WO2008153443A1

WO2008153443A1 - Method for bio-controllable photo-dynamic therapy

Info

Publication number: WO2008153443A1
Application number: PCT/RU2008/000349
Authority: WO
Inventors: Viktor Aleksandrovich Borisov
Original assignee: Viktor Aleksandrovich Borisov
Priority date: 2007-06-13
Filing date: 2008-06-05
Publication date: 2008-12-18
Also published as: RU2341307C1

Abstract

The invention relates to medicine. In order to increase the effectiveness of the bio-controllable photo-dynamic therapy by improving the accuracy of diagnosis of deeply located tumors, to accelerate a rehabilitation period and to increase the selectivity of the laser action, one of the variants of the inventive method consists in diagnosing the tumor and metastasis sites, including the early stages of development thereof, in intravenously or otherwise injecting a photosensitiser and in producing the biochoronotherapy-correlated laser action, wherein the hardware-software 'Constellation' system is used during diagnosis for refining the tumour site and the laser action is carried out by irradiating at a wave length of 660±20 nm, a pulse repetition rate of 22,5±2 kHz, a pulse length of 70±30 ns and a power density of 0.1-0.5 W/cm2.

Description

METHOD OF BIO-CONTROLLED PHOTODYNAMIC THERAPY (OPTIONS).

Technical field

The present invention relates to medicine, in particular to methods for the rehabilitation of cancer patients after surgical treatment, in the recovery period after chemotherapy, radiation therapy, as well as for therapy at an early stage of the disease.

State of the art

The severity of the patient's condition is mainly due to depression of the immune system and intoxication. Known methods of laser photo dynamic destruction of tumors, using special dyes, photosensitizers photogam or photosens to introduce into the tumor tissue, which increase the absorption and thermal destruction of the tumor at lower powers of the order of 1 W (see Stranadko E.F., Skobelkin OK, etc. Five-year experience in the clinical application of photodynamic therapy. // Photodynamic therapy of malignant neoplasms. Materials of the 2nd All-Russian Symposium with international participation. M., 1997, pp. 7-19 and Romodanov A.P., Savenko A.G. and others . Cn special treatment of malignant brain tumors, Ed. St. USSR JN ° 1259532, from 05/18/83).

However, the known methods of photodynamic therapy of malignant tumors do not take into account fluctuations in the heat capacity and thermal conductivity of the tissue in connection with the rhythms of blood supply to the tissue. This reduces the selectivity and locality of the destruction of cancer cells relative to normal.

A known method of selective destruction of cancer cells, including heating the tumor tissue in the range of 42-45 ° C at the time of expiration and diastole of the patient’s heart for a time determined by the types of tumor, its size and localization (see Zaguskin S.L. et al., Method selective destruction of cancer cells. Pat. RF JF ° 2106159, from 09.27.96).

The disadvantages of this method are the complexity and complexity associated with the introduction of ferromagnetic particles into the tissue, insufficient locality of heating.

By technical nature, the closest to the proposed method is the selective destruction of cancer cells, including heating the tumor tissue in the range of 42-45 ⁰ C at the time of expiration and diastole of the patient’s heart for a time determined by the types of tumor, its size and localization, moreover, the tissue is heated with using laser irradiation with a wavelength (l, 264 ± 0.01) μm and a pulse repetition rate (22.5 ± l) kHz at a radiation power density of 0.5-2 W / cm ² (see Pat. N ° 2147847, dated May 6, 1999).

The disadvantages of this method is that it uses only the effect of laser exposure to the destruction of tumors without the use of the introduction of tumor tissue photosensitizers (PS). This reduces the selectivity and effectiveness of the laser.

In addition, due to the lack of photosensitizers in the method of use, the diagnosis of tumors with deep localization. This method is not effective in the rehabilitation treatment of cancer, as it lengthens the rehabilitation process and can mainly be used only for the destruction of cancer cells. Disclosure of invention

The basis of the invention is the task of increasing the effectiveness of biocontrolled photodynamic therapy (rehabilitation selective chronophototherapy) by increasing the accuracy of diagnosis of tumors with deep localization, accelerating the rehabilitation time and increasing the selectivity of laser exposure, as well as eliminating necrotic complications.

This problem is solved by the fact that in the method of biocontrolled photodynamic therapy, for the first embodiment of the invention, the localization of tumors and metastases is preliminarily diagnosed, including the early stages of their development, using the hardware and software “Corrosion” complex, then the chlorin eb photosensitizer is introduced, and laser treatment is performed on tumor at the time of expiration and diastole of the heart, with a wavelength of 660 ± 20 nm, with a pulse repetition rate of 22.5 ± 2 kHz, with a pulse duration of 70 ± 30 ns and a power density of 0.1-0.5 W / cm ² .

In addition, the laser exposure time is from 30 seconds to 5 minutes, while monitoring the retention of the heating temperature of the tumor within 42-45 ° C.

For the second embodiment of the invention, the problem is solved in that in the method of biocontrolled photodynamic therapy after surgery and / or chemotherapy and / or radiation therapy, a chlorin eb photosensitizer is introduced, laser treatment of the tumor at the time of expiration and diastole of the heart, with a wavelength 660 ± 20 nm, with a pulse repetition rate of 22.5 ± 2 kHz, with a pulse duration of 70 ± 30 ns and a power density of 0.1-0.5 W / cm ² , while maintaining control of the heating temperature of the tumor. In addition, the time of laser irradiation in one 5 zone is from 30 seconds to 5 minutes, and control over the retention of the heating temperature of the tumor is carried out within 42-45 ° C.

The essence of the invention lies in the fact that the implementation of the above operations allows you to determine the predisposition to cancer, the localization and prevalence of damage, and

10 also increase the effectiveness of photodynamic therapy using the biofeedback laser exposure to optimize the power density of the laser exposure, identify the boundaries of the tumor and increase cellular immunity, as well as realize the possibility of selective exposure to tumors

15 deep localizations.

The best embodiment of the invention Preliminary diagnosis of tumors and metastases in organs is carried out using the Complex hardware-software "Co-formation" (see Registration Certificate N ° FS

20 662a2004 / 0562-04 of 09/27/2004, as well as an extract from the Protocol JSTs 1 of the Committee on New Medical Technology of the Ministry of Health and Social Development of the Russian Federation of 04/09/2004), which allows to identify violations of the functions and systems of the body and determine the predisposition to oncological diseases, as well as determine the localization and prevalence of

25 defeat. Further, in the diagnosis of tumors and metastases, including the early stages of their development, small amounts of the chlorin eb photosensitizer are administered intravenously (or in another way). When irradiated with light of a strictly defined wavelength (the same as in the treatment process), the photosensitizer accumulated in the tumor begins to fluoresce, which allows the accumulation of diseased cells located on the skin or close to it. Using a video device, fluorescence radiation is displayed on a TV or monitor. This method detects tumors less than 1 mm in size on the surface of the skin. Tumors of this size cannot be determined by any other method. The fluorescence emission spectrometer makes it possible to estimate the amount of PS in a particular place (with a diameter of about 600 μm) and, therefore, tumor cells. Observing the dynamics of the accumulation of FS, the doctor determines the necessary time and radiation power required for rehabilitation.

PS used in the method of photodynamic therapy (PDT) have the following properties: they mainly accumulate in tumors or in inflamed areas, are practically non-toxic, are quickly removed from the body, singlet (excited) oxygen is released under the influence of light, the energy received from light is converted into light longer waves (fluorescence). In the method of photodynamic therapy, FS are used in two important processes - in the diagnostic process, in medical or rehabilitation processes.

Chlorin eb-based preparations exhibit a photodynamic effect when interacting with light with a wavelength of 660-665 nm. This radiation penetrates into the tissues to a depth of 20 mm (according to our data, much deeper), which allows them to be used for tumors of deeper localization. Chlorins are completely eliminated from for several days, have a higher coefficient of accumulation in the tumor (1: 10-20) and practically do not have phototoxicity.

On the patient’s body, pulse sensors (for example, in the form of clothespins on the finger, a photodiode opposite the LED) and breathing sensors (for example, on the diaphragm area in the form of a belt, with which the resistance changes when stretched, or in the form of a thermistor near the nose) are installed on the patient’s body. Signals from the sensors include laser heating of the tumor only at favorable moments of exhalation and diastole of the heart. Heating is ensured by the maximum formation of singlet oxygen at a selected pulse repetition rate of (22.5 ± 2) kHz, with a duration of 70 ± 30 ns and the maximum absorption at a selected wavelength (660 ± 20) nm of singlet oxygen of laser photons at a power density 0.1 - 0.5 W / cm ² . Exposure only during the diastole of the heart during the exhalation phase, when the blood supply to the tissue decreases and, therefore, the heat capacity and thermal conductivity decrease, increases the locality of heating and reduces its inertia. This makes it easier to keep the heating temperature within the range of 42-45 ° C, in which only cancer cells selectively die. The temperature range is controlled by computer-controlled automatic control of the power and duration of the laser irradiation session using ultrasonic temperature measurement of the irradiated tissue.

The laser exposure of these parameters was monitored by ultrasound and differential thermometry to monitor the state of immunity in patients with tumors. Sessions were carried out when controlling the laser using a computer, into which the signals of the pulse and respiration sensors are input. the inertia of the impact with the help of the developed program based on the calculations of fluctuations in heat capacity and thermal conductivity and experiments with contact ultrasound and microwave thermometers. The range of average radiation power density is determined depending on the depth of the tumor.

With photodynamic effects, the body's immune response changes significantly, which is used during the rehabilitation of cancer patients. Taking into account the necessary correction for the difference in the time of arrival of the signal to the pulse sensor and to the area of tumor localization, laser exposure is performed only at the moment of expiration and diastole of the heart. The power density of 100 -500 mW / cm ² depending on the depth of the tumor. Carrier frequency 22.5 kHz, pulse duration 100 ns, exposure time per zone from 30 sec. up to 5 minutes

In order to increase cellular immunity before, during and after the PDT course, a previously developed technique was used using biocontrolled magnetic laser therapy with exposure to phases of increased blood supply during periods of inspiration and systolic of the heart on the thymus, spleen and transcutaneous infusion of blood. The state of cellular and humoral immunity was assessed both by direct generally accepted methods and by indirect assessment of cellular immunity using differential thermometry. Example 1. Patient K., 43 years old. Diagnosis: ovarian cancer, stage 4. Ascites. Pleurisy. Diagnostics was carried out using the hardware-software Complex "Co-stars". A lot of disorders in the system of reproductive organs of the hormonal sphere, signs of impaired liver and biliary tract. Were recommendations of a rehabilitation nature are given. The patient underwent laparocentesis - 6 liters of ascitic fluid were evacuated. Two pleural punctures were performed, 1100 ml of fluid was evacuated. A cytological study was carried out, after which two courses of polychemotherapy were carried out due to the impossibility of surgical intervention. An ultrasound revealed a volumetric formation of the right ovary with a size of 66.5 cm ³ . 10 days after the start of rehabilitation treatment according to the developed method using FS and laser exposure corrected by biochronotherapy, repeated ultrasound examination showed a decrease in volumetric formation to 27.6 cm ³ . Only after this, Patient K. was successfully operated on. In the future, repeated rehabilitation treatment was carried out according to the claimed method and at the moment, the former Patient K. is completely healthy. Example 2. Patient D., 73 years old. He was admitted with a newly diagnosed prostate aenocarcinoma. An ultrasound revealed 2 nodes in the prostate gland, in the left lobe 5.1 x 6.1 mm, in the right lobe 5.9 x 6.6 mm. PSA at admission was 15.9. The results of a microscopic examination after a biopsy: infiltrative growth of adenocarcinoma 5 points according to Glycony (3 + 2). Within 2 weeks, the patient underwent a course of rehabilitation selective chrono-phototherapy according to the invention, after which a repeated ultrasound examination was carried out 10 days later, which revealed a heterogeneous hyperplasia site with a fuzzy outline 1.8x1.6 mm in size. Control PSA study-1.5.

Example 3. Patient M, 13 years old. Diagnosis: gliosarcoma of the brain. Metastases in the spinal cord. Operated in 2004. He entered rehabilitation treatment with complaints of dizziness, gait instability, and nausea. Objectively pallor of the skin, pronounced neurological signs. After a two-week course of rehabilitation treatment according to the invention, the patient's condition improved, the symptoms of intoxication disappeared. The x-ray picture is stable, neurological signs are preserved.

The most representative cases of the use of selective selective rehabilitation chronophototherapy are selected from a significant number of treatment examples for patients with various oncopathologies.

Thus, the proposed method solves the technical problem. In clinical trials for various diseases, the effectiveness of the method of selective chronophototherapy has been proved: in the absence of negative side reactions due to the expansion of the therapeutic range of intensity parameters, in the stability of the therapeutic effect due to the formation of tissue memory and the use of a biological timer instead of physical, in accelerating the therapeutic effect due to the nature of the local pathology due to an adequate ratio of the depths of amplitude modulation by pulse, respiration and tremor, in the absence of hell ptatsii to the level of physiotherapy The effects due to irregular breathing and heart rate of the patient.

The use of chronophototherapy techniques has significantly expanded the indications for PDT. The use of PDT in biocontrol mode and in combination with chronophototherapy to increase cellular immunity allows achieving better results in the rehabilitation of cancer patients. With oncological diseases, the growth of tumors and the development of metastases slows down, immunological and hemodynamic parameters are normalized.

Industrial applicability

The stated advantages of the proposed technical solutions provide the possibility of widespread use in the field of medicine, in particular for the rehabilitation of cancer patients after surgical treatment, in the recovery period after chemotherapy, radiation therapy, as well as for therapy at an early stage of the disease.

Claims

CLAIM

1. A method of biocontrolled photodynamic therapy, the character of which is to preliminarily diagnose the localization of tumors and metastases, including the early stages of their development, using the hardware and software complex “Corrosion”, then introduce the chlorin eb photosensitizer, carry out a laser effect on the tumor at the time of expiration and heart diastoles, with a wavelength of 660 ± 20 nm, with a pulse repetition rate of 22.5 ± 2 kHz, with a pulse duration of 70 ± 30 nsec and a power density of 0.1-0.5 W / cm ² .

2. The method according to claim 1, characterized in that the laser exposure time is from 30 seconds to 5 minutes, while controlling the retention of the heating temperature of the tumor in the range 42-45 ⁰ C.

3. A method of biocontrolled photo dynamic therapy, which is characterized by the fact that after surgery and / or chemotherapy and / or radiation therapy a chlorin eb photosensitizer is administered, laser treatment of the tumor is performed at the moment of expiration and diastole of the heart, with a wavelength of 660 ± 20 nm, s the pulse repetition rate of 22.5 ± 2 kHz, with a pulse duration of 70 ± 30 ns and a power density of 0.1-0.5 W / cm ² , while maintaining control of the heating temperature of the tumor.

4. The method according to p. 3, characterized in that the time of laser exposure to one zone is from 30 seconds to 5 minutes, and the control over the retention of the heating temperature of the tumor is carried out within 42-45 ° C.