532nm (Suwtech Laser, DPGL2200 Photop, Fuzhou, China).
  • the red laser was used for samples with GNR, and the green one for samples with GNS.
  • Temperature elevation over the sample was imaged by radiometric thermal imaging camera (FLIR Systems, Inc., Boston,MA, model A325).
  • the camera has 320X240 pixels and temperature sensitivity of 0.07 degree Celsius.
  • the spatial resolution of the camera is 0.5mm. By adding an extra lens it can achieve a spatial resolution of 0.1 mm, at a working distance of 80 mm.
  • This kind of camera is sensitive to thermal radiation at a wavelength range of 8 to 14 ⁇ and completely blind to lasers and others light sources at the visible or near infrared spectral range.
  • Figure 2 shows the absorbance spectra (UV-vis spectrometer, Shimadzu, UV1650 PC, Japan) of the GNR and GNS, and the wavelength of the lasers used (532 nm and 663 nm, spectrophotometer, USB2000, Ocean Optics Inc., USA).
  • the absorption peak of GNS and GNR is around 515 nm and 690 nm, respectivley.
  • Particle size, shape and uniformity were measured using transmission electron microscopy (TEM) and proved to be 30 nm GNS and 25 nm X 65 nm GNR, with a narrow size distribution (10%) ( Figure 2, right).
  • TEM transmission electron microscopy
  • phantoms containing different concentrations of GNS and GNR, and cancer cells (A431) that were specifically targeted with GNR were irradiated, and their heating profiles were measured.
  • Figure 3 shows temperature difference profiles of irradiated GNR solutions as a function of time for different concentrations of GNR. As demonstrated, after less than 5 seconds of laser irradiation, the temperature profiles of the irradiated GNR solutions are significantly different than those of the control (solution without GNR). The temperature of the control sample remained unchanged during the experiment, while the temperature of the GNR samples was elevated. In addition, it can be seen that there is a positive correlation between the GNR concentrations and temperature elevation.
  • the present invention provides that a low concentration of GNPs (0.02 mg/mL can be easily detected.
  • Red laser was used since the NIR region of the spectrum provides maximal penetration of light due to relatively lower scattering and absorption from intrinsic tissue chromophores. In this region, penetration depth of red light is up to 10 cm, depending on the type of tissue. In comparison, tissue penetration depth of green light (532 nm) is very low (less than 500 ⁇ ), which could be useful for superficial lesions and margin detection during surgery.
  • Figure 4 represents similar results for GNR; when GNR (0.1 mg/mL) were irradiated with 663 nm after 5 seconds the temperature increased by 14°C, while following irradiation with the 532 nm laser, for the same period of time, temperature elevation of only 4.5°C was observed. Temperature elevation of the samples when irradiated with lasers not at the GNPs resonance peak, can be explained by the tail of the resonance peak of the GNS at 690 nm and the "short axis" GNR peak, at 510 nm. In addition, because of the larger cross section of the GNR compared to the GNS, the GNR have higher absorption efficiency that being converted to thermal energy (Figure 4A and 4B).
  • the A431 cells took up 26.3+2.3 ⁇ g of targeted GNR (3.9x10 4 GNR per A431 cell), while parallel cells in the negative control experiment took up only 0.2+0.01 ⁇ g of GNR (3.4x10 GNR per cell).
  • this study demonstrates that photothermal imaging of a tissue or a cell mass such as tumor can be effectively used for viewing tumor margins when targeted with GNPs.
  • GNP-targeted cancer cells By reducing the laser irradiation, GNP-targeted cancer cells can be detected without affecting cell viability. It has been shown that a low concentration of GNPs (0.02 mg/mL), lower than that found in several in vivo studies, can be easily detected.
  • An important advantage of this imaging technique is the use of the absorption properties of GNPs rather than their scattering properties, leading to high contrast between targeted cancer cells and normal background tissue.
  • Example 4 Imaging of cancer tissue borders in-vivof from outside the tissue
  • the presently developed a new optical configuration allows to image in high resolution the borders of a tumor from outside the tissue.
  • the concept involves heating with pulsed laser nano particles that are concentrated at the edges of the tumor and then imaging it with infra-red camera. Avoiding the blurring of the borders of the tumor due to the scattering of the tissue is obtained by properly extracting the first arriving photons scattered from the inspected tissue.
  • MFP mean free path
  • the reduced scattering coefficient can be defined to describe this multiple scattering process as: in which g is the anisotropy function defining the degree of forward scattering, expressed as a probability function of scattering in the forward direction:
  • g is typically 0.8-1.
  • the transport mean free path (TMFP) can then be defined as:
  • the diffusion length in a tissue is defined as:
  • n is the refractive index of the tissue and c is the speed of light
  • n 1.33, [ 1/mm].
  • g 0.9 and thus we obtain
  • T fs 0.44 [psec].
  • the first arriving light photons are the one that have the high spatial resolution and they are separated from the photons that are spatially blurred due to multiple scattering effects.
  • Nano particles can either be directed by labeling towards a specific tumor or as there is more blood vessels surrounding a tumor they will be concentrated at higher concentrations at its boundaries.
  • illuminating the tumor from a distance and even through a tissue using the pulsed laser configuration at the absorption resonance of the NP can heat them up. Heating them even by a few degrees and inspecting them with infra red (IR) camera can allow high quality detection of the boundaries of the tumor.
  • IR infra red
  • the IR photons will be scattered on their way back to the camera and thus although the heating process of the NP can be used to detect the boundaries, at reality the boundaries will be blurred due to this scattering process unless proper adaptation of the illumination and detection scheme is done.
  • the setup we propose aims to overcome this problem.
  • the proposed optical configuration It is aimed to send pulsed beam having temporal width less than 0.4 psec and then interfering the back scattered light with the reference that was also used for the illumination of the tissue.
  • the proposed configuration is described in Fig. 7.
  • the first arriving light information can be extracted not only via pulsed laser and holography/interference but also by sending not pulsed light having very short coherence length corresponding to the temporal length mentioned above (less than 0.4 psec). However, if a non pulsed broad band source (to have sufficiently short coherence length) is used then the extracted energy will be very low and the SNR of the captured image might not be sufficient.

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Abstract

La présente invention concerne un système pour l'imagerie in vivo d'un tissu avec des nanoparticules d'or insérées à l'intérieur, le système comprenant : une composition de nanoparticules d'or cellulaires ; et une caméra d'imagerie thermique configurée pour imager in vivo le tissu. L'invention concerne en outre un procédé pour l'imagerie in vivo d'un tissu ou d'une partie de celui-ci par l'utilisation du système de l'invention.
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