Method of selective destruction of malignant cells by magnetic microcontainers with photodynamic or photothermal dyes

FIELD: medicine.

SUBSTANCE: invention concerns medicine, oncology, and can be used for selective destruction of tumours. For this purpose, a photosensitiser is encapsulated in polymeric microcontainers enclosed in shells that contain magnetite (Fe3O4) nanoparticles, and introduced in the surrounding biological tissue. The external constant magnetic field with its spatial configuration matched with the tumour shape is generated in the tumour bulk. Laser exposure follows within a given period corresponding to maximum accumulation of the microcontainers in the tumour at radiant energy density sufficient for photodynamic or photothermal destruction of the microcontainers shells in the tumour and following photodynamic or photothermal destruction of malignant cells. The photosensitiser is specified with an absorption band chosen with an absorption strip in red and close IR-spectral region 650-1200 nm.

EFFECT: method allows more effective destruction of cancer cells ensured by higher degree of photosensitiser accumulation in the tumour with minimal destruction of the surrounding healthy cells and a surgical procedure without general anaesthesia.

4 cl, 9 dwg

 

The invention relates to the field of biomedical technologies, in particular to the creation of selective laser photodynamic or photothermal destruction of malignant cancer cells based on the magnetic vector delivery of microcapsules with photosensitizers and subsequent resonant laser irradiation of the tumor.

Treatment of malignant tumors in warm-blooded animals or humans the traditional methods of surgery is not always possible because of the nature of tumor localization (for example, in the area of the hard palate or pharynx). In addition, when using technology, when excised more than three centimeters of healthy tissue from the border of the tumor, in most cases develop metastases, and with technologies chemotherapy there are many complications due to deselections impact (see guidelines for chemotherapy of neoplastic diseases. / Under. edit Nieremontowany. - M.: Practical medicine, 2005, s-657).

There is a method of close-focus x-ray radiation therapy with a total focal dose of 100-120 Gr and remote gamma-therapy with radiation destruction of malignant cells, such as melanoma, with a total focal dose of 30-40 Gy (Saganaw. Oncology. - M:Medical information Agency, 2004, s-204).

This method however, despite the prevalence, has the following problems what Adami. In the treatment of such malignancies like melanoma, using remote gamma-therapy, even in combination with immunotherapy, as experience shows, leads to 75-90% of the recurrent tumors, and after 2-6 months develop metastases.

Known neutron capture process for the selective destruction of melanoma (Vnetid, Negroplasty, Amenability. Neutron capture therapy of tumors of the oral cavity in dogs. Russian veterinary journal, 2006, No. 1, p.9-10). The method includes introducing into the blood intravenously L-biphenylamine, which selectively accumulates in certain tumor-melanoma as L-phenylalanine is an essential amino acid, which produce melanin, forming melanocytes contained in melanoma cells. Thus, there is a selective accumulation of L-biphenylamine in melanoma cells. Upon irradiation of spatial areas, commensurate with the tumor, containing L-morenilla beam of slow neutrons generated by the neutron guide from a nuclear reactor, there is a destruction of melanoma cells due to induced secondary local radiation boron.

However, this method has the following disadvantages: the radiation exposure of patients, which is only partially mitigated by using lithium protective apron; complex and very expensive set is the WHC, includes a compact nuclear reactor that requires for maintenance qualified professionals non-medical, in particular nuclear physicists; long time exposure of patients during hours when the monitoring of the cardiovascular system; the use of General anesthesia.

The known method of laser photothermolysis of tumors based on the plasmon resonance of the gold nanoparticles (see P.K.Jain, I.H.El-Sayed, M.A.El-Sayed. Au nanoparticles target cancer. Nanotoday, 2007, v.2, No.1, p.18-29). The method includes the local introduction of the gold plasmon-resonant nanoparticles in the venous blood and the irradiation of the laser radiation with a wavelength matching the absorption band of the nanoparticles and causing local heating of the nanoparticles and, accordingly, necrosis of cancer cells.

However, this method has several disadvantages associated low contrast accumulation of gold nanoparticles in the tumor.

Closest to the proposed method is a method of photodynamic destruction of tumors, including intravenous administration of a photosensitizer and irradiation of the tumor continuous laser radiation with a wavelength matching the absorption band of the photosensitizer (Photodynamic therapy /Ed. T.J.Dougherty/ J.Clin.Laser Med. Surg. 1996, Vol.14, P.219-348; RF Patent №2184578, IPC A61N 5/06).

When the absorption of laser radiation photosensitizer molecules become excited ELEH the throne condition, when the collision of the excited photosensitizer molecules with molecules of oxygen latter goes into an excited singlet state, and the active oxygen molecules within the life time in the singlet state (with a typical lifetime of a few microseconds) when interacting with the plasma cell membrane damage and cell dies due to necrosis. Thus, the destruction of cells occurs only during exposure to laser radiation in a spatial region of irradiation of the laser beam.

Selective photodynamic mechanism of destruction of cancerous tumors based on higher density (contrast) accumulation of the photosensitizer in the tumor cells compared to normal, due to the greater density of blood vessels and their filestreamresult in the tumor compared with healthy biological tissue.

However, this contrast for different types of tumors does not exceed two or three times, which is the main drawback of this method.

Used in medical practice photosensitizers - phthalocyanine, porphyrins, chlorins, have absorption bands of photosensitizers in the ultraviolet or visible region of the spectrum and used lasers cannot effectively penetrate into the tumor due to the strong absorption of optical radiation with biological tissue. To the ome, photodynamic method has low contrast accumulation of photosensitizers in tumor cells.

The objective of the invention is to increase the efficiency of destruction of the bulk of cancer cells by increasing the degree of accumulation in the tumor (contrast) of the photosensitizer with minimal disruption to surrounding healthy cells.

The technical result consists in the efficiency and selectivity of damage to malignant cells during surgery without General anesthesia.

The problem is solved in that the method is selective destruction of tumors involving the introduction of a solution of a photosensitizer and irradiation of the tumor by laser radiation, which coincides with the maximum absorption band of the photosensitizer, according to the decision, for local tumor destruction photosensitizer capsulebuy in polymer microcontainer, the shell which contains nanoparticles of magnetite (Fe3O4) and injected into the biological tissue surrounding the tumor, the tumor volume create external constant magnetic field, the spatial configuration which coincides with the geometric size of the tumor, and the laser irradiation is carried out in the time corresponding to the maximum accumulation of microcontainers in the tumor, when the energy density of radiation, sufficient for photodynamic or f is termicheskogo failure envelopes of microcontainers inside the tumor and subsequent photodynamic or photothermal destruction of cancer cells, this photosensitizer selected absorption band in the red and near IR spectral region 650-1200 K temperature range nm.

Shell microcontainers further comprises gold nanoparticles with plasma resonance, which coincides with the maximum absorption of the photosensitizer at a concentration of gold nanoparticles is not less than 108in cm3.

Shell microcontainers further comprises gold nanoparticles with plasma resonance in the visible and near IR region 500-1200 nm, and local disclosure microcontainers them additionally irradiated by laser radiation, which coincides with the maximum absorption of the plasmon resonance of the gold nanoparticles.

For local failure envelope of microcontainers advanced use of high-frequency alternating magnetic field in the frequency range of tens of kHz to hundreds of MHz.

The invention is illustrated by drawings.

Figure 1 shows a block diagram of the experiment for the destruction of tumors in laboratory rats in vivo on the basis of selective photodynamic or photothermal therapy by irradiation of microcontainers envelope which contains nanoparticles of magnetite (Fe3O4containing within the photosensitizer, resonant laser light, where: 1-the laboratory rat (patient); 2 - malignant tumor; 3 - electromagnet, creating a spatial races is the definition of the magnetic field, coinciding with the shape of the tumor; 4 - microcontainer, the polymer shell which contains nanoparticles of magnetite (Fe2O4), and the inner cavity microcontainer filled with a photosensitizer; 5 - semiconductor laser with fiber-optic light guide, emitting in the red or near infrared spectral region (650-1200 K temperature range nm) with a wavelength matching the absorption band of the photosensitizer.

Figure 2 presents an image of microcontainer, whose shell contains nanoparticles of magnetite (Fe3O4), obtained using THE electron microscope at various magnifications.

Figure 3 presents the two-dimensional scanner systematic scans when probing the cell thickness of 1 mm, filled with a slurry of microcontainer in 50% aqueous glycerin solution in the absence and presence of magnetic field at different points in time. Magnetic field of 0.02 Tesla, created a permanent magnet attached to the outer wall of the cell, of a thickness of 3 mm (inner wall figure 4 shows the bottom)and without magnetic field, b is the suspension through 72 after exposure to a magnetic field, via 120, via 186 C. the Measurements were carried out using a low-coherence optical tomography type OST 3000 Carl Zeiss.

4 shows the process of destruction of microcontainer, content is the future in the shell of magnetic and gold particles without exposure to laser radiation (a), and when irradiated by a laser with a wavelength coinciding with the plasma resonance of the gold nanoparticles (b).

Figure 5 presents the image of gold nanospheres (a), nanorods (b) and nanoblock (b), obtained using an electron microscope.

Figure 6 presents the spectral dependence of the optical density plasmon resonance nanocasting visible and near infrared region: (a) nanospheres, (b) nanorods, (C) - nanoblock under various geometric parameters.

Figure 7 presents thermogram of the irradiation tube type Eppendorf with an aqueous solution of gold nanoblock (the core of SiO2with a diameter of 140 nm and a gold shell thickness of 15 nm with a maximum plasma resonance at a wavelength of 800 nm when the concentration of the nanoparticles 109in ml) by the radiation of a semiconductor laser with wavelength (810 nm) with a power of 1 W for 3 minutes with an energy of 180 J.

On Fig presents thermogram of the irradiation tube type Eppendorf with an aqueous solution of a photosensitizer (indocyanine green-IGG) radiation of a semiconductor laser with wavelength (810 nm), coinciding with the absorption band of the photosensitizer and 1 W for 3 minutes with an energy of 180 J.

Figure 9 presents thermogram of spontaneous tumors cats when introducing 0.1 ml of photosensitizer (indocyanine green-IGG), you shall yuushi photothermolysis tumors when exposed to radiation of a semiconductor laser with wavelength (810 nm), coinciding with the absorption band of the photosensitizer (IGG) with a capacity of 2 watts for 2 minutes.

In the prototype selectivity damage of the tumor is determined by the selectivity of accumulation of the dye in the tumor, which is introduced into the blood. The time of circulation of blood in the human body is 21 seconds. Depending on the type of tumors in various organs, there are different time of maximum accumulation of the dye, while the characteristic time can vary from half an hour to tens of hours. The maximum contrast of the accumulation of photodynamic dyes used in Oncology for malignant tumors, or 2-3 times the contrast of the accumulation of the dye in normal tissues and is associated mainly with pedestrianonly new capillaries that grow into tumors.

We propose a diffusion delivery and retention of dye placed in microcontainer magnetic shell, using a controlled magnetic field. Preliminary experiments performed in media with different viscosity, has shown the principal possibility to control the spatial localization of such magnetic microcontainers.

The method is as follows.

Polymer microcontainer 4, the shell which contains nanoparticles of magnetite (Fe3O4), with the prisoners inside Mick is containerof photosensitizer, introduced into the biological tissue surrounding the tumor 2 of the patient 1. Turn on the external constant magnetic field with 3 spatial configuration commensurate with the tumor 2. Through the time corresponding to the maximum accumulation of magnetic nanoparticles in the tumor 2 (estimates show that depending on the type of tumor, the typical accumulation of the nanoparticles is less than an hour), tumor 2 is irradiated with the laser beam 5 when the energy density of radiation, sufficient for photodynamic or photothermal destruction of membranes microcontainers inside the tumor 2 and subsequent photodynamic or photothermal destruction of cancer cells 2. In this case, the laser wavelength must match the absorption band of the photosensitizer, the photosensitizer selected absorption band in the red and near IR spectral region 650-1200 K temperature range nm.

At Saratov state University the authors developed the technology of polymeric microcontainers, the shell which contains nanoparticles of magnetite (Fe3O4)and gold nanoparticles (Dmitry A. Gorin, Sergey A. Portnov, Olga A. Inozemtseva, Zofia Luklinska, Tony M. Yashchenok, Anton M. Pavlov, Andre G. Skirtach, Helmuth Mohwaldb and Gleb B. Sukhorukov. Magnetic/gold nanoparticle functionalized biocompatible microcapsuleswith sensitivity to laser irradiation. Phys. Chem. Chem. Phys., 2008, 10, 6899-6905).

The size and shape of polymer microcontainers 4, the shell of which will win nanoparticles of magnetite (Fe 3About4), was monitored by means of electron microscopy, which allows to determine the spatial distribution of magnetic nanoparticles in the polymeric shell of microcontainers 4 (figure 2). Traffic control microcontainers 4, the shell which contains nanoparticles of magnetite (Fe3About4), was carried out using a constant magnetic field 3, as shown in figure 3. Using contactless optical diagnostic method based on low-coherence optical tomography type OST 3000 Carl Zeiss, the authors investigated the spatial dynamics of the movement of microcontainers in water-glycerol mixtures with a constant magnetic field 3, which allowed to determine the time of accumulation of magnetic microcontainers in tissues of cancer cells. Figure 3 presents the two-dimensional tomographic scans when probing the cell thickness of 1 mm, filled with the suspension of microcontainers in 50% aqueous glycerin solution in the absence and presence of magnetic field at different points in time. Magnetic field of 0.02 Tesla, created a permanent magnet attached to the outer wall of the cell, 3 mm thick: (a) without magnetic field, (b) the suspension through 72 after exposure to a magnetic field, (C) 120 s, (g) through 186 C.

When the spatial configuration of the external magnetic floor is, coinciding with the spatial configuration of the cancer cells, over time, the accumulation of microcontainers 4 in the tumor 2.

The process of destruction of microcontainer 4 containing shell magnetic and gold particles when irradiated by the laser 5 with a wavelength coinciding with the plasma resonance of the gold nanoparticles presented in figure 4. The concentration of gold and magnetic nanoparticles is 108in cm3.

Microcontainer containing shell gold nanoparticles (nanospheres)with plasma resonance 520-560 nm, which does not coincide with the maximum absorption of the dye inside microcontainer additionally irradiated by laser. As a result of such exposure is thermal partition membrane microcontainer, as shown in figure 5, and then must resonant laser effect on the dye.

In the laboratory dimensional nanosensors Institute of Biophysics physiology of plants and microorganisms, Russian Academy of Sciences the authors developed the manufacturing technology of the gold plasmon-resonant nanoparticles with the ability to control the spectral position of the plasma resonance when changing the geometric parameters of the nanoparticles representing gold nanospheres, nanorods and nanoblock, as shown in figure 5, 6 (Nghiem, Washeteria, Laakmann, Binghamton. Evil is made by CVD plasma resonance for biomedical research. // Nanotechnologies in Russia. 2007, Volume 2, No. 3-4, Pp.69-86). Manufacturing technology plasmon resonance of the gold nanoparticles type nanoblock, nanotesla allow you to get the maximum absorption of the nanoparticles in the spectral region corresponding transparency of biological tissues (650-1200 K temperature range nm).

Laser photothermolysis plasmon resonance of gold nanoparticles by laser radiation are presented in Fig.7. Creating gold nanoblock with a core of silicon oxide (SiO2) with a diameter of 140 nm with a gold nanoblocks thickness of 15 nm allows to get the maximum plasma resonance at a wavelength of 800 nm. As the experiments have shown (Fig.7), and the concentration of gold nanoblock 109in ml of water when exposed to infrared radiation of a semiconductor laser with wavelength (810 nm), 1 W for 3 minutes with an energy of 180 j allows to reach solution temperature more than 70°C, which allows you to manage the destruction of microcontainers, the shell of which is embedded gold nanoparticles.

Inside microcontainers is IR photosensitizer, when laser irradiation with a wavelength matching the absorption band of the dye may occur heating of the dye molecules, the disclosure of microcontainers and local photothermolysis of cancer cells by heating with a temperature of more 43-57°C, or when appropriate photosin is habilitator is photodynamic destruction of tumors.

The experiments allowed to establish the necessary levels of laser energy for technology photothermolysis. On Fig presents thermogram of the irradiation tube type Eppendorf with an aqueous solution of a photosensitizer (indocyanine green-IGG) radiation of a semiconductor laser with wavelength (810 nm), coinciding with the absorption band of the photosensitizer and 1 W for 3 minutes with an energy of 180 j at the temperature of over 70°C.

The lower limit of the energy density used lasers is determined by the temperature of the shell microcontainer necessary for its destruction, and the upper limit is determined by the density level of the laser energy does not cause pathological changes in tissues that do not contain plasmon-resonant nanoparticles and the photosensitizer. The concentration of the plasmon resonance of the gold nanoparticles in the shell microcontainer must be within a certain range. The maximum concentration of the plasmon resonance of the gold nanoparticles is determined by the processes of the formation of clusters, leading to the broadening of the plasma resonance, and the shift of its maximum. The lower bound concentration plasmon resonance of the gold nanoparticles is determined by the efficiency of laser heating of the shell microcontainers, visavisa her gap

The dynamics of heat plasmon resonance of the gold nanoparticles and photosensitisers and spatial distribution of temperature was studied by the authors in the experiment and simulated (Laser photothermolysis of biological tissues using plasmon - resonant nanoparticles. I.L. Maksimova, Akchurin, Tarentum G.S., crisp Bread B.N., Akchurin GML, I. Ermolaev, Skoptsov A.A., Revzin E.M., Tuchin VV, crisp Bread N.G. Quantum electronics, 2008, V. 38, No. 6, s-542). The experiments on irradiation of biological tissues of rats with the introduction of the tumour gold plasmon-resonant nanoparticles and subsequent histological analysis were defined modes of laser irradiation, the caller when photothermolysis of biotissues local cell necrosis (see I.L.Maksimova, G.G.Akchurin, B.N.Khiebtsov, G.S.Terentyuk, G.G.Akchurin, I.A.Ermolaev, A.A.Skaptsov, E.P.Soboleva, N.G.Khiebtsov and V.V. Tuchin. Near-infrared laser photothermal therapy of cancer by using gold nanoparticles: computer simulations and experiment. Medical Laser Application 2007, Vol.22, P.95-105-112).

The process of photothermolysis tumors in laboratory animals on the basis of IR photosensitizer type of Indocyanine - green (IGG) and gold nanoblock investigated in .SPIE, 2007, vol.6645, G.G.AkchurinJr V.A.Bogatyrev, I.L.Maksimova, G.A.Seleverstov, G.S.Terentyuk, B.N.Khiebtsov, N.G.Khiebtsov, V.V.Tuchin. Near-infrared laser photothermal therapy and photodynamic inactivation of cells by using gold nanoparticles and dyes; and presented at the European international conference (1920 November in Brussels Photonics Life 2008, Georgy G. Akchurin, Garif G. Akchurin, Irina M. Maksimova, Boris N. Khiebtsov, Nikolay G. Khiebtsov, Georgy S. Terentyuk, Valery V. Tuchin. Technology ofNIR laser photothermal tissue treatment based on gold plasmon-resonant nanoparticles and ICG dye.

1. Process for the selective destruction of tumors involving the introduction of a solution of a photosensitizer and irradiation of the tumor by laser radiation, which coincides with the maximum absorption band of the photosensitizer, wherein for local tumor destruction photosensitizer capsulebuy in polymer microcontainer, the shell which contains nanoparticles of magnetite (Fe2O4), and injected into the biological tissue surrounding the tumor, the tumor volume create external constant magnetic field, the spatial configuration which coincides with the shape of the tumor, and the laser irradiation is carried out in the time corresponding to the maximum accumulation of microcontainers in the tumor, when the energy density of radiation, sufficient for photodynamic or photothermal destruction of membranes microcontainers inside the tumor and subsequent photodynamic or photothermal destruction of cancer cells, while the photosensitizer selected absorption band in the red and near-IR spectral region 650-1200 K temperature range nm.

2. The method according to claim 1, characterized in that the shell of microcontainers further comprises gold nanoparticles with a plasmon resonance, cos Adumim with maximum absorption of the photosensitizer at a concentration of gold nanoparticles is not less than 10 8in cm3.

3. The method according to claim 1, characterized in that the shell of microcontainers further comprises gold nanoparticles with a plasmon resonance in the visible and near infrared region of 500-1200 nm, and local disclosure of microcapsules them additionally irradiated by laser radiation.

4. The method according to claim 1, characterized in that the local fracture membrane microcontainers advanced use of high-frequency alternating magnetic field in the frequency range of tens of kHz to hundreds of MHz.



 

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8 cl, 5 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to new compounds exhibiting antiproliferative activity of formula (1) where W means N or C-R2; X means -NH-; Y means CH; Z means halogen, -NO2, C2-C3alkynyl-, halogen-C1-C3alkyl- and -C(=O)-C1-C3alkyl, A means a group of formula (i), (ii) or (iii) Q1 means phenyl; B1, B2, B3 and B4 independently mean C-RgRh, N-Ri or O; R1 means hydrogen; R2 means a residue specified from the group including hydrogen, halogen and -OR4; Ra, Rb, Rc, Rd, Re and Rf independently mean hydrogen; Rg and Rh independently mean a residue specified from the group including hydrogen, =O, -OR4 and -NR4C(=O)R5; or mean optionally a residue monosubstituted or twice-substituted with equal or different substitutes and specified from the group including C1-C6alkyl and phenyl, the substitute/substitutes is/are specified from the group including R8/, -OR4, -C(=O)R4, -C(=O)OR4 and -C(=O)NR4R5 where R8/ and other values of radicals are specified in the patent claim, optionally in the form of their pharmacologically noncontaminating acid addition salts. The invention also concerns a pharmaceutical composition.

EFFECT: new compounds have effective biological properties.

8 cl, 6 dwg, 1086 ex

FIELD: medicine.

SUBSTANCE: invention discloses use of nanoparticles containing a matrix of at least one protein containing at least one anti-tumour active substance for preparing a medicinal agent for treating tumours whose resistance to chematherapeutic agents is associated with hyperexpression of P-glycoprotein, wherein the protein matrix includes at least one anti-tumour active substance which is not covalently bonded to said proteins.

EFFECT: doxorubicin nanoparticles in the disclosed medicinal agent and doxorubicin solution had comparable effect on non-resistant neuroblastoma cells; when resistance arose during therapy with cytostatic doxorubicin nanoparticles, the solution and liposomal preparation of doxorubicin were more effective in the disclosed agent.

4 cl, 2 dwg, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to ophthalmology. Method includes application on intermarginal edge of both closed eyes of medicinal composition. Composition consists of 2.0 g of gel "Lamifaren" and 0.2 ml of 30% sodium thiosulphate. After that attachments "Rubin" to apparatus "АМО-АТОС" are tightly pressed to edges of eye socket in laser glasses in rubber rim. After that low-frequency infrared laser radiation of intermarginal edge of eyelids is performed with wavelength 650 nm, power 2.5 W. On the first day of treatment, exposure is performed with modulation frequency 1 Hz. On each of the following days frequency of exposure is increase on 1 Hz daily, maximally to 6 Hz on the fifth day of treatment. In the following 10 days of treatment exposure is performed with modulation frequency 6 Hz. Duration of procedure is increased from 3 minutes- on the first day of treatment - to 7 minutes - by the 5-th day of treatment. The following 10 sessions of procedure are carried out for 7 minutes. Total number of sessions is 15.

EFFECT: method reduces treatment terms due to increase of tissue barrier permeability for applied medications, increases duration of remission.

2 ex, 1 tbl

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