Photosensitiser for photodynamic therapy

FIELD: medicine.

SUBSTANCE: what is presented is using meso-tetra(3-pyridyl)bacteriochlorin of structural formula (I) as a near-infrared photosensitiser for a photodynamic therapy. Doses 1.0-2.5 mg/kg of the declared photosensitiser have provided 70-100% tumour growth inhibition, 80-131% increase in life expectancy and 25-100% animals' recovery by selective tumour collection and fast clearance.

EFFECT: high photoinduced activity on human tumour cells of various epithelial origin and high dose-dependent anti-tumour effectiveness in the animal with tumours of various origins.

5 dwg, 8 ex


The present invention relates to medicine, namely - to the photosensitizers (PS) for photodynamic therapy (PDT) of malignant tumors and other pathological conditions.

Photodynamic therapy is based on the use of FS that have the ability to selective accumulation (affinity) in tumor tissue and irradiation with light of a specific wavelength pass in the activated state, which initiates the formation of cytotoxic agents, singlet oxygen and free radicals that cause the destruction of the structural elements of the tumor tissue.

The successful application of the method of photodynamic therapy for the treatment of malignant tumors stimulates the search for new FS with improved properties. The most promising for PDT of PS with maximum absorption in the far red and near infrared (700-800 nm), the so-called "therapeutic window" where the self absorption of biological tissues is minimal, allowing deeper penetration of radiation into the tissue and, as a result, high efficiency of therapy (Bonnett R. J. Heterocyclic Chem. 2002. V. 39. P. 455-470).

Promising PS for PDT that absorb in the near-infrared range of the spectrum, are bacteriochlorin (tetrahydropalmatine) (Mironov A. F., green M. A., Zebrowski A. G. et al. / / Bioorganic chemistry. 2003. T. 29. VIP. P. 214-221). So, tokad, palladium derivative bacteriochlorin (Tookad), with maximum absorption at 760 nm is allowed to treat prostate cancer.

However, the vast number of bacteriochlorins is a semi-synthetic drugs, which are used as starting compounds are substances of natural origin. Known same bacteriochlorin purely synthetic origin very difficult to reach - out multi-stage syntheses, as a rule, unstable when stored or photochemically unstable occurring as a result of oxidative processes.

The object of the invention is to find FS, which is characterized by absorption in the near-infrared range of the spectrum, high photoinduced activity, high affinity for tumor tissue, reducing side effects by reducing circulation time in the body, which would significantly increase the effectiveness of treatment.

To solve this problem as PS for PDT, the proposed use very affordable pure synthetic bacteriochlorin - meso-Tetra(3-pyridyl)bacteriochlorin (H2Py4BC) of the following formula:

This compound is described as an intermediate in the synthesis of meso-Tetra[1-(4'-bromobutyl)-3-pyridyl]b�of charikleia of tetrabromide (Patent RF №2479585, C07D 487/22, 2013). H2Py4BC received a two-step synthesis based on pyrrole and 3-pyridinediamine. For its solubilization in aqueous solutions used authorized for medical use non-ionic surfactant Cremophor EL (4% solution).

The invention is illustrated by the following figures:

Fig.1 - absorption Spectrum of a solution of 0.41 mg/ml H2Py4BC 4% Cremophor EL.

Fig.2 - fluorescence Spectra of a solution of H2Py4BC in 0.9% NaCl solution (A) containing 10% FBS medium eagle (MEM) (B) during incubation in dark conditions (1-ex tempore, 2 - a month).

Fig.3 - fluorescence Spectra of H2Py4BC in 0.9% NaCl solution (A) containing 10% FBS medium eagle (MEM) (B) during irradiation (1-ex tempore, 2-5 j/cm2, 3-10 j/cm2).

Fig.4 - Photoinduced activity of H2Py4BC against HEp2 cells (solid line) and EJ (dotted line).

Fig.5 - photo-Induced antitumor activity of H2Py4BC in mice with tumor S37 depending on the dose and the interval between injection and irradiation (1 - 2.5 mg/kg, 30 min; 2 - 2.5 mg/kg, 2 h; 3 - 1.0 mg/kg, 30 min; 4 - 1.0 mg/kg, 2 h; 5 - 0.5 mg/kg, 30 min).

The invention is illustrated by the following examples, but is not limited thereto.

Example 1. meso-Tetra(3-pyridyl)bacteriochlorin synthesized according to previously described methods (Patent RF №2479585, C07D 487/22, 2013) the restoration of meso-Tetra(3-�iridis)of the porphyrin diimide, generated under the reaction conditions of n-toluensulfonate, in the presence of dry potassium carbonate in dry pyridine. λmaxnm (lgε), chloroform: 747 (5,05), 683 (3,78), 521 (4,71), 491 (3,78), 380 (5,08), 367 (4,95), 357 (5,00).

The source of meso-Tetra(3-pyridyl)porphyrin obtained by condensation of equimolar amounts of pyrrole 3-pyridinylmethyl in boiling propionic acid in the presence of air.

Example 2. Preparation of solution H2Py4BC 4% Cremophor EL

Attachment H2Py4BC (4,1 mg) and non-ionic surfactant Cremophor EL (0.4 g) was dissolved in 20 ml of chloroform. Mixed solution in the round bottom flask of 1 l magnetic stirrer, heating to 40-55°C for the intensification of the process of dissolution. Then the solvent was evaporated on a rotary evaporator in vacuo at the temperature of the water bath 30 to 40°C. the Resulting film was dossible in vacuum, after which he hydrational by adding 10 ml of phosphate buffer solution (PBS) with pH=7,34. Stirring is carried out until complete dissolution of the film; the resulting solution was filtered through a membrane filter (Millipore, Type GS) with a pore size of 0.22 μm. All the stages of preparation of the solution was carried out with minimal external lighting.

The solutions were kept at a temperature of 6-10°C in the dark place. Absorption spectrum of a solution of 0.41 mg/ml H2Py4BC 4% Cremophor EL are shown in Fig.1 (register relative�Uo 4% solution of Cremophor EL in the cell l=0,02 cm).

Example 3. Evaluation of the stability of H2Py4BC.

Assessment of the stability of FS was performed using fluorescence analysis. Solutions for research were prepared ex tempore, reaching the chosen concentration (5 µg/ml) by serial dilutions of the initial solution. The concentration of the feed solution consisted of 0.41 mg/ml) as the solvent used medium eagle containing 10% FBS and 0.9% NaCl solution. Registration of fluorescence of the solutions was carried out in the dynamics of the contact method on laser spectral analyzer for fluorescent diagnosis "Leba-6" (LLP "BIOSPEC", Russia). The fluorescence was excited He-Ne laser at the wavelength of the generation of 632.8 nm, the spectral range from 600 to 950 nm.

Fig.2 shows fluorescence spectra of a solution of H2Py4BC in 0.9% NaCl solution (A) containing 10% FBS medium eagle (MEM) (B) during incubation in dark conditions. No change in the profile of the spectrum and the fluorescence intensity indicates its stability in the selected time range.

Example 4. Evaluation of photostability H2Py4BC in cell-free environment.

Assessment of fotovytsvetaniya was performed in 0.9% solution of sodium chloride in the medium eagle (MEM) containing 10% FBS, upon irradiation with polychromatic light. As a light source used halogen lamp mo�of 500 W with a broadband filter KS-13 (λ≥680 nm) and a water filter of a thickness of 5 cm. The light dose was 5 and 10 j/cm2when power density 32,0±1.0 mW/cm2. The fluorescence measurement was carried out by contact of the laser spectral analyzer "Leba-06" in the spectral range of 600-950 nm. Fluorescence spectra were recorded immediately after preparation of the solution and after exposure to light.

When irradiated with FS (Fig.3) in 0.9% NaCl solution (A) and in the medium eagle (MEM) (B) was observed only a slight decrease (no more than 18-20%) fluorescence intensity (λmax=745±2 nm) without changing the profile of the spectrum, indicating its photostationary.

Example 5. Photoinduced activity and dark cytotoxicity of H2Py4BC in relation to the culture of human cells and HEp2 EJ.

Studies were performed on human tumor cells. Cell culture epidermoid carcinoma of the hypopharynx (HEp2) and carcinoma of the bladder (EJ) obtained from the Institute of Virology. D. I. Ivanovsky RAMS, which were cultivated at 37°C in a humidified atmosphere containing 5% CO2(standard conditions).

The cells were dispersed into the wells of flat-bottomed 96-well microplate. The test compounds were introduced into the wells 24 hours after seeding, by varying the concentration from 13 to 3200 nm. To assess phototoxicity after 0.5, 2, 4 and 6 hours of incubation with the photosensitizer, cells were irradiated halogen l�the IPA through a broadband filter KS-13 (λ≥680 nm). The power density was 32,0±1.0 mW/cm2, the calculated light dose of 10 j/cm2. Also studies were performed with deletion from FS environment before irradiation, and without removal.

After irradiation the cells were incubated overnight under standard conditions. To assess the cytotoxic activity of the dies were placed in dark conditions for 24 hours. Evaluation of survival rate was determined by visual and colorimetric method using MTT assay. Biologically significant effect is believed inhibition of cell growth in culture by more than 50%. This value was calculated as the average results of three independent tests.

It is revealed that the FS showed maximum photoinduced activity relative to the HEp2 cell cultures and EJ, with 4-hour incubation, IR50was 32±2 nm and 35±3 nm, respectively, with increasing incubation time up to 6 hours value IR50was not changed (Fig.4). Incubation of the cells with the dye at concentrations up to 3200 nm in the absence of light exposure for 24 hours did not affect the growth of cell cultures.

The removal of FCS from the culture medium before exposure to light slightly reduced the effectiveness of photodynamic therapy (15-20%), which indicates the implementation of photoinduced activity mainly due to the activation of intracellular f�.

Thus, the in vitro results showed that H2Py4BC accumulates in the cells and has a high photoinduced activity.

Example 6. The distribution of H2Py4BC in the tumor S37 and fluorescent contrast relative to surrounding tissue.

Assessment of the distribution of FS in tumor and surrounding tissues was performed in mice with sarcoma S37 in the interval from 5 minutes to 48 hours by the method of local fluorescence spectroscopy (LFS). The photosensitizer was injected intravenously at a dose of 2.5 mg/kg. the Fluorescence was recorded by the contact method on laser spectral analyzer for fluorescent diagnosis and monitoring of PDT "Leba-06".

In tumor tissue normalized fluorescence FS reached a maximum of 2.1±0.7 CONV. units) after 5 min and remained at a high level in for 1 hour after administration, and then for 48 hours was reduced by 95% of the maximum value. The highest levels of the normalized fluorescence in the skin (1,8±0,6 CONV. units) was observed 4 hours after the introduction of the FS, in the muscle (3,3±0,3 CONV. units) - after 5 minutes - 2 hours. Maximum fluorescent contrast FS relative to surrounding normal skin tissues were recorded after 5 minutes after injection and was 2.3±0.4 CONV. units, and relatively muscle - 0,9±0,1 CONV. units after 5 minutes and 24 hours after th�.

Example 7. Photo-induced antitumor activity of H2Py4BC in animals with sarcoma S37, vaccinated subcutaneously with the outer side of the right thigh of mice BDF1.

Study of the efficacy of photodynamic therapy was performed on day 7 after tumor inoculation. FS animals were injected once intravenously in doses of 0.5, 1.0 and 2.5 mg/kg. Irradiation was performed using 0.5 and 2 hours after injection of the dye. Was used for irradiation led source (FSUE "SSC "NIOPIK") with a wavelength of 754±14 nm and a power density of 150 mW/cm2(light dose of 150 j/cm2). The control group of animals without effect.

The efficacy of PDT was evaluated using the common in experimental Oncology criteria:

- inhibition of tumor growth SRW=[(VK-Vop)/VK]·100%, where Vopand VK- tumor volume in the experimental and control groups, respectively;

- increased life expectancy, median survival=[(SPop-ALEK)/SPMK]·100%, where the SPMopand ALEK- the average life expectancy in the experimental and control groups, respectively;

- the criterion of cure CI=[PI/No]·100%, where PI and N is the number of cured animals and total number of animals in the experimental group, respectively.

Tumor volume was calculated by the formula: V=d1·d2·d3where d1, d and d3three mutually perpendicular diameter of the tumor.

Measurement of tumor volume was performed for 21 days after irradiation using electronic digital calipers STORMtm 3C301 "Central". The animals were followed for 120 days.

In the experimental groups during the day after irradiation the animals were formed intense edema in the impact zone, which was maintained up to 5-15 days. Biologically significant antitumor effect was obtained when using FS in doses of 1.0 and 2.5 mg/kg irradiation after 30 minutes and 2 hours after administration and reached 70-100% TRO (Fig.5), 25-100% cure animals; life expectancy of animals was increased by 80-131%. The highest antitumor effect (100% TRO and 100% KI) with minimal damaging effect obtained by using the FS at the dose of 2.5 mg/kg exposure 2 hours after administration.

Example 8. Pharmacokinetics H2Py4BC in intact mice.

Pharmacokinetics of H2Py4BC was studied by the method of LFS in the organs and tissues of intact mice at a dose of 2.5 mg/kg on normalized fluorescence (FN).

The maximum of the fluorescence spectrum FS in animal tissues was recorded at 744±2 nm. Fluorescent form of the dye quickly (within 5-30 minutes) to be received in the internal organs and tissues of the body, mainly in the liver, then FN is decreased at different rates. M�ximalaya fluorescence in the blood was determined immediately after intravenous administration and within 4 hours was reduced by 95% of the maximum value and through the night was not recorded.

In the internal organs after 24 hours the level of the normalized fluorescence decreased in the liver by 87%, kidneys - 90%, spleen - 92% of the maximum value. Fluorescent form FS at a dose of 2.5 mg/kg was determined in the kidney and spleen up to 2 days in the liver and the residual amount was determined up to 7 days.

In the skin the maximum value of fluorescence was recorded 4 hours after the introduction of the FS, then its normalized fluorescence decreased and after 24 hours was 50% of the maximum value and after 5 days was not determined. This indicates a rapid elimination of the Federal Assembly of the skin. In the muscle after 24 hours the level of the normalized fluorescence also decreased by 82%, and fat 20%. Fluorescent form FS were determined in the muscle up to 5 days, and in the adipose tissue of the residual amount (26%) were registered more than 7 days.

The data indicate a rapid circulation of H2Py4BC in mammals and its excretion is mainly through the liver with the bile.

Thus, Tetra-(3-pyridyl)bacteriochlorin is highly active FS new generation, absorbing in the near infrared region of the spectrum (λmax=745±2 nm); is storage stable and has a high photostability, exhibits a high photo-induced antitumor activity in vitro (4-hour�Oh incubation of cultures HEp2 and EJ IR 50was 32±2 nm and 35±3 nm, respectively) and in vivo (100% TRO and 100% KI in the application of FCS in a dose of 2.5 mg/kg and irradiation after 2 hours). FS has a fast excretion of animals (after 24 hours the contents in the internal organs is reduced by 87-92% of the maximum value, the residual amount is observed up to 7 days).

The application of meso-Tetra(3-pyridyl)bacteriochlorin structural formula

as a photosensitizer, the near-IR region of the spectrum for photodynamic therapy.


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4 cl

FIELD: medicine.

SUBSTANCE: agent for stimulating substantia Nissl synthesis in spinal cord motor neurons and spinal cord motor neuronal process growth, and a method for stimulating substantia Nissl synthesis in spinal cord motor neurons and spinal cord motor neuronal process growth. The agent represents a swine or foetal adrenal cortical alcohol extract which contains natural corticosteroids in the minor concentrations. The adrenal cortical alcohol extract of swine or foetal animal cells is prepared on the basis of organ preparations.

EFFECT: agent and method using the presented agent enable providing more effective stimulation of substantia Nissl synthesis in the spinal cord motor neurons which possesses an ability to neutralise toxic products and free radicals formed in process of acting, as well as ensuring higher growth of the processes of forming cell-to-cell communications, activating intracellular granular endoplasmic reticulum, increasing an energy level and antioxidant protection against aggressive radicals.

2 cl, 1 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine, namely to psychiatry, and may be used for treating and preventing disorders specified in a group consisting of depressive, affective and anxious disorders, particularly a major depressive disorder. For this purpose, a patient's therapy is added with a stage of administering a therapeutically effective amount of embryonated egg isolate.

EFFECT: group of inventions provides treating the above pathology, including by inhibiting glutamate and neurokinin 2 (NK2) receptors.

15 cl, 12 dwg, 11 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: 15-methyl ether 13,17-bis(N,N-diethylaminoethylamide)chlorine photosensitiser e6 selectively accumulates in tumour tissue.

EFFECT: photosensitiser has absorption in the red spectral region and high photo-induced anti-tumour activity, full retardation of tumour growth and animal cure.

5 dwg, 1 tbl, 6 ex