Device and method for the treatment of tumors

Abstract

Devices, fiber optic systems, and procedures and methods are provided that are capable of transmitting radiation with variable light intensity to specific parts of the human or animal body. In particular, these include laser devices and procedures used in the medical field that emit radiation in the red and infrared range, as well as optical fibers that transmit this radiation to a treatment site, e.g., areas where abnormal cell growth or development occurs, such as tumors, neoplastic and proliferative diseases.

Description

Short description

[0001] The invention relates to radiation-emitting devices and optical fibers for transmitting this radiation to a specific location. In particular, these devices are laser devices used in the medical field that emit radiation in the red and IR range, as well as optical fibers that transmit this radiation to a treatment site, e.g., to sites where abnormal cell growth or development occurs, such as tumors or precursors to tumor development. State of the art

[0002] The term 'tumor' refers to new growths in body tissue (neoplasms) that arise due to dysregulation of cell proliferation. Such neoplasms can affect any type of body tissue and can be benign or malignant. Benign tumors are clearly demarcated from healthy cells, whereas malignant tumors grow into and destroy the surrounding tissue. Despite advances in medical therapy, tumor diseases are one of the most serious medical problems worldwide, and new treatment options are urgently needed. Various therapeutic approaches exist today. Current treatment methods include, for example, surgical removal of the tumor, including using laser-based techniques, chemotherapy, therapies with biological agents such as special antibodies, radiation therapy, or photodynamic therapy (PDT).Laser treatment, in particular, is used in numerous medical fields for various diseases and is a well-known tool, particularly in surgery [1], [2], [3]. PDT, which is also used in tumor therapy, requires the systemic or local ingestion or administration of a drug (a photosensitizer, e.g., Photofrin), followed by appropriate light irradiation. The combination of photosensitizer, light, and the oxygen present in all cells generates reactive oxygen species that damage the irradiated abnormal cells. However, PDT is associated with prolonged photosensitivity in the treated patient, as a portion of the photosensitizer accumulates in the skin [4]. In all of these treatments, large portions of the tissue in the affected area are usually treated or removed, including those surrounding the tumor, to minimize the likelihood of tumor recurrence.While current methods, such as surgery or PDT, often achieve the goal of removing the tumor, they are associated with significant side effects, such as prolonged photosensitivity in patients with PDT. Furthermore, there is no treatment method that allows for easy differentiation between different tissue areas during treatment, for example, combining the destruction of the tumor tissue with a non-destructive treatment in adjacent tissue areas.

[0003] For example, WO 94 / 15666A1, WO 93 / 21842A1, and US Pat. No. 8,292,935B2 present light irradiation devices for the treatment of cancer and dysplasia, but they were designed exclusively for use in combination with photosensitizers during PDT treatment. As noted above, however, this is associated with long-lasting photosensitivity in patients. US20150375194 describes and discloses a quantum dot laser diode for the treatment of tumors and non-tumorous diseases such as inflammation in bacterial infections, but the issue of tissue-differentiating therapy is not addressed. Task of the invention and solution

[0004] The object of the invention is to eliminate or at least mitigate these deficiencies and side effects of existing treatments for tumors and similar diseases or precursors to tumor development. This object is achieved by overcoming these deficiencies and side effects through a light-mediated treatment with a power density suitable for the respective individually tailored case (application) in combination with irradiation in the red and NIR range of the electromagnetic spectrum (600 nm - 3000 nm). More specifically, the light-mediated treatment disclosed herein refers to light irradiation at wavelengths between 600 - 1300 nm, and in particular to irradiations at 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm, or 1270±30 nm, in particular 1270±6 nm and preferably at 1270±3 nm.Light-mediated treatment with such wavelengths is capable of directly exciting the oxygen present in the cells to form singlet oxygen, thereby generating singlet oxygen and other reactive oxygen species through additional biochemical mechanisms. Furthermore, such irradiation, e.g., at 1240–1300 nm, has an immunogenic effect and stimulates the release of cytokines and chemokines, thereby modulating the body's immune response. Furthermore, laser irradiation in the red and near-infrared range can also directly ablate tissue. The present solution utilizes these various mechanisms (device and method) to, on the one hand, directly ablate tumor tissue and, on the other hand, to specifically eliminate tumor cells in the peripheral areas of the tumor at lower intensity while protecting the tissue by directly exciting oxygen and through the immunomodulating effect of this laser radiation.

[0005] Higher radiation intensity and / or the use of pulsed laser radiation make it possible to directly ablate tumor tissue. In the present invention, this is combined with additional device elements that enable the removal of the ablated tissue. This is further combined with irradiation with a low power density, i.e., with an individually adjustable and controllable power density in the peripheral areas and the wider surroundings of the tumor, which mitigates or prevents damage or side effects. Thus—in contrast to existing methods—tumor cells are eliminated while the collagen matrix is ​​preserved, promoting and facilitating the healing process. The treatment promotes the migration of new cells into the affected area and prevents scarring.The homogeneous, low power density desired for irradiating the peripheral areas and the surrounding area of ​​the tumor is achieved by the design of the entire irradiation device, including the fiber optic and applicator components, and by limiting the light irradiance, thus ensuring a specific temperature range. In some embodiments of the present invention, this is achieved through continuous wave (CW) irradiation, which may also have interruptions; in others, the effect is achieved through pulsed red and NIR irradiation. In further embodiments of the present invention, this is achieved through temperature monitoring using sensors, which, via a control loop or an alarm system, ensure that the temperature or power remains below a critical value.To minimize heating of the treated tissue during irradiation in the peripheral areas of the tumor, the absorption peak for the formation of reactive oxygen must be targeted as accurately as possible. Bragg gratings allow laser diodes to emit a precise wavelength in a narrow band, and such sources are preferably used (e.g., 1270±2 nm). Since the absorption peak also depends on the environment and different environments can exist in the zone to be treated (water, fatty tissue, etc.), it may also be useful to mix two (or more) wavelengths (e.g., 1265±2 nm and 1272±2 nm). Narrowband excitation according to the device and method of the present invention makes it possible to increase the proportion of radiation absorption that specifically leads to the excitation of oxygen and the formation of reactive oxygen species, compared to the proportion of radiation absorption that simply leads to tissue heating.As explained above, this lower thermal stress on the tissue preserves the collagen matrix and allows the migration of new cells into the existing matrix, thereby promoting and facilitating the healing process.

[0006] The inventive treatment of tumors and other neoplastic diseases thus includes a device construction that - on the one hand, removal of the tumor tissue using red and NIR irradiation (CW or pulsed laser radiation) - on the other hand, in the peripheral areas and the surroundings of the tumor, red and NIR irradiation of lower intensity allows the destruction of tumor cells while simultaneously protecting the surrounding tissue.

[0007] In the latter case, the treatment according to the invention is based on the light-induced generation of reactive oxygen species at the treatment site and on the immunostimulatory and immunomodulatory effects of this light. These effects can be enhanced by combining PDT with light and a suitable photosensitizer.

[0008] Embodiments of the present invention include devices and / or fiber optic equipment / instruments of various shapes and sizes that enable homogeneous irradiation of neoplastic tissues and their surroundings in the red and near-infrared range, primarily between 600 and 1300 nm. The invention utilizes laser irradiation between 600 and 1300 nm, specifically between 1240 and 1300 nm, to ablate neoplastic tissue with higher light intensity and, at lower light intensity, to directly stimulate oxygen in the tissue surrounding the tumor, thereby eliminating any remaining degenerated cells. This occurs without overheating the intercellular matrix, allowing it to be preserved and new cells to colonize the matrix and the surface.Deeper in the tissue, the low intensity and dose of radiation can stimulate cell proliferation and cellular activity to support the healing process and shorten the recovery time of the treated area.

[0009] Typically, fiber optic devices such as diffusers, frontal directional illumination probes, balloon catheters, etc., are connected to a laser source and used for irradiation. Pulsed radiofrequency sources (MHz range or higher) can also be used. Temperature monitoring and additional cooling can be employed to prevent overheating of the treatment zone. Raman spectroscopy can also be used to characterize the tissue and delineate the zone, or the device can be combined with optical coherence tomography (OCT) for diagnosis and treatment monitoring.

[0010] Furthermore, the device according to the invention described here and the associated method according to the invention can also be combined with other light-based treatment methods, such as photodynamic therapy (PDT) (see the Fig. and their explanations). The particular advantage of the device and method described here lies in the fact that the generation of reactive oxygen species at the treatment site occurs both indirectly – through excitation of the photosensitizer – and directly through the excitation of oxygen in the treatment area. Such photosensitizers can be approved PDT dyes such as temoporfin, talaporfin, talaporfin sodium, padeliporfin, verteporfin, HpD, porfimer sodium, chlorin e6, fimaporfin, redaporfin, photochlor, protoporphyin IX, ALA (as a photosensitizer prodrug), IRDye700DX, methylene blue, or safranin. In addition, such photosensitizers can also be endogenous protoporphyrin IX or other endogenous photosensitizers. Added to this is the immunostimulatory and immunomodulatory effect of light.This allows the amount of photosensitizer used to be significantly reduced, which is associated with fewer side effects of the treatment. The combination with another light-based treatment method, such as PDT, has the additional advantage that different tissue areas can be treated differently. For example, the tumor area can be treated using a photosensitizer and a suitable wavelength - corresponding to the absorption spectrum of the photosensitizer - and the peripheral areas can be treated with laser irradiation of 600 - 1300 nm, especially 1240 - 1300 nm, in order to treat these areas in a tissue-sparing manner and to utilize the immune-stimulating effect of light at this wavelength. Furthermore, the combination of two wavelengths in the device and method described here can also be used to stimulate two absorption transitions of oxygen and thus increase the efficiency of the treatment.

[0011] The basic structure of the device or the general scheme according to the present invention is shown in the Fig. shown.

[0012] It shows a device according to the invention for red and NIR irradiation.

[0013] The device consists of an optical source with a wavelength of 600–3000 nm and an optical delivery system for the radiation to the treated area. In a preferred embodiment, the device consists of a light source with a wavelength of 1240–1300 nm and an optical delivery system for the radiation to the treated area.

[0014] The optical unit for the combined light delivery to the treated area can be a fiber bundle or a solid optical fiber. The optical fiber can be a single-mode or multimode fiber (quartz-quartz or quartz-polymer), a hollow-core quartz fiber, or a balloon fiber.

[0015] When combining the device and method described here with other light-based treatment methods, such as PDT, radiation of a second wavelength is required. This combination of two light sources as an embodiment of the present invention is described in Fig. shown.

[0016] Fig. shows the basic structure of an inventive device for red and NIR irradiation with the option for combining two irradiation wavelengths.

[0017] The general scheme is in Fig. The device contains two light sources at 600–3000 nm. In a preferred embodiment, one of these is a light source at 1240–1300 nm. The device contains a wavelength combiner for the two wavelengths and an optical delivery system for directing the combined radiation to the treated area. A bundle of optical fibers or a free-space multiplexer containing a dichroic mirror and collimating lenses, or a fused fiber wavelength division multiplexer (WDM) can be used as the wavelength combiner.

[0018] The optical unit for the combined light delivery to the treated area can be a fiber bundle or a solid optical fiber. The optical fiber can be a single-mode or multimode fiber (quartz-quartz or quartz-polymer), a hollow-core quartz fiber, or a balloon fiber. To irradiate the affected area with the most uniform intensity possible, it can be advantageous to design the transmission fiber with a square core cross-section, resulting in top-hat radiation intensity distributions.

[0019] Partial areas can also be helpful in the transmission path.

[0020] Briefly, the embodiments comprise light-emitting and light-conducting devices for delivering selectively a) a higher power density of red and NIR irradiation to directly ablate tumor tissue and neoplastic tissue. b) a low power density of red and NIR irradiation to treat peripheral areas of the tumor.

[0021] The embodiments include devices for delivering red and NIR radiation with adjusted power density in combination with cooling and temperature control.

[0022] The above and other objects, features and advantages of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings. Detailed description of the embodiments

[0023] The embodiments include devices that provide red and NIR irradiation with either low or high power density (see Fig. ). These versions can be combined with a cooling unit and temperature control to prevent overheating of the treated area (see Fig. For irradiating peripheral areas, a few watts of laser power may be sufficient, ranging from 1 to 10 watts, depending on the size of the irradiated area. Another option to prevent overheating is cooling at the exit surface or the irradiated surface. Cooling agents, such as those used in other laser treatments, can also be used.

[0024] For tissue ablation, higher light doses and power levels can be selected, which, depending on the treatment case, can range from 1.5 to 2.0 Gy per session and 7.5 to 10 Gy per week. In the peripheral areas of the tumors, the invention allows for a much lower, gentler treatment with the lower power intensities in the preferred range of 2 watts to 4 watts at, for example, 20-50 J / cm2, a power intensity designed to avoid excessive heating and thus damaging the tissue.

[0025] Fig. illustrates an example of a device according to the present invention that enables red and NIR irradiation with optionally low or high power density and cooling and temperature control.

[0026] Fig. shows an illustrative example of a device according to the present invention, which enables red and NIR irradiation with optionally low or high power density and cooling and temperature control, with the option for combining two irradiation wavelengths.

[0027] In addition, such devices can be equipped with a balloon fiber to enable even illumination of the area to be treated. This is Fig. illustrated.

[0028] Out of Fig. is the visualization of a red or NIR irradiation device with optionally low or high power density, equipped with a balloon fiber.

[0029] Out of Fig. is the visualization of a red and NIR irradiation device with optionally low or high power density, equipped with a balloon fiber, with the option of combining two irradiation wavelengths.

[0030] In a preferred embodiment of the present invention, the device for irradiation in the red and NIR range is a laser that emits radiation between 600 and 1300 nm. In a particularly preferred embodiment, the irradiation device is a laser that operates at wavelengths of 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm, or 1270±30 nm.

[0031] In a preferred embodiment, the laser, which delivers NIR radiation between 1240 and 1300 nm, is combined with a cooling device and a temperature control device. In another particularly preferred embodiment, the laser, which operates at a wavelength between 1240 and 1300 nm, is equipped with a balloon fiber to enable uniform illumination of the area to be treated.

[0032] The embodiments also include the combination of such red and NIR radiation lasers with a Raman or OCT device for diagnosis or therapy monitoring. The laser systems can operate in both CW and pulsed laser modes.

[0033] In another embodiment, the device and method of the present invention are combined with a PDT treatment in the manner illustrated above, using a photosensitizer and light irradiation with a suitable wavelength corresponding to the absorption spectrum of the photosensitizer. Such photosensitizers can be, for example, tetrapyrrole systems such as porphyrins, chlorins, bacteriochlorins, or phthalocyanines, or their metal complexes. In a preferred embodiment, the device and method of the present invention are combined with a PDT treatment, wherein the photosensitizer is selected from the group consisting of temoporfin, talaporfin, talaporfin sodium, padeliporfin, verteporfin, HpD, porfimer sodium, chlorin e6, fimaporfin, redaporfin, photochlor, protoporphyin IX, ALA (as a photosensitizer prodrug), IRDye700DX, methylene blue, or safranin.Such photosensitizers can also be endogenous protoporphyrin IX or other endogenous photosensitizers. In this case, the device and method of the present invention are used, among other things, to irradiate peripheral regions of the PDT-treated area to counteract tumor recurrence.

[0034] The following example is intended to provide those skilled in the art with a full and illustrative disclosure and description of how to make a device according to the present invention and to illustrate its operation, but is not intended to limit the scope of what the inventor considers to be the invention.

[0035] In the Fig. Explanations and examples are shown. Examples

[0036] Example of a laser system according to the apparatus and method of the present invention

[0037] Fig. shows the example of a laser system according to the apparatus and method of the present invention.

[0038] Explanation: The laser consists of a light source with a wavelength of, for example, 1265 nm and a second light source with a wavelength in the range of 600–3000 nm, a beam combiner, and an optical delivery cable, which ensure the delivery of the combined beams (of, for example, 1265 nm or preferably 1267 nm in combination with 600–3000 nm) to the treatment area. The laser with a wavelength of, for example, 1267 nm can have a fiber-coupled or free-space output. The second laser with a wavelength of 600–3000 nm can also have a fiber-coupled or free-space output.

[0039] The laser beam of the first laser with a wavelength of e.g. 1265 nm and the laser beam of the second laser are combined by a beam combiner.

[0040] The beam combiner can be manufactured in several ways. It can be a free-space optical system containing collimating and focusing lenses as well as dichroic and reflecting mirrors ( Fig. , or a fused single-mode wavelength division multiplexer (WDM) that connects single-mode fibers ( Fig. or multimode fibers ( Fig. ). This can also be done on the basis of a coupler, which is an arrangement of single-mode or multimode fibers drawn in a polymer layer and having an optical contact (GTWave technology, Fig. ).

[0041] It is also possible to combine the light beams simply by using a fiber bundle ( Fig. 7e).

[0042] The combined light beam (1265 nm plus 600-3000 nm) is delivered to the surgical site via a special delivery cable. This can be a quartz-quartz fiber, a quartz-polymer fiber, a hollow-core fiber, or a balloon fiber.

[0043] The invention also relates to a device and a method in which at least one rinsing device is used for the treatment of tumors, neoplastic and proliferative diseases.

[0044] Having described preferred embodiments of the invention with reference to the accompanying example, it is to be understood that the invention is not limited to the precise embodiments and that various changes and modifications may be made therein by those skilled in the art without departing from the scope of the invention as defined in the appended claims.

[0045] The device and the method with the various embodiments of the invention can also be equipped with a control and computing unit, with or without a combination of photodynamic therapy (PDT), whereby a control program can make the treatment stages variable depending on the measurement data of the previous treatment stage(s). References [1] D. Condor, C. Culcitchi, R. Blum, O. Baru, S. Buduru, A. Kui, I. Tig, A Review of CO2 Laser-Mediated Therapy for Oral Mucosal Lesions, Appl. Sci., 11, 7744 (2021) [2] E. Khalkhal, M. Rezaei-Tavirani, MR Zali, Z. Akbari, The Evaluation of Laser Application in Surgery: A Review Article, J. Lasers Med. Sci., 10 (Suppl 1), pp. S104-S111 (2019). [3] DJ Jordan, P. Mafi, R. Mafi, M. Malahias, A. El Gawad, The Use of LASER and its Further Development in Varying Aspects of Surgery, Open Med. J., 3 (Suppl-3, M2), pp. 288-299 (2016). [4] JH Correia, JA Rodrigues, S Pimenta, T Dong, Z Yang, Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions, Pharmaceutics, 13, 1332 (2021). QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] WO 93 / 21842A1

[0003] US 8292935B2

[0003] US 20150375194

[0003] Cited non-patent literature

[0000] D. Condor, C. Culcitchi, R. Blum, O. Baru, S. Buduru, A. Kui, I. Tig, A Review of CO2 Laser-Mediated Therapy for Oral Mucosal Lesions, Appl. Sci., 11, 7744 (2021

[0045] E. Khalkhal, M. Rezaei-Tavirani, M. R. Zali, Z. Akbari, The Evaluation of Laser Application in Surgery: A Review Article, J. Lasers Med. Sci., 10 (Suppl 1), pp. S104-S111 (2019

[0045] D. J. Jordan, P. Mafi, R. Mafi, M. Malahias, A. El Gawad, The Use of LASER and its Further Development in Varying Aspects of Surgery, Open Med. J., 3 (Suppl-3, M2), S. 288-299 (2016

[0045] J. H. Correia, J. A. Rodrigues, S. Pimenta, T. Dong, Z. Yang, Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions, Pharmaceutics, 13, 1332 (2021

[0045]

Claims

[1] Device for treating tumors, consisting of at least one laser emitting radiation at 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm or 1240±30 nm, and a fiber optic device transmitting this radiation to the treatment site. [2] A device for treating tumors according to claim 1, comprising a laser emitting radiation at 1267±3 nm and a fiber optic device transmitting this radiation to the treatment site. [3] Device for treating tumors according to claim 1, consisting of two separately controllable lasers, - wherein one laser emits radiation at 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm or 1270±30 nm and - the second laser emits radiation at 1240 - 1300 nm, in particular at 1267±3 nm - and a fiber optic device that transmits this radiation to the treatment site. [4] Device for treating tumors according to at least one of claims 1 to 3, wherein the optical unit for supplying light to the treated area is a fiber bundle or an optical fiber, wherein the optical fiber may be a single-mode or multi-mode fiber (quartz-quartz or quartz-polymer) or a hollow-core quartz fiber or balloon fiber. [5] Device according to at least one of claims 1 to 4, which is used in the treatment of tumor diseases and / or neoplastic tissue. [6] Device according to at least one of claims 1 to 4, which is used for light-mediated immunomodulation of tumors, neoplastic and proliferative diseases, cancerous and precancerous and cancerous lesions. [7] Device according to at least one of claims 1 to 4, which is used for the treatment of tumors, neoplastic and proliferative diseases, which operates in continuous wave (CW) or pulsed mode. [8] Method for treating tumors with at least one laser, - wherein the laser emits radiation at 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm or 1270±30 nm and - and a fiber optic device through which this radiation is transmitted to the treatment site. [9] Method for treating tumors with two separately controllable lasers, - wherein one laser emits radiation at 627±10 nm, 690±10 nm, 760±10 nm, 810±10 nm, 920±10 nm, 1065±30 nm or 1270±30 nm and - the second laser emits radiation at 1240 - 1300 nm, in particular at 1267±3 nm, - and a fiber optic device that transmits these radiations to the treatment site. [10] Method according to at least one of claims 8 and 9 for emitting light which is suitable for converting oxygen from the ground state into singlet oxygen or for exciting oxygen in the ground state to singlet oxygen, for the treatment of tumors, neoplastic and proliferative diseases. [11] Method according to at least one of claims 8 to 10 for the treatment of tumors, neoplastic and proliferative diseases in which at least one rinsing device is used. [12] Method according to at least one of claims 8 to 11 for the treatment of tumors, neoplastic and proliferative diseases in which at least one temperature control and / or at least one cooling option is used. [13] Method according to at least one of claims 8 to 12 for the treatment of tumors, neoplastic and proliferative diseases, in which a unit is used for diagnosing the treated tissue areas. [14] Method according to at least one of claims 8 to 13 for the treatment of tumors, neoplastic and proliferative diseases in combination with photodynamic therapy with a photosensitizer. [15] Method according to at least one of claims 8 to 14 for the treatment of tumors, neoplastic and proliferative diseases in which a photodynamic therapy with a photosensitizer from the group of temoporfin, talaporfin sodium, padeliporfin, verteporfin, HpD, porfimer sodium, ALA (as photosensitizer prodrug), methylene blue or safranin is combined.

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