JP2013208331A - Photodynamic therapy system accompanying temperature adjustment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a system capable of controlling the depth of therapy on a tissue surface layer by adjusting the binding rate of a photosensitive substance and a protein such as serum protein by adjusting the temperature of a target tissue for therapy, and varying the reaction efficiency of the photodynamic therapy.SOLUTION: A system for controlling the depth of therapy of the photodynamic therapy by temperature adjustment includes: (i) a light beam irradiation device for irradiating a target tissue for therapy with a light beam; and (ii) a cooling device for cooling the target tissue for therapy. The photodynamic therapy is performed on the surface layer of the target tissue for therapy by: having the cooling device cool the surface of the target tissue for therapy in which a photodynamic therapeutic agent is present; reducing the binding rate of the photodynamic therapeutic agent present in the surface layer of the target tissue for therapy and serum protein by cooling; increasing the ratio of the free photodynamic therapeutic agent on the surface of the target tissue for therapy; and having the light beam irradiation device irradiate the target tissue for therapy with the light beam.

Description

  The present invention relates to photodynamic therapy, and in particular, in photodynamic (PDT) therapy, a method for controlling treatment depth with temperature control and a system or apparatus capable of controlling treatment depth with temperature control About.

  Photodynamic therapy (also called photodynamic therapy: PDT, photochemical therapy) is being studied for application to various treatments in addition to endoscopic treatment of early cancer. PDT is a photosensitizer such as a porphyrin derivative that is administered by intravenous injection or other method, and lesions such as cancerous tissue are observed, which are selectively absorbed and accumulated in the tissue lesions to be treated. This is a treatment method that destroys the tissue by irradiating light such as laser light, and uses the property that the photosensitizer is selectively accumulated in the lesion and the property that it is sensitized by light. It is a thing. The photosensitizer taken into the lesion by the light irradiation is excited, and the energy of the sensitizer is transferred to the oxygen present in the lesion to generate active oxygen. The active oxygen necroses the cells in the lesion. The mechanism of making it advocated is proposed.

  In conventional photodynamic therapy, treatment depth control is performed by laser light (see Patent Document 1). Specifically, treatment depth control is widely performed by the irradiation dose of laser light and the oscillation wavelength. When the irradiation dose of laser light is changed, the energy fluence in the tissue is changed, so that the production amount of active oxygen is changed. In this method, the treatment depth can be controlled depending on whether or not the amount of active oxygen production is equal to or greater than the treatment threshold. In addition, when the wavelength of the laser light is changed, the light attenuation coefficient of the tissue changes, so that the energy fluence in the tissue changes and the treatment depth can be controlled.

  On the other hand, in photodynamic therapy, a method for changing the temperature of a tissue to be treated has been reported. For example, a method of performing photodynamic therapy by heating a tissue to be treated or adjusting pH to increase the tissue permeability of a drug (see Patent Document 2) is also described. A method has been reported in which the surface of the skin, which is a tissue to be treated, is maintained at 38 to 43 ° C., the treatment efficiency is improved, and tissue damage due to heat is prevented (see Patent Document 3).

Japanese Patent No. 4504917 US2003 / 0093057 Publication US2004 / 0225339

  In the case of the treatment depth control by adjusting the irradiation dose of the conventional method described in Patent Document 1 or the like, the treatment depth controllability is inferior for a tissue having a thickness equal to or shorter than the light penetration length of the laser beam. Since the intensity of light attenuates exponentially in living tissue and varies depending on the blood content at the treatment site, the adjustment is critical. In addition, regarding the treatment depth control by adjusting the wavelength of the laser beam, in addition to requiring a complicated device for adjusting the wavelength of the laser beam, the absorption spectrum characteristics change depending on the tissue state and the surrounding environment. Depth control is difficult, and treatment depth control in the conventional method has not been precise.

  Further, in the methods described in Patent Document 2 and Patent Document 3, the temperature of the tissue to be treated has been adjusted, but the method described in Patent Document 2 is intended to increase the permeability of the drug. In addition, the method described in Patent Document 3 aims to maintain the temperature of the tissue to be treated in this temperature range because 38 to 43 ° C. is a temperature suitable for photodynamic treatment.

  In the present invention, by adjusting the temperature of the target treatment tissue near the laser light irradiation site, to adjust the binding rate between the photosensitive substance and proteins such as serum proteins, to change the reaction efficiency of photodynamic treatment, It is an object of the present invention to provide a system or apparatus and a method capable of controlling a treatment depth on a tissue surface.

  The present inventors have found that, in photodynamic therapy using a photosensitive substance, the protein binding rate of the photosensitive substance decreases at low temperatures. As a result, by irradiating the target treatment site with the excitation light of the photosensitizer and simultaneously cooling the target treatment site, the protein binding rate of the photosensitizer decreases at the temperature-decreased, and photodynamic treatment The reaction efficiency increases. That is, it has been found that the treatment depth can be controlled by adjusting the tissue temperature, and the present invention has been completed.

That is, the present invention is as follows.
[1] A system for controlling the treatment depth of photodynamic therapy by adjusting temperature,
(i) a light irradiation device for irradiating the tissue to be treated with light; and
(ii) includes a cooling device for cooling the tissue to be treated;
The cooling device cools the surface of the tissue to be treated where the photodynamic therapeutic agent is present, and the cooling reduces the binding rate between the photodynamic therapeutic agent and the serum protein present on the surface layer of the tissue to be treated, thereby treating Increase the ratio of free photodynamic therapeutic agent in the surface layer of the target tissue,
A system for performing photodynamic treatment on a surface layer portion of a treatment target tissue by causing the light irradiation apparatus to irradiate the treatment target tissue with light.
[2] A system for controlling the treatment depth of photodynamic therapy by adjusting temperature,
(i) a light irradiation device for irradiating the tissue to be treated with light;
(ii) a cooling device for cooling the tissue to be treated,
(iii) a temperature monitoring device for monitoring the temperature of the tissue to be treated, and
(iv) including a control device that controls light irradiation from the light irradiation device according to the temperature of the tissue cooled by the cooling device;
The cooling device cools the surface of the tissue to be treated where the photodynamic therapeutic agent is present, and the cooling reduces the binding rate between the photodynamic therapeutic agent and the serum protein present on the surface layer of the tissue to be treated, thereby treating Increase the ratio of free photodynamic therapeutic agent in the surface layer of the target tissue,
The control device receives temperature information from the temperature monitoring device, causes the cooling device to cool the tissue to be treated to a predetermined temperature, and irradiates the light when the temperature of the tissue to be treated is within a predetermined temperature range. A system that irradiates a device with light and performs photodynamic treatment on a surface layer of a tissue to be treated.
[3] The system according to [2], wherein the control device further controls the radiation dose and / or irradiance of the light beam irradiation device.
[4] The tissue to be treated is skin or viscera, and the target disease of photodynamic treatment is selected from the group consisting of skin disease, cancer, heart disease, neurological disease and vascular disease. [1] to [3] One of the systems.
[5] The system according to any one of [1] to [4], wherein the light beam used for treatment is selected from the group consisting of laser light, LED, halogen light, incandescent light, and light emitted from a discharge lamp.
[6] The system according to any one of [1] to [5], wherein the cooling device is selected from the group consisting of an electronic cooling device, a heat conduction cooling device, and a convection cooling device.
[7] The system according to any one of [1] to [6], wherein the surface layer of the tissue to be treated is maintained at 1 to 35 ° C. by the cooling device.
[8] The system according to any one of [1] to [7], wherein the photodynamic therapeutic agent is talaporfin sodium.
[9] The system according to any one of [1] to [8], wherein the treatment depth controlled during the photodynamic treatment is a site having a depth of 1 to 5 mm from the tissue surface.
[10] The system according to any one of [1] to [9], further including a catheter to be inserted into a living body, wherein the catheter includes a light irradiation device and a cooling device.

  Using the system of the present invention, the temperature of the tissue surface of the treatment site where the PDT drug is present is adjusted, and the PDT drug in the vicinity of the surface is released and irradiated with light. The treatment depth of the surface tissue can be controlled by the mechanical treatment. Specifically, the surface of the treatment target is cooled because the photodynamic treatment efficiency is increased by setting the temperature of the treatment site to be lower than the body temperature (about 37 ° C. in the case of humans). In the cooling by heat conduction from the surface, the tissue temperature can be controlled in millimeters. Therefore, the apparatus and method of the present invention are suitable as a method for accurately controlling the treatment depth in the range of about 1 to 5 mm from the surface. Although the heat conduction characteristics of a living tissue vary depending on the blood flow volume of the tissue, it does not change from moment to moment and is almost stable for each organ. Therefore, accurate control can be performed by using the system or apparatus of the present invention.

It is a figure which shows an example of the system of this invention. It is a figure which shows the relationship between Q band absorption peak wavelength and albumin concentration of talaporfin sodium. It is a figure which shows the temperature dependence of the serum protein binding rate of talaporfin sodium.

Hereinafter, the present invention will be described in detail.
The present invention is a light irradiation system or device that can be used for PDT (photodynamic therapy, photochemical therapy), and controls the temperature of the tissue to be treated, which is the treatment site, to treat the depth of treatment, that is, the surface tissue damaged by PDT treatment. It is a system or device that can control the treatment depth of the part, or a photodynamic treatment system with temperature adjustment.

(1) Photodynamic therapy (PDT) with the system of the present invention.
PDT (photodynamic therapy, photochemical therapy) is a photosensitizer (PDT drug, photodynamic therapy drug, photosensitizer), light that can excite PDT drug, and the energy of the excited PDT drug. This is a treatment that uses a photochemical reaction that damages or destroys the affected area due to the presence of oxygen.

  When a light beam is irradiated to a lesion such as cancer, the accumulated PDT drug, which is a photosensitive substance, increases its energy level in the molecule from the singlet state of the ground state, and is converted into an excited triplet state. When this state is reached, the photosensitizer is photoactivated, and the active triplet oxygen (3O2) is converted into highly active singlet oxygen (3O2) by direct generation of active free radicals or indirect intramolecular energy conversion. 1O2). These two photoactivation reactions occur simultaneously, and both products directly act to damage cells.

  When performing PDT, it is necessary to administer a photosensitive substance (PDT drug). However, the PDT drug used in combination with the system of the present invention is not limited, and a known PDT drug may be used in combination with light having the absorption wavelength. It is possible to select the PDT drug and the light type as appropriate. As the wavelength of the light beam, the absorption wavelength in the Soret band of the PDT drug or the absorption wavelength in the Q band may be appropriately selected. As the PDT drug to be used, any drug having a Q-band absorption wavelength near 630 nm to a drug having an absorption wavelength on the longer wavelength side can be used. As a PDT drug, for example, ATX-S10 (670 nm), which is a chlorin-based drug (Iminochlorin aspartic acid derivative, Toyo Hikaru Kogyo Co., Ltd., transferred to Photochemical Laboratories Co., Ltd., JP-A-6-80671) NPe6 (664nm) (Taraporfin sodium, Rezaphyrin (registered trademark), mono-L-aspartyl chlorin e6, Japanese Patent No. 2961074), mTHPC (652nm), SnET2 (660nm) (tin etiopurpurin, Mirabant Medical Technologies) AlPcS (675 nm) (chloro aluminum sulphonated phthalocyanine), BPD-MA (690 nm) (benzoporphyrin derivative monoacid ring A, QLT), Lu-tex (732 nm) (Lutetium Texaphyrin) and the like. Examples of hematoporphyrin derivatives include porfimer sodium (photofurin) (630 nm), ALA (635 nm) (LEVULAN, Aminolevulinic Acid) and the like. For administration of these PDT drugs, the drug is dissolved in an appropriate buffer solution such as a phosphate buffered salt solution, and pharmaceutically acceptable additives are added as necessary. Examples of additives include solubilizers such as organic solvents, pH adjusters such as acids and bases, stabilizers such as ascorbic acid, excipients such as glucose, and isotonic agents such as sodium chloride.

The administration method is not limited, and may be administered by intravenous injection, intramuscular injection, subcutaneous injection, oral administration or the like. Moreover, you may administer directly to a lesioned part. For example, when a disease to be treated exists in the body such as the digestive tract or the heart, a drug administration means such as a needle or a drug injection part is arranged on the catheter, and the drug can be locally administered as a drug delivery catheter. Good. The dose of the PDT drug is not limited, and is 0.01 to 100 mg / kg body weight, preferably 1 to 5 mg / kg body weight when systemically administered by intravenous injection or the like. In the case of local administration, for example, a drug prepared at several μg / mL to several mg / mL may be administered by injection or the like directly into the lesion site from several μL to several mL. As will be described later, since the accumulation degree of the drug in the lesion can be monitored by the apparatus of the present invention, additional administration may be performed according to the monitoring result. Administration includes application to the skin and the like.
The time from drug administration or application to light irradiation may be several minutes, hours or days.

(2) Disease to be treated by the system of the present invention The lesion of the disease to be treated by the system for controlling the treatment depth of the photodynamic treatment by temperature adjustment of the present invention is a cell abnormality such as abnormal cell proliferation in the tissue. The lesion is a lesion with a disease, and the lesion can be treated by stopping the progression of the disease by damaging the cells of the tissue lesion or preventing the spread. The lesioned part of the disease to be treated by the light irradiation apparatus of the present invention is a lesioned part of the surface layer tissue present in the shallow part of the tissue. The tissues include tissues such as skin having a surface outside the body and tissues such as viscera having a surface inside the body. In the present invention, a lesion site of a disease to be treated may be referred to as a treatment site, and a tissue that is a treatment target including the treatment site may be referred to as a treatment target tissue.
The subject to be treated is a human or a non-human animal such as a non-human mammal that can suffer from the following diseases.

  In the present invention, the depth of the shallow portion is not limited, but a portion having a depth of about 0.05 mm to 10 mm, 0.05 mm to 7 mm, 0.05 mm to 5 mm, 0.05 mm to 3 mm, or 0.05 mm to 1 mm from the surface irradiated with the light beam. Say. By using the system of the present invention, it is possible to treat a region having a depth within the above range by accurately controlling the depth in millimeter units. In particular, it is suitable for treatment of a site having a depth of 1 to 5 mm from the surface.

  The diseases that can be treated using the device of the present invention include all diseases that can be treated by PDT treatment. Examples of such diseases include skin diseases including cancer, cancers other than skin, heart diseases such as arrhythmia and cardiomyopathy, neurological diseases, and vascular diseases such as arteriosclerosis. Any disease that can be the subject of clinical treatment is included.

  Skin diseases include actinic keratosis, Bowen's disease, superficial or nodular basal cell carcinoma, extramammary Paget's disease, cutaneous lymphoma, sun cheilitis, basal cell macular syndrome, etc., vulgaris Acne, sebaceous glands, sebaceous hyperplasia, wart of refractory limbs (warts), warts, bowen-like papulosis, wart-like epidermal growth disorder, seborrheic keratosis, Darier's disease, psoriasis vulgaris, alopecia areata, cutaneous sarcoidosis, tendon sarcoidosis, scleroderma, morphia, lichen planus, sclerosing atrophy lichen, ring granulomas, diabetic fatty necrosis, skin and nail mycosis Non-neoplastic diseases such as cutaneous leishmaniasis, wounds, bruises, blemishes, freckles and the like. Other skin cosmetic procedures are also targeted.

Examples of cancers other than skin include prostate cancer, bladder cancer, esophageal cancer, rectal cancer, colon cancer, cervical cancer, endometrial cancer, biliary tract cancer, stomach cancer, pancreatic cancer and the like.
Arrhythmias such as atrial fibrillation can be treated by ablating abnormal electrical conduction sites in the myocardium.

(3) Depth control method by the system of the present invention
In PDT treatment, an administered PDT drug can bind to in vivo proteins such as in vivo serum proteins. In general, when a drug such as a therapeutic drug is administered to a living body, the drug binds to a serum protein, and the drug exists in two states, a bound form that is bound to the protein and an unbound form (free form) that is not bound to the protein. . The binding type and the non-binding type are reversible, and the abundance ratio of both is determined by the affinity with the protein specific to each drug.

  When a PDT drug is administered by intravenous injection, the PDT drug is transported through the blood, during which almost all PDT drug binds to serum proteins. Serum albumin, lipoprotein, glycoprotein, globulin, etc. are mentioned as the serum protein to which the PDT drug binds. Among them, some PDT drugs such as water-soluble drugs such as talaporfin sodium bind to serum albumin having a large amount in blood with a high probability. Serum albumin has site I (warfarin site), site II (diazepam site) and site III (digitoxin site) as sites for drug binding, and PDT drug binds to site II (diazepam site). Also, porphyrin-based fat-soluble drugs such as photofurin bind to low density lipoprotein. When a PDT drug is bound to a serum protein, active oxygen such as singlet oxygen is less likely to be generated, and the efficiency of PDT treatment is reduced.

  The binding rate between the PDT drug and the serum protein varies depending on the temperature. The binding rate is high at a temperature of about 37 ° C., which is close to human body temperature, but the binding rate decreases as the temperature decreases. The change in the binding rate with temperature varies depending on the concentration of PDT drug and the concentration of serum protein. For example, in vitro, when 15 μM bovine serum albumin and 60 μM talaporfin sodium are mixed and the temperature is changed, about 83% talaporfin sodium binds to serum albumin at 37 ° C., and about 24 to 26 ° C. Reduce to 69%. That is, reducing the temperature from 37 ° C. to 24-26 ° C. increases the amount of free talaporfin sodium that is not bound to serum albumin by about 14%. When a PDT drug is administered to a living body, since the temperature (body temperature) of the living body is about 37 ° C. in humans, most of the administered PDT drug binds to serum proteins.

  In the present invention, in the state where the PDT drug is present at the site to be treated by the PDT treatment, by reducing the temperature of the site, the binding rate of the PDT drug and serum protein can be reduced, Increases the proportion of free PDT drug. As a result, the PDT treatment effect by the PDT drug is increased. With almost all PDT drugs bound to serum proteins, only a few percent to a few tens of PDT drugs become free PDT drugs, which significantly improves PDT treatment efficiency.

  In the present invention, in the state where the PDT drug is present in the lesion site of the tissue to be treated for PDT treatment, the lesion site is cooled to lower the temperature and increase the treatment efficiency. By adjusting the cooling site, the amount of free PDT drug increases only at the cooled site, and the PDT drug is present in a bound state bound to the serum protein at the non-cooled site. When the treatment target tissue is irradiated with laser light, it is cooled, singlet oxygen is efficiently generated only at the site where the free PDT drug is present, and cells at that site die. On the other hand, the PDT treatment effect does not appear in the area that has not been cooled, so the cells do not die.

  In fact, even when trying to cool a specific part, the cooling part spreads due to heat conduction, the temperature increases as it gets away from the cooled part, and the body part keeps the body temperature without being cooled further. Yes. Corresponding to the temperature distribution according to the distance from the cooling site, the binding rate of the PDT drug to the protein at each site changes. The binding rate of the PDT drug is determined by the concentration of the PDT drug in the treatment site and its surroundings and the temperature distribution in the treatment site and its surroundings. That is, by controlling the PDT drug concentration at the treatment site and further controlling the cooling temperature and the cooling time, it is possible to control a region with high PDT treatment efficiency. Accordingly, when the system of the present invention is used, the temperature inside the tissue is controlled in millimeters even when the surface of the tissue to be treated is cooled and the superficial tissue inside the tissue is cooled by heat conduction. be able to. Although the thermal conductivity of living tissue varies depending on the blood flow volume of the tissue, the fluctuation range is not large and is more stable in organs and tissues. By using the system of the present invention, the temperature of the tissue Can be controlled accurately and eligible PDT treatment can be performed.

  For example, reduce the dose of PDT drug to the body, the concentration of PDT drug at the treatment site, the concentration at which the PDT therapeutic effect is not obtained even if irradiated with light in the state where the PDT drug is bound to serum protein You just have to control it. In this case, the PDT therapeutic effect can be exhibited only at the site where the free PDT drug is localized by cooling the site where the PDT drug is present and making the PDT drug free. If the treatment site is cooled from the surface, the cooling temperature is appropriately controlled, and only the vicinity of the surface is cooled, the concentration of free PDT drug increases only in the cooled part, and the extent to which free PDT exerts PDT treatment effect It is possible to limit the portion existing at the concentration of only the shallow portion from the surface, and as a result, the treatment can be performed in a shallow region. That is, the PDT treatment using the device of the present invention is effective for PDT treatment of a surface layer tissue that is a site located at a shallow portion with respect to the surface of the tissue that is the treatment site, that is, the site from the tissue surface. is there. According to the present invention, in such a case, the concentration of free PDT drug at the treatment site is increased and the treatment threshold for light is decreased. As a result of the lowering of the treatment threshold, treatment of that part becomes possible.

By cooling the tissue to be treated from the surface, the temperature decreases particularly near the surface. At this time, by controlling the degree of cooling, only the part to be treated has to be lowered to a certain temperature. By cooling, the treatment site may be maintained at a temperature lower than the body temperature and irradiated with a therapeutic light beam. At this time, the light beam may be irradiated after cooling, or the light beam may be irradiated while cooling.
In the present invention, PDT treatment may be performed within a few minutes to several hours after administration of a PDT drug, and early treatment (early PDT treatment) is also possible.

(4) Configuration and Control Method of System of the Present Invention A treatment depth control system for photodynamic therapy by temperature adjustment that can be used for the PDT treatment of the present invention is a light beam irradiation apparatus for irradiating at least a treatment site with a light beam. (Light irradiation means) and a cooling device for cooling the treatment site. The light beam irradiation device is a device that generates a light beam and irradiates the treatment site with the light beam. The light beam irradiation device includes a light beam generation device (light beam generation unit) that generates a light beam, a light beam irradiation site that irradiates the light beam, and a light beam transmission site (light beam transmission unit) that transmits the light beam from the light beam generation device to the light beam irradiation site. Also good. When treating skin or the like outside the living body, the treatment site may be irradiated directly with the light generated from the light generator. On the other hand, when treating tissues such as the digestive tract, heart, blood vessels, and prostate in a living body, a catheter having a light irradiation site is used, and a device in which the light irradiation unit and the light generator are connected to a light transmission site is used. A catheter including a light irradiation site may be inserted into a living body, light may be generated by an in vitro light generation device, and light may be irradiated from the light irradiation site to the treatment site in the living body through the light transmission site.

  The apparatus of the present invention can also be referred to as a photodynamic treatment system capable of controlling the treatment depth by adjusting the temperature. The entire system can also be called a device.

  Although the kind of light irradiated for treatment in the apparatus of the present invention is not limited, a light capable of generating a photochemical reaction in the PDT drug and generating active oxygen such as singlet oxygen can be used. As such a light irradiation device, a single or multiple wavelength oscillation laser device that generates laser light, an LED (Light Emitting Diode) that generates LED light, a fluorescent lamp that generates fluorescence, a halogen lamp that generates halogen light, Examples include incandescent lamps, discharge lamps that use arc discharge or glow discharge, and optical parametric oscillators (OPO) with variable wavelength. Among these, a laser apparatus is preferable. The irradiation wavelength is from 400 nm to 800 nm, and light having a wavelength close to the absorption wavelength of the PDT drug to be used may be used. Depending on the type of light beam, a light beam in a specific wavelength region may be extracted as appropriate using a filter or the like and irradiated with the light beam. As the laser, a semiconductor laser, an excimer die laser, a dye laser, a double wave of a variable wavelength near infrared laser, or the like can be preferably used. The light beam may be a pulse beam such as a pulse laser or a continuous beam such as a continuous laser. Here, the pulsed light means that having a pulse width of 1 ms or less. Moreover, continuous light can be interrupted using a light chopper and irradiated as a pulsed beam. The light beam used in the apparatus of the present invention is preferably a continuous laser and a semiconductor laser.

The irradiance (W / cm ² ) or radiation dose (J / cm ² ) of the light generated by the light irradiation device and applied to the treatment site of the tissue to be treated is appropriately determined according to the size of the lesion to be treated. be able to. Examples of the irradiance of the irradiation light, include a range of ^{10mW / cm 2 ~5MW / cm 2} , 1~500J / cm 2 or more can be exemplified as the examples of the radiation dose. Furthermore, when using pulsed light, it is necessary to adjust the repetition frequency of the irradiated pulsed light in order to increase the PDT treatment efficiency. This is because the energy of the PDT drug excited by the light irradiation is transferred to the surrounding oxygen and the oxygen changes to active oxygen and acts on the cells. As a result, the oxygen concentration in the part irradiated with the light temporarily decreases. This is because it is necessary to wait for the next pulse beam irradiation until oxygen is diffusely supplied from the surroundings. That is, when the repetition frequency is too high, the supply of oxygen is not in time, and the PDT treatment efficiency is lowered, and when the repetition frequency is too low, the light irradiation time becomes too long to be established as PDT treatment. Therefore, there is a certain range in the repetition frequency at which good treatment efficiency can be obtained. The repetition frequency may be appropriately changed depending on the oxygen concentration of the site to be treated and the PDT drug accumulation amount, and an appropriate repetition frequency can be determined by using the model imitating a living tissue as described above. The range of the repetition frequency is not limited, but is, for example, 1 Hz to 1 kHz.

  As a cooling device, a device for cooling a treatment site by heat conduction cooling using a gel-like or plate-like coolant; cooling with air using cooling gas or cooling air, or cooled physiological saline A convection cooling device that cools the treatment site by convection cooling using a liquid such as water or oil; an electronic cooling device that cools by heat transfer such as a Peltier cooling device. The Peltier cooling device is a device that uses a Peltier effect to cool a cooling unit such as metal using a semiconductor element. Among these, the electronic cooling device is preferable because it can electronically perform highly accurate temperature control.

  What is necessary is just to cool a treatment site | part using these cooling devices and to make the temperature of a treatment site | part lower than the body temperature of the test subject to treat. When the subject is a human, the normal body temperature of human is about 37 ° C, so it is cooled to 1 to 35 ° C, preferably 1 to 30 ° C, more preferably 5 to 25 ° C, particularly preferably about 5 to 15 ° C. do it.

  When using the heat conduction cooling device, the heat conduction cooling device is brought into contact with the surface of the treatment site of the tissue to be treated, and the treatment site is cooled to the above temperature. When a convection cooling device is used, a cooled gas or liquid is applied to the surface of the treatment site using the device to cool the treatment site to the above temperature. Moreover, when using an electronic cooling device, a cooling part is made to contact the surface of a treatment site | part, and a treatment site | part is cooled to the said temperature.

  In the system of the present invention, the light irradiation device and the cooling device may be included as one unit in one device, or may be used in combination as another device. In any case, in the present invention, it is referred to as a treatment depth control device for photodynamic therapy by temperature adjustment including a light irradiation device and a cooling device.

  The system of the present invention may have a temperature monitoring device (temperature monitoring means). The temperature monitoring device has a temperature sensor, and can monitor the temperature of the surface or inside of the treatment site being cooled. As the temperature sensor, a thermocouple, a resistance temperature detector, a radiation thermometer, or the like can be used. The temperature sensor may be a contact type sensor or a non-contact type sensor. Furthermore, the temperature cooling device may have a feedback control device (control means), and the feedback control device can maintain the temperature of the treatment site constant during the treatment period.

  In the case of a system including a catheter, a cooling device may be included in the catheter, the catheter may be inserted into the living body, and the treatment site may be cooled by the cooling device when the treatment site is irradiated with light or before irradiation.

  Furthermore, the treatment depth control system for photodynamic therapy by temperature adjustment according to the present invention is a control for irradiating a therapeutic light beam according to the temperature when the temperature of the treatment site of the tissue to be treated is lowered to a certain temperature. You may have a device (control means). The control device receives temperature information of the treatment site cooled by the cooling device by being input from the temperature monitoring device, and irradiates the treatment site with light when the temperature drops to a certain temperature. Can be made. With this control device, it is possible to irradiate therapeutic light only when the temperature of the treatment site is within a certain range. In addition, the control device receives the temperature information, operates the cooling device based on the temperature information, and cools the tissue to be treated to an appropriate predetermined temperature. By such control, it is possible to monitor the temperature of the treatment site during PDT treatment and maintain the treatment site of the tissue to be treated at a constant temperature and irradiate light while cooling. When the temperature falls below the predetermined temperature range or when the temperature rises, the light irradiation can be stopped and the irradiance and / or the irradiation amount can be controlled by the control device. For example, depending on the size, severity, shape, optical characteristics, and surrounding tissue environment of the treatment target tissue, the irradiance and / or radiation dose may be increased or decreased so that treatment can be performed more reliably. .

  Furthermore, the system of the present invention may include a device (means) for monitoring the PDT drug concentration at the treatment site of the tissue to be treated and / or a device (means) for monitoring the oxygen concentration. This apparatus monitors fluorescence derived from PDT drugs, fluorescence derived from phosphorescence and oxygen. When the apparatus includes a catheter, it may have a transmission unit (transmission means) for transmitting fluorescence derived from PDT drug, phosphorescence or fluorescence derived from oxygen to the detector. For example, since the porphyrin ring of the PDT drug generates fluorescence when excited, the amount of the PDT drug can be measured by measuring the fluorescence. Moreover, since phosphorescence is quenched according to the oxygen concentration, the oxygen concentration can also be measured by measuring phosphorescence. Alternatively, an oxidized fluorescent indicator whose fluorescence intensity is increased by active oxygen may be used, or a phenomenon in which a ruthenium complex is fixed to a light transmission part and a fluorescence reaction of the ruthenium complex is quenched by the oxygen concentration may be used.

  When the temperature of the treatment site of the treatment target tissue is lowered to a certain temperature, the control device (control means) for irradiating the therapeutic light beam is a device for monitoring these PDT drug concentration and / or oxygen concentration It may have a function of processing information on the PDT drug concentration and oxygen concentration obtained in (1). In this case, the control device has a function of processing not only the temperature information of the treatment site but also PDT drug concentration information and / or oxygen concentration information. That is, temperature information and PDT drug concentration information and / or oxygen concentration information are received from a device that monitors the PDT drug concentration and / or oxygen concentration, and based on the received information, a specific treatment depth is calculated by the arithmetic processing unit of the control device. Then, it is determined whether or not the treatment site can be treated, and light is irradiated based on the determined result.

  Said control apparatus is also an apparatus which controls the action | operation of a light irradiation apparatus or a cooling device based on the information input by the monitor apparatus (monitor means).

  When the system includes a catheter, a commonly used catheter can be used, and its diameter and the like are not limited. A catheter suitable for the treatment site can be used. The means for transmitting the light beam to the treatment site includes a light beam irradiation site for irradiating the light beam located near the distal end of the catheter toward the treatment site, and a quartz optical fiber for transmitting the light beam from the light beam generator to the light beam irradiation unit, Includes optical fibers such as plastic optical fibers. In the present invention, “near the distal end” means a portion near the end opposite to the end (proximal end) connected to the light generating device, and the distal end and the distal end. It refers to the part of about several tens of centimeters. The quartz fiber is contained in the catheter, and is connected to the light generating device at one end and connected to the light irradiation site at the other end. As the quartz fiber used in the present invention, fibers having a diameter of about 0.05 to 1 mm can be used in a wide variety of diameters as long as they can be accommodated in the catheter and transmit light energy. The diameter can be changed as appropriate in the case where a supply means or the like is included.

  FIG. 1 shows an example of the system of the present invention. The system shown in FIG. 1 includes a light generator 1, a control device 2, a part 3 including a light irradiation part and a cooling device, and a light transmission part 4. A light beam generator, a light beam irradiation part, and a light beam transmission part are referred to as a light beam irradiation apparatus. The light irradiation site and the cooling device are close to each other. For example, the light irradiation site and the cooling device may be included in the catheter. The light beam generated by the light beam generation device is carried to the light beam irradiation site through the light beam transmission site, and is irradiated from the light beam irradiation site. Further, the treatment site of the tissue to be treated is cooled by the cooling device before the light irradiation or simultaneously with the light irradiation. The control unit receives temperature information of the treatment site and controls the operation of the cooling device and the light irradiation device.

(5) Method of using the system of the present invention When treatment is performed using the system of the present invention, a PDT drug is first administered to a subject. Administration may be performed, for example, by intravenous injection. Wait for the PDT drug to be present at the treatment site of the subject, and cool the treatment site with a cooling device. Since the PDT treatment using the system of the present invention is preferably an early PDT treatment, the time from the administration of the PDT drug to the irradiation of light and the initiation of the PDT treatment is several minutes to several days.

  Cooling by the cooling device is performed until a certain amount of the PDT drug bound to serum albumin present at the treatment site becomes free. Here, “a certain amount becomes free” means, for example, that several percent to several tens of percent of the PDT drug present at the treatment site becomes free.

  When the temperature of the treatment site decreases to a desired temperature, the treatment site is irradiated with light using a light irradiation device. Here, the “desired temperature” means that when the subject is a human relative to the temperature of the treatment site in an uncooled state, the normal body temperature of the human is about 37 ° C., so 1 to 35 ° C., preferably 1 It is about -30 degreeC, More preferably, it is 5-25 degreeC, Most preferably, it is about 5-15 degreeC.

  By irradiating with light, a photochemical reaction occurs in the free PDT drug, and PDT treatment is performed at the cooled site where the free PDT drug exists, and the cells in that part can be damaged.

At this time, the light irradiation may be controlled by a control unit (control means) for irradiating the therapeutic light according to the temperature.
For example, when the treatment site is a skin lesion, after the PDT drug is administered or applied, the surface of the skin lesion is cooled by a cooling device, and the skin is irradiated with light. A light beam may be irradiated after cooling, or a light beam may be irradiated while cooling.

In addition, when the treatment site is in a living body, a device including a catheter is used, a catheter including a light irradiation site and a cooling device is inserted into the living body, moved to the lesion, and the surface of the lesion is cooled by the cooling device. What is necessary is just to irradiate a lesion part with a light beam. A light beam may be irradiated after cooling, or a light beam may be irradiated while cooling.
Sunlight may be used as the light beam. In this case, after the PDT drug is administered to the subject, the treatment site is cooled, and the treatment site may be exposed to sunlight by sun bathing or the like.

  The present invention will be specifically described by the following examples, but the present invention is not limited to these examples.

Example 1 Relationship between Q-band absorption peak wavelength of talaporfin sodium and albumin concentration Talaporfin sodium, bovine serum albumin (BSA) and physiological saline were mixed to prepare a solution. The talaporfin sodium concentration was 30 μM, and the BSA concentrations were 0 and 76 μM. The solution was put in a cuvette having an optical path length of 1 cm, and an absorption spectrum in the Q band (600 nm band) was measured with a spectrophotometer (UV-3600, Shimadzu Corporation) at room temperature (24 to 26 ° C.).

  The results are shown in FIG. As shown in the figure, it was confirmed that by adding albumin, the absorption peak in the Q band of talaporfin sodium shifts to the longer wavelength side. The higher the albumin concentration, the narrower the peak width and the greater the absorbance.

Example 2 Temperature dependence of serum protein binding rate of talaporfin sodium (1) Serum protein binding rate of talaporfin sodium at 24-26 ° C. Talaporfin sodium, bovine serum albumin (Bovine Serum Albumin: BSA) and physiological saline Mix to make a solution. The talaporfin sodium concentration was 4 conditions of 0, 3, 30, and 60 μM, and the BSA concentration was 10 conditions of 0, 0.15, 0.38, 1.5, 3.8, 15, 32, 76, 152, and 304 μM. The solution was put in a cuvette having an optical path length of 1 cm, and an absorption spectrum was measured at room temperature (24 to 26 ° C.) using a spectrophotometer (UV-3600, Shimadzu Corporation) with N = 4. The serum protein binding rate was calculated using the following formula for the obtained results.

  In the formula, A indicates the absorption peak wavelength [nm] when the absorption spectrum is shifted to the longest wavelength (assuming that the serum protein binding rate is 100%), and B indicates the absorption peak wavelength [nm] when BSA 0 μM is added (serum C represents the absorption peak wavelength [nm] of an arbitrary solution.

(2) Serum protein binding rate of talaporfin sodium at 37 ° C. Talaporfin sodium, bovine serum albumin (BSA) and physiological saline were mixed to prepare a solution. The talaporfin sodium concentration was 4 conditions of 0, 3, 30, and 60 μM, and the BSA concentration was 5 conditions of 0.15, 1.5, 3.8, 15, and 152 μM. The solution was placed in a cuvette having an optical path length of 1 cm, and a thermostat unit (TCC-240A, Shimadzu Corporation) was connected to the spectrophotometer to heat the cuvette. The solution temperature was measured over time with a plate thermocouple and a digital pen recorder, and the absorption spectrum was measured when the solution temperature was 37 ° C.

From the obtained results, the serum protein binding rate was calculated in the same manner as in the experiment at 24-26 ° C. in (1).
The results are shown in FIG. As shown in the figure, it was suggested that when the serum protein binding rate decreases due to cooling, the amount of free talaporfin sodium increases, and thus the PDT efficiency improves. For example, the serum protein binding rate under conditions of 37 ° C., BSA concentration 15 μM, and drug 60 μM is 83%, but when cooled to 24-26 ° C., the serum protein binding rate is 69%, and 14% of the drug is released.

  The apparatus of the present invention can be used for any treatment utilizing photodynamic treatment such as dermatology, respiratory surgery, obstetrics and gynecology, and cardiovascular medicine.

DESCRIPTION OF SYMBOLS 1 Light beam generator 2 Control apparatus 3 Light irradiation site | part and cooling device 4 Light beam transmission part

Claims (10)

A system for controlling the treatment depth of photodynamic therapy by adjusting temperature,
(i) a light irradiation device for irradiating the tissue to be treated with light; and
(ii) includes a cooling device for cooling the tissue to be treated;
The cooling device cools the surface of the tissue to be treated where the photodynamic therapeutic agent is present, and the cooling reduces the binding rate between the photodynamic therapeutic agent and the serum protein present on the surface layer of the tissue to be treated, thereby treating Increase the ratio of free photodynamic therapeutic agent in the surface layer of the target tissue,
A system for performing photodynamic treatment on a surface layer portion of a treatment target tissue by causing the light irradiation apparatus to irradiate the treatment target tissue with light. A system for controlling the treatment depth of photodynamic therapy by adjusting temperature,
(i) a light irradiation device for irradiating the tissue to be treated with light;
(ii) a cooling device for cooling the tissue to be treated,
(iii) a temperature monitoring device for monitoring the temperature of the tissue to be treated, and
(iv) including a control device that controls light irradiation from the light irradiation device according to the temperature of the tissue cooled by the cooling device;
The cooling device cools the surface of the tissue to be treated where the photodynamic therapeutic agent is present, and the cooling reduces the binding rate between the photodynamic therapeutic agent and the serum protein present on the surface layer of the tissue to be treated, thereby treating Increase the ratio of free photodynamic therapeutic agent in the surface layer of the target tissue,
The control device receives temperature information from the temperature monitoring device, causes the cooling device to cool the tissue to be treated to a predetermined temperature, and irradiates the light when the temperature of the tissue to be treated is within a predetermined temperature range. A system that irradiates a device with light and performs photodynamic treatment on a surface layer of a tissue to be treated.   The system according to claim 2, wherein the control device controls the radiation dose and / or irradiance of the light beam irradiation device.   The treatment target tissue is skin or viscera, and the target disease of photodynamic treatment is selected from the group consisting of skin disease, cancer, heart disease, neurological disease and vascular disease. The system described in.   The system according to any one of claims 1 to 4, wherein the light beam used for treatment is selected from the group consisting of laser light, LED, halogen light, incandescent light and light emitted from a discharge lamp.   The system according to any one of claims 1 to 5, wherein the cooling device is selected from the group consisting of an electronic cooling device, a heat conduction cooling device and a convection cooling device.   The system according to any one of claims 1 to 6, wherein a surface layer of the tissue to be treated is maintained at 1 to 35 ° C by a cooling device.   The system according to any one of claims 1 to 7, wherein the photodynamic therapeutic agent is talaporfin sodium.   The system according to any one of claims 1 to 8, wherein a treatment depth controlled during photodynamic treatment is a site having a depth of 1 to 5 mm from a tissue surface.   Furthermore, the system of any one of Claims 1-9 which has a catheter inserted in a biological body, and this catheter contains a light irradiation apparatus and a cooling device.

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