CA2144209C - Method and apparatus for an efficient photodynamic treatment - Google Patents
Method and apparatus for an efficient photodynamic treatment Download PDFInfo
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- CA2144209C CA2144209C CA002144209A CA2144209A CA2144209C CA 2144209 C CA2144209 C CA 2144209C CA 002144209 A CA002144209 A CA 002144209A CA 2144209 A CA2144209 A CA 2144209A CA 2144209 C CA2144209 C CA 2144209C
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- 238000002428 photodynamic therapy Methods 0.000 title abstract description 24
- 238000000034 method Methods 0.000 title description 3
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 230000005855 radiation Effects 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 239000003365 glass fiber Substances 0.000 claims abstract description 4
- 230000002977 hyperthermial effect Effects 0.000 claims abstract description 4
- 230000003595 spectral effect Effects 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 10
- 238000000576 coating method Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 230000003287 optical effect Effects 0.000 claims description 10
- 238000002834 transmittance Methods 0.000 claims description 10
- 239000011521 glass Substances 0.000 claims description 6
- 239000005388 borosilicate glass Substances 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 abstract description 2
- 239000005304 optical glass Substances 0.000 abstract description 2
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- 206010028980 Neoplasm Diseases 0.000 description 22
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000005284 excitation Effects 0.000 description 6
- 239000003504 photosensitizing agent Substances 0.000 description 6
- 238000000862 absorption spectrum Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 206010020843 Hyperthermia Diseases 0.000 description 3
- 239000003570 air Substances 0.000 description 3
- 230000036031 hyperthermia Effects 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 230000003966 vascular damage Effects 0.000 description 3
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 108010064719 Oxyhemoglobins Proteins 0.000 description 2
- 208000006787 Port-Wine Stain Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 229960002749 aminolevulinic acid Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
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- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- 238000012986 modification Methods 0.000 description 2
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- 229910052760 oxygen Inorganic materials 0.000 description 2
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- 201000000849 skin cancer Diseases 0.000 description 2
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- 206010001497 Agitation Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 206010057040 Temperature intolerance Diseases 0.000 description 1
- 239000012080 ambient air Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- QIFOFCWBJPAXTM-UHFFFAOYSA-N chembl375232 Chemical compound C1=CC(C(=O)O)=CC=C1C(C1=CC=C(N1)C(C=1C=CN=CC=1)=C1C=CC(=N1)C(C=1C=CN=CC=1)=C1C=CC(N1)=C1C=2C=CN=CC=2)=C2N=C1C=C2 QIFOFCWBJPAXTM-UHFFFAOYSA-N 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000004035 chlorins Chemical class 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
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- 230000008543 heat sensitivity Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000006552 photochemical reaction Methods 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- -1 phtalocya-nin Chemical compound 0.000 description 1
- 150000004032 porphyrins Chemical class 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- NFACJZMKEDPNKN-UHFFFAOYSA-N trichlorfon Chemical compound COP(=O)(OC)C(O)C(Cl)(Cl)Cl NFACJZMKEDPNKN-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0613—Apparatus adapted for a specific treatment
- A61N5/062—Photodynamic therapy, i.e. excitation of an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F7/00—Heating or cooling appliances for medical or therapeutic treatment of the human body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0601—Apparatus for use inside the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N2005/002—Cooling systems
- A61N2005/005—Cooling systems for cooling the radiator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
- A61N2005/0659—Radiation therapy using light characterised by the wavelength of light used infrared
Abstract
The present invention relates to an improved apparatus for a therapeutic treatment of malignant solid tumors, consisting of a combined photodynamic therapy and hyperthermic treatment, said apparatus comprising a lamp possessing a narrow beam light, a mirror, an optical glass lenses system, a dicroic filter, a glass fiber optics bundle and an effective air-cooling system. This apparatus provides the administration of between 100 to 150 mw/cm2 of red radiation in the range of between 600 to 750 nm band at a temperature of up to 46°C. Clinical results from three different hospitals show that by this apparatus a success of more than 85% were achieved even after one single treatment.
Description
zl4~zo9 -1=
METHOD AND APPARATUS FOR AN EFFICIENT
PHOTODYNAMIC TREATMENT
The present invention relates to an apparatus for in-vivo treatment of tumors. More particularly, the inven-tion relates to an improved apparatus for an efficient photodynamic therapy as an in-vivo treatment of tumors.
BACKGROUND OF THE INVENTION
As known Photodynamic Therapy (hereinafter referred to as PDT), is recognised as an useful treatment for certain solid tumors, including skin cancer and internal organs such as colon, vagina, bladder and others. The PDT treatment is based on a systemic or topical adminis-tration of a tumor-localizing photosensitizes reagent, such as porphirin, aminolevulinic acid (ALA), phtalocya-nin, chlorine etc., which after illumination and excita-tion with visible light in the presence of oxygen, give rise to highly reactive and cytotoxic singlet molecular oxygen which leads to tumor regression (see Figure 1).
In our previous U.S. Patent No. 5,344,434, an apparatus for a PDT treatment was described. The apparatus comprises the following components:
- a Xe-lamp possessing a narrow beam light with half angle divergence of up to 10~, possessing an intensity of at least 2mW/nm with a special region in the range of 610 to 750 nm;
METHOD AND APPARATUS FOR AN EFFICIENT
PHOTODYNAMIC TREATMENT
The present invention relates to an apparatus for in-vivo treatment of tumors. More particularly, the inven-tion relates to an improved apparatus for an efficient photodynamic therapy as an in-vivo treatment of tumors.
BACKGROUND OF THE INVENTION
As known Photodynamic Therapy (hereinafter referred to as PDT), is recognised as an useful treatment for certain solid tumors, including skin cancer and internal organs such as colon, vagina, bladder and others. The PDT treatment is based on a systemic or topical adminis-tration of a tumor-localizing photosensitizes reagent, such as porphirin, aminolevulinic acid (ALA), phtalocya-nin, chlorine etc., which after illumination and excita-tion with visible light in the presence of oxygen, give rise to highly reactive and cytotoxic singlet molecular oxygen which leads to tumor regression (see Figure 1).
In our previous U.S. Patent No. 5,344,434, an apparatus for a PDT treatment was described. The apparatus comprises the following components:
- a Xe-lamp possessing a narrow beam light with half angle divergence of up to 10~, possessing an intensity of at least 2mW/nm with a special region in the range of 610 to 750 nm;
- a glass tense to focus the beam of the light;
- a red filter to provide a spectral region of above 610 nm;
- a 45~ dichroic mirror to remove produced heat, and - a light guide in the range of 3 to 12 mm diameter, which provides a minimum irradiance of 50 mW/cm2.
The apparatus described in the above patent was found to be useful with a wide variety of photosensitizers contrary to what is claimed in some prior patent appli-cations such as German 411 2275 41 and PCT 94/09850, that a narrow band filtering, does enable excitation of specific photosensitizers only. In additon to that, the broad band excitation mentioned in the invention descri-bed in our above prior U.S. patent, enables utilization of PDT photo-products, having an absorption maxima extended by 30 to 50 nm from the absorption maxima of the photosensitizes.
The Xe short arc and metal halide short arc lamps are most preferred being able to produce the arc image of the highest radiance. However, these lamps are very inefficient generators of spectral energy. Thus, with a Xe lamp of 300 W input electrical energy only about 50 W
are transformed into light, i.e. from ultra-violet to near infra-red, while other 250 W are transformed into - 3 - 2i~4zo9 heat. The available spectral intensity in the spectral interval of 100 nm bandwidth is only 5 W. Therefore, in order to produce a spectrally filtered intensity, 45 W
of undesired light must be filtered out. In this manner, the overall balance shows that only 2% of the electrical input are transformed into the desired spectral output, while the balance of 295 W of heat and unwanted light are most undesirable.
It is also known that PDT involves damage to the tumor vascular bed, which in turn causes disruption of tumor blood flow and ultimately to a tissue necrosis. The vascular damage produced by the PDT treatment in the tumor, reduces its efficiency in cooling the tumor.
Hyperthermia or heating of the tumor to the moderate temperature of up to 46~ has been proven to be of clinically value. It has been published (S.Kimmel et. al, Lasers & Surgery medicine, 12: 432-440, 1992) that a combination of PDT with Hyperthermic therapy (hereafter referred to HPT) will result a 40% decrease of the irradiation dose required to produce vascular damage.
Various mechanisms for the synergism of PDT and I~PT, were suggested which can be concluded as follows:
- The PDT treatment increases the heat sensitivity of the tumor cells, due to a decrease of the pH.
- The HPT enhances the photosensitization due to an increased blood flow.
- The damage repair inactivation by each of the modalities enhances another effect.
Among other disadvantages of the heat and unwanted light, it should be mentioned the failure which might occur to the lamp, to the optical and electronics ele-ments as well as the hazards to the operating personnel of the apparatus.
There are some prior patents which deal with the problem of cooling means, such as Xenon lamps, in order to decrease the disadvantages involved by their use. Thus, according to the U.S. Patent No. 4,298,005, it is suggested to use a ventilator for cooling the housing of the apparatus.
In the U.S. Patent No. 5,036,242, it is suggested a liquid-cooled lamp, having a passage for the flow of the liquid coolant and a passage for heated fluid outlet;
the liquid-air heat exchanger is positioned in the flow circuit conduit by heat exchange with air.
In a very recent U.S. Patent No. 5,285,363, it is sug-Bested a method and device for removing heat generated from a Xenon-lamp, by using a heat transfer unit which is located adjacent: to a mirror positioned in the path of the ~~eam to transmit infra-red light.
The above brief review of the prior art, clearly indicates the long felt need for an improved apparatus to deal with the subject of the present invention.
The present invention is directed towards the provision of an improved apparatus for an efficient treatment of tumors which overcomes the disadvantages of the known apparatus and. towards the provision of an improved apparatus for an efficient treatment of tumors wherein the unwanted light is removed while the generated heat is dissipated.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with one aspect of the present invention, there is provides an apparatus for an efficient simultaneous photodynamic and hyperthermic treatment, said apparatus having an optical axis, said apparatus comprising (a) a lamp for emitting a narrow beam light with half angle divergence of up to 10°, having an intensity of at least 20 mW/nm of red radiation in the spectral region of 600 to 750 nm and at least 2 mW/nm of infrared radiation in the spectral region of 1100 to 1700 nm, said lamp generating heat when emitting said beam light; (b) a "hot" mirror, comprising a hard, all-dielectric filter coating deposited on a borosilicate glass, having a transmittance of at least 60% between 600 and 750 nm and at least 5% between 1200 and 1700 nm, while reflecting the radiation between 750 and 1200 nm; (c) a glass lens system, optionally having an anti-reflection coating; (d) a dichroic filter made of a hard, all-dielectric coating deposited on glass, having at least 60% transmittance above 600 nm while having a negligible transmittance below 600 nm; (e) a glass fiber optics bundle having a diameter between 1 and 12 mm as a separate unit or as part of an endoscope; said elements (a)-(e) being aligned along the optical axis of the apparatus; and (f) an effective air-cooling system to decrease the internal heating of the apparatus, which provides an internal temperature in the apparatus below a maximum temperature of 50°C.
Figure l, illustrates a typical absorption spectra of photosen:~itizers.
Figure 2, illustrates a typical absorption spectra of tissue constitutents.
Figure 3, is a schematic illustration of the improved apparatus according to the present invention which combines the PDT and HPT treatments of solid tumor.
Figure 4, illustrat:es the spectral distribution of a preferred embodiments.
DETF.ILED DESCRIPTION OF THE INVENTION
Hyperthermia has been proved to be selectively letal to various malignant cells in the range of 41° to 46°C, thus being considered to be a clinical value.
According to the present invention, it was found that the combination of PDT and HPT when applied simultaneously, is much more effective and provides better results than the two separate individual treatments. The benefit from this combination, besides the decrea:~e of about 40% of - 7 - z144zo9 the irradiation dose required to produce vascular damage is also a better penetration.
The photochemical reaction enhancement at elevated temperatures which results from the PDT, does produce a strong cytotoxic effect and reduces the required treat ment dosage. On the ather hand, the thermal penetration depth in the tissue which is generally in the range of 3 to 7 nm, is higher than the optical penetration of between 1 to 3 mm at 630 nm. Therefore, shallow tumors might be treated by PDT alone, but an efficient treat-went could not be achieved in case of deeper tumors.
It was found that the apparatus according to the present invention, produces a moderate heating of the tumor to a temperature in the range of between 41 to 46~C and most preferably to about 45~C. This effect called hyperther-mia, imparts a synergistic effect when combined with the PDT treatment. As a result, the overall efficiency in treating deep tumors is greatly enhanced.
According to a most preferred embodiment, the treatment will consist from the administration of between 100 to 150 mw/cm2 of red radiation in the range of between 600 to 750 nm band and simultaneously a heating of the tumor to a temperature of up to 46~C. The total time of treatment will be about 20 minutes, including only about - $ - 2144209 minutes of pure PDT, reaching the above maximum temperature and a simultaneous HPT treatment for about minutes.
The hyperthermal treatment may be obtained by a direct 5 heating of the tumor. However, for a better control of the maximum temperature produced, an optical irradiation is preferred. For example, by a simultaneous irradiation at 1.2 to 1.7 um, the required heating of a tumor could be produced with a irradiance of only 30 to 70 mw/sq.cm.
10 for a period of about 20 minutes. A preferred apparatus according to the present invention is characterized by a simultaneous illumination in the range of between 600 to 750 nm in the "red" and between 1200 to 1700 nm in the near infra-red. The ratio between the power emitted in 15 the "red" to the power emitted in the near Infra-red is preferably between 2:1 and 5:1 and most preferably between 3:1. A preferred mode for applying the heating is by a C02 laser or NdYaG laser. The resulting spectrum of the preferred embodiment is shown in Figure 4.
DETAILED DESCRIPTION OF THE FIGURES.
Figure 1, illustrates typical absorption spectra of monomeric porphyrin, chlorins and phthalocya-nines.
_ g _ Figure 2, illustrates typical absorption spectra of melanin, hemoglobin, oxyhemoglobin and water which involves the mechanisms for the synergistic effect which may include several contributions .
Figure 3, describe: the apparatus according to the present invention which comprises the following main components:
(a) A lamp possessing a narrow beam light with half angle divergence of up to 10°, having an intensity of at least 20 mW/nm at a spectral region in the range of 600 to 750 nm and intensity of at least 2 mW/nm in the spectral region of: 1200 to 1700 nm.
(b) A "hot" mirror, comprising a hard all-dielect-ri.c filter coating deposited on a TEMPAXTM glass, having a transmittance of at least 60~c in the range of 600 to 750 nm and at least 5% in the range of 1200 to 1700 nm range, while reflecting the radiation between the 750 t:o 1200 nm range. According to a preferred embodiment, the angle of the mirror relative to the axis may be varied in order to change the ratio of the transmit-- 1° - 2144209 tance in those two bands.
The ratio between the transmittance at the 600 to 750 nm and 1200 to 1700 nm may be changed by rotating the mirror from its axis, between 0~
and 45~ relative to the optical axis.
(c) An optical glass lenses system to focus the beam of the light, preferably with a broad band Anti-Reflection coating for the visible spectrum.
comprising a hard all-dielectric coating.
(d) A dichroic filter comprising a hard all-dielec-tric coating having at least 60% transmittance above 600nm.
(e) A glass fiber optics bundle, having an input diameter in the range of 1 to 12 mm, preferably 6 mm and length of 0.5 m to 2.5 m and most pre-ferably 1.5 m, as a separate unit or as a part of endoscope.
(f) An effective air-cooling system for the removal of the unwanted light and dissipation of the generated heat, so that the internal temperature in the apparatus will not exceed 50~C. According to a preferred embodiment, this cooling is obtained by two or more fans, which provides an - " - 2144209 internal temperature in the apparatus of not above 46~C. The most preferred embodiment includes 4 fans to dissipate hot air and an inlet system for ambient air.
(g) A power supply;
(h) A timer to control the length of exposure.
(i) An electronic control card.
Figure 4, illustrates the "red" dual band spectral distribution, correlating the normalized spectrum as a function of wavelength (in nano-meters).
From Figure 2, the following conclusions can be drawn:
- The absorption of oxyhemoglobin in the 600-750nm range does result in a temperature increase which causes an increase in molecular oxygen concentration due to dissociation. This effects counter the effect of oxygen depletion during the PDT.
- The absorption of hemoglobin in the blood vessels is in the range of 600 to 750 nm,which produces an increase in the temperature and an enhanced PDT reaction rate.
The clinical results in three different hospitals using the apparatus according to the present invention for skin cancer treatments of 150 patients, show a success of 85% even after one single treatment.
- ,2 - 2144209 The apparatus according to the present invention, can be also incorporated in other systems, thus providing additional useful functions as known in the art. Thus for instance, by adding a violet filter in the range of 400-450 nm, using the means of the filter wheel, it could be used for excitation of photosensitizers in the photodynamic diagnostics. On the other hand, the incorporation of a green filter in the spectral range of 505-590 nm using the means of the filter wheel, may be used far the superficial PDT treatment or for various dermatologic applications such as removal of tatoos and portwine stains.
The addition of distal hand-piece to the fiber optics bundle far dermatologic application, will enable a substantially uniform illumination of up to 3 cm diameter tumors.
Fluorescence spectrometer enabling real-time fluorescen ce measurements excited by violet filter, can be used for cancer diagnostics known in the art as "optical biopsy".
Other functions which could incorporate the apparatus accarding to the present invention are:
Endoscopes for different applications, such as colon, bronchi, gastro, etc.
RGB (red-green-blue) and CCD (charge-coupled-device) cameras to provide multi-spectral vieweing through the above endoscopes.
The addition of white filter in the spectral range of between 400 to 700 nm using the means of the filter wheel may be used far the endoscopic observation.
The apparatus was found also to be used with a broad types of photosensitizers as known in the art and also when narrow band filters enable excitation of only specific photosensitizers. Furthermore, the broad band excitation used in the present invention, enables the utilization of PDT photoproducts, having the absorption maxima removed by 30 to 550 nm from the absorption maxima of the photosensitizer used.
While the invention has been described and illustrated in respect to some particular features, it should be understood that the description does not limiting it, a person skilled in the art after reading the present specification, will be in a position to insert slight modifications, without being outside the invention as covered by the appended Claims. Thus for example, modifications to the electronic components: g, h and i, (see Figure 3) will unable pulsed high power operations .- 2144209 of the above device in the dermatological applications such as portwine stains and tattos removal.
- a red filter to provide a spectral region of above 610 nm;
- a 45~ dichroic mirror to remove produced heat, and - a light guide in the range of 3 to 12 mm diameter, which provides a minimum irradiance of 50 mW/cm2.
The apparatus described in the above patent was found to be useful with a wide variety of photosensitizers contrary to what is claimed in some prior patent appli-cations such as German 411 2275 41 and PCT 94/09850, that a narrow band filtering, does enable excitation of specific photosensitizers only. In additon to that, the broad band excitation mentioned in the invention descri-bed in our above prior U.S. patent, enables utilization of PDT photo-products, having an absorption maxima extended by 30 to 50 nm from the absorption maxima of the photosensitizes.
The Xe short arc and metal halide short arc lamps are most preferred being able to produce the arc image of the highest radiance. However, these lamps are very inefficient generators of spectral energy. Thus, with a Xe lamp of 300 W input electrical energy only about 50 W
are transformed into light, i.e. from ultra-violet to near infra-red, while other 250 W are transformed into - 3 - 2i~4zo9 heat. The available spectral intensity in the spectral interval of 100 nm bandwidth is only 5 W. Therefore, in order to produce a spectrally filtered intensity, 45 W
of undesired light must be filtered out. In this manner, the overall balance shows that only 2% of the electrical input are transformed into the desired spectral output, while the balance of 295 W of heat and unwanted light are most undesirable.
It is also known that PDT involves damage to the tumor vascular bed, which in turn causes disruption of tumor blood flow and ultimately to a tissue necrosis. The vascular damage produced by the PDT treatment in the tumor, reduces its efficiency in cooling the tumor.
Hyperthermia or heating of the tumor to the moderate temperature of up to 46~ has been proven to be of clinically value. It has been published (S.Kimmel et. al, Lasers & Surgery medicine, 12: 432-440, 1992) that a combination of PDT with Hyperthermic therapy (hereafter referred to HPT) will result a 40% decrease of the irradiation dose required to produce vascular damage.
Various mechanisms for the synergism of PDT and I~PT, were suggested which can be concluded as follows:
- The PDT treatment increases the heat sensitivity of the tumor cells, due to a decrease of the pH.
- The HPT enhances the photosensitization due to an increased blood flow.
- The damage repair inactivation by each of the modalities enhances another effect.
Among other disadvantages of the heat and unwanted light, it should be mentioned the failure which might occur to the lamp, to the optical and electronics ele-ments as well as the hazards to the operating personnel of the apparatus.
There are some prior patents which deal with the problem of cooling means, such as Xenon lamps, in order to decrease the disadvantages involved by their use. Thus, according to the U.S. Patent No. 4,298,005, it is suggested to use a ventilator for cooling the housing of the apparatus.
In the U.S. Patent No. 5,036,242, it is suggested a liquid-cooled lamp, having a passage for the flow of the liquid coolant and a passage for heated fluid outlet;
the liquid-air heat exchanger is positioned in the flow circuit conduit by heat exchange with air.
In a very recent U.S. Patent No. 5,285,363, it is sug-Bested a method and device for removing heat generated from a Xenon-lamp, by using a heat transfer unit which is located adjacent: to a mirror positioned in the path of the ~~eam to transmit infra-red light.
The above brief review of the prior art, clearly indicates the long felt need for an improved apparatus to deal with the subject of the present invention.
The present invention is directed towards the provision of an improved apparatus for an efficient treatment of tumors which overcomes the disadvantages of the known apparatus and. towards the provision of an improved apparatus for an efficient treatment of tumors wherein the unwanted light is removed while the generated heat is dissipated.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with one aspect of the present invention, there is provides an apparatus for an efficient simultaneous photodynamic and hyperthermic treatment, said apparatus having an optical axis, said apparatus comprising (a) a lamp for emitting a narrow beam light with half angle divergence of up to 10°, having an intensity of at least 20 mW/nm of red radiation in the spectral region of 600 to 750 nm and at least 2 mW/nm of infrared radiation in the spectral region of 1100 to 1700 nm, said lamp generating heat when emitting said beam light; (b) a "hot" mirror, comprising a hard, all-dielectric filter coating deposited on a borosilicate glass, having a transmittance of at least 60% between 600 and 750 nm and at least 5% between 1200 and 1700 nm, while reflecting the radiation between 750 and 1200 nm; (c) a glass lens system, optionally having an anti-reflection coating; (d) a dichroic filter made of a hard, all-dielectric coating deposited on glass, having at least 60% transmittance above 600 nm while having a negligible transmittance below 600 nm; (e) a glass fiber optics bundle having a diameter between 1 and 12 mm as a separate unit or as part of an endoscope; said elements (a)-(e) being aligned along the optical axis of the apparatus; and (f) an effective air-cooling system to decrease the internal heating of the apparatus, which provides an internal temperature in the apparatus below a maximum temperature of 50°C.
Figure l, illustrates a typical absorption spectra of photosen:~itizers.
Figure 2, illustrates a typical absorption spectra of tissue constitutents.
Figure 3, is a schematic illustration of the improved apparatus according to the present invention which combines the PDT and HPT treatments of solid tumor.
Figure 4, illustrat:es the spectral distribution of a preferred embodiments.
DETF.ILED DESCRIPTION OF THE INVENTION
Hyperthermia has been proved to be selectively letal to various malignant cells in the range of 41° to 46°C, thus being considered to be a clinical value.
According to the present invention, it was found that the combination of PDT and HPT when applied simultaneously, is much more effective and provides better results than the two separate individual treatments. The benefit from this combination, besides the decrea:~e of about 40% of - 7 - z144zo9 the irradiation dose required to produce vascular damage is also a better penetration.
The photochemical reaction enhancement at elevated temperatures which results from the PDT, does produce a strong cytotoxic effect and reduces the required treat ment dosage. On the ather hand, the thermal penetration depth in the tissue which is generally in the range of 3 to 7 nm, is higher than the optical penetration of between 1 to 3 mm at 630 nm. Therefore, shallow tumors might be treated by PDT alone, but an efficient treat-went could not be achieved in case of deeper tumors.
It was found that the apparatus according to the present invention, produces a moderate heating of the tumor to a temperature in the range of between 41 to 46~C and most preferably to about 45~C. This effect called hyperther-mia, imparts a synergistic effect when combined with the PDT treatment. As a result, the overall efficiency in treating deep tumors is greatly enhanced.
According to a most preferred embodiment, the treatment will consist from the administration of between 100 to 150 mw/cm2 of red radiation in the range of between 600 to 750 nm band and simultaneously a heating of the tumor to a temperature of up to 46~C. The total time of treatment will be about 20 minutes, including only about - $ - 2144209 minutes of pure PDT, reaching the above maximum temperature and a simultaneous HPT treatment for about minutes.
The hyperthermal treatment may be obtained by a direct 5 heating of the tumor. However, for a better control of the maximum temperature produced, an optical irradiation is preferred. For example, by a simultaneous irradiation at 1.2 to 1.7 um, the required heating of a tumor could be produced with a irradiance of only 30 to 70 mw/sq.cm.
10 for a period of about 20 minutes. A preferred apparatus according to the present invention is characterized by a simultaneous illumination in the range of between 600 to 750 nm in the "red" and between 1200 to 1700 nm in the near infra-red. The ratio between the power emitted in 15 the "red" to the power emitted in the near Infra-red is preferably between 2:1 and 5:1 and most preferably between 3:1. A preferred mode for applying the heating is by a C02 laser or NdYaG laser. The resulting spectrum of the preferred embodiment is shown in Figure 4.
DETAILED DESCRIPTION OF THE FIGURES.
Figure 1, illustrates typical absorption spectra of monomeric porphyrin, chlorins and phthalocya-nines.
_ g _ Figure 2, illustrates typical absorption spectra of melanin, hemoglobin, oxyhemoglobin and water which involves the mechanisms for the synergistic effect which may include several contributions .
Figure 3, describe: the apparatus according to the present invention which comprises the following main components:
(a) A lamp possessing a narrow beam light with half angle divergence of up to 10°, having an intensity of at least 20 mW/nm at a spectral region in the range of 600 to 750 nm and intensity of at least 2 mW/nm in the spectral region of: 1200 to 1700 nm.
(b) A "hot" mirror, comprising a hard all-dielect-ri.c filter coating deposited on a TEMPAXTM glass, having a transmittance of at least 60~c in the range of 600 to 750 nm and at least 5% in the range of 1200 to 1700 nm range, while reflecting the radiation between the 750 t:o 1200 nm range. According to a preferred embodiment, the angle of the mirror relative to the axis may be varied in order to change the ratio of the transmit-- 1° - 2144209 tance in those two bands.
The ratio between the transmittance at the 600 to 750 nm and 1200 to 1700 nm may be changed by rotating the mirror from its axis, between 0~
and 45~ relative to the optical axis.
(c) An optical glass lenses system to focus the beam of the light, preferably with a broad band Anti-Reflection coating for the visible spectrum.
comprising a hard all-dielectric coating.
(d) A dichroic filter comprising a hard all-dielec-tric coating having at least 60% transmittance above 600nm.
(e) A glass fiber optics bundle, having an input diameter in the range of 1 to 12 mm, preferably 6 mm and length of 0.5 m to 2.5 m and most pre-ferably 1.5 m, as a separate unit or as a part of endoscope.
(f) An effective air-cooling system for the removal of the unwanted light and dissipation of the generated heat, so that the internal temperature in the apparatus will not exceed 50~C. According to a preferred embodiment, this cooling is obtained by two or more fans, which provides an - " - 2144209 internal temperature in the apparatus of not above 46~C. The most preferred embodiment includes 4 fans to dissipate hot air and an inlet system for ambient air.
(g) A power supply;
(h) A timer to control the length of exposure.
(i) An electronic control card.
Figure 4, illustrates the "red" dual band spectral distribution, correlating the normalized spectrum as a function of wavelength (in nano-meters).
From Figure 2, the following conclusions can be drawn:
- The absorption of oxyhemoglobin in the 600-750nm range does result in a temperature increase which causes an increase in molecular oxygen concentration due to dissociation. This effects counter the effect of oxygen depletion during the PDT.
- The absorption of hemoglobin in the blood vessels is in the range of 600 to 750 nm,which produces an increase in the temperature and an enhanced PDT reaction rate.
The clinical results in three different hospitals using the apparatus according to the present invention for skin cancer treatments of 150 patients, show a success of 85% even after one single treatment.
- ,2 - 2144209 The apparatus according to the present invention, can be also incorporated in other systems, thus providing additional useful functions as known in the art. Thus for instance, by adding a violet filter in the range of 400-450 nm, using the means of the filter wheel, it could be used for excitation of photosensitizers in the photodynamic diagnostics. On the other hand, the incorporation of a green filter in the spectral range of 505-590 nm using the means of the filter wheel, may be used far the superficial PDT treatment or for various dermatologic applications such as removal of tatoos and portwine stains.
The addition of distal hand-piece to the fiber optics bundle far dermatologic application, will enable a substantially uniform illumination of up to 3 cm diameter tumors.
Fluorescence spectrometer enabling real-time fluorescen ce measurements excited by violet filter, can be used for cancer diagnostics known in the art as "optical biopsy".
Other functions which could incorporate the apparatus accarding to the present invention are:
Endoscopes for different applications, such as colon, bronchi, gastro, etc.
RGB (red-green-blue) and CCD (charge-coupled-device) cameras to provide multi-spectral vieweing through the above endoscopes.
The addition of white filter in the spectral range of between 400 to 700 nm using the means of the filter wheel may be used far the endoscopic observation.
The apparatus was found also to be used with a broad types of photosensitizers as known in the art and also when narrow band filters enable excitation of only specific photosensitizers. Furthermore, the broad band excitation used in the present invention, enables the utilization of PDT photoproducts, having the absorption maxima removed by 30 to 550 nm from the absorption maxima of the photosensitizer used.
While the invention has been described and illustrated in respect to some particular features, it should be understood that the description does not limiting it, a person skilled in the art after reading the present specification, will be in a position to insert slight modifications, without being outside the invention as covered by the appended Claims. Thus for example, modifications to the electronic components: g, h and i, (see Figure 3) will unable pulsed high power operations .- 2144209 of the above device in the dermatological applications such as portwine stains and tattos removal.
Claims (6)
1. An apparatus for an efficient simultaneous photodynamic and hyperthermic treatment, said apparatus having an optical axis, said apparatus comprising:
(a) a lamp for emitting a narrow beam light with half angle divergence of up to 10°, having an intensity of at 20 mW/nm of red radiation in the spectral region of 600 to 750 nm and at least
(a) a lamp for emitting a narrow beam light with half angle divergence of up to 10°, having an intensity of at 20 mW/nm of red radiation in the spectral region of 600 to 750 nm and at least
2 mW/nm of infrared radiation in the spectral region of 1100 to 1700 nm, said lamp generating heat when emitting said beam light;
(b) a "hot" mirror, comprising a hard, all-dielectric filter coating deposited on a borosilicate glass, having a transmittance of at least 60% between 600 and 750 nm and at least 5%
between 1200 and 1700 nm, while reflecting the radiation between 750 and 1200 nm;
(c) a glass lens system, optionally having an anti-reflection coating;
(d) a dichroic filter made of a hard, all-dielectric coating deposited on glass, having at least 60% transmittance above 600 nm while having a negligible transmittance below 600 nm;
(e) a glass fiber optics bundle having a diameter between 1 and 12 mm as a separate unit or as part of an endoscope; said elements (a) - (e) being aligned along the optical axis of the apparatus;
and (f) an effective air-cooling system to decrease the internal heating of the apparatus, which provides an internal temperature in the apparatus below a maximum temperature of 50°C.
2. The apparatus according to claim 1, wherein the angle of said hot mirror relative to the optical axis may be varied in order to change the ratio of transmittance in the two radiation ranges.
(b) a "hot" mirror, comprising a hard, all-dielectric filter coating deposited on a borosilicate glass, having a transmittance of at least 60% between 600 and 750 nm and at least 5%
between 1200 and 1700 nm, while reflecting the radiation between 750 and 1200 nm;
(c) a glass lens system, optionally having an anti-reflection coating;
(d) a dichroic filter made of a hard, all-dielectric coating deposited on glass, having at least 60% transmittance above 600 nm while having a negligible transmittance below 600 nm;
(e) a glass fiber optics bundle having a diameter between 1 and 12 mm as a separate unit or as part of an endoscope; said elements (a) - (e) being aligned along the optical axis of the apparatus;
and (f) an effective air-cooling system to decrease the internal heating of the apparatus, which provides an internal temperature in the apparatus below a maximum temperature of 50°C.
2. The apparatus according to claim 1, wherein the angle of said hot mirror relative to the optical axis may be varied in order to change the ratio of transmittance in the two radiation ranges.
3. The apparatus according to claim 1 or 2, wherein said air-cooling system comprises at least two fans which provides an internal temperature in the apparatus of not above 45°C.
4. The apparatus according to any one of claims 1 to 3, wherein the ratio between power emitted in the 600-750 nm red radiation region to power emitted in the 1100-1700 nm Infra-red radiation region is between 2:1 to 5:1.
5. The apparatus according to any one of claims 1 to 4, wherein the heating of step (a) is obtained by irradiation of said lamp in the range of between 1.2 to 1.7 µm.
6. The apparatus according to any one of claims 1 to 5, wherein said heating of step (a) is obtained by a CO2, laser or Nd:YAG laser.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL108918A IL108918A (en) | 1994-03-10 | 1994-03-10 | Apparatus for efficient photodynamic treatment |
| IL108,918 | 1994-03-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2144209A1 CA2144209A1 (en) | 1995-09-11 |
| CA2144209C true CA2144209C (en) | 2001-07-31 |
Family
ID=11065913
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002144209A Expired - Fee Related CA2144209C (en) | 1994-03-10 | 1995-03-08 | Method and apparatus for an efficient photodynamic treatment |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US5707401A (en) |
| CA (1) | CA2144209C (en) |
| DE (1) | DE19507980C2 (en) |
| GB (1) | GB2287652B (en) |
| IL (1) | IL108918A (en) |
| ZA (1) | ZA951948B (en) |
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- 1995-02-28 GB GB9504032A patent/GB2287652B/en not_active Expired - Fee Related
- 1995-03-07 DE DE19507980A patent/DE19507980C2/en not_active Expired - Fee Related
- 1995-03-08 CA CA002144209A patent/CA2144209C/en not_active Expired - Fee Related
- 1995-03-09 ZA ZA951948A patent/ZA951948B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9504032D0 (en) | 1995-04-19 |
| CA2144209A1 (en) | 1995-09-11 |
| IL108918A (en) | 1997-04-15 |
| US5707401A (en) | 1998-01-13 |
| IL108918A0 (en) | 1994-06-24 |
| GB2287652A (en) | 1995-09-27 |
| DE19507980A1 (en) | 1995-09-14 |
| DE19507980C2 (en) | 2002-01-10 |
| ZA951948B (en) | 1995-11-13 |
| GB2287652B (en) | 1997-10-15 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |