Photoinitiator process of destruction of malignant cells in living organisms

 

(57) Abstract:

The invention relates to methods of destruction of malignant cells in living organisms and can be used for the treatment of solid tumors, for programmed cell death in biological and medical research, for photodynamic therapy of cancer. The aim of the invention is to increase the efficiency of the process of destruction of malignant cells in living organisms. The technical effect is achieved by using as photoinitiator photolysis of malignant cells in living organisms tidimensional dye of the formula

,

(X = CH3C6H4SO-3). The proposed photoinitiator polymethine has a number of advantages compared with the known photoinitiators. Due to the positive charge of the polymethine selectively accumulates in cancer cells, effectively inhibits the growth of solid tumors in mice and destroys the malignant cells in vitro. At lower doses of irradiation efficiency 1.5-4.0 times higher than the efficiency of known photoinitiator of cryptocyanine that it is important for the treatment of deep-lying cells in the tumor. 1 Il., table 2.

The invention relates to spooley, for programmed cell death in biological and medical research, for photodynamic therapy of cancer.

Known application of porphines, such as Photofrin II as photoinitiator destruction of cells under the action of red light. The most likely mechanisms of photodynamic porphines as other dyes, consider their vodoprivredna education or singlet oxygen mechanism of type I or radicals (the mechanism of type II). Mechanisms of type I and II lead to the accumulation in the cells of active forms of oxygen, photomodification uses of cell membranes, disruption of the functioning of the cells and, ultimately, to cell death. Porfiry are not sufficiently effective, their use requires very large therapeutic doses. So, a 50% survival rate of mice with melanoma is achieved by the application of Photofrin II in a dose of 10 mg of dye per 1 kg of body weight of the mouse with a total dose of 500 j/cm2light with a wavelength of 630 nm.

It is also known application as photoinitiator photolysis cell phtalocyanine dyes. Chloroaluminium phthalocyanine sulfonate is the most effective dye from this class: concentration 1,310-5mol/l (11-12 mg/kg) of annih works assumed what phthalocyanines act as exogenous sensitizers, and the mechanisms of type I and II are not met. However, in further work, this assumption was not confirmed and received evidence that phthalocyanines initiate photolysis cells by the mechanism of type I formation of singlet oxygen. Phthalocyanines are not widely used in photodynamic therapy, which may be due to their lack of efficiency and difficulties in their synthesis and purification.

It is also known the use of cyanine dyes of the formula

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as photoinitiator photolysis cell. Cyanine dyes have certain advantages in comparison with the previous dyes: they are selective on - cableways in malignant cells and kept them in longer than in healthy cells, due to increased membrane potential of malignant cells. Therefore, cyanine dyes are promising photoinitiators selective photolysis of malignant cells in tumors. For example, merocyanine-540 shown that cyanine dyes are photoinitiator radical-chain oxidation of lipids. The destruction of 90% of malignant cells in their presence usually p is the cure. Of these dyes are the most famous cryptocyanine (R1=R2= C2H5), which inhibits the development of tumors in mice the repetition of the procedure of injection of the dye, followed by irradiation of the tumor. The mechanism of photodynamic action of cryptocyanine is photoinitiator oxidative processes, leading to the accumulation in the cell products that inhibit oxido-reductase that leads to the subsequent slow death of malignant cells [2]

The data show that the effectiveness of the known dyes used for PDT is insufficient. The aim of the invention is to increase the efficiency of the process of destruction of malignant cells in living organisms.

This effect is achieved by using as photoinitiator photolysis of malignant cells in living organisms tidimensional dye of the formula

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The compound of formula (I) is used as a spectral sensitizer silver halide photographic emulsions to spectrum 650-790 nm with a maximum sensitization at 745-750 nm [1]

Get the compound (I) interaction of the Quaternary salt of 2-methyl-3-ethyl-5-methoxy-6-met the Ave ethyl ester p-toluene-sulfonic acids with subsequent condensation of the resulting compounds of the formula

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with the Quaternary salt of 2-methyl-3-ethyl-5-methoxy-6-methylthiotetrazole formula (II) in the presence of triethylamine in an environment of pyridine at boiling or in the environment of dimethylacetamide at a temperature of 150-155o[1]

Compound I (polymethine) available, utilized in industrial production at the pilot plant Kazan "Tasma".

Application polymethine as photoinitiator photolysis of malignant cells in living organisms can significantly improve the efficiency of photolysis at lower doses compared with analogue cryptocyanine. Cells injected with polymethines with its concentrations of 1-4 mg/kg and irradiated with light with wave lengths 660-760 nm to dose 10-130 j/cm2.

The following examples illustrate the invention but do not restrict it.

Example 1. From the abdominal cavity of the mouse syringe is taken 0.1 ml of ascitic fluid containing tumor cells R, bred buffer Hanks solution to a concentration of 1106cells/ml In the resulting cell suspension R add polymethine to the concentration of 510-6mol/l and incubated for 30 min to saturate the cells polymethines. Then 1 ml of cells leave for control in the dark, and another 1 ml of cell irradiation of Idenix of N cells after irradiation was measured by bromide staining by ethidium and fluorescenceactivated. To determine the effectiveness of polymethine towards cryptocyanine perform the same procedure, but instead of polymethine use cryptocyanine. The effectiveness of polymethine E is defined as the value of E=N1/N0where N1and N0the number of damaged cells when used as photoinitiator polymethine and cryptocyanine respectively. Measurement of N1and N0give N1=12% N0=5% E=2,4 (PL.1). Thus, at the dose of 10 j/cm2the effectiveness of polymethine 2.4 times higher than that of cryptocyanine.

Example 2. Perform analogously to example 1, but with the difference that the irradiation dose of 30 j/cm2. Measurement of N1and N0give N1=16% N0=4% E=4,0 (PL.1). Thus, at the dose of 30 j/cm2the effectiveness of polymethine 4 times higher than cryptocyanine.

Example 3. Perform analogously to example 1, but with the difference that the radiation dose is 60 j/cm2. Measurement of N1and N0give N1=21% N0=14% and E=1,5 (PL. 1). This shows that at a dose of 60 j/cm2the effectiveness of polymethine 1.5 times higher than cryptocyanine.

Example 4. From the abdominal cavity of the mouse syringe is taken 0.1 ml of ascitic fluid containing about the suspension of cells L1210 add polymethine to the concentration of 510-6mol/l and incubated for 10-30 min to saturate the cells polymethines. Then 1 ml of cells leave for control in the dark, and another 1 ml of cells irradiated at room temperature by light with wavelengths 660-760 nm to dose of 130 j/cm2. On painting fluorescenceactivated observed damage 100% of the cells and in the control of 5% of the cells.

Example 5. Receipt of L1210 cells with the addition of polymethine and their irradiation performed analogously to example 4 with the difference that the cell suspension is diluted with saline to a concentration of 2107cells/ml, and the training is conducted to a dose of 60 j/cm2. Irradiated cell suspension injected intraperitoneally healthy mice hybrids C57/DBA 0.2 ml of suspension per mouse, and monitor the development in mice lymphoid leukemia L1210. As the death of mice determine the time t100, t60and t40life expectancy 100% 60% and 40% of mice, respectively, from the onset of the disease. All three values of t100, t60and t40exceed 120 days (table.2), indicating complete destruction of L1210 cells in their photolysis in vitro using as photoinitiator polymethine.

Examples 6-10. Perform analogously to example 5, but at other concentrations, F. the data table.2, photolysis in vitro in the presence 510-7mol/l of photoinitiator significantly increases the lifespan of mice, and the effectiveness of the proposed photoinitiator polymethine significantly higher than known photoinitiator of cryptocyanine at lower doses.

Increased the effectiveness of the proposed photoinitiator at lower doses is important for the destruction of deep-lying cells in solid tumors who receive a smaller dose of radiation than cells in the surface layers of the tumor.

Example 11. From the abdominal cavity of the mouse is taken 0.1-0.5 ml of ascitic fluid containing tumor cells R, bred it with a saline solution so that 0.1 ml of the suspension contained 1,5105cells R and injected with 0.1 ml of the resulting suspension mice-hybrids S/TWO subcutaneously in the shoulder area of the forelimb for the development of solid tumors. The average mass growing tumor determine its weighting after opening mice. On the 5th day of tumor development begin conducting photodynamic therapy, which is as follows: mice injected polymethine intraperitoneally at the rate of 1 mg photoinitiator on 1 kg of body weight of the mouse and leave the mice in the dark for 1 day for on the to a dose of 80 j/cm2under General anesthesia for fixing the mouse.

Data on the development of the tumor before and after photodynamic therapy is shown in the drawing.

As follows from the drawing, already a single use of photodynamic therapy with the proposed photoinitiation polymethine stops the growth of solid tumor R mice-hybrids S/TWO. Pathologic-anatomic analysis also shows the complete cessation of sprouting blood vessels in the tumor, indicating a high efficiency of the proposed photoinitiator.

Example 12. Is comparative and is similar to example 11, but without using polymethine. The data obtained is shown in the drawing and show that without the use of polymethine rapid tumor growth, leading to death of the mice.

Polymethine were injected intraperitoneally (1 mg/kg) per day before irradiation with red light. Radiation treatment of the tumor was performed once daily for 40 min under General anesthesia for fixing the mouse. Date procedures in the drawing indicated by the arrow. Point on the 11th day are average (20 mice per point), other individual.

Thus, the proposed photoinitiator polymethine has Radome accumulates in malignant cells and keep them longer than in healthy cells, due to increased membrane potential of malignant cells, which is important for selective photolysis of malignant cells. Polymethine effectively inhibits the growth of solid tumors in mice and destroys the malignant cells in vitro. At lower doses of irradiation efficiency 1.5-4.0 times higher than the efficiency of known photoinitiator of cryptocyanine that it is important for the treatment of deep-lying cells in the tumor. Finally, polymethine is available compound utilized in industrial production.

Application tidimensional dye of the formula

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as photoinitiator process of destruction of malignant cells in living organisms.

 

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