WO2023137775A1 - 复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置 - Google Patents

复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置 Download PDF

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WO2023137775A1
WO2023137775A1 PCT/CN2022/073655 CN2022073655W WO2023137775A1 WO 2023137775 A1 WO2023137775 A1 WO 2023137775A1 CN 2022073655 W CN2022073655 W CN 2022073655W WO 2023137775 A1 WO2023137775 A1 WO 2023137775A1
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fluorescence
light
wavelength
fluorescent
tracer
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PCT/CN2022/073655
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English (en)
French (fr)
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许德冰
杨其峰
赵海东
朱新德
郭昌盛
张则腾
杨聪
王倩
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济南显微智能科技有限公司
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission

Definitions

  • the invention relates to the technical field of lymphatic fluorescent tracing, in particular to the application of mitoxantrone hydrochloride injection for futashu tracing as a fluorescent tracer and a fluorescent imaging device used therefor.
  • Biopsy or lymphatic dissection of sentinel lymph nodes to determine the location and extent of lymphatic dissection is a very important link in malignant tumor surgery.
  • medical clinical methods mainly include fluorescent tracing method and dye method.
  • Fluorescent tracer method adopts emerging fluorescent detection technology, which has been used in medical treatment for more than 10 years. Although many substances can produce fluorescence, not all substances that can produce fluorescence can be used as medical fluorescent tracers. At present, there are only four drugs known to have fluorescent spectral properties for clinical use: sodium fluorescein, 5-ALA, methylene blue, and indocyanine green. For these four fluorescent drugs, different manufacturers have developed different fluorescent devices for clinical application. The central wavelength of fluorescence of fluorescein sodium is 550nm, and it is currently used for fundus angiography, intraoperative detection of glioma, etc., and is called yellow fluorescence. The central wavelength of fluorescence of 5-ALA is 660nm.
  • the fluorescence center wavelength of methylene blue is 690nm, and it is currently used for lymphangiography and detection of sentinel lymph nodes.
  • the central wavelength of indocyanine green is 830nm, currently used for lymphangiography, sentinel lymph node detection flap blood supply observation.
  • Sodium fluorescein and 5-ALA fluorescence belong to the category of visible light, which have poor penetrability to human tissues and are usually not used for lymphography.
  • indocyanine green and methylene blue are commonly used clinically. At present, these two fluorescent tracer drugs have the following shortcomings in practical application:
  • Methylene blue is highly irritating to the human body, and it is clearly stipulated in the Pharmacopoeia that it cannot be used for subcutaneous injection, which limits the clinical application of this drug.
  • Indocyanine green is a strong fluorescent substance. Once the lymphatic vessels are damaged during the operation, indocyanine green will flow out with the lymph fluid and permeate the wound surface, causing fluorescent pollution, making it difficult to distinguish lymphatic vessels and lymph nodes. Doctors need to have extremely high skills to avoid the occurrence of fluorescent pollution.
  • the tracers commonly used in the dye method mainly include methylene blue and nano-carbon, both of which have their own defects when applied to lymphography: methylene blue is strongly irritating to the human body, and when used for sentinel lymphatic detection, the dyed area must be removed during surgery, so the indications are limited; nano-carbon is a black dye, which is difficult to be metabolized in the human body, and has a greater impact on patients undergoing secondary surgery.
  • the technical problem to be solved by the present invention is to make up for the deficiencies of the prior art, and to provide the application of mitoxantrone hydrochloride injection for Futashu tracer as a fluorescent tracer and a fluorescent imaging device for it.
  • the technical solution of the present invention is:
  • mitoxantrone hydrochloride injection for futashu tracer as a fluorescent tracer is characterized in that: after the mitoxantrone hydrochloride injection for futashu tracer is mixed with mammalian serum, a smooth-surfaced spherical bioself-assembled nanocrystal is formed through non-covalent interaction, and the particle size of the nanocrystal is ⁇ 100 nm.
  • the nanocrystals generate fluorescence with a central wavelength of 740 nm under the irradiation of light with a wavelength of 600-710 nm.
  • the fluorescent imaging device is specifically one of a fluorescent imaging system for in vitro use, a fluorescent endoscope, and a fluorescent microscope, including a light source, a video camera and a computer.
  • the laser is used to emit light with a wavelength of 600-710nm.
  • the excitation fluorescence includes excitation fluorescence I
  • the excitation fluorescence I is fluorescence with a wavelength of 710-800nm;
  • the camera includes a spectroscopic device and a photosensitive element.
  • K is converted into an electrical signal and sent to the computer for imaging.
  • the CMOS photosensitive element I is used to sense the sub-beam I and converted into an electrical signal and sent to the computer for fluorescence imaging of the nanocrystal.
  • the CMOS photosensitive element I is equipped with a filter I.
  • the filter I is a long-wave pass filter, used to transmit light with a wavelength greater than 710nm, and the cut-off depth ⁇ OD3.
  • the optical filter I is a band-pass optical filter, which allows light with a wavelength of 710-800 nm to pass through, and the cut-off depth is ⁇ OD3.
  • the central wavelength of the light emitted by the laser is 638nm ⁇ 15nm or 660nm ⁇ 15nm or 685nm ⁇ 15nm.
  • the photosensitive element of the camera also includes a CMOS photosensitive element II.
  • the wavelength of the excited fluorescence II is fluorescence with a wavelength of 650-710 nm.
  • the reflected light and excited fluorescence II are divided into a sub-beam K with a wavelength band of 400-650 nm and a sub-beam II with a waveband of 650-710 nm after passing through the spectroscopic device.
  • Optical filter II, optical filter II is a band-pass optical filter, which allows light with a wavelength of 650-710nm to pass through, and the cut-off depth is ⁇ OD3.
  • the photosensitive element of the camera also includes a CMOS photosensitive element III.
  • the wavelength of the excited fluorescent III is fluorescence of 800-1000 nm, and the reflected light and excited fluorescent III are divided into a sub-beam K with a wavelength band of 400-650 nm and a sub-beam III with a wavelength band of 400-650 nm and a sub-beam III of 800-1000 nm.
  • 000nm light passes through, cut-off depth ⁇ OD3;
  • CMOS photosensitive element III is used to sense light with a wavelength of 800-1000nm and convert it into an electrical signal and send it to the computer for fluorescence imaging of indocyanine green.
  • the visible light source is an LED lamp.
  • Mitoxantrone Hydrochloride Injection used as a lymphatic staining tracer has the advantages of non-dispersion, fast staining, and thorough metabolism. At the same time, it forms nanocrystals with new fluorescence spectral characteristics after being mixed with mammalian serum. The nanocrystals produce fluorescence with a wavelength of 710-810nm under the irradiation of light with a wavelength of 600-710nm. So that it can become a new generation of lymphatic fluorescent tracer drugs.
  • Fig. 1 is the visible light image of the chicken pectoralis major muscle after injecting mitoxantrone hydrochloride injection for futashu tracer in Example 2 of the present invention
  • Fig. 2 is the fluorescence image of the chicken pectoralis major muscle after injecting Futashu tracing mitoxantrone hydrochloride injection in Example 2 of the present invention
  • Fig. 3 is the spectrogram derived in the embodiment of the present invention 2;
  • Fig. 4 is the structural diagram of embodiment 3, 4, 5 of the present invention.
  • Fig. 5 is a structural diagram of light sources in Embodiments 3, 4, and 5 of the present invention.
  • FIG. 6 is a structural diagram of a camera in Embodiment 3 of the present invention.
  • Fig. 7 is a structural diagram of a camera in Embodiment 4 of the present invention.
  • Fig. 8 is a structural diagram of a camera in Embodiment 5 of the present invention.
  • Fig. 9 is a structural diagram of a camera in Embodiment 6 of the present invention.
  • the fluorescence center wavelength of traditional Mitoxantrone Hydrochloride is 690nm, while the fluorescence center wavelength of Futashu Mitoxantrone Hydrochloride Injection for Tracer is 740nm, which has very good penetration relative to biological tissues. It can be used as one of the most essential characteristics of fluorescent tracers.
  • Mitoxantrone Hydrochloride Injection for Tracing Futasu itself does not have the above-mentioned new fluorescence spectral characteristics.
  • Mitoxantrone Hydrochloride Injection for Lymphatic Staining which is used as a lymphatic staining tracer, not only has the advantages of non-dispersion, fast staining, and thorough metabolism, but also has new fluorescence spectrum characteristics, and Mitoxantrone Hydrochloride Injection for Tracing of Futashu is a product officially approved for tracing lymph nodes in thyroid surgery areas in China. It has been clinically verified to have good safety and lymphatic tracing effect, and at the same time, it does not specifically stain parathyroid glands. Good dyeability and new fluorescence spectrum characteristics solve the defects of traditional fluorescent tracers at the same time, and can be directly used as a new generation of lymphatic fluorescent tracer drugs.
  • Mitoxantrone Hydrochloride Injection which was newly launched in June 2021, adopts bio-self-assembled nanocrystal technology. After local injection, under physiological conditions, drug molecules and mammalian serum will spontaneously form spherical bio-self-assembled nanocrystals (particle size ⁇ 100nm) through non-covalent interactions. Fluorescence with a central wavelength of 740nm is produced.
  • nanocrystals is ⁇ 100nm, and it does not enter capillaries (endothelial cell gap 30-50nm), but can enter capillary lymphatics (endothelial cell gap 120-500nm), which enables it to achieve good lymphatic tracing effect and also has the characteristics of non-staining specificity for parathyroid glands.
  • the osmotic pressure adjustment mechanism is used to accelerate the return of drugs to the lymphatic circulation, so that the nanocrystals gather and stay in the lymph nodes, and realize the blue staining of the thyroid gland and its drainage area lymph nodes.
  • Mitoxantrone Hydrochloride Injection for Mitoxantrone for Tracing of Futashu is already a marketed medical drug, its molecular structure and pharmacological information are all known technologies, so there is no need to elaborate on its pharmacology in this application.
  • Preparation materials 1 bottle of mitoxantrone hydrochloride injection for Futashu tracer, 1 bottle of standard calf serum, 1 test tube, 1 set/set of self-made fluorescence camera device, which can emit excitation light with a central wavelength of 660nm and can be imaged by sensing light with a wavelength of 740 ⁇ 10nm.
  • Preparation materials 1 syringe, 1 piece of chicken pectoralis major muscle, 1 bottle of mitoxantrone hydrochloride injection for Futashu tracer, 1 set/set of self-made fluorescence camera device, which can emit excitation light with a central wavelength of 660nm and can be imaged by sensing light with a wavelength of 740 ⁇ 10nm.
  • the spectral data of the excitation light and the excitation fluorescence were derived by a self-made fluorescence camera device. It can be found that under the irradiation of the excitation light with a center wavelength of 660nm, the center wavelength of the fluorescence generated by the injection of Futashu Tracer Mitoxantrone Hydrochloride Injection after injection is 740nm. As shown in Figure 3, the horizontal axis in the figure is the wavelength, and the vertical axis is the light intensity.
  • mitoxantrone hydrochloride injection for tracer of Futashu is used as the fluorescent tracer
  • those skilled in the art can understand that the mitoxantrone hydrochloride injection for tracer of Futashu should be injected into the mammal, not the chicken pectoralis major muscle.
  • the invention discloses a fluorescence camera device, which is applied to the fluorescence tracer of mitoxantrone hydrochloride injection for Futasu tracer.
  • light source 4 is used for outward output emission light, generation reflected light after emission light is reflected, camera 1 is by sensing reflected light and exciting fluorescence imaging;
  • Camera 1 comprises lens 11, spectroscopic device and photosensitive element, as shown in Fig.
  • the interface 5 is connected, and the light guide interface 5 is used to connect the light guide element, and the light guide element is used to guide the light to a desired place.
  • the light source 4 includes the visible light source placed in the inner cavity of the housing 402, the exciting light source and the light-transmitting lens 405.
  • the visible light source is an LED lamp 401
  • the exciting light source is a laser 403, and a two-color film is provided on the light-transmitting lens 405.
  • the dichroic film on the light lens 405 is reflected and emitted from the light outlet 404 .
  • the LED lamp 401 is used to emit visible light with a wavelength of 400-650nm
  • the laser 403 is used to emit light with a wavelength of 600-710nm.
  • this embodiment selects a laser that can emit light with a central wavelength of 660nm ⁇ 15nm.
  • those skilled in the art can also choose a laser that can emit light with a central wavelength of 638nm ⁇ 15nm or 685nm ⁇ 15nm, but the latter two are not as good as this embodiment.
  • the effect achieved by the laser is good.
  • camera comprises lens 11, spectroscopic device and photosensitive element
  • spectroscopic device comprises first prism 12 and second prism 13
  • first prism 12 and second prism 13 are triangular prisms
  • the three sides of first prism 12 are respectively face a1201, face b1202, face c1203
  • the three sides of second prism 13 are respectively face d1301, face e1302, face f1303.
  • the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13 are bonded face to face, and a coating A is interposed between the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13.
  • the coating A is used to transmit light with a wavelength less than 710 nm and reflect light with a wavelength greater than 710 nm.
  • the photosensitive element includes CMOS photosensitive element K14 and CMOS photosensitive element I15.
  • the CMOS photosensitive element K14 is used to sense light with a wavelength band of 400-650nm, and converts the optical signal into an electrical signal, and sends the electrical signal to the computer for visible light imaging;
  • the CMOS photosensitive element I15 is used to sense light with a wavelength band of 710-800nm, converts the optical signal into an electrical signal, and sends the electrical signal to the computer for visible light imaging.
  • the mixed light passes through the lens 11, the surface a1201 of the first prism 12, and the surface b1202 of the first prism 12 to the coating A, and the coating A divides the mixed light into two beams of light, one beam is light with a wavelength of less than 710nm, and the other beam is light with a wavelength greater than 710nm; the light with a wavelength of less than 710nm passes through the coating A, the surface d1301 of the second prism 13, and the surface f1303 of the second prism 13 to the CMOS photosensitive element K14:
  • the light with a wavelength greater than 100 nm is reflected by the coating A and then goes to the surface a1201 of the first prism 12, and then to the CMOS photosensitive element I15 from the surface c1203 of the first prism 12.
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of mitoxantrone hydrochloride injection for Futashu tracer, an appropriate amount of mitoxantrone hydrochloride injection for Futashu tracer is injected into a mammal, and the injection site is imaged.
  • the light source 4 emits visible light with a wavelength of 400-650nm through the LED lamp 401, and the laser 403 is used to emit excitation light with a central wavelength of 660nm ⁇ 15nm.
  • the mixed light of these two kinds of light When the mixed light of these two kinds of light is irradiated to the injection site, it will produce the mixed light of two other kinds of light, that is, the reflected visible light with a wavelength of 400-650nm and the fluorescence with a central wavelength of 740nm generated by the excitation of nanocrystals.
  • the CMOS photosensitive element K14 senses the sub-beam K and sends it to the computer for imaging
  • the CMOS photosensitive element I15 senses the sub-beam I and sends it to the computer for fluorescence imaging of the nanocrystal.
  • the invention discloses a dual-tracing fluorescent camera device, which can be applied to the fluorescent tracing of mitoxantrone hydrochloride injection for Futashu tracing and the fluorescent tracing of methylene blue.
  • camera comprises lens 11, spectroscopic device and photosensitive element
  • spectroscopic device comprises first prism 12, second prism 13 and the 3rd prism 16, and first prism 12 and second prism 13 are triangular prisms
  • the 3rd prism 16 is quadrangular prisms
  • the three sides of first prism 12 are respectively face a1201, face b1202, face c1203, and the three sides of second prism 13 are respectively face d1301, face e1302 , surface f1303, and the two opposite sides of the third prism 16 are respectively surface g1601 and surface h1602.
  • the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13 are bonded face to face, and a coating A is interposed between the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13.
  • the coating A is used to transmit light with a wavelength less than 710 nm and reflect light with a wavelength greater than 710 nm.
  • the surface f1303 of the second prism 13 and the surface g1601 of the third prism 16 are bonded face to face, and a coating B is interposed between the surface f1303 of the second prism 13 and the surface g1601 of the third prism 16.
  • the coating B is used to transmit light with a wavelength less than 650 nm and reflect light with a wavelength greater than 650 nm.
  • the photosensitive element includes CMOS photosensitive element K14, CMOS photosensitive element I15 and CMOS photosensitive element II17.
  • CMOS photosensitive element K14 is used to sense light with a wavelength band of 400-650nm, convert the optical signal into an electrical signal, and send the electrical signal to the computer for visible light imaging;
  • CMOS photosensitive element II17 is used to sense light with a wavelength band of 650-710nm, and converts the optical signal into an electrical signal, and sends the electrical signal to the computer for visible light imaging.
  • the filter II is a band-pass filter, specifically narrow-band type , so that light with a wavelength of 690 ⁇ 10nm passes through, and the cut-off depth is ⁇ OD3.
  • the mixed light sequentially passes through the lens 11, the surface a1201 of the first prism 12, and the surface b1202 of the first prism 12 to the coating A, and the coating A divides the mixed light into two beams of light, one beam is light with a wavelength less than 710nm, and the other beam is light with a wavelength greater than 710nm;
  • the light with a wavelength greater than 710nm is reflected by the coating A and goes to the surface a1201 of the first prism 12, the surface c1203 of the first prism 12 to the CMOS photosensitive element I15;
  • the light with a wavelength of less than 710nm passes through the coating A, the surface d1301 of the second prism 13, and the surface f1303 of the second prism 13 to the coating B, and the coating A divides the light with a wavelength of less than 710nm into two beams, one of which is the light with a wavelength of less than 650nm, and the other is the light with a wavelength of more than 650nm;
  • the light with a wavelength greater than 650nm is reflected by the coating B and then goes to the surface d1301 of the second prism 13, the surface e1302 of the second prism 13 to the CMOS photosensitive element II17;
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of mitoxantrone hydrochloride injection for Futashu tracer, an appropriate amount of mitoxantrone hydrochloride injection for Futashu tracer is injected into a mammal, and the injection site is imaged.
  • the light source 4 emits visible light with a wavelength of 400-650nm through the LED lamp 401, and uses the laser 403 to emit excitation light with a central wavelength of 660nm ⁇ 15nm.
  • the mixed light of these two kinds of light When the mixed light of these two kinds of light is irradiated to the injection site, it will produce the mixed light of two other kinds of light, that is, the reflected visible light with a wavelength of 400-650nm and the fluorescence with a central wavelength of 740nm generated by the excitation of Futasu nanocrystals.
  • the CMOS photosensitive element K14 senses the sub-beam K and sends it to the computer for imaging
  • the CMOS photosensitive element I15 senses the sub-beam I and sends it to the computer for fluorescence imaging of the nanocrystal.
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of methylene blue, the methylene blue is injected into the body of a mammal, and the injection site is imaged.
  • the light source 4 emits visible light with a wavelength of 400-650nm through the LED lamp 401, and uses the laser 403 to emit excitation light with a central wavelength of 660nm ⁇ 15nm.
  • the mixed light of these two kinds of light is irradiated to the injection site, it will produce the mixed light of the other two kinds of light, that is, the reflected visible light with a wavelength of 400-650nm and the fluorescence with a central wavelength of 690nm generated by the excitation of methylene blue.
  • the CMOS photosensitive element K14 senses the sub-beam K and sends it to the computer for imaging
  • the CMOS photosensitive element II17 senses the sub-beam II and sends it to the computer for fluorescence imaging of methylene blue.
  • the spectroscopic device of the fluorescence imaging device for double tracking in this embodiment can separate the mixed light into visible light, futasula nanocrystal fluorescence and methylene blue fluorescence.
  • Different photosensitive elements are respectively imaged for visible light, futasula nanocrystal fluorescence and methylene blue fluorescence.
  • the computer synthesizes the images formed by the light in each band, and can present a composite image of optical image, futasula nanocrystal fluorescence image and methylene blue fluorescence image, which can be viewed intuitively by doctors.
  • the invention discloses a dual-tracing fluorescent camera device, which can be applied to the fluorescent tracing of mitoxantrone hydrochloride injection for Futashu tracing and the fluorescent tracing of indocyanine green.
  • camera comprises lens 11, spectroscopic device and photosensitive element
  • spectroscopic device comprises first prism 12, second prism 13 and the 3rd prism 16, and first prism 12 and second prism 13 are triangular prism shape
  • the 3rd prism 16 is quadrangular prism shape
  • the three sides of first prism 12 are respectively face a1201, face b1202, face c1203, and the three sides of second prism 13 are respectively face d1301, face e1302 , surface f1303, and the two opposite sides of the third prism 16 are respectively surface g1601 and surface h1602.
  • the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13 are bonded face to face, and a coating C is interposed between the surface b1202 of the first prism 12 and the surface d1301 of the second prism 13.
  • the coating C is used to transmit light with a wavelength less than 800 nm and reflect light with a wavelength greater than 800 nm.
  • the face f1303 of the second prism 13 and the face g1601 of the third prism 16 are bonded face to face, and a coating D is interposed between the face f1303 of the second prism 13 and the face g1601 of the third prism 16.
  • the coating D is used to transmit light with a wavelength less than 710 nm, and reflect light with a wavelength greater than 710 nm.
  • the photosensitive element includes CMOS photosensitive element K14, CMOS photosensitive element I15 and CMOS photosensitive element III18.
  • CMOS photosensitive element K14 is used to sense light with a wavelength band of 400-650nm, convert the optical signal into an electrical signal, and send the electrical signal to the computer for visible light imaging;
  • Filter I is set in front of element I15, and filter I is a band-pass filter, specifically a narrow-band type, allowing light with a wavelength of 740 ⁇ 10nm to pass through, and the cut-off depth is ⁇ OD3;
  • CMOS photosensitive element III18 is used to sense light with a wavelength band of 800-1000nm, and converts the optical signal into an electrical signal, and sends the electrical signal to the computer for visible light imaging. Type, let the light with a wavelength of 830 ⁇ 10nm pass through, and the cut-off depth is ⁇ OD3.
  • the mixed light sequentially passes through the lens 11, the surface a1201 of the first prism 12, and the surface b1202 of the first prism 12 to the coating C, and the coating C divides the mixed light into two beams of light, one of which is light with a wavelength less than 800nm, and the other is light with a wavelength greater than 800nm;
  • the light with a wavelength greater than 800nm is reflected by the coating C to the surface a1201 of the first prism 12, the surface c1203 of the first prism 12 to the CMOS photosensitive element III18;
  • the light with a wavelength of less than 800nm sequentially passes through the coating C, the surface d1301 of the second prism 13, and the surface f1303 of the second prism 13 to the coating D, and the coating D divides the light with a wavelength of less than 800nm into two beams of light, one of which is light with a wavelength of less than 710nm, and the other is light with a wavelength of greater than 710nm;
  • the light with a wavelength greater than 710nm is reflected by the coating D and then goes to the surface d1301 of the second prism 13, the surface e1302 of the second prism 13 to the CMOS photosensitive element I15;
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of mitoxantrone hydrochloride injection for Futashu tracer, an appropriate amount of mitoxantrone hydrochloride injection for Futashu tracer is injected into a mammal, and the injection site is imaged.
  • the light source 4 emits visible light with a wavelength of 400-650nm through the LED lamp 401, and uses the laser 403 to emit excitation light with a central wavelength of 660nm ⁇ 15nm.
  • the mixed light of these two kinds of light When the mixed light of these two kinds of light is irradiated to the injection site, it will produce the mixed light of two other kinds of light, that is, the reflected visible light with a wavelength of 400-650nm and the fluorescence with a central wavelength of 740nm generated by the excitation of Futasu nanocrystals. and the sub-beam I, the CMOS photosensitive element K14 senses the sub-beam K and sends it to the computer for imaging, and the CMOS photosensitive element I15 senses the sub-beam I and sends it to the computer for fluorescence imaging of the nanocrystal.
  • indocyanine green When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of indocyanine green, indocyanine green is injected into the body of a mammal, and the injection site is imaged.
  • the light source 4 emits visible light with a wavelength of 400-650nm through the LED lamp 401, and uses the laser 403 to emit excitation light with a central wavelength of 660nm ⁇ 15nm.
  • the mixed light of these two kinds of light is irradiated to the injection site, it will produce the mixed light of two other kinds of light, that is, the reflected visible light with a wavelength of 400-650nm and the fluorescence with a central wavelength of 830nm generated by the excitation of indocyanine green.
  • the CMOS photosensitive element K14 senses the sub-beam K and sends it to the computer for imaging
  • the CMOS photosensitive element III18 senses the sub-beam III and sends it to the computer for fluorescence imaging of indocyanine green.
  • the spectroscopic device of the fluorescent imaging device for double tracking in this embodiment can separate the mixed light into visible light, futasulin nanocrystal fluorescence and indocyanine green fluorescence.
  • Different photosensitive elements are respectively sensitized to visible light, futasula nanocrystal fluorescence and indocyanine green fluorescence and then imaged separately.
  • the computer synthesizes the images formed by the light in each band, and can present a composite image of optical image, futasula nanocrystal fluorescence image and indocyanine green fluorescence image, which can be viewed intuitively by doctors.
  • a fluorescent camera device for three tracers can be applied to the fluorescent tracer of methylene blue, mitoxantrone hydrochloride injection for tracer of Futasu and the fluorescent tracer of indocyanine green.
  • the photosensitive element includes CMOS photosensitive element II17, CMOS photosensitive element I15 and CMOS photosensitive element III18.
  • CMOS photosensitive element II17 is used to sense light with a wavelength band of 650-710nm, convert the optical signal into an electrical signal, and send the electrical signal to the computer for visible light imaging.
  • CMOS photosensitive element II17 is used to sense light with a wavelength band of 650-710nm, convert the optical signal into an electrical signal, and send the electrical signal to the computer for visible light imaging.
  • CMOS photosensitive element II17 Pass, cut-off depth ⁇ OD3
  • CMOS photosensitive element I15 is used to sense light with a wavelength of 710-800nm, convert the optical signal into an electrical signal, and send the electrical signal to the computer for visible light imaging.
  • filter I in front of the CMOS photosensitive element I15.
  • a filter III in front of the CMOS photosensitive element II17, and the filter III is a band-pass filter, specifically a narrow-band filter, which allows light with a wavelength of 830 ⁇ 10nm to pass through, and the cut-off depth is ⁇ OD3.
  • the mixed light sequentially passes through the lens 11, the surface a1201 of the first prism 12, and the surface b1202 of the first prism 12 to the coating C, and the coating C divides the mixed light into two beams of light, one of which is light with a wavelength less than 800nm, and the other is light with a wavelength greater than 800nm;
  • the light with a wavelength greater than 800nm is reflected by the coating C to the surface a1201 of the first prism 12, the surface c1203 of the first prism 12 to the CMOS photosensitive element III18;
  • the light with a wavelength of less than 800nm sequentially passes through the coating C, the surface d1301 of the second prism 13, and the surface f1303 of the second prism 13 to the coating D, and the coating D divides the light with a wavelength of less than 800nm into two beams of light, one of which is light with a wavelength of less than 710nm, and the other is light with a wavelength of greater than 710nm;
  • the light with a wavelength greater than 710nm is reflected by the coating D and then goes to the surface d1301 of the second prism 13, the surface e1302 of the second prism 13 to the CMOS photosensitive element I15;
  • indocyanine green When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of indocyanine green, indocyanine green is injected into the body of a mammal, and the injection site is imaged.
  • the light source 4 is used to emit excitation light with a central wavelength of 660nm ⁇ 15nm through a laser 403.
  • the indocyanine green When it irradiates the injection site, the indocyanine green is excited to generate fluorescence with a central wavelength of 830nm.
  • the fluorescent light with a central wavelength of 830nm is guided to the CMOS photosensitive element III18 after passing through the spectroscopic device.
  • the CMOS photosensitive element III18 senses the indocyanine green fluorescence and sends it to the computer for fluorescence imaging of the indocyanine green.
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of mitoxantrone hydrochloride injection for Futashu tracer, an appropriate amount of mitoxantrone hydrochloride injection for Futashu tracer is injected into a mammal, and the injection site is imaged.
  • the light source 4 is used to emit excitation light with a central wavelength of 660nm ⁇ 15nm through a laser 403.
  • the fluorescent light with a central wavelength of 740nm is excited by the nanocrystals of Fortasil, and the fluorescent light with a central wavelength of 740nm is guided to the CMOS photosensitive element I15 after passing through the spectroscopic device.
  • the fluorescence imaging device of this embodiment When the fluorescence imaging device of this embodiment is applied to the fluorescence tracing of methylene blue, the methylene blue is injected into the body of a mammal, and the injection site is imaged.
  • the light source 4 is used to emit excitation light with a center wavelength of 660nm ⁇ 15nm through a laser 403.
  • methylene blue When it irradiates the injection site, methylene blue is excited to generate fluorescence with a center wavelength of 690nm.
  • the fluorescence with a center wavelength of 690nm is guided to the CMOS photosensitive element II17 after passing through the spectroscopic device.
  • the CMOS photosensitive element II17 senses the methylene blue fluorescence and sends it to the computer for fluorescence imaging of the methylene blue.
  • the spectroscopic device of the fluorescent imaging device for three tracers in this embodiment can separate the mixed light into methylene blue fluorescence, futasulin nanocrystal fluorescence and indocyanine green fluorescence.
  • Different photosensitive elements are respectively imaged after being sensitized to methylene blue, futasula nanocrystal fluorescence and indocyanine green fluorescence.
  • the computer synthesizes the images formed by the light of each band, and can present a composite image of methylene blue fluorescence image, futasula nanocrystal fluorescence image and indocyanine green fluorescence image, which can be viewed intuitively by doctors.
  • fluorescence camera system fluorescence endoscope, and fluorescence microscope used in vitro all include visible light sources, excitation light sources, spectroscopic devices, and cameras, the principles of fluorescence excitation and fluorescence imaging are basically the same. Under the teachings of this example, those skilled in the art can make relevant improvements to the existing fluorescence camera systems, fluorescence endoscopes, and fluorescence microscopes used in vitro.

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Abstract

一种盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置，该示踪用盐酸米托蒽醌注射液与哺乳动物的血清混合之后，通过非共价相互作用形成表面光滑的类球形生物自组装纳米晶，纳米晶的粒径≈100nm，所述纳米晶具有荧光光谱特性，在波长为600～710nm的光照射下，产生波长为710～810nm的荧光；荧光摄像装置用于示踪用盐酸米托蒽醌注射液荧光示踪成像。

Description

复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置 技术领域
本发明涉及淋巴荧光示踪技术领域，具体涉及复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置。
背景技术
对前哨淋巴结进行活检或淋巴清扫，确定淋巴位置及清扫范围，是恶性肿瘤外科手术中非常重要的一个环节。淋巴示踪技术中，医用临床方法主要包括荧光示踪法和染料法。
荧光示踪法采用的是新兴的荧光探测技术，荧光探测技术在医疗上的应用已经有10余年的历史，虽然许多物质都可以产生荧光现象，但是并非所有可产生荧光现象的物质都可以用作医疗荧光示踪剂。目前，用于临床的已知具有荧光光谱特性的药物只有如下四种：荧光素钠，5-ALA，亚甲蓝，吲哚菁绿。针对这四种荧光药物，不同厂家开发出了不同的荧光设备，以应用于临床。荧光素钠的荧光中心波长为550nm，目前用于眼底造影、脑胶质瘤术中探查等，被称为黄荧光。5-ALA的荧光中心波长为660nm，目前用于手术显微镜荧光模组，在脑胶质瘤术中探查的应用较多。亚甲蓝的荧光中心波长为690nm，目前用于淋巴管造影、前哨淋巴结的探查。吲哚菁绿的中心波长为830nm，目前用于淋巴管造影、前哨淋巴结探查皮瓣血供观测。荧光素钠以及5-ALA荧光属于可见光范畴，对人体组织的穿透性较差，通常不用于淋巴造影。针对淋巴管造影以及淋巴结荧光显像，目前临床上常用吲哚菁绿以及亚甲蓝，目前这两种荧光示踪药物在实际应用中存在着如下不足之处：
亚甲蓝对于人体具有强烈刺激，药典中明确规定其不能用于皮下注射，故而限制了该药物在临床上的应用；吲哚菁绿是一种强荧光物质，在手术过程中，淋巴管一旦破损，吲哚菁绿将随着淋巴液流出，弥漫在创面，造成荧光污染，从而很难再分辨出淋巴管与淋巴结，需要医生具有极高的使用技巧才能避免荧光污染的发生。
染料法中常用的示踪剂主要有亚甲蓝和纳米碳，二者应用于淋巴造影时均存在各自的缺陷：亚甲蓝对人体具有强刺激性，应用与前哨淋巴探查，手术中 须对染色区域切除，适应症受限；纳米碳是一种黑色染料，其在人体中很难被代谢掉，对于二次手术的患者影响较大。
在2021年6月，新上市了一种染料法用淋巴示踪剂——复他舒示踪用盐酸米托蒽醌注射液，将该品注射到肿瘤周缘组织后，能够靶向区域淋巴结并将其蓝染，从而起到淋巴示踪的作用，可广泛适用于甲状腺癌等区域引流淋巴结示踪，该品具有不弥散、染色快，代谢彻底的优点。
技术解决方案
本发明要解决的技术问题是弥补现有技术的不足，提供了复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置。
要解决上述技术问题，本发明的技术方案为：
复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途，其特征是：所述复他舒示踪用盐酸米托蒽醌注射液与哺乳动物的血清混合之后，通过非共价相互作用形成表面光滑的类球形生物自组装纳米晶，纳米晶的粒径≈100nm，所述纳米晶具有荧光光谱特性，在波长为600～710nm的光照射下，产生波长为710～810nm的荧光。
进一步地，所述纳米晶在波长为600～710nm的光照射下，产生中心波长为740nm的荧光。
进一步地，将所述复他舒示踪用盐酸米托蒽醌注射液应用于淋巴荧光示踪。
一种如上所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，所述荧光摄像装置具体为体外使用荧光摄像系统、荧光内窥镜、荧光显微镜中的一种，包括光源、摄像机和计算机，光源用于向外输出发射光，发射光被反射后产生反射光，摄像机通过感应反射光和激发荧光成像；光源包括可见光源和激发光源，可见光源用于发出波长为400～650nm的可见光，激发光源为激光器，激光器用于发出波长为600～710nm的光，当激发荧光包括激发荧光Ⅰ时，激发荧光Ⅰ是波长为710～800nm的荧光；摄像机包括分光装置和感光元件，感光元件包括CMOS感光元件K和CMOS感光元件Ⅰ；反射光和激发荧光Ⅰ经分光装置后被分成波段为400～650nm的分光束K和710～800nm的分光束Ⅰ，CMOS感光元件K用于感应分光束K并转换为电信号发送至计算 机进行成像，CMOS感光元件Ⅰ用于感应分光束Ⅰ并转换为电信号发送至计算机对所述纳米晶进行荧光成像，CMOS感光元件Ⅰ前设有滤光片Ⅰ。
进一步地，所述滤光片Ⅰ为长波通滤光片，用于使波长大于710nm的光透过，截止深度≥OD3。
进一步地，所述滤光片Ⅰ为带通型滤光片，使波长为710～800nm的光通过，截止深度≥OD3。
进一步地，所述激光器发出的光的中心波长为638nm±15nm或660nm±15nm或685nm±15nm。
进一步地，所述摄像机的感光元件还包括CMOS感光元件Ⅱ，当激发荧光包括激发荧光Ⅱ时，激发荧光Ⅱ的波长为650～710nm的荧光，反射光和激发荧光Ⅱ经分光装置后被分成波段为400～650nm的分光束K和650～710nm的分光束Ⅱ，CMOS感光元件Ⅱ用于感应分光束Ⅱ并转换为电信号发送至计算机对亚甲蓝进行荧光成像，CMOS感光元件Ⅱ前设有滤光片Ⅱ，滤光片Ⅱ为带通型滤光片，使波长为650～710nm的光通过，截止深度≥OD3。
进一步地，所述摄像机的感光元件还包括CMOS感光元件Ⅲ，当激发荧光包括激发荧光Ⅲ时，激发荧光Ⅲ的波长为800～1000nm的荧光，反射光和激发荧光Ⅲ经分光装置后被分成波段为400～650nm的分光束K和800～1000nm的分光束Ⅲ，CMOS感光元件Ⅲ前设有滤光片Ⅲ，滤光片Ⅲ为带通型滤光片，使波长为800～1000nm的光通过，截止深度≥OD3；CMOS感光元件Ⅲ用于感应波长为800～1000nm的光并转换为电信号发送至计算机对吲哚菁绿进行荧光成像。
进一步地，所述可见光源为LED灯。
有益效果
本发明可以达到的有益效果为：
(1)作为淋巴染色示踪剂使用的复他舒示踪用盐酸米托蒽醌注射液在具备不弥散、染色快，代谢彻底等优点的同时，通过与哺乳动物的血清混合之后形成了具备新的荧光光谱特性的纳米晶，该纳米晶在波长为600～710nm的光照射下，产生波长为710～810nm的荧光，所产生的荧光相对生物组织具有非常良好的穿透性，有效弥补了传统荧光示踪剂所存在的缺陷，使之可以成为新一代的淋巴荧光 示踪药物。
(2)针对复他舒示踪用盐酸米托蒽醌注射液的新的荧光光谱特性所开发的荧光摄像装置，与复他舒示踪用盐酸米托蒽醌注射液共同应用于淋巴荧光示踪，使医生可以观察到被组织覆盖的淋巴管与淋巴结，使得前哨淋巴结探查更加精准，淋巴结清扫更加彻底，减少遗漏，特别适用于微小淋巴结的探查。
本发明的附图说明如下：
图1是本发明实施例2中注射复他舒示踪用盐酸米托蒽醌注射液后的鸡胸大肌肉的可见光图像；
图2是本发明实施例2中注射复他舒示踪用盐酸米托蒽醌注射液后的鸡胸大肌肉的荧光图像；
图3是本发明实施例2中导出的光谱图；
图4是本发明实施例3、4、5的结构图；
图5是本发明实施例3、4、5中的光源结构图；
图6是本发明实施例3中的摄像机结构图；
图7是本发明实施例4中的摄像机结构图；
图8是本发明实施例5中的摄像机结构图；
图9是本发明实施例6中的摄像机结构图；
图中：1-摄像机，2-光学适配器，3-目镜，4-光源，401-LED灯，402-外壳，403-激光器，404-出光口，405-透光镜片；5-导光接口，6-镜体；11-镜头，12-第一棱镜，1201-面a，1202-面b，1203-面c，13-第二棱镜，1301-面d，1302-面e，1303-面f，14-CMOS感光元件K，15-CMOS感光元件Ⅰ，16-第三棱镜，1601-面g，1602-面h，17-CMOS感光元件Ⅱ，18-CMOS感光元件Ⅲ。
本发明的最佳实施方式
下面结合附图和具体实施方式对本发明作进一步详细的说明。
发明人意外发现，于2021年6月新上市的复他舒示踪用盐酸米托蒽醌注射液与哺乳动物的血清混合之后具备了新的荧光光谱特性，这种新的荧光光谱特性有别于传统的盐酸米托蒽醌的荧光光谱特性，传统的盐酸米托蒽醌的荧光中心波长为690nm，而复他舒示踪用盐酸米托蒽醌注射液的荧光中心波长为740nm，相对生物组织具有非常良好的穿透性，这是使其可以作为荧光示踪剂最本质的特 点之一。但是，复他舒示踪用盐酸米托蒽醌注射液本身并没有上述新的荧光光谱特性。
作为淋巴染色示踪剂使用的复他舒示踪用盐酸米托蒽醌注射液在具备不弥散、染色快，代谢彻底等优点的同时，又具备了新的荧光光谱特性，并且复他舒示踪用盐酸米托蒽醌注射液是国内正式被批准用于甲状腺手术区域引流淋巴结的示踪的产品，经临床验证具有良好的安全性和淋巴示踪效果，同时对甲状旁腺特异性不染色。良好的染色性及新的荧光光谱特性其同时解决了传统荧光示踪剂所存在的缺陷，可以直接作为新一代的淋巴荧光示踪药物使用。
关于为什么复他舒示踪用盐酸米托蒽醌注射液的荧光光谱特性与传统的盐酸米托蒽醌的荧光光谱特性有很大的不同，发明人对其展开了细致的研究，最终发现：
于2021年6月新上市的复他舒示踪用盐酸米托蒽醌注射液，采用了生物自组装纳米晶体技术，将其局部注射后，在生理条件下，药物分子与哺乳动物的血清通过非共价相互作用自发形成类球形生物自组装纳米晶(粒径≈100nm)，分布均匀、表面光滑，由于其具有的此种纳米颗粒结构，使之具有了新的荧光光谱特性，即在波长为500～730nm的光照射下，产生中心波长为740nm的荧光。
上述
Figure PCTCN2022073655-appb-000001
纳米晶的粒径≈100nm，其不进入毛细血管(内皮细胞间隙30-50nm)，但可进入毛细淋巴管(内皮细胞间隙120-500nm)，这使其在实现良好的淋巴示踪效果的同时还具备对甲状旁腺特异性不染色的特点。
Figure PCTCN2022073655-appb-000002
应用渗透压调节机制，加快药物回流至淋巴循环，使纳米晶聚集并滞留在淋巴结，实现甲状腺及其引流区域淋巴结蓝染。
由于复他舒示踪用盐酸米托蒽醌注射液已经是上市的医用药品，其分子结构及药理信息均为公知技术，故本申请中无需再对其药理进行详细阐述。
实施例1
将复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂，本实施例操作如下：包括如下步骤：
(1)准备材料：复他舒示踪用盐酸米托蒽醌注射液1瓶，标准小牛血清1瓶，试管1个，自制荧光摄像装置1台/套，自制荧光摄像装置可以发射出中心波长为660nm的激发光，并可以通过感应波长为740±10nm的光进行成像。
(2)在试管中加入复他舒示踪用盐酸米托蒽醌注射液和标准小牛血清，二者的体积比为1:1，而后摇晃混匀，静置8min。
(3)使自制荧光摄像装置的光源发出中心波长为660nm的激发光，并照射试管中的混合物，通过自制荧光摄像装置的摄像头针对波长为740±10nm的光进行成像，通过屏幕可以清晰地看到摄像机所采集的荧光图像。
本发明的实施方式
实施例2
(1)准备材料：注射器1个，鸡胸大肌肉1块，复他舒示踪用盐酸米托蒽醌注射液1瓶，自制荧光摄像装置1台/套，自制荧光摄像装置可以发射出中心波长为660nm的激发光，并可以通过感应波长为740±10nm的光进行成像。
(2)用注射器抽取复他舒示踪用盐酸米托蒽醌注射液0.75ml，在鸡胸大肌肉上选取三个区，分别为P区、Q区和R区，在P区的表皮上注射0.25ml注射液，即注射深度为0mm；在Q区的皮下注射0.25ml注射液，注射深度为5mm；在R区的皮下注射0.25ml注射液，注射深度为10mm；等待8min，如图1所示。
(3)使自制荧光摄像装置的光源发出中心波长为660nm的激发光，并照射上述鸡胸大肌肉(需要包括P区、Q区和R区)，将自制荧光摄像装置的摄像头对准P区、Q区和R区，通过屏幕可以清晰地看到摄像机所采集的荧光图像，如图2所示。
经发明人反复验证，其穿透性非常良好。通过自制荧光摄像装置导出激发光及激发荧光的光谱数据，可以发现，在中心波长为660nm的激发光的照射下，注射后的复他舒示踪用盐酸米托蒽醌注射液所产生的荧光中心波长为740nm，如图3所示，图中横轴为波长，纵轴为光的强度。
当将复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂时，本领域技术人员可以理解，是要将复他舒示踪用盐酸米托蒽醌注射液注射至哺乳动物，而非鸡胸大肌肉。
实施例3
一种荧光摄像装置，应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪。包括光源4、摄像机1、镜体6和计算机，光源4用于向外输出发射光，发射光被反射后产生反射光，摄像机1通过感应反射光和激发荧光成像；摄像机1包括镜头 11、分光装置和感光元件，如图4所示：目镜3设置于镜体6上，摄像机1的镜头11通过光学适配器2与目镜3相连，光源4的外壳402上设有出光口404，光源4的出光口404与镜体6山的导光接口5相连，导光接口5用于连接导光元件，导光元件用于将光导向至所需处。
如图5所示：光源4包括置于外壳402内腔中的可见光源、激发光源和透光镜片405，可见光源为LED灯401，激发光源为激光器403，透光镜片405上设有双色膜，LED灯401发出的光与激光器403发出的光呈90°设置，LED灯401发出的光穿透透光镜片405及双色膜经出光口404射出，激光器403发出的光经透光镜片405上的双色膜反射后从出光口404射出。LED灯401用于发出波长为400～650nm的可见光，激光器403用于发出波长为600～710nm的光，根据激光器403的市场产品规格，本实施例选用了可以发出中心波长为660nm±15nm的光的激光器，当然，本领域技术人员也可以选择可以发出中心波长为638nm±15nm或685nm±15nm的光的激光器，只是后二者不如本实施例所选用的激光器所实现的效果好。
如图6所示：摄像机包括镜头11、分光装置和感光元件，分光装置包括第一棱镜12和第二棱镜13，第一棱镜12和第二棱镜13均为三棱柱状，第一棱镜12的三个侧面分别为面a1201、面b1202、面c1203，第二棱镜13的三个侧面分别为面d1301、面e1302、面f1303。
第一棱镜12的面b1202与第二棱镜13的面d1301面对面贴合，且第一棱镜12的面b1202与第二棱镜13的面d1301之间夹设有镀膜A，镀膜A用于使波长小于710nm的光透过，使波长大于710的光反射。
感光元件包括CMOS感光元件K14和CMOS感光元件Ⅰ15，CMOS感光元件K14用于感应波段为400～650nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像；CMOS感光元件Ⅰ15用于感应波段为710～800nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅰ15前设有滤光片Ⅰ，滤光片Ⅰ为带通型滤光片，使波长为740±10nm的光通过，截止深度≥OD3。
混合光依次通过镜头11、第一棱镜12的面a1201、第一棱镜12的面b1202至镀膜A，镀膜A将混合光分为两束光，一束光为波长小于710nm的光，另一 束光为波长大于710nm的光；波长小于710nm的光依次透过镀膜A、第二棱镜13的面d1301、第二棱镜13的面f1303至CMOS感光元件K14；波长大于100nm的光被镀膜A反射后依次至第一棱镜12的面a1201、第一棱镜12的面c1203至CMOS感光元件Ⅰ15。
将本实施例的荧光摄像装置应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪时，将复他舒示踪用盐酸米托蒽醌注射液适量注射至哺乳动物体内，对该注射处进行成像。光源4通过LED灯401发出波长为400～650nm的可见光，通过激光器403用于发出中心波长为660nm±15nm的激发光，这两种光的混合光照射至注射处时，会产生另外两种光的混合光，即反射的波长为400～650nm的可见光和纳米晶被激发产生的中心波长为740nm的荧光，此两种混合光经分光装置后被分成波段为分光束K和分光束Ⅰ，CMOS感光元件K14感应分光束K并发送至计算机进行成像，CMOS感光元件Ⅰ15感应分光束Ⅰ并发送至计算机对纳米晶进行荧光成像。
实施例4
一种双示踪用荧光摄像装置，可以应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪和亚甲蓝的荧光示踪。
本实施例的双示踪用荧光摄像装置与实施例3的区别在于摄像机不同，其余均与实施例3相同。
如图7所示：摄像机包括镜头11、分光装置和感光元件，分光装置包括第一棱镜12、第二棱镜13和第三棱镜16，第一棱镜12和第二棱镜13均为三棱柱状，第三棱镜16为四棱柱状，第一棱镜12的三个侧面分别为面a1201、面b1202、面c1203，第二棱镜13的三个侧面分别为面d1301、面e1302、面f1303，第三棱镜16的两个相对的侧面分别为面g1601和面h1602。
第一棱镜12的面b1202与第二棱镜13的面d1301面对面贴合，且第一棱镜12的面b1202与第二棱镜13的面d1301之间夹设有镀膜A，镀膜A用于使波长小于710nm的光透过，使波长大于710的光反射。
第二棱镜13的面f1303与第三棱镜16的面g1601面对面贴合，且第二棱镜13的面f1303与第三棱镜16的面g1601之间夹设有镀膜B，镀膜B用于使波长小于650nm的光透过，使波长大于650的光反射。
感光元件包括CMOS感光元件K14、CMOS感光元件Ⅰ15和CMOS感光元件Ⅱ17，CMOS感光元件K14用于感应波段为400～650nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像；CMOS感光元件Ⅰ15用于感应波段为710～800nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅰ15前设有滤光片Ⅰ，滤光片Ⅰ为带通型滤光片，具体为窄带型，使波长为740±10nm的光通过，截止深度≥OD3；CMOS感光元件Ⅱ17用于感应波段为650～710nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅱ17前设有滤光片Ⅱ，滤光片Ⅱ带通型滤光片，具体为窄带型，使波长为690±10nm的光通过，截止深度≥OD3。
混合光依次通过镜头11、第一棱镜12的面a1201、第一棱镜12的面b1202至镀膜A，镀膜A将混合光分为两束光，一束光为波长小于710nm的光，另一束光为波长大于710nm的光；
波长大于710nm的光被镀膜A反射后依次至第一棱镜12的面a1201、第一棱镜12的面c1203至CMOS感光元件Ⅰ15；
波长小于710nm的光依次透过镀膜A、第二棱镜13的面d1301、第二棱镜13的面f1303至镀膜B，镀膜A将波长小于710nm的光分为两束光，一束光为波长小于650nm的光，另一束为波长大于650nm的光；
波长大于650nm的光被镀膜B反射后依次至第二棱镜13的面d1301、第二棱镜13的面e1302至CMOS感光元件Ⅱ17；
波长小于650nm的光依次透过镀膜B、第三棱镜16的面g1601和第三棱镜16的面h1602至CMOS感光元件K14。
将本实施例的荧光摄像装置应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪时，将复他舒示踪用盐酸米托蒽醌注射液适量注射至哺乳动物体内，对该注射处进行成像。光源4通过LED灯401发出波长为400～650nm的可见光，通过激光器403用于发出中心波长为660nm±15nm的激发光，这两种光的混合光照射至注射处时，会产生另外两种光的混合光，即反射的波长为400～650nm的可见光和复他舒纳米晶被激发产生的中心波长为740nm的荧光，此两种混合光经分光装置后被分成波段为分光束K和分光束Ⅰ，CMOS感光元件K14感应 分光束K并发送至计算机进行成像，CMOS感光元件Ⅰ15感应分光束Ⅰ并发送至计算机对纳米晶进行荧光成像。
将本实施例的荧光摄像装置应用于亚甲蓝的荧光示踪时，将亚甲蓝注射至哺乳动物体内，对该注射处进行成像。光源4通过LED灯401发出波长为400～650nm的可见光，通过激光器403用于发出中心波长为660nm±15nm的激发光，这两种光的混合光照射至注射处时，会产生另外两种光的混合光，即反射的波长为400～650nm的可见光和亚甲蓝被激发产生的中心波长为690nm的荧光，此两种混合光经分光装置后被分成波段为分光束K和分光束Ⅱ，CMOS感光元件K14感应分光束K并发送至计算机进行成像，CMOS感光元件Ⅱ17感应分光束Ⅱ并发送至计算机对亚甲蓝进行荧光成像。
此实施例的双示踪用荧光摄像装置的分光装置可以将混合光分离出可见光、复他舒纳米晶荧光和亚甲蓝荧光，不同的感光元件分别针对可见光、复他舒纳米晶荧光和亚甲蓝荧光进行感光后分别成像，计算机将各自波段光所成的像进行合成，可以呈现出光学图像、复他舒纳米晶荧光图像和亚甲蓝荧光图像的复合图像，供医生直观进行观看。
实施例5
一种双示踪用荧光摄像装置，可以应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪和吲哚菁绿的荧光示踪。
本实施例的双示踪用荧光摄像装置与实施例3的区别在于摄像机不同，其余均与实施例3相同。
如图8所示：摄像机包括镜头11、分光装置和感光元件，分光装置包括第一棱镜12、第二棱镜13和第三棱镜16，第一棱镜12和第二棱镜13均为三棱柱状，第三棱镜16为四棱柱状，第一棱镜12的三个侧面分别为面a1201、面b1202、面c1203，第二棱镜13的三个侧面分别为面d1301、面e1302、面f1303，第三棱镜16的两个相对的侧面分别为面g1601和面h1602。
第一棱镜12的面b1202与第二棱镜13的面d1301面对面贴合，且第一棱镜12的面b1202与第二棱镜13的面d1301之间夹设有镀膜C，镀膜C用于使波长小于800nm的光透过，使波长大于800的光反射。
第二棱镜13的面f1303与第三棱镜16的面g1601面对面贴合，且第二棱 镜13的面f1303与第三棱镜16的面g1601之间夹设有镀膜D，镀膜D用于使波长小于710nm的光透过，使波长大于710的光反射。
感光元件包括CMOS感光元件K14、CMOS感光元件Ⅰ15和CMOS感光元件Ⅲ18，CMOS感光元件K14用于感应波段为400～650nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像；CMOS感光元件Ⅰ15用于感应波段为710～800nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅰ15前设有滤光片Ⅰ，滤光片Ⅰ为带通型滤光片，具体为窄带型，使波长为740±10nm的光通过，截止深度≥OD3；CMOS感光元件Ⅲ18用于感应波段为800～1000nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅱ17前设有滤光片Ⅲ，滤光片Ⅲ带通型滤光片，具体为窄带型，使波长为830±10nm的光通过，截止深度≥OD3。
混合光依次通过镜头11、第一棱镜12的面a1201、第一棱镜12的面b1202至镀膜C，镀膜C将混合光分为两束光，一束光为波长小于800nm的光，另一束光为波长大于800nm的光；
波长大于800nm的光被镀膜C反射后依次至第一棱镜12的面a1201、第一棱镜12的面c1203至CMOS感光元件Ⅲ18；
波长小于800nm的光依次透过镀膜C、第二棱镜13的面d1301、第二棱镜13的面f1303至镀膜D，镀膜D将波长小于800nm的光分为两束光，一束光为波长小于710nm的光，另一束为波长大于710nm的光；
波长大于710nm的光被镀膜D反射后依次至第二棱镜13的面d1301、第二棱镜13的面e1302至CMOS感光元件Ⅰ15；
波长小于710nm的光依次透过镀膜D、第三棱镜16的面g1601和第三棱镜16的面h1602至CMOS感光元件K14。
将本实施例的荧光摄像装置应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪时，将复他舒示踪用盐酸米托蒽醌注射液适量注射至哺乳动物体内，对该注射处进行成像。光源4通过LED灯401发出波长为400～650nm的可见光，通过激光器403用于发出中心波长为660nm±15nm的激发光，这两种光的混合光照射至注射处时，会产生另外两种光的混合光，即反射的波长为400～650nm 的可见光和复他舒纳米晶被激发产生的中心波长为740nm的荧光，此两种混合光经分光装置后被分成波段为分光束K和分光束Ⅰ，CMOS感光元件K14感应分光束K并发送至计算机进行成像，CMOS感光元件Ⅰ15感应分光束Ⅰ并发送至计算机对纳米晶进行荧光成像。
将本实施例的荧光摄像装置应用于吲哚菁绿的荧光示踪时，将吲哚菁绿注射至哺乳动物体内，对该注射处进行成像。光源4通过LED灯401发出波长为400～650nm的可见光，通过激光器403用于发出中心波长为660nm±15nm的激发光，这两种光的混合光照射至注射处时，会产生另外两种光的混合光，即反射的波长为400～650nm的可见光和吲哚菁绿被激发产生的中心波长为830nm的荧光，此两种混合光经分光装置后被分成波段为分光束K和的分光束Ⅲ，CMOS感光元件K14感应分光束K并发送至计算机进行成像，CMOS感光元件Ⅲ18感应分光束Ⅲ并发送至计算机对吲哚菁绿进行荧光成像。
此实施例的双示踪用荧光摄像装置的分光装置可以将混合光分离出可见光、复他舒纳米晶荧光和吲哚菁绿荧光，不同的感光元件分别针对可见光、复他舒纳米晶荧光和吲哚菁绿荧光进行感光后分别成像，计算机将各自波段光所成的像进行合成，可以呈现出光学图像、复他舒纳米晶荧光图像和吲哚菁绿荧光图像的复合图像，供医生直观进行观看。
实施例6
一种三示踪用荧光摄像装置，可以应用于亚甲蓝、复他舒示踪用盐酸米托蒽醌注射液的荧光示踪和吲哚菁绿的荧光示踪。
本实施例的三示踪用荧光摄像装置与实施例5的区别在于摄像机的感光元件不同，其余均与实施例5相同。
如图9所示：感光元件包括CMOS感光元件Ⅱ17、CMOS感光元件Ⅰ15和CMOS感光元件Ⅲ18，CMOS感光元件Ⅱ17用于感应波段为650～710nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅱ17前设有滤光片Ⅱ，滤光片Ⅱ带通型滤光片，具体为窄带型，使波长为690±10nm的光通过，截止深度≥OD3；CMOS感光元件Ⅰ15用于感应波段为710～800nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅰ15前设有滤光片Ⅰ，滤光片Ⅰ为带通型滤光片， 具体为窄带型，使波长为740±10nm的光通过，截止深度≥OD3；CMOS感光元件Ⅲ18用于感应波段为800～1000nm的光，并将光信号转换为电信号，将电信号发送至计算机进行可见光成像，CMOS感光元件Ⅱ17前设有滤光片Ⅲ，滤光片Ⅲ带通型滤光片，具体为窄带型，使波长为830±10nm的光通过，截止深度≥OD3。
混合光依次通过镜头11、第一棱镜12的面a1201、第一棱镜12的面b1202至镀膜C，镀膜C将混合光分为两束光，一束光为波长小于800nm的光，另一束光为波长大于800nm的光；
波长大于800nm的光被镀膜C反射后依次至第一棱镜12的面a1201、第一棱镜12的面c1203至CMOS感光元件Ⅲ18；
波长小于800nm的光依次透过镀膜C、第二棱镜13的面d1301、第二棱镜13的面f1303至镀膜D，镀膜D将波长小于800nm的光分为两束光，一束光为波长小于710nm的光，另一束为波长大于710nm的光；
波长大于710nm的光被镀膜D反射后依次至第二棱镜13的面d1301、第二棱镜13的面e1302至CMOS感光元件Ⅰ15；
波长小于710nm的光依次透过镀膜D、第三棱镜16的面g1601和第三棱镜16的面h1602至CMOS感光元件Ⅱ17。
将本实施例的荧光摄像装置应用于吲哚菁绿的荧光示踪时，将吲哚菁绿注射至哺乳动物体内，对该注射处进行成像。光源4通过激光器403用于发出中心波长为660nm±15nm的激发光，照射至注射处时，吲哚菁绿被激发产生的中心波长为830nm的荧光，中心波长为830nm的荧光经分光装置后被导向至CMOS感光元件Ⅲ18，CMOS感光元件Ⅲ18感应吲哚菁绿荧光并发送至计算机对吲哚菁绿进行荧光成像。
将本实施例的荧光摄像装置应用于复他舒示踪用盐酸米托蒽醌注射液的荧光示踪时，将复他舒示踪用盐酸米托蒽醌注射液适量注射至哺乳动物体内，对该注射处进行成像。光源4通过激光器403用于发出中心波长为660nm±15nm的激发光，照射至注射处时，复他舒纳米晶被激发产生的中心波长为740nm的荧光，中心波长为740nm的荧光经分光装置后被导向至CMOS感光元件Ⅰ15，CMOS感光元件Ⅰ15感应复他舒纳米晶荧光并发送至计算机对复他舒纳米晶进 行荧光成像。
将本实施例的荧光摄像装置应用于亚甲蓝的荧光示踪时，将亚甲蓝注射至哺乳动物体内，对该注射处进行成像。光源4通过激光器403用于发出中心波长为660nm±15nm的激发光，照射至注射处时，亚甲蓝被激发产生的中心波长为690nm的荧光，中心波长为690nm的荧光经分光装置后被导向至CMOS感光元件Ⅱ17，CMOS感光元件Ⅱ17感应亚甲蓝荧光并发送至计算机对亚甲蓝进行荧光成像。
此实施例的三示踪用荧光摄像装置的分光装置可以将混合光分离出亚甲蓝荧光、复他舒纳米晶荧光和吲哚菁绿荧光，不同的感光元件分别针对亚甲蓝、复他舒纳米晶荧光和吲哚菁绿荧光进行感光后分别成像，计算机将各自波段光所成的像进行合成，可以呈现出亚甲蓝荧光图像、复他舒纳米晶荧光图像和吲哚菁绿荧光图像的复合图像，供医生直观进行观看。
注：由于体外使用荧光摄像系统、荧光内窥镜、荧光显微镜均包括可见光源、激发光源、分光装置和摄像机，荧光激发及荧光摄像的原理基本相同，在本实施例的教导下，本领域技术人员完全可以对现有的体外使用荧光摄像系统、荧光内窥镜、荧光显微镜做出相关改进。
在本发明的描述中，“内”、“外”、“上”、“下”、“前”、“后”等指示方位或位置关系的词语，仅是为了便于描述本发明，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此不能理解为对本发明的限制。
以上所述仅是本发明的其中一种实施方式，本发明的保护范围并不仅局限于上述实施例，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明思路的前提下所做出的若干改进和润饰均为本发明的保护范围。

Claims (10)

  1. 复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途，其特征是：所述复他舒示踪用盐酸米托蒽醌注射液与哺乳动物的血清混合之后，通过非共价相互作用形成表面光滑的类球形生物自组装纳米晶，纳米晶的粒径≈100nm，所述纳米晶具有荧光光谱特性，在波长为600～710nm的光照射下，产生波长为710～810nm的荧光。
  2. 如权利要求1所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途，其特征是：所述纳米晶在波长为600～710nm的光照射下，产生中心波长为740nm的荧光。
  3. 如权利要求1或2所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途，其特征是：将所述复他舒示踪用盐酸米托蒽醌注射液应用于淋巴荧光示踪。
  4. 一种如权利要求1-3任一项所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述荧光摄像装置具体为体外使用荧光摄像系统、荧光内窥镜、荧光显微镜中的一种，包括光源(4)、摄像机(1)和计算机，光源(4)用于向外输出发射光，发射光被反射后产生反射光，摄像机(1)通过感应反射光和激发荧光成像；光源(4)包括可见光源和激发光源，可见光源用于发出波长为400～650nm的可见光，激发光源为激光器(403)，激光器(403)用于发出波长为600～710nm的光，当激发荧光包括激发荧光Ⅰ时，激发荧光Ⅰ是波长为710～800nm的荧光；摄像机(1)包括分光装置和感光元件，感光元件包括CMOS感光元件K(14)和CMOS感光元件Ⅰ(15)；反射光和激发荧光Ⅰ经分光装置后被分成波段为400～650nm的分光束K和710～800nm的分光束Ⅰ，CMOS感光元件K(14)用于感应分光束K并转换为电信号发送至计算机进行成像，CMOS感光元件Ⅰ(15)用于感应分光束Ⅰ并转换为电信号发送至计算机对所述纳米晶进行荧光成像，CMOS感光元件Ⅰ(15)前设有滤光片Ⅰ。
  5. 如权利要求4所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述滤光片Ⅰ为长波通滤光片，用于使波长大于710nm的光透过，截止深度≥OD3。
  6. 如权利要求4所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用 途中所用的荧光摄像装置，其特征是：所述滤光片Ⅰ为带通型滤光片，使波长为710～800nm的光通过，截止深度≥OD3。
  7. 如权利要求4所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述激光器(403)发出的光的中心波长为638nm±15nm或660nm±15nm或685nm±15nm。
  8. 如权利要求6所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述摄像机(1)的感光元件还包括CMOS感光元件Ⅱ(17)，当激发荧光包括激发荧光Ⅱ时，激发荧光Ⅱ的波长为650～710nm的荧光，反射光和激发荧光Ⅱ经分光装置后被分成波段为400～650nm的分光束K和650～710nm的分光束Ⅱ，CMOS感光元件Ⅱ(17)用于感应分光束Ⅱ并转换为电信号发送至计算机对亚甲蓝进行荧光成像，CMOS感光元件Ⅱ(17)前设有滤光片Ⅱ，滤光片Ⅱ为带通型滤光片，使波长为650～710nm的光通过，截止深度≥OD3。
  9. 如权利要求4或8所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述摄像机(1)的感光元件还包括CMOS感光元件Ⅲ(18)，当激发荧光包括激发荧光Ⅲ时，激发荧光Ⅲ的波长为800～1000nm的荧光，反射光和激发荧光Ⅲ经分光装置后被分成波段为400～650nm的分光束K和800～1000nm的分光束Ⅲ，CMOS感光元件Ⅲ(18)前设有滤光片Ⅲ，滤光片Ⅲ为带通型滤光片，使波长为800～1000nm的光通过，截止深度≥OD3；CMOS感光元件Ⅲ(18)用于感应波长为800～1000nm的光并转换为电信号发送至计算机对吲哚菁绿进行荧光成像。
  10. 如权利要求4所述的复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的用途中所用的荧光摄像装置，其特征是：所述可见光源为LED灯(401)。
PCT/CN2022/073655 2022-01-18 2022-01-25 复他舒示踪用盐酸米托蒽醌注射液作为荧光示踪剂的应用及用于其的荧光摄像装置 WO2023137775A1 (zh)

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