Photosensibilizing agent, liposomal formulation of photosensibilizing agent and method for carrying out photodynamic therapy

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a photosensibilizing compound representing phenylthio-substituted derivative of phthalocyanine of the general formula (I): wherein R means hydrogen atom (H), t-C4H9; M means HH, AlOH, Zn. Also, invention relates to its liposomal formulation representing the composition of mixture of lipids (lecithin, cholesterol, cardiolipin) and a photosensibilizing agent, and to a method for carrying out the photodynamic therapy using this formulation. Photosensibilizing agents show high elimination rate from normal tissues, provide the deep therapeutic effect on tumor tissues, non-toxic properties and perspective for their using in oncology and other branches of medicine.

EFFECT: valuable medicinal properties of compound.

4 cl, 3 dwg, 9 ex

 

The present invention relates to medicine, and more specifically to the photosensitizers for photodynamic therapy (PDT) of tumors and other diseases, drug forms-based photosensitizers and methods of photodynamic therapy.

Photodynamic therapy is based on the use of drugs, photosensitizers, which when introduced into the body accumulate predominantly in the tumor. At the next light, for example laser, irradiation of pathological part of its molecules catalyze the formation of cytotoxic agents, in particular singlet oxygen that destroys the tumor cells.

The disadvantage commonly used in clinical practice photosensitizers based on derivatives of hematoporphyrin (R. Bonnett. Photosensitizers of the porphyrin and phthalocyanine series for photodynamic therapy. Chem. Soc. Rev., 24(1), 19-33, 1995) is the low intensity of the absorption in the long wavelength band (625-640 nm), which is a photoexcitation of the sensitizer. At the same time, the self absorption of biological tissue in this spectral region significantly. This leads to the small penetration depth of the radiation in the tissue, leading to significant losses outside of the tumor and complicates the treatment of tumors of large size. In addition, this leads to the need to use large doses of photosensitizer and t is repetitsionnogo radiation, that in turn causes significant side effects.

Photosensitizers based chlorines (dihydroporphyrin) have a more intense long-wavelength absorption band shifted to the red compared with porphyrins. Among them should be mentioned water-soluble mono-L-especillay e6I(drugs NPe6, MACE) and other various forms of chlorin e6metal complexes of purpurin, absorbing in the region of 660 nm, and synthetic chlorins - 5,10,15,20-tetrakis(m-hydroxyphenyl)chlorin (drugs], m-CNRS, foscan) and derivatives benzoporphyrin (benzoporphyrin monocerata, ring (A) with maximum absorption at 690 nm. Lateley complex texaphyrin soluble in water and has a maximum absorption of more than 730 nm (R. Bonnett, see above). However, these compounds generally are too complex and expensive technology or absorb in the region of intrinsic absorption of biological tissue, or extinction coefficient is low.

Some of these drawbacks are absent in photosensitizer based on sulfonated phthalocyanine hydroxylamine ("photosense")absorbing at 675 nm with an extinction coefficient greater than 105l·mol-1·cm-1(Eaaaat. New sensitizers for photodynamic therapy. Ross. chem. journal, 42(5), 9-16, 1998). Absorption nests bilibiran tissues in this area 3-4 times lower than in the area 625-640 nm, which allows to increase the depth of the photodynamic treatment. In the method of PDT using this photosensitizer it is introduced into the body in an aqueous solution. "Photosense" and the way of PDT with its use are the closest analogues proposed in this application of photosensitizers and method of PDT. However, in the field of absorption "Photosense" the self absorption desensibilisation tissue remains significant, which leads to a significant loss of energy therapeutic radiation and does not allow PDT deep layers of tumors.

It is known that the self absorption of the fabric is reduced to the minimum values only at wavelengths greater than 700 nm. Therefore, for effective PDT photosensitizers must have a maximum absorption in the field next 700 nm.

In the present invention solves the problem of increasing the efficiency of PDT deep tumor tissue through the creation and use of photosensitizers for PDT with intense absorption in the spectral region with wavelengths over 700 nm. This task is solved by the fact that as a photosensitizer for photodynamic therapy offers penaltypoints phthalocyanine General formula

where R=H, t-C4H9; M=NN, AlOH, Zn.

The specified weight is and decided by the that offers a liposomal form of the photosensitizer, which is the composition of a mixture of lipids (lecithin, cholesterol, cardiolipin), a photosensitizer according to claim 1.

This task is solved in that in the method of photodynamic therapy using liposomal form of the photosensitizer according to claim 2.

The presence in positions 3 benzene rings of the macrocycle of paneltop significantly shifts the long-wavelength absorption band corresponding phthalocyanines in the red region compared to their unsubstituted and tert-butyl-substituted analogues. This allows the use of these compounds as photosensitizers that are sensitive in the near IR region of the spectrum.

The invention is illustrated figure 1-3.

Figure 1 shows absorption spectra penaltypoints phthalocyanine in biological tissue:

1-Tetra-3-phenyldiethanolamine zinc,

2-Tetra-3-phenyldiethanolamine hydroxylamine,

3-bezmetallny Tetra-3-phenylthio-Tetra-3-tert-butyl-phthalocyanine.

Figure 2 shows the dependence of average group volume of tumors Ehrlich F1 mice after photodynamic therapy with liposomal Tetra-3-phenyldiethanolamine hydroxylamine:

1 - control group 2 - group after PDT.

Figure 3 shows the dependence of the average group volume of tumors Ehrlich F1 mice after PDT the liposomal Bezmaternykh Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine:

1 - control group 2 - group after PDT.

Synthesis fenitization phthalocyanines effected on the basis of 3-phenylthiohydantoin (Derkacheva V.M., E.A. Lukyanets GOH, 50(10), 2313-2318, 1980) or 3-phenylthio-5-tert-butylphthalocyanine (Dolotov O.V., Bundeena NI, Derkacheva V.M., Negrimovskii V.M., Minin CENTURIES, Larin G.M., Potassium O.L., E.A. Lukyanets GOH, 62(9), 2064-2075, 1992). The interaction of these phthalodinitrile with salts of the respective metals were obtained metal complexes, and for the synthesis of Bezmaternykh phthalocyanine was used demeterova in the acidic environment of the lithium complexes obtained in turn by heating phthalodinitrile with the lithium alcoholate solution dimethylaminoethanol.

Liposomal form penaltypoints phthalocyanines produced by the method of Bergama (Bangham) (Liposomes: a practical approach, in D. Rickwood and B.D. Hames (eds.) Practical Approach Series, Oil Press at Oxford University Press, Oxford, 1990; Preparation of liposomes, in G.Gregoriadis (ed.), Liposome technology, Vol.1, CRC Press, Boca Raton, FL, 1984), redispersible aqueous solution of sucrose thin homogeneous film of lecithin multilayer liposomes (MSL), formed by evaporation in vacuum on a rotary evaporator solution of a mixture of lipids and fenitization phthalocyanine in chloroform. The mixture of lipids include lecithin, cholesterol and cardiolipin in a molar ratio of 12:6:(0,1-1), the mixture of lipids: phenylthiomethyl f is alaziani" was (14-16):1. Reducing the size of liposomes was carried out by ultrasonic sonically and extrusion.

The following examples illustrate the present invention.

Example 1. Bezmetallny Tetra-3-phenyldiethanolamine. To a solution of dimethylaminoethyl lithium obtained from 0.012 g (1.71 mmol) of lithium in 2.5 ml of dimethylaminoethanol add 1.01 g (4.3 mmol) of 3-phenylthiohydantoin. The mixture is boiled for 8 hours, then cooled and diluted with 100 ml of methanol. After the usual cleaning and drying the precipitate obtain 0.69 g (68%) besmearing Tetra-3-phenyldiethanolamine. Found, %: C 71.09; N, 3.71; N, 12.02; S 13.51. C56H34N8S4. Calculated, %: C 71.01; N, 3.62; N, 11.83; S 13.54. λmaxnm (lg ε) in trichlorobenzene: 740 (5.09), 712 (5.04), 674 (4.50), 641 (4.45), ˜435 (4.28), ˜400 (4.41), 336 (4.85).

Example 2. Bezmetallny Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine. To a solution of dimethylaminoethyl lithium obtained from 0.017 g (2.43 mmol) of lithium in 4.5 ml of dimethylaminoethanol add 1.81 g (6.2 mmol) of 3-phenylthio-5-tert-butylphthalocyanine. The mixture is boiled for 7 hours, then cool and add 25 ml of 4% hydrochloric acid, after the usual purification of the reaction product chromatografic on SiO2(eluent is a mixture of benzene: hexane 1:1). After evaporation of the solvent and drying obtain 0.86 g (47%) besmearing Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine. Found,%: C 73.66; H 5.60; N, 9.30; S at 10.82. C72H N8S4. Calculated, %: C 73.81; H 5.68; N, 9.56; S 10.95. λmaxnm (lg ε) in chloroform: 746 (5.18), 717 (5.16), 681 (4.68), 648 (4.59), ˜450, ˜375, 337 (4.94).

Example 3. Tetra-3-phenyldiethanolamine zinc. A mixture of 0.24 g (1 mmol) 3-phenylthiohydantoin, 0.18 g (3 mmol) of urea, 0.06 g (0.27 mmol) of zinc acetate dihydrate, 0.28 g of sodium sulfate and a catalytic amount of ammonium molybdate are heated 1 h at 180-185°C. After the usual cleaning and drying of the reaction product obtain 0.14 g (55%) of Tetra-3-phenyldiethanolamine zinc. Found, %: C 66.58; N, 3.19; N, 11.30; S 12.78. C56H32N8S4Zn. Calculated, %: C 66.56; N, 3.19; N, 11.09; S 12.69. λmaxnm (lg ε) in 1% solution of pyridine in trichlorobenzene: 715 (5.17), 688 square (4.44), 640 (4.41), 435 (4.16), 390 (4.32), 337 (4.63).

Example 4. Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine zinc. Carefully pounded mixture of 0.29 g (1 mmol) 3-phenylthio-5-tert-butylphthalocyanine, 0.06 g (0.33 mmol) of anhydrous zinc acetate, 0.06 g (1 mmol) of dry urea and a catalytic amount of ammonium molybdate are heated 45 minutes at 200-210°C and 45 min at 220-230°C. After chromatography was carried out on Al2About3a mixture of benzene and chloroform (1:1), and then 1% pyridine in benzene obtain 0.14 g (45%) of Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine zinc. Found, %: C 70.31; N, 5.21; N, 9.09; S 10.27. C72H64N8S4Zn. Calculated, %: C 70.02; N, 5.22; N, 9.07; S 10.38. λmax nm (lg ε) in chloroform: 721 (5.35), 647 (4.64), ˜440 square, 341 (4.89).

Example 5. Tetra-3-phenyldiethanolamine hydroxylamine. Carefully pounded mixture of 1.88 g (8 mmol) of 3-phenylthiohydantoin, 0.34 g (2.6 mmol) of aluminum chloride, 0.5 g (8 mmol) of dry urea and a catalytic amount of ammonium molybdate are heated for 50 min from 160 to 225°C, then incubated for 40 min at 225-230°C. After chromatography was carried out on Al2About3first, benzene, and then a mixture of chloroform obtain 1.32 g (66%) of Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine hydroxylamine. Found, %: C 67.77; N, 3.14; N, 11.29; S 12.86. C56H33AlN8OS4. Calculated, %: From 68.00; N, 3.36; N, 11.33; S 12.97. λmaxnm (lg ε) in chloroform: 736 (5.32), 657 (4.36), ˜460, 340 (4.68).

Example 6. Liposomal form Tetra-3-phenyldiethanolamine hydroxylamine.

Sample of lecithin (0.65 g) and cholesterol (0.15 g) are combined and dissolved in 5 ml of chloroform. To the solution was added 2.7 ml of 0.5% ethanolic solution of cardiolipin. Then the solution is transferred into a round bottom flask and to it was added a solution of 0.007 g of Tetra-3-phenyldiethanolamine hydroxylamine in 5 ml of chloroform. The flask contents are stirred and evaporated on a rotary evaporator at 20-25°until a homogeneous lipid film. Then in the flask add 10 ml of water for injection and shaken in an ultrasonic in the mn to the total obliteration of the film from the walls of the flask and education liposomal emulsion. The size of the resulting liposomes, measured on the device Submicron Particle Sizer NICOMP-380, was 450±50 nm.

Example 7. Liposomal form besmearing Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine.

Sample of lecithin (0.63 g) and cholesterol (0.12 g) are combined and dissolved in 5 ml of chloroform. To the solution was added 2.7 ml of 0.5% ethanolic solution of cardiolipin. Then the solution is transferred into a round bottom flask and to it add a solution of 0.005 g besmearing Tetra-3-phenylthio-Tetra-5-tert-butylphthalocyanine in 5 ml of chloroform. The flask contents are stirred and evaporated on a rotary evaporator at 20-25°until a homogeneous lipid film. Then in the flask add 10 ml of water for injections and shaken in an ultrasonic bath until complete obliteration of the film from the walls of the flask and education liposomal emulsion. The size of the resulting liposomes, measured on the device Submicron Particle Sizer NICOMP, was 230±150 nm.

Below are examples of the proposed method of photodynamic therapy.

Example 8. Group F1 mice with Ehrlich tumor (ELD) was injected into the tail vein of liposomal form of Tetra-3-phenyldiethanolamine hydroxylamine (example 6) at a dose of 4 mg/kg weight of the animal. The second group of mice of the control.

After injection of the photosensitizer in the tumor is irradiated by radiation from the lamp light source with a wavelength of 725 nm, tightly the grassroots power of 300 mW/cm 2and dose density of 350 j/cm2. One day after irradiation in tumor formed necrosis. This group identified therapeutic effect compared with the control and inhibition of tumor growth is more than 80% (figure 2).

Example 9. The group of BDF1 mice with a solid form of leukemia R injected into the tail vein of liposomal form besmearing Tetra-phenylthio-Tetra-5-tert-butylphthalocyanine (example 7) in a dose of 4 mg/kg weight of the animal, the second group of mice of the control.

After injection of the photosensitizer in the tumor of mice of the first group irradiated with radiation from the lamp light source with a wavelength of 730 nm, power density of 300 mW/cm2and dose density of 350 j/cm2. One day after irradiation in tumors formed necrosis. When comparing treated groups with the control revealed inhibition of tumor growth by more than 90% (figure 3), in some cases, there was complete destruction of the tumor.

The proposed photosensitizers provide a deep therapeutic effect on the tumor, have a high rate of excretion of normal tissues, non-toxic and are promising for applications in Oncology and other areas of medicine.

1. The photosensitizer, representing fenitization phthalocyanine derivative of General formula:

where R=H, t-C4H 9; M=NN, AlOH, Zn.

2. Liposomal form of the photosensitizer, which is the composition of a mixture of lipids (lecithin, cholesterol, cardiolipin), a photosensitizer according to claim 1.

3. The method of photodynamic therapy using a photosensitizer based on phthalocyanine derivatives, characterized in that the use of liposomal form of the photosensitizer according to claim 2.



 

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