RU2290150C2 - Photodynamic therapy method for treating intraocular neoplasm cases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: method involves carrying out transpupillary irradiation of melanoma with low intensity laser radiation of wavelength 633 nm at a dose of 2.5 J or wavelength of 890 nm at a dose of 1.2 J. Photosensitizer of chlorine row is intravenously injected in water-soluble pharmaceutical dosage form at a dose of (0.8-1.1 mg/kgx0.7) during 10 min. 1 h later after having introduced the photosensitizer, spectral fluorescent diagnosis is carried out. Melanoma fluorescence being detected on the background of surrounding tissues, The same photosensitizer is intravenously introduced in liposomal form as bolus injection at a dose of (0.8-1.1 mg/kgx0.3). Tumor edge is transpupillary irradiated allover its perimeter field-by-field with laser at 670 nm wavelength with power density equal to 60-80 J/cm² with neighboring fields overlapping by 5% of area, 10-15 min later after the injection. Then, the whole neoplasm surface is exposed to laser radiation of wavelength 662 nm and power density equal to 100-120 J/cm² with neighboring fields overlapping by 5% of area. Irradiation is carried out moving in circle from periphery to the center.

EFFECT: dosed treatment sessions; making blood vessel feeding the tumor empty; enhanced effectiveness in killing tumor cells and stopping tumor growth; reduced recurrence risk.

Description

The invention relates to medicine, and more specifically to ophthalmology, and can be used to treat small-sized intraocular neoplasms (according to the classification of J. Sields, 1983).

A known method of photodynamic therapy of intraocular neoplasms (Barbazetto IA, Lee TC, Rolling IS, Chang S, Abramson DH. Treatment of choroidal melanoma using photodynamic therapy. Am J Ophthalmol. - 2003. - Vol.135. - No.6. - P. 898-899), including intravenous administration of a photosensitizer and transpupillary laser irradiation of the neoplasm. However, when using this method in half the cases it is not possible to stop the growth of the intraocular neoplasm. Photodynamic therapy in this method is ineffective and not optimized in the area of exposure, power and time of exposure, requires multiple repeated sessions.

The objective of the invention is to increase the effectiveness of photodynamic therapy in the treatment of intraocular neoplasms.

The technical result is the dosed holding of treatment sessions, the launching of vessels supplying the tumor, the death of tumor cells, complete arrest of tumor growth, and a reduction in the risk of relapse. The technical result is achieved due to the fact that:

1) transpupillary irradiation of an intraocular neoplasm with low-intensity laser radiation prior to intravenous administration of FS improves blood microcirculation in the irradiated area, which leads to a more intense accumulation of PS in the tumor tissue;

2) the chlorine-type photosensitizers (PSs) used are characterized by a high degree of purity, low toxicity, tropism for cells with high mitotic activity, are able to accumulate in tumor cells, and even in small doses exhibit high photochemical activity under laser irradiation;

3) enter the FS of the chlorin series in a water-soluble form; this form has a higher tropism for tumor cells;

4) inject FS of the chlorin series in liposome form; the use of a liposome dosage form provides a high contrast accumulation of the photosensitizer in the tumor-feeding choroidal and retinal vessels due to the mechanism of passive targeting of liposomes;

5) the sequence of administration of water-soluble and liposome forms of PS and the time intervals between the introduction of PS and SFD and the introduction of PS and laser irradiation are necessary and sufficient for the accumulation of PS in tumor cells and vessels supplying the tumor, respectively;

6) spectral-fluorescence diagnostics can be used to determine whether the accumulation of the photosensitizer in the tumor tissue, sufficient and necessary for the therapeutic effect, has occurred in comparison with the surrounding tissue;

7) the following, after the intravenous administration of FS and spectral fluorescence diagnostics, transpupillary irradiation of the tumor edge along its entire perimeter with laser radiation with specified parameters causes blood stasis and light-induced thrombosis of blood vessels supplying the neoplasm, excludes dissemination and migration of tumor cells;

8) transpupillary irradiation of the entire neoplasm surface in a circle from the periphery to the center with laser radiation with specified parameters causes the death of tumor cells to a depth of about 3 mm, and also eliminates the dissemination and migration of tumor cells;

9) irradiation during PDT with laser fields with overlapping adjacent fields over 5% of the area ensures uniform exposure;

10) the used ranges of the dose of the FS and the parameters of laser irradiation are necessary and sufficient for the implementation of the photoinduced photochemical reaction to obtain the therapeutic effect necessary to achieve the specified technical result.

The claimed technical result can be obtained only by using the totality of the techniques of the proposed method.

The method is as follows.

Carry out transpupillary irradiation of the intraocular neoplasm with low-intensity laser radiation with a wavelength of 633 nm at a dose of 2.5 J or with a wavelength of 890 nm at a dose of 1.2 J. Then a chlorine-type photosensitizer is introduced intravenously in a water-soluble dosage form, for example, photolon, radachlorin, photoditazine, in a dose calculated (0.8-1.1 mg / kg × 0.7) for 10 minutes. 1 hour after the end of the intravenous administration of FS, spectral-fluorescence diagnostics of the accumulation of FS in the neoplasm is carried out. In the course of spectral-fluorescence diagnostics, the contrast of PS accumulation in the intraocular neoplasm is monitored, and when fluorescence of the neoplasm appears compared to the surrounding tissue, chlorine-type PS in liposome form is injected bolus, for example, it may be E6 trisodium salt (photolon), or photosensitizer including the alkaline salt of 13-carboxy-17- [2-carboxyethyl] -15-carboxymethyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin (chlorin e6) amount of 80-90%, alkaline salt of 13-carboxy-17- [2-carb hydroxyethyl] -15-formyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin (purpurine 5) in an amount of 5-20%, as well as an alkaline salt of 13-carboxy -17- [2-carboxyethyl] -15-carboxy-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethylporphyrin (chlorin p6) in the amount of the rest (radachlorin), or bis-N-methylglucamonic salt of chlorin e6 (photoditazine), at a dose of 0.8-1.1 mg / kg × 0.3) and 10-15 minutes after the end of administration, the edge of the tumor is transpillary around its entire perimeter laser radiation fields with a wavelength of 670 nm at an energy density of 60-80 J / cm ² with overlapping neighboring fields on 5% of the area. The wavelength of 670 nm corresponds to the maximum absorption of light radiation of the FS of the chlorine series in the liposome form, which was established by spectrophotometry. Then, the entire neoplasm surface is transpupillary irradiated with laser fields with a wavelength of 662 nm at an energy density of 100-120 J / cm ² with overlapping adjacent fields over 5% of the area, and the irradiation is carried out in a circle from the periphery to the center. The wavelength of 662 nm corresponds to the maximum absorption of light radiation of the FS of the chlorine series in a water-soluble form.

The patient in the water-soluble and liposomal form is given the same photosensitizer, with 70% of the total dose of PS being administered in the water-soluble form, and 30% in the liposome form.

All actions with the photosensitizer are carried out in a dark environment, ensuring the inability to penetrate into the room in direct sunlight. This condition is well known and standard for PDT sessions.

The liposome form of the FS of the chlorin series is obtained, for example, as follows. In a round bottom flask, 50 mg of egg phosphatidylcholine (SFC) and 7.5 mg of cholesterol (Chol) are mixed, 5 ml of chloroform are added, purged with argon or another inert gas, evaporated to constant weight on a rotary evaporator. Then dried for 10 hours in a vacuum oil pump. To weigh. A FS solution (5 mg / ml) is added to the lipid film in the flask, shaken so that all lipids are dispersed (if necessary, voiced in an ultrasound bath), frozen in liquid nitrogen, thawed at 40-60 ° C. They are pressed successively through filters with pores of 400 nm, 200 nm, 100 nm by 19 times. Put on a column with Sepharose CL-4B, 2 fractions are distinguished: a free volume fraction containing liposomes with an incorporated FS and a fraction of an unincorporated FS. If necessary, the liposomal PS fraction is concentrated (for example, by ultrafiltration).

The invention is illustrated by the following examples.

Example 1. Patient G., 74 years old. As a result of a comprehensive ophthalmologic examination in the CF of the State Institution MNTK "MG", the choroid melanoma (MX) of the right eye was diagnosed.

Ophthalmoscopically on the fundus, peripapillary to the upper nasal side of the optic nerve disc (optic nerve disc) was determined to be irregular in shape, with fuzzy borders, a gray-yellow colored focus that promoted into the vitreous. On the fluorescence fundus angiogram in the area of the formation, characteristic heterogeneous (“spotted”) hyperfluorescence was observed, which confirmed the diagnosis (MX). Ultrasound examination (seroscale B-scan) made it possible to clarify the size of the neoplasm: base diameter - 8 by 10 mm; thickness at the top of the tumor is 3 mm.

The patient is treated according to the proposed method.

Carried out transpupillary irradiation of the intraocular neoplasm with low-intensity laser radiation with a wavelength of 890 nm in a dose of 1.2 J. Then photolon was administered intravenously at a dose of (0.8 mg / kg × 0.7) for 10 minutes. 1 hour after the end of the intravenous administration of FS, spectral-fluorescence diagnostics of the accumulation of FS in the neoplasm was performed. When fluorescence of the neoplasm appeared compared with the surrounding tissue, the trisodium salt of chlorin E6 (photolone) was administered intravenously bolus at a dose of 0.8 mg / kg × 0.3, and 10 minutes after the end of administration, the edge of the tumor was transpillary irradiated along its entire perimeter laser radiation fields with a wavelength of 670 nm at an energy density of 80 J / cm with overlapping adjacent fields on 5% of the area. Then the entire neoplasm surface was transpupillary irradiated with laser fields with a wavelength of 662 nm at an energy density of 120 J / cm ² with overlapping neighboring fields over 5% of the area, and irradiation was carried out in a circle from the periphery to the center.

During the control ultrasound B-scan after 3 months, a regression of the neoplasm was noted, with a decrease in the tumor prominence to 2 mm, and in the period of 6 months to 1.5 mm. In the observation period of up to 1.5 years, a further flattening of the chorioretinal scar was noted both ophthalmoscopically and according to B-scan data. At the indicated time, no signs of relapse of the neoplasm and metastasis were found.

Example 2

Patient C., 59 years old. He was examined in the Kaluga branch of the State Scientific and Technical Center "Eye Microsurgery" with a diagnosis of Initial age-related cataracts of both eyes. Suspected presence of an intraocular neoplasm (choroid melanoma (MX)) of the left eye.

On admission, visual acuity on the affected eye was 0.1 n / k. The neoplasm was localized in the equatorial region, in the lower temporal quadrant. The dimensions of MX, according to the data of ultrasonic B-scanning, were: the width of the base - 12 mm, the length - 14 mm with the size of the prominence - 5 mm at the top of the tumor.

The patient is treated according to the proposed method.

Carried out transpupillary irradiation of the intraocular neoplasm with low-intensity laser radiation with a wavelength of 633 nm at a dose of 2.5 J. Then photoditazine was administered intravenously at a dose of 1.1 mg / kg × 0.7 for 10 minutes. 1 hour after the end of the intravenous administration of FS, spectral-fluorescence diagnostics of the accumulation of FS in the neoplasm was performed. When fluorescence of the neoplasm appeared compared with the surrounding tissue, the bis-N-methylglucamon salt of chlorin e6 (photoditazine) was administered intravenously bolus at a dose of (1.1 mg / kg × 0.3) and 15 minutes after the end of the administration, the edge of the tumor was irradiated around its perimeter, laser radiation fields with a wavelength of 670 nm at an energy density of 60 J / cm ² with overlapping neighboring fields by 5% of the area. Then, the entire neoplasm surface was transpupillary irradiated by laser fields with a wavelength of 662 nm at an energy density of 100 J / cm ² with overlapping neighboring fields over 5% of the area, and irradiation was carried out in a circle from the periphery to the center.

At the control examination after 3 months, visual acuity in the operated eye was 0.12. When examining the fundus in the area of a remote neoplasm, an extensive atrophic chorioretinal lesion with rough pigmentation was determined. There were no signs of relapse of MX within 1 year.

According to the proposed method, 11 patients were treated. In all cases, the claimed technical result was achieved.

Thus, the inventive method provides a dosed conduct of treatment sessions, the launching of vessels supplying the tumor, the death of tumor cells, the complete arrest of tumor growth.

Claims (1)

A method for the photodynamic treatment of choroid melanoma, including intravenous administration of a photosensitizer (PS) and transpupillary laser irradiation of a neoplasm, characterized in that they first carry out transpillary irradiation of the neoplasm with low-intensity laser radiation with a wavelength of 633 nm at a dose of 2.5 J or with a wavelength of 890 nm in a dose 1.2 J, and as a PS, chlorine-type PS is administered intravenously in a water-soluble dosage form at a dose of (0.8-1.1 mg / kg × 0.7) for 10 minutes, 1 hour after the end of PS administration spending spectral fluorescence diagnostics (SFD) of PS accumulation in an intraocular neoplasm and when neoplasm fluorescence appears compared to the surrounding tissue, the same FS in liposome form is administered intravenously in a dose of (0.8-1.1 mg / kg × 0, 3) and 10-15 minutes after the end of administration, the edge of the tumor is transpillary irradiated along its entire perimeter with laser radiation with fields with a wavelength of 670 nm at an energy density of 60-80 J / cm ² with overlapping neighboring fields over 5% of the area, then the entire converting surface mations laser radiation fields with a wavelength of 662 nm at an energy density of 100-120 J / cm ² with an overlap of adjacent fields at 5% of the area, the irradiation is carried out in a circle from the periphery toward the center.