Method for selective destruction of melanoma

FIELD: medicine; oncology.

SUBSTANCE: method includes introduction of solution of chemical compound of amino acid L-phenylalanine with gold or silver nanoparticles intravenously prior to radiation. At that minimum concentration of nanoparticles is 108 cm-3, and maximum concentration is 1012 cm-3. Plasma resonance of nanoparticles has spectral maximum in the area of biotissues transparency at the wave length of 750-1200 nm. These nanoparticles are gold or silver nanoshells with core of silicon dioxide or nanorods. Radiation of melanoma is performed at least after 1 hour and not more than after 4 hours after solution introduction, laser beam with length of radiation wave that coincides with spectral maximum of nanoparticles plasma resonance absorption. At that radiation is done by sequence of laser impulses with duration of laser impulse in the range of 10 microseconds - 100 ns at minimum porosity of three and higher, at energy density of at least 20 J/cm2, but not more than 200 J/cm2.

EFFECT: local performance of melanoma destruction with minimum destruction of surrounding healthy cells.

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The invention relates to the field of biomedical technologies, in particular to the creation of a non-invasive laser selective photothermolysis of malignant melanoma cells based on plasmon resonance of gold or silver nanoparticles. In the treatment of such tumors like melanoma 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), and even if excised more than three centimeters of healthy tissue from the border of the tumor, in most cases develop metastases and chemotherapy, there are many complications (guidelines for chemotherapy of neoplastic diseases, under. ed Nieremontowany. M. Practical medicine. 2005, s-657; white R. Cancer of the small domestic animals. M: Aquarium, 2003).

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 melanoma cells with a total focal dose of 30-40 Gy (Saganaw. Oncology. M: Medical news Agency. 2004, s-204; Stephen J. Withrow E. G. MacEwen Small animal clinical oncology - 2001, p.305-308).

This method however, despite the prevalence, has the following disadvantages. In the treatment of melanoma using the distance the ion 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.

There 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; Stranadko. The analysis of the direct results of PDT of malignant tumors. New advances in laser medicine. - M - SPb., 1993, n.218). Selective photodynamic mechanism of destruction of cancer cells based on higher density (contrast) accumulation of the photosensitizer in the tumor cells compared to normal, due to the greater density of blood vessels in the tumor compared with healthy biological tissue.

However, this contrast for different tumors does not exceed two or three times. When the absorption of laser radiation by the photosensitizer dye molecules are transferred to an excited electronic state and the collision with the molecules of oxygen dissolved in tissues, bring it from the unexcited to an excited electronic singlet state, with a typical lifetime of a few microseconds. During this time, molecules of singlet oxygen, having the characteristic is Cherny path, commensurate with the size of the cells in the interaction with the plasma membrane of cells, damage it, and the 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.

Photodynamic way in the destruction of melanoma cells has several disadvantages. The absorption coefficient of melanin up to 104-3cm-1in the ultraviolet and violet region and decreases to 102cm-1in the red area, so the penetration depth of laser radiation less than hundreds of microns. Used in the practice of 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 melanoma. In addition, photodynamic method has low contrast accumulation of photosensitizers in tumor cells.

Closest to the proposed method is 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 that the selective behaviour is about accumulating in certain tumors, 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.

1. The radiation exposure of patients, which is only partially mitigated by using lithium protective apron.

2. Complex and very expensive to install, including a compact nuclear reactor that requires for maintenance qualified professionals non-medical, in particular nuclear physicists.

3. Long time exposure of patients during hours when the monitoring of the cardiovascular system.

4. General anesthesia.

The present invention is to improve the locality of the method of selective destruction of melanoma with minimal destruction of surrounding healthy cells of the tissue.

The technical result is the effective damage of malignant melanoma cells is a surgery without General anesthesia.

The problem is solved in that in the method for selective destruction of melanoma, including intravenous solution of amino acids L-phenylalanine and irradiation of melanoma, according to the solution as a solution using a chemical compound amino acids L-phenylalanine with gold or silver nanoparticles, which is a gold or silver nanoblock or nanorods with a minimum concentration of 108cm-3and maximum concentrations of 1012/cm-3plasma resonance, with a spectral maximum in the area of transparency of biological tissues at a wavelength of 750-1200 nm, irradiation of melanoma spend a laser beam at a wavelength that coincides with the spectral maximum absorption of the plasma resonance of the nanoparticles, while for the local destruction of melanoma cells the radiation produces a sequence of laser pulses with the duration of the laser pulse in the range of 10 μs to 100 NS with a minimum duty cycle of three or more when the energy density of at least 20 j/cm2but not more than 200 j/cm2.

The invention is illustrated by drawings.

Figure 1 shows a block diagram of the experiment for the destruction of melanoma lab rats in vivo on the basis of the pulsed laser photothermolysis using the plasmon resonance of gold or silver dropping the data nanoparticles, where 1 laboratory rat, 2 - a chemical compound L-phenylalanine with gold or silver plasmon-resonant nanoparticles, consisting of nanoblock or nanorods; 3 - malignant - melanoma; 4 - pulse infrared (750-1200 nm) semiconductor laser with fiber-optic light guide.

Figure 2 - image of the gold nanoparticles obtained using the electron microscope: (a) nanospheres with a diameter of 5 nm, (b) gold nanoblock diameter of 90 nm with a core of silicon dioxide, (b) gold nanorods with a diameter of 15 nm and a length of 50 nm.

Figure 3 - dependence of the extinction coefficient (absorption and scattering) as a function of wavelength (nm) while changing the geometric parameters of the nanoparticles: (a) gold nanospheres, (b) gold nanorods with a length to diameter of from 1 to 6; (b) gold shell thickness of 2 nm diameter core of silicon dioxide is from 10 to 90 nm.

Figure 4 - thermogram of the heating efficiency of the gold plasmon resonance nanoblock when exposed to continuous wave and pulsed laser radiation with a wavelength of 810 nm with the same average optical power of 2 watts and exposure time of 1 minute.

Figure 5 - experimental thermogram uneven heating along the depth of the cell when exposed to a laser beam plasmon-resonant gold nanoblock to vary the concentration of: (a) N=5·109ml-1(b) - N/8=0.61·109ml-1.

Figure 6 presents a photograph of laboratory rats when exposed to radiation of a semiconductor laser used for heating plasmon-resonant nanoparticles using continuous (crosses) and pulse mode (points) with the same average density of laser energy.

Figure 7 presents thermogram of the efficacy of laser photothermolysis of tissues with introduced at varying depths in the gold plasmon resonance of nanoparticles: (a) control without nanoparticles; (b) unutilised the introduction of a volume of 0.1 ml of SiO2/Au to a depth of 5 mm; (b) subcutaneous administration; (g) intradermal injection.

On Fig histological slice of tissue to a lab rat after vnutrimyshechnogo introduction plasmon resonance nanoblock to a depth of 5 mm with subsequent exposure to radiation of a semiconductor laser with a wavelength of 810 nm for 30 seconds, with a capacity of 2 watts in continuous mode, (a) - shot in the dark field, (b) image in transmitted light.

Figure 9 histological slice from the epidermis to the muscle tissue after vnutrimyshechnogo the introduction of the gold plasmon resonance nanoblock to a depth of 5 mm when exposed to radiation of a semiconductor laser with a wavelength of 810 nm for 10 seconds: (a) pulse mode, pulse duration 1 MS, SLE is a possibility 5; (b) continuous mode with the same laser energy of 20 j.

Figure 10 - the destruction of mucosal melanoma of the oral cavity in dogs laser photothermolysis based on plasmon resonance of nanoparticles: (a) photograph (b) thermogram.

The method is as follows.

A person or an animal intravenously, for example, the laboratory rat 1 in the tail vein using an insulin syringe is injected solution consisting of chemical compounds 2 L-phenylalanine with gold or silver plasmon resonance nanoblocks or nanorods (bioconjugate) at a concentration of not less than 108cm-3and not more than 1012cm-3dissolved in saline solution, not less than 1 hour and not more than 4 hours, corresponding to the optimal accumulation of nanoparticles into cancer - melanoma 3, produce the irradiation of melanoma pulsed semiconductor laser 4 with a wavelength coinciding with the maximum of the plasma resonance of the nanoparticles, which lies in the transparency of biological tissues (750-1200 nm)over time, which is determined by the corresponding level of energy density impinging laser beam is not less than 20 j/cm2and not more than 200 j/cm2. It should be noted that as the pulse laser micro - and nanosecond duration can be used in isulan solid-state lasers YAG garnet with neodymium with a wavelength of 960 and 1064 nm.

The lower limit of the energy density used lasers is determined by the temperature of the tissue containing the nanoparticles, causing necrosis of tumor cells, 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.

In the laboratory dimensional nanosensors IBPM RAS the authors developed the technology and really made plasmon-resonant nanoparticles with the ability to control the spectral position of the plasmon resonance of gold or silver nanoparticles when changing the geometric parameters of the nanoparticles as shown in figure 4 (Nghiem, Washeteria, Laakmann, Binghamton. Gold nanostructures with plasma resonance for biomedical research // nanotechnologies in Russia. 2007. Vol.2. No. 3-4. Pp.69-86; Khiebtsov N.G., Trachuk L.A., Melnikov A.G. Proc. SPIE, 2004. V.5475, 1-11).

From a comparison of the laser heating of the cell with plasmon-resonant gold nanoblocks volume of 2 ml (figure 5) with continuous maximum temperature 57,4° (C) and pulse (maximum temperature 40,7° (C) (duration laser pulses of 2 MS and the temporal distance between pulses 14 MS, duty cycle 7) irradiation under the same average laser energy 150 j (in continuous mode, the laser power of 2.5 watts for 1 minute). It is easy to see that under the impulse impact cuvette is heated on 17°With less as compared with continuous heating, which experimentally proves the locality heating plasmon-resonant gold nanoblock, due to the finiteness of time setting temperature.

The concentration of the plasmon resonance of gold or silver nanoparticles must be within a certain range. The maximum concentration of plasmon-resonant gold or silver nanoparticles is determined by the processes of the formation of clusters and the broadening of the plasma resonance. The lower bound concentration plasmon resonance of gold or silver nanoparticles is determined by the efficiency of laser heating. Figure 5. shows experimental thermogram uneven heating of plasmon-resonant gold nanoblock on the depth of the irradiation of the laser beam at various concentrations. Tube type Eppendorf with gold plasmon resonance nanoblocks, dissolved in saline solution volume of 2 ml with different concentrations of nanoparticles 5·109ml-1(a) and 0.61·109ml (8 different times) when exposed to continuous laser radiation with a wavelength of 810 nm, which coincides with the maximum absorption of the nanoparticles with the same average laser power of 2 W and time exposed is of 2 minutes.

In this case, as shown by control experiments on irradiation of biological tissues of rats with the introduction of the tumour gold plasmon-resonant nanoparticles (6) and histological analysis (Fig) were identified modes of laser radiation, in particular, the duration of the optical pulses, the temporal distance between them and the density of laser energy, the caller when photothermolysis of biotissues local necrosis of melanoma cells (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, V.22).

As shown in Fig in laserage photothermolysis based on plasmon-resonant nanoparticles according to histological studies observed the destruction and fragmentation of striated muscle, slight swelling. In the picture in dark box are clearly visible nanoparticles located in the area of iscertainly striated muscle.

The results of the comparison of laser photothermolysis under pulsed and continuous laser irradiation are presented in Fig.9, which shows the histological slice from the epidermis to the muscle tissue after intramuscular gold plasmon resonance nanoblock to a depth of 5 mm When exposed to radiation is poluprovodnikov laser with a wavelength of 810 nm for 10 seconds: (a) pulse mode, pulse width 1 MS, duty cycle 5; (b) continuous mode with the same laser energy of 20 j, it follows that when the pulse effect is observed only swelling and loosening of the connective tissue, cellular infiltration, indicating an inflammatory process. When continuous exposure (b), laser photothermolysis arise foci of destekli in the dermis in the form of homogenization and swelling of the basic substance and collagen fibers.

When the pulse heating of gold nanoparticle laser pulse duration determines the locality of heating the nanoparticles of the surrounding tissue. Estimates show that irradiation of nanosecond pulses the effective radius of the heating of the surrounding tissue is not more than 1 micron (B.N. Khlebtsov, V.P. Zharov, Melnikov A.G., V.V. Tuchin, Khlebtsov N.G. Optical amplification of photothermal therapy with gold nanoparticles and nanoclusters. Nanotechnology, 2006; 17, 5267-5179).

However, the observed effect defragmentation plasmon-resonant gold nanoblock when energy of a single laser pulse > 2 MJ and a duration of 4 NS, causing the destruction of nanoblock or local melting of the nanorods leads to the restriction on the laser intensity at the top and its minimum duration. (G.Akchurin, .Khlebtsov, G.Akchurin, V.Tuchin, V.Zharov, N.Khiebtsov. Laser-induced phonodestruction of silica/gold nanoshells under single nanosecond pulses. Nanothechnology, 207, V.18).

Thus, the parameters of the laser pulse exposure was determined experimentally on tissue phantoms and in vivo spontaneous tumors in animals, with subsequent histological analysis and the minimum duration of the laser pulse was limited to the condition specified in the claims.

Conducted on patented technique of laser photothermolysis based on plasmon resonance of gold nanoblock melanoma of the mucous membrane of the mouth in dogs and cats caused scar tissue without remission and metastasis within several months to one year.

Process for the selective destruction of melanoma, including the irradiation of melanoma, characterized in that, in addition to exposure, intravenous solution chemical compounds amino acids L-phenylalanine with gold or silver nanoparticles, which is a gold or silver nanoblock with a core of silicon dioxide or nanorods with a minimum concentration of 108cm-3and maximum concentrations of 1012cm-3plasma resonance, with a spectral maximum in the area of transparency of biological tissues at a wavelength of 750-1200 nm, irradiation of melanoma spend not less than 1 h and not more than 4 h after injection of the solution to a laser beam with a wavelength that matches with actrally maximum absorption of the plasma resonance of the nanoparticles, when this radiation is produced by a sequence of laser pulses with the duration of the laser pulse in the range of 10 μs to 100 NS minimum duty cycle is three or more, when the energy density of at least 20 j/cm2but not more than 200 j/cm2.



 

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27 cl, 73 ex

FIELD: medicine; oncology.

SUBSTANCE: method is based on introduction in patient's organism of cytostatic preparation with mechanism of action based on interchain cross-linking within DNA molecule of cancer cells with preparation of fragmented allogen DNA with the fragments of biologically active dimension and composing entire gene of physiologically and genetically healthy donor.

EFFECT: method enables to activate recombination cell system and to provide homologous integration of DNA preparation into recipient gene.

3 cl, 5 dwg, 1 tbl, 1 ex

FIELD: medicine; therapy and cardiology.

SUBSTANCE: biophysical indices are determined in points of heart and pericardium meridians acupuncture. Corporal points of heart and pericardium meridians acupuncture are exposed to laser radiation with wave length of 0.63 mcm with outlet power density of 0.1-10 mW/cm2 and beam diameter of 1.5-0.1 mm. Radiation is dosed according to dynamics of electropotential value in every point of acupuncture. Laser therapy is carried out in combination with intake of activated acid and alkaline water according to regimen that provides rise in consumption of acid water from 1/3 of glass to 1/2 of glass - in the end of treatment, and alkaline water from 1 to 7-8 glasses accordingly. The whole course is realised against the background of diet with reduction of food calorie and fat content and graduated physical exercise.

EFFECT: normalisation of vessel walls elasticity, better tolerance of physical activity.

1 ex

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