JP2014177421A - Sensitizer for proton beam therapy and proton beam therapeutic method using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sensitizer for proton beam therapy capable of dramatically improving a killing effect on a malignant tumor and a cancer curative ratio due to proton beam therapeutic methods, and a new proton beam therapeutic method using the radiosensitizer.SOLUTION: A substance containing a fluorinated porphyrinoid binding a boron compound or a metal complex thereof is employed as a sensitizer for proton beam therapy and also a proton beam therapeutic method is employed in which this radiosensitizer is administered to a mammal and then a tumor tissue with accumulated radiosensitizer is irradiated with proton beam.

Description

  The present invention relates to a proton beam sensitizer capable of improving the killing effect of a malignant tumor (cancer cell) by proton beam therapy, which is a kind of radiation therapy, and a novel proton beam therapy method using the radiosensitizer. Is.

  In recent years, as a treatment for malignant tumors, research on radiation therapy, which has a smaller burden on the body than surgery and anticancer chemotherapy, has been promoted. Among them, proton therapy, which irradiates malignant tumors with hydrogen nuclei (protons) accelerated by a particle accelerator, is considered promising as a treatment with fewer side effects because normal cells receive less damage than X-ray irradiation. ing.

  By the way, in the field of PDT (photodynamic therapy) in which treatment is performed by irradiating with visible laser light, light having a predetermined wavelength (630 to 670 nm) is accumulated in the tumor tissue and accumulated in the tumor tissue. Photosensitizers (porphyrin compounds, chlorin compounds, etc.) that have the effect of killing tumor cells by photochemical reaction when receiving a red laser) have been used.

  In addition, in the past, sensitizers that are effective not only for PDT but also effective for BNCT (boron neutron supplementation therapy) in which treatment is performed by irradiating neutrons have been found. A patent application was filed after confirming the effectiveness of a fluorinated porphyrin to which a cage-like borane compound was bound (see Patent Document 1) (Japanese Patent Application No. 2012-98918).

  However, in the field of proton beam therapy, the improvement of the proton beam therapy apparatus that enhances the therapeutic effect is progressing (see, for example, Patent Documents 2 and 3). Although attempts have been made to use various drugs in combination at universities, medical institutions, research institutions, etc. in Japan and overseas, there have not yet been reports of substances exhibiting remarkable antitumor effects.

  In recent years, the introduction of proton beam therapy equipment has been energetically promoted in Japan, but there is also a problem that the therapeutic effect is not as good as that of carbon beam irradiation with high energy of particle beam. . Of course, although proton beam irradiation is more advantageous in terms of apparatus cost and running cost, further improvement in the therapeutic effect is demanded.

RU2402554 Japanese Patent Laid-Open No. 10-71213 Japanese Patent Laid-Open No. 11-299906

  The present invention has been made in the above technical background, and the object thereof is a sensitizer for proton beam treatment capable of dramatically improving cancer cure rate by proton beam therapy, It is another object of the present invention to provide a novel proton beam therapy that can significantly improve the killing effect of malignant tumors by using the radiosensitizer.

  Means employed by the present inventor for solving the above-described problems will be described with reference to the accompanying drawings.

  That is, the present invention is characterized in that a substance containing a fluorinated porphyrinoid bound with a boron compound or a metal complex thereof is used as a sensitizer for proton beam treatment administered before proton irradiation to a tumor tissue. There is. The “polyphyllinoid” referred to here includes porphyrin, chlorin, phthalocyanine, corol and the like.

  In addition, it is desirable in terms of therapeutic effect to use a substance having 40 or more boron atoms in one molecule as the sensitizer. In that case, a substance containing a porphyrinoid or a metal complex thereof bound with a cage-like borane compound can be preferably used. For the same reason, a substance having 40 or more hydrogen atoms in one molecule and a substance having 16 fluorine atoms in one molecule should be used as the sensitizer. Is desirable.

Furthermore, if the sensitizer is further specified, it is desirable to use a substance containing a fluorinated porphyrin represented by the following chemical formula or a metal complex thereof.

(M and R in the structural formula on the left side take any combination of [a] to [h] on the right side.)

Further, among substances represented by the above chemical formula, it is desirable to use a substance containing a fluorinated porphyrin represented by the following chemical formula.

(M and R in the structural formula on the left take the combination of [c] on the right.)

  On the other hand, the radiosensitizer can be used in a method for treating a mammal affected by a malignant tumor, and in that case, radiation containing a fluorinated porphyrinoid or a metal complex bound with a boron compound. After the sensitizer is administered to the mammal, treatment is performed by irradiating the tumor tissue in which the radiosensitizer has been accumulated with a proton beam.

  Furthermore, in order to further improve the effect of the proton beam treatment, the tumor tissue in which the radiosensitizer is accumulated is irradiated with a visible laser beam having a wavelength of 630 to 675 nm simultaneously with the proton beam irradiation, and PDT is used in combination. You can also.

  In the present invention, prior to proton beam irradiation, when a substance into which a fluorine atom and a boron atom have been introduced is administered as a sensitizer to a porphyrin derivative that has already been recognized to accumulate tumors, the antitumor effect due to proton beam irradiation is remarkable. It was found to increase. Although the sensitization mechanism has not been elucidated at the present time, it is considered that one of the factors is that Auger electrons generated during proton beam irradiation increase by administration of the sensitizer.

  Moreover, since the irradiation amount of the proton beam at the time of treatment can be reduced by the administration of the sensitizer, the exposure risk and the damage to the normal tissue in the proton beam treatment can be minimized. In addition, it has been confirmed that the therapeutic effect is further improved by using PDT together, and therefore, the development of a new treatment method combining other radiation therapy can be expected.

  As described above, the use of the sensitizer for proton beam treatment of the present invention not only can improve the therapeutic effect of malignant tumors, but also reduces the dose (number of times) of proton beams required for treatment than before. Therefore, the physical and economic burden on the patient can be reduced, and the practical utility value of the present invention in the medical field is very high.

It is a graph which shows the change of the tumor size obtained by the demonstration test [1] of the therapeutic effect. It is a graph which shows the change of the tumor size obtained by the verification test [2] of the therapeutic effect.

  Next, specific embodiments and preferable conditions for carrying out the present invention will be described.

[Sensitizer for proton therapy]
First, in the present invention, a drug containing a porphyrinoid or a metal complex thereof bound with a boron compound is used as a radiosensitizer for proton beam therapy. The porphyrinoids include porphyrin, chlorin, phthalocyanine, corol and the like, and porphyrins with particularly high tumor accumulation properties are preferred.

  In addition, the boron compound introduced into the porphyrinoid is not limited as long as it is a substance rich in boron atoms, but the number of boron atoms present in one molecule of the radiosensitizer is particularly 40 or more. It is desirable to select the boron compound to be introduced in such a manner.

  Furthermore, with respect to the boron compound, it is preferable to select a substance in which the number of hydrogen atoms present in one molecule of the radiosensitizer is 40 or more in order to promote the generation of Auger electrons. Examples of an ideal boron compound that satisfies these conditions include a cage-like borane compound.

The boron compound may be introduced at any position of the porphyrinoid cyclic compound. For example, in the case of a porphyrin ring or chlorin ring represented by the following chemical formula, the boron compound is introduced at any position of R. Also good.

  On the other hand, for the porphyrinoid metal complex, palladium, copper, vanadium, manganese, iron, ruthenium, technetium, chromium, cobalt, nickel, copper, zinc, germanium, indium, tin, yttrium, gold, platinum, barium, Those having tungsten, gadolinium or the like as a central metal are included.

Furthermore, it is desirable to use a substance whose solubility has been improved by introducing a fluorine atom in the radiosensitizer of the present invention. From the viewpoint of therapeutic effect, it exists in one molecule of the radiosensitizer. It is desirable that the number of fluorine atoms is 16. Specific fluorinated porphyrinoids that satisfy this condition include fluorinated porphyrins represented by the following [Chemical Formula 1] (left side).

  In addition, when the fluorinated polyphyllin of the above [Chemical Formula 1] (left side) is employed, it is desirable to take any combination of [a] to [h] on the right side at the positions of M and R. These are all fluorinated porphyrins or metal complexes to which a cage-like borane compound is bound, but the use of [c] porphyrin is particularly preferred in terms of therapeutic effect.

[Proton therapy]
Next, the proton beam treatment method of the present invention will be described. First, the radiosensitizer for proton beam treatment described above is administered to a mammal, and then left waiting for a predetermined time until the radiosensitizer accumulates in a malignant tumor. Thereafter, the mammal is taken to a proton beam irradiation device, and proton irradiation is performed on the tumor.

  At the time of drug administration, the concentration and amount of the radiosensitizer are adjusted to a level that is not harmful, and the method of administering the radiosensitizer (oral administration, intravenous administration, subcutaneous administration, etc.) It selects suitably according to the kind of radiosensitizer. In addition, the time from drug administration to proton irradiation is adjusted taking into account the time required to accumulate the radiosensitizer in the tumor and the time until the radiosensitizer is excreted from the body. To do.

  Also, the intensity and irradiation dose of the proton beam to be irradiated are adjusted to a level and intensity that do not adversely affect normal cells. In addition, proton beam irradiation can be performed in a plurality of times, thereby reducing the dose of one irradiation and reducing the burden on normal cells.

  Furthermore, when a malignant tumor is present on the surface, PDT can be used in combination to improve the therapeutic effect. Specifically, the therapeutic effect can be improved by irradiating the tumor tissue in which the radiosensitizer has been accumulated with visible laser light having a wavelength of 630 to 675 nm simultaneously with the proton beam irradiation.

  In addition, when using the PDT together, by using a multi-wavelength laser irradiation apparatus capable of simultaneously irradiating laser light of a plurality of wavelengths, by simultaneously irradiating laser light of two wavelengths of 630 to 640 nm and 660 to 670 nm, The therapeutic effect can be further improved.

  By the way, in the present invention, PDD (photodynamic diagnosis) can also be used together, so that the tumor in which the radiosensitizer is accumulated is irradiated with a blue laser having a wavelength of 395 to 415 nm during or after the irradiation of the proton beam, The position, size, and shape of the malignant tumor can be visually confirmed by causing the radiosensitizer in the tumor to emit red fluorescence.

“Therapeutic effect confirmation test [1]”
In this confirmation test [1], the following test method using a cell sample of a malignant tumor was used to examine the effect of radiosensitizers, proton irradiation, or a combination of these on the therapeutic effect. Confirmed by measuring.

<Test method>
The test method of this test will be described. First, cultured cells (cell number: 5.6 × 10 ⁶ cells / 0.1 ml) derived from rat brain tumor (C6) are transplanted into rats. Then, on the 8th day after the transplantation (one day before irradiation), a radiosensitizer containing 3.3 mM of the porphyrin of the following [Chemical Formula 2] is intraperitoneally administered to the rats.

  In this confirmation test, the porphyrin of [Chemical Formula 2] is referred to as “Compound-B” for convenience. In this test, two groups of rats having the tumor cells transplanted and two groups of non-transplanted rats are prepared (4-6 rats in each group).

  Then, after administration of the radiosensitizer (Compound-B), 200 MeV proton beam irradiation is performed 5 Gy per day (4 times in total) during the period of 9 to 12 days after transplantation. In addition, this proton beam irradiation is performed with respect to 1 group which transplanted the tumor cell, and 1 group which has not transplanted. In this test, proton beam irradiation was performed using the particle accelerator of Wakasawan Energy Research Center.

<Measurement of tumor size>
Then, when it was investigated how the size of a tumor changed with progress of time about said 4 groups, the result shown in FIG. 1 was obtained. From the results shown in FIG. 1, the group that combined administration of the radiosensitizer (Compound-B) and proton beam irradiation showed a remarkable antitumor effect than the other groups.

"Therapeutic effect confirmation test [2]"
Next, in this confirmation test [2], in addition to the four groups used in the above confirmation test [1], a group in which a radiosensitizer (Compound-B) is administered to perform PDT, a radiosensitizer is administered. In addition, a group in which proton beam irradiation and PDT were used in combination, and a group in which a radiosensitizer (Compound-B) was administered and proton beam irradiation and PDT were used in combination were added for testing.

The PDT was performed by irradiating a visible laser beam of 665 nm at a rate of 60 J / cm ² per day (4 times in total) using a semiconductor laser irradiation device during a period of 9 to 12 days after the transfer. Moreover, about the group which uses PDT and proton beam irradiation together, it tested by irradiating a laser beam simultaneously from the surface side where the tumor is exposed, and a proton beam from the back side.

<Measurement of tumor size>
And when the change of the magnitude | size of the tumor was investigated about said 3 added group, the result shown in FIG. 2 was obtained. In addition, from the results of FIG. 2, it was confirmed that the antitumor effect was further improved in the group in which the radiosensitizer (Compound-B) was administered and PDT and proton irradiation were used in combination. did it.

Further, Table 1 below shows the data obtained by performing regression analysis by fitting an exponential curve on the data shown in FIG. 2 and calculating the slope of the exponential curve. The numerical value in parentheses beside the inclination is a ratio of the inclination of each group compared with the inclination (100%) of the group that has not performed any treatment. In addition, since the coefficient of determination (R ² ) is 0.9 or more except for the group in which the PDT was performed by administering the radiosensitizer, it can be seen that the accuracy of fitting the curve regression is sufficiently high.

  In recent years, in the medical field and veterinary medical field, there is a demand for a method for treating malignant tumors that has excellent therapeutic effects and less burden on the body. Among them, the “sensitizer for proton beam therapy and the proton beam therapy using the same” according to the present invention is a useful technique that can be an innovative improvement measure for proton beam therapy that is being introduced. The utility value of is very large.

Claims (11)

  A sensitizer containing a fluorinated porphyrinoid bound to a boron compound or a metal complex thereof, wherein the sensitizer is administered before irradiating a proton beam to a tumor tissue.   The sensitizer for proton beam treatment according to claim 1, wherein the number of boron atoms present in one molecule is 40 or more.   The sensitizer for proton beam therapy according to claim 1 or 2, wherein the number of hydrogen atoms present in one molecule is 40 or more.   The sensitizer for proton beam therapy according to any one of claims 1 to 3, wherein the number of fluorine atoms present in one molecule is 16.   The sensitizer for proton beam treatment according to any one of claims 1 to 4, which contains a porphyrinoid or a metal complex thereof bound with a caged borane compound. The sensitizer for proton beam treatment according to claim 5, which contains a fluorinated porphyrin represented by the following chemical formula or a metal complex thereof.

(M and R in the structural formula on the left side take any combination of [a] to [h] on the right side.) The sensitizer for proton beam treatment according to claim 6, which contains a fluorinated porphyrin represented by the following chemical formula.

(M and R in the structural formula on the left take the combination of [c] on the right.)   A method of treating a mammal affected with a malignant tumor, comprising administering a sensitizer containing a fluorinated porphyrinoid or a metal complex thereof to which a boron compound is bound, to a tumor tissue in which the sensitizer has accumulated. A proton beam therapy using a sensitizer for proton beam therapy, characterized by irradiating with a proton beam. 9. A proton beam treatment method using a sensitizer for proton beam therapy according to claim 8, wherein a sensitizer containing a fluorinated porphyrin represented by the following chemical formula or a metal complex thereof is administered.
(M and R in the structural formula on the left side take any combination of [a] to [h] on the right side.) A sensitizer containing a fluorinated porphyrin represented by the following chemical formula is administered. The proton beam treatment method using a sensitizer for proton beam therapy according to claim 9.
(M and R in the structural formula on the left take the combination of [c] on the right.)   The tumor tissue in which the sensitizer is accumulated is irradiated with a visible laser beam having a wavelength of 630 to 675 nm simultaneously with the proton beam irradiation, and PDT is used in combination. Proton therapy using sensitizers for proton therapy.