Photosensitizing agents for photodynamic therapy

FIELD: medicine, in particular photosensitizing agents for photodynamic therapy.

SUBSTANCE: invention relates to quaternary phthalocyanines of general formula MPc(CH2X)nCln, wherein Pc is phthalocyanine rest C32H16N8; M is Zn, AlY; n = 6-8; X is Y is Cl, OH, OSO3H, useful as photosensitizing agents in photodynamic therapy having high photoinduced activity in vivo and in vitro.

EFFECT: new class of effective photosensitizing agents useful in treatment of various tumors by photodynamic therapy.

1 dwg, 8 ex

 

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

Photodynamic therapy is based on the use of natural or synthetic photosensitizers (PS), which have trapnest to tumor tissue. When exposed to light of a certain wavelength FS enters the activated state, which initiates the formation of cytotoxic agents, in particular of free radicals and singlet oxygen, causing the destruction of tumor tissue.

Currently in clinical practice using FS belonging to the class of hematoporphyrin, such as Photofrin-2 and Photohem that are used for the treatment of tumors of different surface locations (Van Lier J.Phtalocyanines as sensitizers for PDT of cancer // Photodynamic Therapy of Neoplastic Disease, CRS Press, Boca Raton, FL, 1990, vol.1, pp.279-291). The shortcomings of the Federal Assembly of this class are: absorption at a wavelength of 620-640 nm, which allows you to hit the tumor depth up to 0.5 cm; low absorption intensity at the maximum (the value of extinction ε=3000), the low selectivity of accumulation in the tumor tissue; slow excretion from the body and, consequently, increased skin photosensitivity.

Advantages in some respects have FS on the basis of chlorine, for example, Radachlorin photoditazine. Preparation on the basis of chlorin e6photoditazine with maximum absorption at 662 nm has a higher selectivity of accumulation in the tumor and the penetrating ability of the tissues (Romanko US, Tsyb A.F., Kaplan M.A., etc. the Effect of photodynamic therapy with photodithazine on morpho-functional characteristics of sarcoma M1 // Bulletin of experimental biology and medicine. 2004. T. No. 12. S-665).

Prospective FS are derivatives of phthalocyanine, for example photosense. The Photosens based on sulfonated derivatives of aluminum phthalocyanine has a maximum absorption in the longwave region of the spectrum (λmax=675 nm), high molar extinction coefficient ε (over 100,000), high quantum yield of fluorescence (RF Patent N 2220722. A 61 K 31/409, 2004). This allows for photo-induced necrosis to a depth of up to 1.0 cm, and conduct multiple courses of PDT using a single injection of photosense (Vakulovsky Mrs x, Schoenthal V. Photodynamic therapy and fluorescence diagnosis in patients with skin cancer of the head and neck // proceedings of the 6th Annual Russian Oncology conference. Moscow. 2002. P.44-45).

However, during clinical studies were identified shortcomings photosense: not enough high selectivity of accumulation in tumor cells, longer retention in the tissues and, as a consequence, Velicina phototoxicity skin.

The task of the invention is to increase the effectiveness of treatment of cancer using photodynamic therapy based on the FS, high trapnest to tumor tissue, the absorption in the longwave region of the spectrum (675-700 nm), reduction of side effects by reducing the circulation time in the body and high Pho-conduciveness activity.

To solve this problem as PS for PDT the use of positively charged phthalocyanines cationic quaternionic chloro-tizanidine phthalocyanines with different lateral substituents and the Central metal atoms following General formula:

where PC=phthalocyanine residue C32H16N8,

M=Zn, AlY,

n=6÷8,

Y=Cl, OH, OSO3H, for example:

ZnPcChol8- octakis(2-hydroxyethylaminomethyl)phthalocyanine zinc octaploid;

AlPcChol8- octakis(2-hydroxyethylaminomethyl)phthalocyanine chloramine octaploid;

ZnPcPym8- octakis(pyridiniomethyl)phthalocyanine zinc octaploid;

AlPcPym8- octakis(pyridiniomethyl)phthalocyanine chloramine octaploid;

ZnPcTmed8- octakis(N-(2-(dimethylamino)ethyl)-N,N-dimethylaminomethyl)phthalocyanine zinc octol the reed;

ZnPcThea8- octakis(N,N,N-three(2-hydroxyethyl)ammoniated)phthalocyanine zinc octaploid;

ZnPcPmed8- octakis(N,N-dimethyl-N-(2-trimethylaminoethyl)ammoniated)phthalocyanine zinc actionid octaploid.

The present invention is illustrated by the following examples.

Example 1

To 2.5 g (2.58 mmol) octakis(chloromethyl)phthalocyanine zinc (found, %: Cl 29.05; calculated, %: Cl 29.36), obtained as described in patent No. 844338, 1953, add 5 ml of dimethylformamide and 5 ml of N,N-dimethylaminoethanol. The mixture is stirred for 2 h at 100°C, the precipitation is filtered off, washed with acetone and dried, yielding 3.4 g (78.3%) octakis(N-(2-hydroxyethyl)-N,N-dimethylaminomethyl)phthalocyanine zinc octaploid (ZnPcChol8). The electronic absorption spectrum, λmaxnm (N2O): 679-680. Found, %: C 51.41; H 6.84; N, 13.07; Cl 15.88. Calculated for C72H112AlCl8N16O8Zn, %: 51.50; N, 6.72; N, 13.35; Cl 16.89.

Example 2

Analogously to example 1 from hexachlorodisilane phthalocyanine zinc (found, %: Cl 24.98; calculated for ZnPc(CH2Cl)6, %: Cl at 24.48) get hexacis(N-(2-hydroxyethyl)-N,N-dimethylaminomethyl)phthalocyanine zinc hexachloride (ZnPcChol6). The electronic absorption spectrum, λmaxnm (H2O): 677-679.

Example 3

Heated at boiling mixture of 0.150 mg octakis(chloromethyl)phthalocyanine zinc and 2 ml of pyridine for the of 1 h, the mixture is then filtered, washed with acetone and dried, yielding 0.228 g (87.6%) octakis(pyridiniomethyl)phthalocyanine zinc octaploid (ZnPcPym8). The electronic absorption spectrum, λmaxnm (N2): 679-680.

Example 4

Analogously to example 3 of octakis(chloromethyl)phthalocyanine chloramine get octakis(pyridiniomethyl)phthalocyanine chloramine octaploid (AlPcPym8). The electronic absorption spectrum, λmaxnm (N2): 680. Found, %: C 59.09; N, 4.36; N, 13.49; Cl 18.41. Calculated for C80H64AlCl9N16, %: 60.22; N, 4.04; N, 14.04; Cl 19.99.

Example 5

To 0.50 g (0.51 mmol) octakis(chloromethyl)phthalocyanine zinc add 2 ml of dimethylformamide and 3 ml of N,N,N',N'-tetramethylethylenediamine. After the dissolution of the original phthalocyanine mixture is stirred for 1 h at 100°deposited precipitate was separated, washed with dimethylformamide, acetone and dried, yielding 0.71 g (73%) octakis(N-(2-(dimethylamino)ethyl)-N,N-dimethylaminomethyl)phthalocyanine zinc octaploid (ZnPcTmed8). The electronic absorption spectrum, λmaxnm (N2): 679. Found, %: 55.45; N, 7.68; N 17.09; Cl 15.05. Calculated for C88H152Cl8N24Zn, %: 55.70; N, 8.08; N 17.70; Cl 14.92.

Example 6

A mixture of 0.1 g of the complex obtained in example 5, 5 ml of methanol and 3 ml under the conditions stirred at 40°C for 3 hours the Precipitate was separated, washed with methanol and dried, yielding 0.2 g (75%) octakis(N,N-dimethyl-N-(2-(trimethylammonio)ethyl)ammoniated)phthalocyanine zinc attitide of octaploid (ZnPcPmed 8). The electronic absorption spectrum, λmaxnm (N2O): 680. Found, %: C is the 38.20; N, 5.65; N, 10.75; Cl 9.05. Calculated for C96H176Cl8I8N24Zn, %: C 38.04; N, 5.85; N, 11.08; Cl 9.35.

Example 7

Analogously to example 3 from hexachlorodisilane aluminum phthalocyanine with a degree of substitution approximately equal to six (found, %: Cl 23.27; calculated for BUT3SOAlPc(CH2Cl)6, %: Cl 22.93) get hexacis(pyridiniomethyl)-phthalocyanine hydrosulfate the hexachloride (AlPcPym6). The electronic absorption spectrum, λmaxnm (N2O): 680-682.

Example 8

Analogously to example 1 from hexachlorodisilane aluminum phthalocyanine (found, %: Cl 23.27; calculated for BUT3SOAlPc(CH2Cl)6, %: Cl 22.93) get hexacis(N-(2-hydroxyethyl)-N,N-dimethylaminomethyl)phthalocyanine hydro-sulfasalazine the hexachloride (AlPcChol6). The electronic absorption spectrum, λmaxnm (N2O): 680-682.

The study of photoinduced activity in vitro was carried out on 2 cell lines: epidermoid carcinoma of the hypopharynx person (Ner) and human lung adenocarcinoma (A 549). For cell culture used Wednesday Needle-MEM (Ner, And 549) supplemented with 2 mM L-glucamine and 8-10% fetal calf serum. Cultivation was carried out at 37°C in a humid atmosphere with 5% CO2. To EDI dissipated into the wells of flat-bottomed 96-well microplate ("Costar", USA) in 100 μl of cell suspension at a concentration of 0.5×105cells/ml After 24 hours has brought in well 50 μl of the test compounds in serial dilutions and incubated for 2 hours under standard conditions and then was irradiated with a halogen lamp (500 W through a water filter with a thickness of 5 cm and a broadband filter KS-13 (λ≥640 nm). The power density was 14±2 mW/cm2the exposure time is 13-15 min, the calculated light dose of 10 j/cm2.

After irradiation, the cells were incubated under standard conditions for 24 hours. To assess the cytotoxic activity of the cells were placed in dark conditions for 24 hours. Cell survival was determined by visually estimating using light microscopy morphological changes of cells, and a colorimetric method using the MTT-test.

The level of inhibition of cell growth was calculated by the formula (1):

where IL is the level of inhibition of cell growth in culture,

ODo- the optical density in the experience,

ODto- the optical density in the control.

Biologically significant effect believed inhibition of cell growth in culture for more than 50%. Value IR50and IR90appropriate concentrations of test compound at which there is 50 and 90% inhibition of growth of culture, the upper margin of the Ali as the average of three independent tests.

Substance ZnPcChol8has photoactivity against two of the investigated cell cultures, and values IR50and IR90similar values. Upon irradiation in the presence of the test compound in the incubation medium (incubation time 2 hours) concentration IR50is 0.24±0.08 μm (culture ner 2) and 0.29±0.09 μm (culture And 549), and IR90- 1.31±0.08 μm and 1.30±0.08 μm, respectively.

Derivatives of phthalocyanine zinc ZnPcTmed8, ZnPcThea8and ZnPcPmed8have high photoinduced activity against cell culture Ner: value IR50these compounds was 0.3±0.1 μm, 0.69±0.4 μm and 0.18±0.2 μm, respectively. Dark toxicity FS on the culture of cells in the investigated range of concentrations was not detected.

Specific activity in vivo positively charged FS studied in animals with transplantable tumors. Investigated the fluorescence properties on the ability of FS to accumulate in the tumor, assessing the level of normalized fluorescence (Tn) in the tissues of mice, as well as antitumor photoinduced activity dyes. All FS accumulated in tumor tissue and were destroyed by radiation.

Normalized fluorescence was determined in tissues of mice inoculated subcutaneously in the thigh lymphocytic leukemia P-388. Content ZnPcChol8assessment is ivali fluorescent method for laser diagnostic unit LESA" (LLP "BIOSPEC", Moscow) on the basis of He-Ne laser with wavelength generation 633 nm contact method of ex vivo at different observation period from 5 seconds to 72 hours. The integral intensity of the fluorescence in the range 641-724 nm was normalized to the integrated intensity of a signal is the inverse of diffuse scattering of the exciting laser radiation, thus determined normalized fluorescence (Tn) in the tissue.

ZnPcChol8was injected intravenously at a dose of 1.0 mg/kg during the study was assessed Tn dye and counted the ratio of Tn in the tumor to Tn in the skin and muscle, thereby determining the index of selectivity (Cs) accumulation of PS in the tumor compared with surrounding tissues.

Studies have shown that ZnPcChol8has a maximum fluorescence in the tissues of mice at 696 nm. In muscle, the drug accumulates within 5 minutes, and in tumor tissue P-388 and skin maximum value Tn is achieved after 30 minutes. In the tissues of the body the drug is delayed for 1 hour and then rapidly excreted (see drawing).

A drawing. Normalized fluorescence (Tn) ZnPcChol8in the tissues of mice with tumor P-388.

ZnPcChol8has trapnest to tumor tissue P-388. The maximum value of the indices of selectivity, which is registered in 30 minutes after administration of the drug is 3.3±0.6 (Fn tumor/Tn leather) and 3.9±0.7 (Fn tumor/Tn is ISCA).

The study of specific antitumor activity of substances in vivo were performed on mice hybrids BDF1the females with leukemia P-388 on the 6th-7th day of growth using different doses of the dye and radiation mode. Tumor P-388 were inoculated subcutaneously in the thigh by 0.7×106cells/mouse. FS was injected intravenously at a dose of 1 mg/kg, the interval between the introduction of the FS, and irradiation was 5, 15, 30 and 60 minutes. As the radiation source used unit ATU-1 on the basis of halogen lamps 150 watt fiber optic bundle and filters KC-10 and SES-26 (wavelength - 600-800 nm). The power density (100-300 mW/cm2) was controlled using a power meter IMPRES (NGOs "Plus"), a light dose of 90-270 j/cm2. Before irradiation the wool over the tumor was removed. As the anesthesia was applied 5% solution ketamini at a dose of 2.5 mg/mouse intraperitoneally. The duration of observation of the animals continued to die. As control was used mice-carriers of tumour, not subjected to any impact.

The efficacy of PDT with ZnPcChol8was evaluated by inhibition of tumor growth (SRW) and the increase in life expectancy (UPG), which was calculated by the formulas (2) and (3):

where Vop- tumor volume, equal to d1×d2×d31d2and d3three mutually perpendicular diameters of the tumor, ALE - the average life expectancy in the experimental and control group.

PDT ZnPcChol8led to development of edema with subsequent formation of necrotic scab in the radiation zone, which disappeared after 8-10 days after irradiation. The efficacy of PDT has an effect of light dose. Thus, the dose of light from 90 to 270 j/cm2leads to ascending values of the TRO with ZnPcChol8from 47.1÷75.2% to 93.6÷97.1%.

The dose ZnPcChol8from 0.5 to 1.0 mg/kg also leads to an increase in SRAW from 55.9÷68.6% to 93.6÷97.1% for all the follow-up period (15 days). With further increase of the dose up to 2 mg/kg TRO remains high (85.3-91.2%). Their life expectancy is increased by 38.8% at the dose of 1 mg/kg and 23.1% at the dose of 2 mg/kg

When exposed through different intervals of time Δt 5, 15, 30 and 60 minutes after injection of dye at a dose of 1 mg/kg and light dose equal to 270 j/cm2the healing effect was higher when the Δt 15 and 30 minutes: TRO is 87.8-100% and 95.2-100%, and UPJ - 31.4% and 38.8%, respectively. Increased spacing Δt up to 60 minutes leads to a reduction in the TRO - 73.7-91.2%.

The study of photoinduced activity in vivo in mice with tumor Colo 26 were performed on mice of Balb/c female on the 6th-7th day of tumor growth. Adenocarcinom is in the large intestine of the mouse Colo 26 were inoculated subcutaneously in the thigh by 0.05× 106cells/mouse. Substance ZnPcChol8was injected intravenously at a dose of 1 mg/kg Interval between intravenous FS, and irradiation was 30 minutes. As the radiation source used led source red light with maximum absorption at 685 nm with a regulator of the density of luminous power (25-100 mW/cm2); light dose of 90 j/cm2. Before irradiation the wool over the tumor was removed. Anesthesia was applied 5% solution ketamini at a dose of 2.5 mg/mouse intraperitoneally. As control was used mouse-carriers of tumour, not subjected to any impact. The efficacy of PDT with ZnPcChol8was evaluated according to the criterion of cure (CI), which was calculated by the formula (4).

where Nand- the number of treated animals,

Nototal number of animals in the experimental group.

PDT ZnPcChol8(the dose of 1.0 mg/kg) leads to complete tumor resorption Colo 26 (Kand=100%), regardless of the irradiation conditions - 100, 50 and 25 mW/cm2, 90 j/cm2that Δt 30 minutes.

Proposed in the present invention the compound is positively charged phthalocyanines with different lateral substituents and the Central metal atoms have high opuholevidnoe have a high photo-induced activity in vitro and in vivo and represent a new class effect is different photosensitizers, which can be used for treatment by PDT of tumors of various localizations.

Quaternion phthalocyanines of General formula

Mrs(CH2X)nCln,

where PC is the phthalocyanine residue With32H16N8,

M - Zn, AlY,

n=6÷8,

Y - Cl, HE, OSO3N

as photosensitizers for photodynamic therapy.



 

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