Non-invasive cancer treatment

Abstract

A device (1) for treating a cancerous target site is provided. The device comprises an electromagnetic emitter (10) comprising one or more electrodes with an electrically insulating coating for preventing electrical contact between the electrodes and the target site. The electromagnetic emitter (10) is configured to provide a tumor treatment field at the target site through the one or more electrodes, the tumor treatment field being a non-ionizing alternating electromagnetic field having a frequency of 10 kHz to 300 kHz and further having a magnetic flux density of 0.1 pT to 1 mT. The device further comprises a heat source (20) configured to provide heating at the target site to induce a hyperthermia at the target site. The device is configured to independently apply the non-ionizing alternating electromagnetic field and the heating. The device comprises an electronic controller for electronically controlling the electromagnetic emitter and the heat source.

Description

Technical Field

[0001] This disclosure relates to an apparatus for treating a cancerous target site. More specifically, this disclosure relates to an apparatus configured to provide a non-ionizing alternating electromagnetic field and localized heating at the target site. This disclosure also relates to related methods for treating cancerous sites and compositions for treating cancerous target sites. Background Technology

[0002] Non-invasive methods of cancer treatment are important, especially for cancers that are difficult to remove surgically, such as glioblastoma. The goal is to develop new non-invasive cancer treatments that effectively reduce or eliminate cancer cells at target sites in the body.

[0003] Radiation therapy is a cancer treatment that uses ionizing radiation to kill malignant cells at a target site. Ionizing radiation is delivered to the target site, causing damage through direct or indirect effects on DNA and other cellular molecules. In direct effects, radiation strikes molecules such as DNA directly, disrupting their molecular structure. This structural change leads to cell damage and even cell death, thus providing a mechanism for treating malignant cells.

[0004] Another form of treatment, called alternating electric field therapy or tumor therapeutic field (TT field), applies a non-ionizing electric field to the target site. The mechanism by which TT fields can be used for cancer treatment differs from that of radiotherapy. Specifically, during the formation of the mitotic spindle, microtubule components deform. Tumor cells undergo mitosis for extended periods during interphase. As cleavage grooves form in late mitosis, all polar molecules and dipoles within the cell undergo dielectrophoresis under the influence of the TT field, accumulating within the grooves and ultimately leading to cell membrane rupture. Mitotic outcomes induced by TT field application include abnormal chromosome segregation, which triggers various forms of cell death.

[0005] Hyperthermia is a known method for treating cancerous sites. However, effectively targeting cancerous sites is challenging. On one hand, surrounding tissues may also be affected by hyperthermia, especially when the cancerous site is heated to high temperatures. On the other hand, if the cancerous site is not heated to a sufficiently high temperature, it may not be effectively destroyed. Furthermore, while applying heat to a cancerous site may lead to cell damage or even cell death at the site, the cancerous site may tolerate the heat if it is not applied correctly and accurately with the correct dosage. For example, if hyperthermia also heats the surrounding healthy tissue in addition to the cancerous growth, blood flow will be enhanced, and the nutrient supply to the cancerous tissue may be higher. Therefore, in some cases, the increased blood flow due to heating facilitates the transport of nutrients that can reach the cancerous site and thus have the opposite effect, or at least result in ineffective treatment. Furthermore, different stages of the cell cycle in cancer cells have been observed to exhibit different levels of heat resistance. Moreover, elevated cell temperature can transiently upregulate heat shock genes encoding heat shock proteins (HSPs). The mechanism responsible for the heat shock response is an autoregulatory cycle; HSPs typically retain the responsible transcription factor (HSF-1) inactive, but upon heating, HSPs bind to unfolded proteins with higher affinity, triggering the release of HSF-1 from the HSP, thereby initiating HSP gene transcription. Once protein damage / aggregation recovers after HSP heat shock, substrate-free HSPs themselves may attenuate the response by rebinding HSF-1. Therefore, HSP levels rise transiently after heating but gradually decline during prolonged stress-free periods. The upregulation of HSPs is closely associated with a transient state of cellular tolerance to a subsequent second heat shock. It is believed that elevated HSP levels protect cells from protein damage induced by further heating through their molecular chaperone activity. Therefore, there is a need to provide more accurate and reliable hyperthermia to deliver the required heat to cancerous sites to avoid any tolerance to cancer cell heating due to deviations from the desired applied heat.

[0006] Many hyperthermia methods require the application of a mediator (such as a nanoparticle fluid) to the site. The target site is then indirectly heated, for example, by heating the mediator through an electric field. An electric field with the same or similar frequency range as the TT field can be used to heat the mediator. This may be considered advantageous because cancerous sites are attacked via hyperthermia and through the TT field mechanism. However, because the mediator is a fluid injected into the patient's body, the heating location is difficult to control when applying electromagnetic radiation.

[0007] The hope is to find more effective cancer treatments than the aforementioned methods. Summary of the Invention

[0008] The problem addressed by this invention is to provide a more effective treatment for cancer, which is achieved by providing a device for treating cancerous target sites, the device comprising:

[0009] The electromagnetic transmitter is configured to provide a non-ionizing alternating electromagnetic field at the target location;

[0010] A heat source is configured to provide heating at the target site to induce hyperthermia at the target site;

[0011] The device is configured to independently apply a non-ionizing alternating electromagnetic field and generate heat. Specifically, the heat source is configured to provide direct heating to the target area.

[0012] It should be noted in this article that the heat source can be any heat source that heats a specific target area without the use of a medium (e.g., directly rather than indirectly via a medium).

[0013] In a preferred embodiment, the device is configured to provide a non-ionizing alternating electromagnetic field at the target site for a first time period and direct heating at the target site for a second time period. The second time period may partially or completely overlap with the first time period. For example, the first time period may begin simultaneously with the second time period, or it may begin a predetermined amount of time after the start of the first time period, or it may begin at the end of the first time period. Preferably, the first and second time periods completely overlap, such that the TT field and heating are applied to the site simultaneously, thereby providing a synergistic effect on the cells in the target site, as discussed in further detail below.

[0014] It should be noted that the order of the first time period and the second time period can be repeated two or more times. For example, the device can be configured to apply a non-ionizing alternating electromagnetic field for a first time period, and then apply heating for a second time period after a predetermined time following the start of the first time period. Subsequently, the device can be configured to again apply a non-ionizing alternating electromagnetic field for the first time period, and then apply heating for a second time period after a predetermined time following the start of the first time period. The lengths of the first and second time periods, and their start times relative to each other, can be configured by the user or according to one or more schedules stored in the device's memory.

[0015] Preferably, the device is configured to provide a non-ionizing alternating electromagnetic field at the target site for a first period of time, lasting from 1 minute to 24 hours.

[0016] In another preferred embodiment, the device is further configured to provide heating at the target site for a second time period lasting from 1 minute to 360 minutes. Heating can be simultaneously applied to a non-ionizing alternating electromagnetic field for a third time period. The third time period can be all or part of the second time period.

[0017] In another preferred embodiment, the electromagnetic transmitter is configured to provide an alternating electromagnetic field with a frequency of 10 kHz to 500 kHz, more preferably 10 kHz to 300 kHz, and even more preferably 100 kHz to 300 kHz. It has been observed that the therapeutic effect of the tumor treatment field is significantly increased when the frequency is below 300 kHz.

[0018] In another preferred embodiment, the electromagnetic transmitter is configured to provide an alternating electromagnetic field at the target site with a magnetic flux density of 0.1 pT to 1 mT, or 0.1 pT to 100 μT, or 100 μT to 1 mT and / or an electric field strength of 1 V / cm to 3 V / cm.

[0019] In another preferred embodiment, the electromagnetic transmitter is configured to provide a variable electromagnetic field with a magnetic flux density of 0.5 μT to 1 mT, and more preferably 8 μT to 1 mT, at the target site.

[0020] In another preferred embodiment, the heat source is configured to heat the target area to a temperature of at least 42°C, and preferably between 42°C and 57°C. Heating the target area to a temperature of at least 42°C will produce a thermal effect on the target area, which is equivalent to extreme ultra-high temperature.

[0021] In another preferred embodiment, the heat source includes an ultrasonic transmitter configured to provide ultrasonic irradiation to a target site, optionally wherein the ultrasonic irradiation has one or more focused regions in the target site. The one or more focused regions may be provided by a single transducer or multiple transducers.

[0022] In a further preferred embodiment, the heat source includes one or more of the following:

[0023] An electromagnetic transmitter is configured to provide electromagnetic radiation to a target location.

[0024] A fluid pump configured to deliver fluid to a target location and a heater configured to heat the fluid before it reaches the target location; and / or

[0025] A conductive heat emitter is configured to deliver heat to a target area via thermal conduction.

[0026] In yet another preferred embodiment, the device further includes an electronic controller for electronically controlling the electromagnetic transmitter and the heat source.

[0027] Another aspect of the invention relates to a method for treating a cancerous target site using an apparatus according to the foregoing embodiments, wherein the apparatus can employ any configuration disclosed herein, and wherein the method is preferably implemented by appropriately positioning an emitter 10 and a heat source 20 on a patient. For example, the applicator of the electromagnetic emitter 10 can be placed at a predetermined point on the patient's body, and the heat source 20 (e.g., regarding...) Figure 2The described transducer 204 can also be appropriately positioned. The method includes:

[0028] In step S1, an electromagnetic transmitter 10 is used to provide a non-ionizing alternating electromagnetic field to supply magnetic flux density at the target location.

[0029] In step S2, heat (more specifically, direct heat) is provided to the target area using heat source 20. This can also be done simultaneously with or before or after providing an electromagnetic field to the target area 30 for a predetermined time. In some embodiments, an alternating electromagnetic field may be provided only to generate magnetic flux density at the target area without heating for a first time period, and then both may be provided to the target area simultaneously.

[0030] Optionally, in step S3, the anticancer composition is provided to the target site. The anticancer composition can be administered by any suitable means, such as orally or intravenously. It should be noted that the anticancer composition can be provided before or simultaneously with steps S1, S2, and S4, or at a predetermined time after steps S1, S2, or S4.

[0031] Examples of anticancer compositions that can be used to carry out the present invention are described in detail throughout the present invention.

[0032] Optionally, in step S4, in addition to the anticancer compound, a glutathione (GSH) depleting composition is also provided to the target site. The GSH depleting composition can be administered by any suitable method, such as orally or intravenously. It should be noted that the GSH depleting composition can be provided before or simultaneously with steps S1, S2, and S3, or at a predetermined time after steps S1, S2, or S3, preferably at a predetermined time after step S3. Examples of GSH depleting compositions that can be used to practice the invention are described in detail throughout this invention.

[0033] In step S5, direct heating is stopped, and in step S6, the non-ionizing alternating electric field is stopped. It should be noted that steps S5 and S6 can occur simultaneously, or direct heating can be stopped before the non-ionizing alternating electromagnetic field is stopped, so that only the non-ionizing alternating electromagnetic field is applied for a predetermined time after direct heating is stopped.

[0034] Another aspect of the invention relates to an anticancer composition for use in a method of treating a cancerous target site using an apparatus according to the foregoing embodiments, wherein the apparatus can employ any configuration disclosed herein, and wherein the method is preferably implemented by suitably positioning an emitter 10 and a heat source 20 on a patient. For example, the applicator of the electromagnetic emitter 10 can be placed at a predetermined point on the patient's body, and the heat source 20 (e.g., transducer 204) can also be suitably positioned. The method includes:

[0035] In step S1, an electromagnetic transmitter 10 is used to provide a non-ionizing alternating electromagnetic field to supply magnetic flux density at the target location.

[0036] In step S2, heat (more specifically, direct heat) is provided to the target area using heat source 20. This can be done simultaneously with or before or after a predetermined time period when an electromagnetic field is also provided to the target area 30. In some embodiments, an alternating electromagnetic field may be provided only to generate magnetic flux density at the target area without heating for a first time period, and then both may be provided to the target area simultaneously.

[0037] In step S3, the anticancer composition is provided to the target site. The anticancer composition can be administered by any suitable means, such as oral or intravenous. It should be noted that the anticancer composition can be provided before or simultaneously with steps S1, S2, and S4, or at a predetermined time after steps S1, S2, or S4. Examples of anticancer compositions that can be used to practice the present invention are described in detail throughout this invention.

[0038] Optionally, in step S4, in addition to the anticancer compound, a glutathione (GSH) depleting composition is also provided to the target site. The GSH depleting composition can be administered by any suitable method, such as orally or intravenously. It should be noted that the GSH depleting composition can be provided before or simultaneously with steps S1, S2, and S3, or at a predetermined time after steps S1, S2, or S3, preferably at a predetermined time after step S3. Examples of GSH depleting compositions that can be used to practice the invention are described in detail throughout this invention.

[0039] In step S5, direct heating is stopped, and in step S6, the non-ionizing alternating electric field is stopped. It should be noted that steps S5 and S6 can occur simultaneously, or direct heating can be stopped before the non-ionizing alternating electromagnetic field is stopped, so that only the non-ionizing alternating electromagnetic field is applied for a predetermined time after direct heating is stopped. Attached Figure Description

[0040] The implementation scheme will now be explained in detail by way of non-limiting example only, with reference to the accompanying drawings described below.

[0041] Figure 1 A schematic diagram of a device for treating cancerous target sites according to one or more embodiments is shown;

[0042] Figure 2 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0043] Figure 3 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0044] Figure 4 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0045] Figure 5 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0046] Figure 6 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0047] Figure 7 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0048] Figure 8 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0049] Figure 9 A schematic diagram of a device for treating cancerous target sites is shown according to one or more other embodiments;

[0050] Figure 10 A schematic diagram of a device for treating cancerous target sites according to one or more embodiments is shown;

[0051] Figure 11 A schematic diagram of a method for treating a cancerous target site using the device according to the present disclosure is shown;

[0052] Figure 12Experimental data demonstrating the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), stigmatae (“PT”), and their combinations on U87MG cells are presented. The TT field was applied at 300 kHz for 240 minutes (from minute 0 to minute 240), with a mean magnetic flux density of 8 μT. Hyperthermia was applied at 42°C for 10 minutes (from minute 120 to minute 130). 20 μM stigmatae was applied for 120 minutes (from minute 120 to minute 240). Data show the mean viable cell count across 5 experiments, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #.

[0053] Figure 13 In vitro experimental data on the effect of exposure to an oscillating magnetic field on the cell viability of U87MG(ATCC) cells are presented;

[0054] Figure 14 In vitro experimental data showing the effect of heat exposure on the cell viability of U87MG cells;

[0055] Figures 15A to 15F Microscopic images of in vitro U87MG cell cultures exposed to different external treatments are shown, along with control images;

[0056] Figure 16 In vitro experimental data on the effects of exposure to electromagnetic fields, heat, and temozolomide (TMZ) on the cell viability of U87MG cells are presented;

[0057] Figure 17 In vitro experimental data show the effects of exposure to electromagnetic fields, heat, and resveratrol or its derivatives on the cell viability of U87MG cells;

[0058] Figure 18 In vitro experimental data show the effect of cell exposure to an oscillating magnetic field on the cell viability of AsPC1 (pancreatic adenocarcinoma, ATCC).

[0059] Figure 19 In vitro experimental data on the effect of heat exposure on AsPC1 cell viability are presented;

[0060] Figure 20 Experimental data showing the in vitro effects of TT field (“TTF”), thermotherapy (“HT”), pterostilbene (“PT”) and combinations thereof on AsPC1 cells are presented;

[0061] Figures 21A to 21H Microscopic images of in vitro AsPC1 cell cultures exposed to different external treatments and control images are shown.

[0062] Figure 22 Experimental data showing the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), gemcitabine (“GEM”), pterostilbene (“PT”) and combinations thereof on AsPC1 cells are presented.

[0063] Figure 23 In vitro experimental data on the effect of exposure to an oscillating magnetic field on the cell viability of A2058 (melanoma, ATCC) cells are presented.

[0064] Figure 24 In vitro experimental data on the effect of heat exposure on the cell viability of A2058 cells are presented;

[0065] Figure 25 Experimental data showing the in vitro effects of TT field (“TTF”), thermotherapy (“HT”), pterostilbene (“PT”) and combinations thereof on A2058 cells are presented;

[0066] Figures 26A to 26H Microscopic images of in vitro A2058 cell cultures exposed to different external treatments and control images are shown.

[0067] Figure 27 Experimental data showing the in vitro effects of TT field (“TTF” and “TTF” are used interchangeably), hyperthermia (“HT”), paclitaxel (“PAC”), and combinations thereof on A2058 cells are presented. Detailed Implementation

[0068] This invention relates to an apparatus configured to provide a non-ionizing alternating electromagnetic field and hyperthermia to a target site, wherein the electromagnetic field and hyperthermia can be provided independently. The electromagnetic field can be applied, for example, by a magnetic applicator that provides magnetic flux density in the target site. In hyperthermic treatment involving mediators, an alternating electromagnetic field that can also be absorbed by the mediator is provided. However, the tumor therapeutic effect of the electromagnetic field may be reduced when the mediator absorbs electromagnetic energy. This invention overcomes this problem by providing hyperthermia independently, allowing both treatments to be provided to the cancerous site without reducing the effectiveness of the other. In this invention, the tumor therapeutic effect is due to the combined application of the electromagnetic field and direct hyperthermia. The electromagnetic field can be introduced using a magnetic field applicator. In some further examples of this disclosure, the treatment may also include the administration of an anticancer composition.

[0069] As used herein, the terms “tumor therapeutic field,” “TT field,” or “TTF” can be understood as referring to an oscillating electromagnetic field applied to a target site. Specifically, the electromagnetic field is generated by an applicator that is electrically isolated from the target site, such that current does not flow between the target site and the applicator.

[0070] Figure 1A schematic diagram of an apparatus 1 for treating a cancerous target site 30 is shown. The apparatus includes an electromagnetic emitter 10 and a heat source 20. The electromagnetic emitter 10 is configured to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. The heat source 20 is configured to provide direct heating 25 at the target site 30 to induce hyperthermia. In one configuration, the apparatus 1 is configured to provide a non-ionizing alternating electromagnetic field and direct heating at the target site 30 for a predetermined time period. The target site 30 may include at least a cancerous growth and may also include some tissue surrounding the cancerous growth. In some embodiments, the apparatus 1 may be configured to provide a non-ionizing alternating magnetic field 15.

[0071] As disclosed herein, hyperthermia can be defined as a temperature rise above 37.5°C. Therefore, the device disclosed herein can be configured to heat a target area to a temperature above 37.5°C. It should be noted that hyperthermia is defined as a temperature above 37.5°C to 38.3°C (depending on the reference value used) and occurs without a change in the body temperature set point. In contrast, hyperpyrexia is an extreme increase in body temperature, classified, depending on the source, as a core body temperature greater than or equal to 40.0 or 41.0°C; the range of hyperpyrexia includes conditions considered severe (≥40°C) and extreme (≥42°C). The difference between hyperpyrexia and hyperthermia is that in hyperpyrexia, the body's temperature regulation system is set above normal, and the body generates heat to reach that temperature. Conversely, hyperthermia refers to a rise in body temperature above the set point due to external factors.

[0072] In addition, it is worth noting that thermal ablation is a surgical procedure that uses heat, cold, microwaves, and electric current to evaporate (ablate) cancer cells and tumors by heating them to above 50°C.

[0073] In a preferred embodiment, the device is configured to heat the target site to a temperature of 39°C to 52°C (heating above 39°C increases the sensitivity of cancerous growth to other therapies such as TT therapy, chemotherapy, and radiotherapy) and preferably to a temperature of at least 41.1°C (advantageously, temperatures above this can cause irreversible damage to cells). Preferably, the heat source is configured to heat the target site to a temperature of at least 42°C, and more preferably 42°C to 57°C. Heating the target site to at least 42°C produces a thermal effect on the target site, which is equivalent to extreme heat.

[0074] The heat source 30 can be any suitable heat source for providing direct heating to the target portion 30, and can include electromagnetic heating, such as capacitive radio frequency heating, radiative radio frequency heating, microwave heating, infrared heating and laser heating, ultrasonic heating, heating via a heating fluid, heating via a conductive heat emitter, or any other suitable method of heating the target portion 30 independently of the non-ionizing alternating electromagnetic field 15. The heat source 30 can be any heat source that heats the target portion without using a medium (e.g., directly rather than indirectly via a medium).

[0075] In any of the embodiments disclosed herein, the electromagnetic emitter 10 may be configured to provide an electromagnetic field 15 with a frequency of 10 kHz to 500 kHz, and more preferably 10 kHz to 300 kHz. The electromagnetic field may have a magnetic flux density of 0.1 pT to 1 mT, or 0.1 pT to 100 μT, or 100 μT to 1 mT, and / or a corresponding electric field of 1 V / cm to 3 V / cm, depending on the tissue impedance (i.e., taking into account the possible field attenuation as the field travels from the electromagnetic emitter 10 to the target site 30, which can be determined based on the impedance generated by different types of tissue present between the electromagnetic emitter 10 and the target site 30). As mentioned above, the electromagnetic field 15 is non-ionizing, and its mechanism at cancerous sites differs from that of ionizing radiation discussed in the Background section of this disclosure. Furthermore, due to the relatively low intensity of the oscillating field, the electromagnetic field 15 itself does not provide direct heating to the target site 30.

[0076] It will be understood that in any of the embodiments disclosed herein, the electromagnetic transmitter 10 and the heat source can be powered by any energy source, and can be powered by the same or different energy sources. Similarly, each of the electromagnetic transmitter 10 and the heat source 20 may include a user interface for selecting operating parameters (frequency, field strength, amplitude, etc.) for each transmitter, or the transmitter 10 and the heat source 20 may include a pre-programmed sequence for the user to emit electromagnetic radiation and heat according to a selectable predetermined program.

[0077] In any of the embodiments disclosed herein, the device may further include a temperature-sensing element for measuring the temperature of the target site 30. For example, the device may include an implantable temperature-sensing probe configured to be implanted near the target site 30 to measure and indicate the temperature of the target site 30. The probe may include, for example, a thermocouple, a thermistor, and / or a fiber optic sensor. In other embodiments, non-invasive temperature measurement methods, such as infrared sensing, CT thermometry, or magnetic resonance thermometry, may be used.

[0078] Figure 2 A schematic diagram of an electromagnetic transmitter 10 and a heat source 200 according to one or more embodiments is shown.

[0079] The electromagnetic emitter 10 may include one or more sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. Applicators 14 may be configured to be placed on or near the surface of the patient's body 35 and electrically insulated from the patient's body (i.e., not forming a closed circuit between the source 12 and the patient's body). In some embodiments, applicators 14 may include one or more electrodes having an electrically insulating coating to prevent electrical contact between the electrodes and the patient's surface and thus with the target site. It should be noted that even when applicators are placed on the surface of the patient's body 35, they remain electrically insulated from the body by, for example, the presence of an electrically insulating coating. The source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14. In some embodiments, the applicator 14 may include a coil having positive and negative terminals. One or more sources may be configured to provide alternating current through the coil to generate a magnetic field outside the coil. The coil may include any number of turns, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, or 100, 500 or more.

[0080] Figure 2 The heat source 200 shown may be an ultrasonic transmitter and may include an ultrasonic source 202 that transmits ultrasonic signals to one or more transducers 204. The transducers 204 are configured to deliver focused ultrasonic irradiation 205 to a target site 30. For example, one or more transducers 204 may include one or more piezoelectric transducers. One or more transducers 204 may include one or more plastic and / or ceramic transducers. A coupling medium (not shown) may be disposed on a patient body 35 between the transducers 204 and the patient body 30 to improve the transmission of ultrasonic waves from the transducers 204 into the patient body 30 (i.e., reduce ultrasonic wave reflection). The coupling medium is defined herein as any suitable solid or liquid (or combination thereof) for improving the transmission of ultrasonic waves from the transducers 204 into the patient body 30. The shape of the transducers 204 may be selected to select the amount of focused ultrasound, and the shape of the transducers 204 may be selected to focus ultrasonic irradiation 205 onto one or more focused areas in the target site 30. For example, one or more transducers 204 may be 3D printed or otherwise manufactured into a custom shape configured to propagate focused ultrasonic irradiation to one or more focused regions within the target site 30.

[0081] The ultrasonic transmitter 200 can be configured to provide acoustic energy at a frequency of 0.5 to 10 MHz to provide heating at the target site 30.

[0082] In some embodiments, the ultrasonic transmitter 200 may include one or more multi-transducer arrays or phased arrays, planar devices, or bowl-shaped sources. Furthermore, the ultrasonic transmitter 200 may be configured to emit ultrasonic radiation within a gap. That is, the ultrasonic transmitter 200 may include one or more transducers or other emitting components mounted on a conduit, configured to be inserted into the body 35 at or near the target site 30 to emit ultrasonic radiation to one or more points at the target site 30 to provide the desired heating.

[0083] Although Figure 2 The specific configuration of the ultrasound transmitter is shown, but it should be noted that any suitable ultrasound transmitter can be used. For example, any high-intensity focused ultrasound (HIFU) device, such as MRI-guided focused ultrasound, can be used.

[0084] An ultrasonic transmitter 200 is configured to emit ultrasonic radiation 205 toward a target site 30 to induce heating at the target site. Specifically, the ultrasonic transmitter 200 is configured to heat the target site to a predetermined temperature, preferably 42°C or lower, and maintain the temperature at the predetermined temperature while applying an electromagnetic field. It should be understood that the ultrasonic transmitter 200 can be configured to heat the target site 30 by providing ultrasonic radiation with a predetermined frequency and amplitude, which induces the desired heating at the target site 30. The ultrasonic radiation can be a continuous wave or a pulsed wave. For a given frequency, amplitude, and type of ultrasonic radiation, the amount of heating at the target site can be determined through conventional experiments.

[0085] What will be understood is that, for Figure 2 In one implementation, the power output of source 202 and the duration of ultrasonic irradiation can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein the device applies heat to achieve and maintain a target temperature at the target site 30.

[0086] Figure 3 A schematic diagram of an electromagnetic transmitter 10 and a heat source 300 according to one or more embodiments is shown. Figure 2In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0087] Heat source 300 includes one or more antennas or applicators 304 configured to provide an electromagnetic field 305 to directly heat target portion 30. Heat source 300 includes one or more electromagnetic sources 302 to drive one or more antennas or applicators 304 to provide the heating electromagnetic field 305. Electromagnetic field 305 has a field strength and frequency that causes heating of the target portion. The frequencies of electromagnetic fields 305 have sufficient difference (e.g., at least an order of magnitude difference) to allow electromagnetic fields 305 and 15 to interact independently with target portion 30 (i.e., to allow negligible electromagnetic interference between fields). The frequency of electromagnetic field 305 can be, for example, higher than 1 MHz to induce dielectric heating of target portion 30 through molecular dipole rotation, polarization, and / or vibration, or Ohm's law. The number and configuration of antennas or applicators 304, including their position, relative amplitude, and phase, can be selected to produce constructive and / or destructive interference and induce heating only in a specific volume including target portion 30. Antennas or applicators 304 can include a single antenna, a pair of antennas, and a 2D or 3D antenna array or phased array.

[0088] In some embodiments, the electromagnetic source 302 is a radio frequency (RF) source configured to operate at frequencies from 8 MHz to 30 MHz (e.g., 8 MHz, 13.56 MHz, or 27.12 MHz) to induce capacitive heating. One or more antennas or applicators 304 include a pair of metallic applicators with the target site 30 positioned between them. Optionally, the applicators may be coupled to a water sac or other medium to transfer a field into the body 35. When the RF field is applied to the applicator, power is transferred to the target site 30 and causes heating. This technique can be used for both superficial and deep tumors by focusing the generated electric field at the target site 30 through the selection of applicators with different configurations. Alternatively, the applicators may be provided as coplanar, or one or more applicators may be configured to be placed within the body 35 within an insulated conduit. Alternatively, a single applicator coupled to an external ground plane may be used. In all these configurations, the RF field generated at the target site causes direct heating.

[0089] In some embodiments, the electromagnetic source 302 is an RF source configured to operate at frequencies from 60 MHz to 150 MHz. One or more antennas or applicators 304 include one or more antennas placed externally to the body. The electromagnetic field generated in this frequency range penetrates deep into the body, thus being suitable for heating deep target areas 30. Similarly, one or more antennas may include a pair of antennas with the target area 30 positioned between them. The antennas may be coupled to a water sac or other medium to transfer the electromagnetic field into the body 35.

[0090] In some embodiments, the electromagnetic source 302 is a microwave (MW) source configured to operate at frequencies from 400 MHz to 2.5 GHz (e.g., 433 MHz, 915 MHz, or 2.45 GHz). One or more antennas may comprise a pair of antennas or an array of one or more antennas, with the target portion 30 positioned between the antennas. The antennas may be recoupled to a water sac or other medium to transfer the electromagnetic field into the body 35.

[0091] What will be understood is that, for Figure 3 In one implementation, the power output of source 302 and the duration of application can be selected to achieve a predetermined amount of heating at target location 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of target location 30, wherein heat is applied to achieve and maintain a target temperature at target location 30.

[0092] Figure 4 A schematic diagram of an electromagnetic transmitter 10 and a heat source 400 according to one or more embodiments is shown. Figure 2 and Figure 3 In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0093] The heat source 400 includes an electromagnetic source 402 and one or more electromagnetic transmitters 404 configured to penetrate the body 35 such that a distal portion of the transmitter can be positioned within a target site 30. One or more transmitters 404 are electrically connected to the electromagnetic source 402 such that current is applied to the transmitters 404. The one or more transmitters 404 may include one or more monopole, dipole, slotted, or helical coil microwave antennas, resistively coupled radio frequency (RF) electrodes, localized current field electrodes, or capacitively coupled RF conduit electrodes. The capacitively coupled electrodes may be configured to be contained within a low-loss conduit, such as a nylon or polytetrafluoroethylene (PTFE) conduit.

[0094] In some embodiments, the electromagnetic source 402 is configured to provide an alternating current with a frequency range of 350 kHz to 30 MHz to one or more transmitters 404, which induces a current in the tissue region near the needle, thereby heating the tissue. In other embodiments, the electromagnetic source 402 is configured to provide an alternating current with a frequency range of 900 MHz to 2.5 GHz (e.g., 915 MHz or 2.45 GHz) to one or more transmitters 404, which causes dielectric heating of the tissue surrounding the needle.

[0095] In other embodiments, the transmitter 404 includes a plurality of electrodes configured to be implanted around the target site 30, and the electromagnetic source 402 is configured to provide a series of very short (e.g., about 100 μs) DC pulses between the electrodes. The voltage of the pulses and the positioning of the electrodes are configured to provide a high field strength (e.g., from about 100 V / cm to 3000 V / cm). Such pulses have been observed to provide heating to the target site 30.

[0096] What will be understood is that, for Figure 4 In one implementation, the power output of source 402 and the duration of application can be selected to achieve a predetermined amount of heating at the target location 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target location 30, wherein heat is applied to achieve and maintain the target temperature at the target location 30.

[0097] Figure 5 A schematic diagram of an electromagnetic transmitter 10 and a heat source 500 according to one or more embodiments is shown. Figures 2 to 4In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0098] The heat source 500 includes one or more infrared light sources 504 configured to provide infrared radiation 505 to the target area 30, and an energy source 502 for powering the one or more infrared lights. The infrared light sources 504 can emit infrared light of any frequency, and particularly frequencies above 300 GHz. The penetration depth of infrared radiation is typically 1 cm or less, thus the device is suitable for target areas 30 located on the surface of the body 35.

[0099] Furthermore, the power output of the energy source 502 and the duration of the applied radiation can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein heat is applied to achieve and maintain the target temperature at the target site 30.

[0100] Figure 6 A schematic diagram of an electromagnetic transmitter 10 and a heat source 600 according to one or more embodiments is shown. Figures 2 to 5 In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0101] The heat source includes a laser source 604 and an energy source 602 configured to power the laser source. The laser source 604 can be configured to emit laser radiation toward a target site 30 to cause heating at the target site. The laser radiation can be optically guided directly to the target site via an optical fiber to cause localized ablation of the target site 30. The laser source 604 can be configured to emit laser radiation with a wavelength of 900 nm to 1100 nm at any suitable intensity to cause the desired heating at the target site 30. The laser source 604 can be configured to operate at a power of 0.5 W to 15 W (e.g., 15 W at 980 nm or 12 W at 1064 nm). The laser source 604 can be rotated and linearly moved to target multiple regions within one or more target sites 30.

[0102] The power output of the energy source 602 and the duration of the applied laser radiation can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein heat is applied to achieve and maintain a target temperature at the target site 30. For example, the device may include an MRI device to perform magnetic resonance thermometry to monitor the temperature of the target site 30 during heating.

[0103] Figure 7 A schematic diagram is shown of an electromagnetic transmitter 10 and a heat source 700 for heating a target portion 30 according to one or more embodiments. Figures 2 to 6 In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to form a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0104] The heat source 700 includes a heater 702, a pump 704, a fluid output 706, and a fluid input 708. The fluid output 706 is configured to fluidly connect to a body portion 35 located upstream of the target site 30, and the fluid input 708 is configured to fluidly connect to a body portion 35 located downstream of the target site 30. When connected, a fluid loop is formed from the target site 30 to the pump 704 and back to the target site 30. The fluid loop can be configured to form in any fluid system of the body 35, such as a blood vessel, kidney, or similar system. The heater 702 is configured to heat the fluid to a desired temperature as it passes through the heat source 700, and then deliver the fluid to the target site 30 via the fluid output 706. Thus, the fluid loop provides a continuous source of heated fluid to the target site 30. It should be noted that the fluid may be the patient's blood, or alternatively, the heat source 700 may include a fluid reservoir (not shown) configured to be heated and added to the fluid loop. For example, the fluid may include a chemotherapy composition, an anticancer drug or the like, or may include a biocompatible solution, such as a saline solution or the like.

[0105] Heater 702 can be any suitable heater, such as a resistance heater or an electromagnetic heater configured to heat the fluid by emitting, for example, microwave radiation. Heater 702 can be located outside the body 35 or can be configured to be implanted in the body 35.

[0106] The amount of heat provided by the heat source 700 and the duration of application of the heat source 700 can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein heat is applied to achieve and maintain the target temperature at the target site 30.

[0107] Figure 8 A schematic diagram is shown of an electromagnetic transmitter 10 and a heat source 800 for heating a target portion 30 according to one or more embodiments. Figures 2 to 7 In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0108] The heat source 800 includes a heater 802, a reservoir 805, a pump 804, and a fluid output 806. The fluid output 806 is configured to be fluidly connected to a target site 30. In use, the pump 804 is configured to pump fluid from the reservoir 805 to the target site 30 via the fluid output 806. The heater 802 is configured to heat the fluid in the reservoir 805 to a desired temperature before pumping the fluid to the target site 30. The fluid may include a chemotherapy composition, an anticancer drug, or the like, or may include a biocompatible solution, such as a saline solution or the like.

[0109] The amount of heat provided by the heat source 800, the amount of fluid provided from the storage unit 805, and the duration of application of the heat source 800 can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein heat is applied to achieve and maintain a target temperature at the target site 30.

[0110] Figure 9 A schematic diagram is shown of an electromagnetic transmitter 10 and a heat source 900 for heating a target portion 30 according to one or more embodiments. Figures 2 to 8 In such cases, the electromagnetic emitter 10 may include one or more electromagnetic sources 12 (e.g., one or more current or voltage sources) electrically connected to one or more applicators 14. The applicator 14 may be configured to be placed on the surface of the patient's body 35. The electromagnetic source 12 may be configured to provide an alternating electromagnetic field to the applicator 14, which in turn generates a magnetic flux density at the target site 30 to provide a non-ionizing alternating electromagnetic field 15 at the target site 30. It will be understood that any number of applicators 14 may be used depending on the type of target site, and the intensity of the magnetic flux density obtained at the target site 30 can be readily calculated based on the settings by superimposing the electromagnetic fields emitted by each applicator 14.

[0111] The heat source 900 includes a heat emitter 904 configured to provide conductive heating to the target site 30. The heat source may include an energy source 902 (e.g., a power source) that powers the heat emitter 904, or the heat emitter 904 may be preheated or chemically self-heating (e.g., through an exothermic chemical reaction). The heat emitter 904 may be disposed on the surface of the body 35 or may be configured to be implanted inside the body to provide heat to the target site 30 at a location near the target site. For example, the heat emitter 904 may be an implantable resistance heater configured to be powered by a power source 902. The heat emitter 904 may be configured to heat a localized area of ​​the body 35 or may be configured to heat the entire body 35.

[0112] The amount of heat provided by the heat source 900 and the duration of application of the heat source 900 can be selected to achieve a predetermined amount of heating at the target site 30. This can be determined through prior empirical measurements, or the device can additionally include a thermometer component for measuring the temperature of the target site 30, wherein heat is applied to achieve and maintain the target temperature at the target site 30.

[0113] Figure 10 A schematic diagram of a device 1 for treating cancerous target sites, according to one or more embodiments, is shown. Figure 1 In such a case, the device includes an electromagnetic emitter 10 and a heat source 20. The electromagnetic emitter 10 is configured to provide magnetic flux density at the target site. The heat source 20 is configured to provide direct heating at the target site to induce hyperthermia at the target site via any of the mechanisms disclosed herein. In one configuration, the device 1 is configured to simultaneously provide a non-ionizing alternating electromagnetic field and direct heating at the target site. The electromagnetic emitter 10 and the heat source 20 can be in any suitable configuration and can be employed in various ways. Figures 2 to 9 The configuration shown.

[0114] Figure 10 The illustrated apparatus 1 also includes a controller 40 for controlling the transmitter 10 and the heat source 20. The controller includes a first control interface 41 for controlling the operation of the electromagnetic transmitter 10 and a second control interface 42 for controlling the operation of the heat source 20. The controller 40 is configured to provide control signals to the transmitter 10 and the heat source 20 via the control interfaces 41 and 42. The transmitter 10 and the heat source 20 can receive the control signals via any suitable form of communication, whether wired or wireless, such as optical, fiber optic, Ethernet, or the like, or any suitable wireless communication. The controller 40 can also be configured to power one or more of the transmitter 10 and the heat source 20, or one or more of the transmitter 10 and the heat source 20 can be powered independently of the controller 40.

[0115] The controller 40 also includes one or more of a user interface 43, a memory 44, and a processor 45. The user interface 43 allows the user to manually control the operation of the transmitter 10 and the heat source 20, for example, by controlling the operating parameters of the transmitter 10 and the heat source 20 and turning their operation on or off. The user interface 43 may allow the user to select the operating sequence of the transmitter 10 and the heat source 20 for a certain period of time. The memory 44 may contain instructions that, when executed by the processor 45, cause the transmitter 10 and the heat source 20 to operate according to any suitable sequence, including the operating sequence disclosed herein.

[0116] Memory 44 may include one or more volatile or non-volatile memory devices, such as DRAM, SRAM, flash memory, read-only memory, ferroelectric RAM, hard disk drive, floppy disk, magnetic tape, optical disk, or the like. Similarly, processor 45 may include one or more processing units, such as a microprocessor, GPU, CPU, multi-core processor, or similar processor. Controller 40 may also be implemented in software, hardware, or any combination thereof to perform the operating sequences disclosed herein.

[0117] Figure 11 A schematic diagram is shown of a method for treating a cancerous target site using the device according to this disclosure. The device can be employed in any configuration disclosed herein. In implementation... Figure 11 Prior to this method, the transmitter 10 and the heat source 20 can be appropriately positioned on the patient. For example, the applicator of the electromagnetic transmitter 10 can be placed at a predetermined point on the patient's body, and the heat source 20 (e.g., transducer 24) can also be appropriately positioned.

[0118] In step S1, an electromagnetic transmitter 10 is used to provide a non-ionizing alternating electromagnetic field to supply magnetic flux density at the target location.

[0119] In step S2, heat (more specifically, direct heating) is provided to the target area using heat source 20. This can be done simultaneously with or before or after a predetermined time when an electromagnetic field is also provided to the target area 30. In some embodiments, an alternating electromagnetic field may be provided only to generate magnetic flux density at the target area without heating for a first time period, and then both may be provided to the target area simultaneously.

[0120] Optionally, in step S3, the anticancer composition is provided to the target site. The anticancer composition can be administered by any suitable means, such as oral or intravenous. It should be noted that the anticancer composition can be provided before or simultaneously with steps S1, S2, and S4, or at a predetermined time after steps S1, S2, or S4.

[0121] As used herein, the term "anticancer composition" refers to a composition comprising an agent that at least partially inhibits the occurrence or progression of cancer, including complete or partial inhibition of cancer-related symptoms. As used herein, the term "cancer" refers to a disease characterized by uncontrolled cell division (or increased resistance to survival or apoptosis), and the ability of said cells to invade other adjacent tissues (invasion) and spread via lymphatic vessels and blood vessels to other areas of the body where such cells would normally not be present (metastasis), circulate in the bloodstream, and then invade normal tissues elsewhere in the body. Tumors are classified as benign or malignant based on their ability to spread through invasion and metastasis: benign tumors are tumors that cannot spread through invasion or metastasis, i.e., they grow only locally; while malignant tumors are tumors that can spread through invasion and metastasis. An anticancer composition may comprise one or more anticancer compositions, including… Figures 12 to 27 One or more of those disclosed in the document.

[0122] As used herein, the term cancer preferably refers to solid tumors and / or invasive tumors.

[0123] As used in this article, "solid tumor" is understood to be an abnormal mass of tissue that does not typically contain cysts or fluid-filled areas. Different types of solid tumors are named according to the type of cells that form them. Examples of solid tumors include sarcomas, carcinomas, and lymphomas. Leukemia (blood cancers) typically does not form solid tumors.

[0124] As used in this article, "invasive tumor" is understood as a tumor with an abnormal tumor structure that simultaneously exhibits prominent growth nodules and invasive growth.

[0125] Preferably, the present invention relates to cancers, including but not limited to the following types: breast cancer; biliary tract cancer; bladder cancer; brain cancer, including glioblastoma (particularly glioblastoma multiforme) and medulloblastoma; cervical cancer; head and neck cancer; choriocarcinoma; colon cancer, colorectal cancer; endometrial cancer; esophageal cancer; gastric cancer; intraepithelial neoplasia, including Bowen's disease and Paget's disease; liver cancer, hepatocellular carcinoma; lung cancer, pleural mesothelioma; oral cancer, including squamous cell carcinoma; parotid gland cancer; ovarian cancer, including cancers arising from epithelial cells, stromal cells, germ cells, and mesenchymal cells. Ovarian cancer; pancreatic cancer; prostate cancer; kidney cancer, adrenal cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma; skin cancer, including melanoma, Merkel cell carcinoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma; cervical cancer, endometrial cancer; testicular cancer, including germ cell tumors such as seminoma, non-seminomatous tumors (teratoma, choriocarcinoma), stromal tumors, and germ cell tumors; thyroid cancer, including thyroid adenocarcinoma and medullary carcinoma; and kidney cancer, including adenocarcinoma and Wilms' tumor.

[0126] In the specific implementation plan, the cancer is melanoma. As used herein, the term "melanoma" refers to a malignant skin tumor of melanocytes, including but not limited to melanoma, metastatic melanoma, melanoma originating from melanocytes or melanocyte-associated nevus cells, melanoma carcinoma, melanocyte epithelioma, melanosarcoma, in situ melanoma, superficial spreading melanoma, modular melanoma, lentigines-like malignant melanoma, acral lentigines-like melanoma, invasive melanoma, and familial atypical nevus melanoma (FAM-M) syndrome. Furthermore, the term "melanoma" refers not only to primary melanoma but also to "melanoma metastasis," which, as used herein, refers to the spread of melanoma cells to local lymph nodes and / or distant organs. Given that melanomas contain multiple cell populations characterized by different growth rates, karyotypes, cell surface properties, antigenicity, immunogenicity, invasion, metastasis, and sensitivity to cytotoxic drugs or biologics, this event occurs frequently. Melanoma frequently metastasizes to the brain, lungs, lymph nodes, and skin. Other cancers are known to those skilled in the art.

[0127] Figure 12 Experimental data demonstrating the in vitro effects of a TT field (“TTF”), hyperthermia (“HT”), stigmatae (“PT”), and their combinations on U87MG cells are presented. The TT field was applied at 300 kHz for 240 minutes (from minute 0 to minute 240), with a mean magnetic flux density of 8 μT. Hyperthermia was applied at 42°C for 10 minutes (from minute 120 to minute 130). 20 μM stigmatae was applied for 120 minutes (from minute 120 to minute 240). Data show the mean viable cell count across five experiments, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #. A solenoid was used to apply the magnetic field, with a magnetic flux density of approximately 100 μT at the central axis of the solenoid. The solenoid is placed at a certain distance from the cell culture, so that the average electric field strength on the surface of the culture flask to which the cells are attached is 8 μT.

[0128] It should be noted that, as previously pointed out, and as... Figure 12 As can be seen, the anticancer effects of hyperthermia enhanced by non-ionizing alternating electromagnetic fields (TT fields) have been discovered. Specifically, this combination allows for hyperthermia at much lower temperatures (42°C or lower) while still reducing cell viability. This also means that a larger volume of tissue heated by hyperthermia can be targeted. Therefore, the device disclosed herein provides an effective method for treating cancerous sites by applying a TT field and directly heating the cancerous site (i.e., without a mediator). Further, as Figure 12As shown, the combination of TT field, thermotherapy, and styrax effectively eliminated all cells in vitro. Since the dosage of styrax is well-tolerated in vivo, the combined therapy is not expected to produce any substantial side effects in vivo.

[0129] Figure 13 In vitro experimental data on the effects of exposure to various oscillating magnetic fields on cell viability of U87MG (ATCC) cells are presented. Different cell cultures were exposed to one of the following magnetic fields: 24 μT at 100 kHz; 12 μT at 200 kHz; 8 μT at 300 kHz; or 6 μT at 400 kHz. Cell viability was measured at each frequency after 1, 2, 3, 4, and 5 hours. Five independent experiments were performed at each frequency and time point. Data for each frequency show the mean cell viability and standard deviation over time (from left to right, 1 hour to 5 hours) for the five corresponding experiments. Comparisons between different groups were performed using two-way ANOVA. It can be seen that cell viability decreased at all frequencies, and the effect was further enhanced at frequencies equal to or below 300 kHz. Data were assigned letters “a” to “f” based on statistical tests applied to the data. Data with the same letter were considered statistically similar, while data with different letters were considered significantly different (P < 0.01).

[0130] Figure 14 In vitro experimental data on the effect of heat exposure on the cell viability of U87MG cells are presented. Different cell cultures were heated to temperatures of 37°C, 38°C, 39°C, 40°C, 41°C, or 42°C. Five independent experiments were performed at each temperature and time point. Data for each temperature show the mean cell viability and standard deviation of the five corresponding experiments after 5 minutes and 10 minutes of exposure at that temperature. Hyperthermia equivalent to extreme fever (41°C or above) significantly reduced the viability of U87MG cells. Data marked with * indicate a p-value (Student's t-test) less than 0.01 compared to data at 37°C at the corresponding time point, and data marked with + indicate a p-value less than 0.01 compared to data at 5 minutes at the same temperature after 10 minutes.

[0131] Figures 15B to 15F Microscopic images of in vitro U87MG cell cultures after exposure to different external treatments are shown. Figure 15A Microscopic images showing control in vitro U87MG cell cultures that were not exposed to any external treatment and maintained at a physiological internal temperature of 37°C. Figure 15B Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 8 μT at 300 kHz for 0 to 240 minutes are shown. Figure 15C The image shows cell cultures exposed to 42°C for 10 minutes from minute 120 to minute 130. Figure 15D Cell cultures exposed to 20 μM styrax from 120 to 240 minutes are shown. Figure 15E Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 8 μT at 300 kHz from 0 to 240 minutes and exposed to 20 μM argentide from 120 to 240 minutes are shown. Figure 15E Cell cultures exposed to an electromagnetic field with a flux density of approximately 8 μT at 300 kHz from 0 to 240 minutes, to heating at 42 °C for 10 minutes from 120 to 130 minutes, and to 20 μM styrax (PT) from 120 to 240 minutes are shown. It should be noted that the combination of TTF+HT+PT completely eliminated all U87MG growing cells. This therapy showed similar efficacy in other glioblastoma lines, such as C6 and GL261.

[0132] Figure 16 This study presents in vitro experimental data on the effects of exposure to an electromagnetic field with a magnetic flux density of approximately 8 μT at 300 kHz for approximately 240 minutes (data labeled "TTF"), exposure to a temperature of 42 °C for approximately 10 minutes (data labeled "HT"), and exposure to 50 μM temozolomide (data labeled "TMZ"), as well as combinations thereof, on the cell viability of U87MG cells. Data are presented as the mean of five independent experiments. Data marked with * indicate a p-value (Student's t-test) less than 0.01 compared to the control. Data marked with + indicate a p-value (Student's t-test) less than 0.01 compared to the TTF-only data. Data marked with + indicate a p-value (Student's t-test) less than 0.01 compared to the TTF+HT data.

[0133] Figure 17The data show exposure to an electromagnetic field with a magnetic flux density of approximately 8 μT at 300 kHz for approximately 240 minutes (data labeled "TTF"); exposure to a temperature of 42 °C for approximately 10 minutes from minute 120 to 130 (data labeled "HT"); exposure to 20 μM resveratrol from minute 210 to 240 (data labeled "R"); exposure to 20 μM resveratrol triphosphate from minute 210 to 240 (data labeled "R-triP"); exposure to 20 μM 4'-butyric acid-3,5-dihydroxyphosphonate from minute 210 to 240 (data labeled "B-diOH-s"); exposure to 20 μM 3-glucoside-5,4'-dihydroxyphosphonate from minute 210 to 240 (data labeled "G-diOH-s"); and exposure to 20 μM resveratrol from minute 210 to 240 (data labeled "G-diOH-s"). In vitro experimental data on the effects of 3-amide-5,4'-dihydroxyazine (data labeled "A-diOH-s") and its combinations on the cell viability of U87MG cells. Data are the mean and standard deviation of four independent experiments. Data marked with * indicate a p-value (Student's t-test) less than 0.01 compared to control. Data marked with + indicate a p-value (Student's t-test) less than 0.01 compared to TTF alone. Data marked with + indicate a p-value (Student's t-test) less than 0.01 compared to TTF+HT. It was observed that resveratrol and its derivatives did not eliminate all U87MG cells grown in vitro, but a significant decrease in cell viability was observed in TTF+HT+G-diOH-s.

[0134] The therapeutic effects of heating in combination with tumor therapeutic fields and exposure to PT have also been observed in other in vitro cell lines, such as A2058 (melanoma), AsPC-1 (pancreatic cancer), A549 (lung cancer), MCF-7 (breast cancer), HT-29 (colorectal cancer), PC-3 (prostate cancer), SK-OV-3 (ovarian cancer), and HepG2 (liver cancer).

[0135] Figure 18In vitro experimental data on the effects of exposure to various oscillating magnetic fields on the cell viability of AsPC1 (pancreatic adenocarcinoma, ATCC) cells are presented. Different cell cultures were exposed to one of the following magnetic fields: 2 μT at 100 kHz; 1.5 μT at 200 kHz; 0.7 μT at 300 kHz; or 0.5 μT at 400 kHz. Cell viability was measured at each frequency after 1, 2, 3, 4, and 5 hours for each cell culture. Five independent experiments were performed at each frequency and time point. Data for each frequency show the mean cell viability and standard deviation over time (from left to right, 1 hour to 5 hours) for the five corresponding experiments. Comparisons between different groups were performed using two-way ANOVA. It can be seen that cell viability decreased at frequencies equal to or below 200 kHz. Data were assigned letters “a” and “b” according to the statistical tests applied to the data. Data with the same letter were considered statistically similar, while data with different letters were considered significantly different (P < 0.01).

[0136] Figure 19 In vitro experimental data on the effect of heat exposure on AsPC1 cell viability are presented. Different cell cultures were heated to temperatures of 37°C, 42°C, 47°C, or 52°C. Five independent experiments were performed at each temperature and time point. Data for each temperature show the mean cell viability and standard deviation of the five corresponding experiments after exposure to that temperature for 5, 10, and 20 minutes. Heating to 47°C or higher significantly reduced AsPC1 cell viability. Data marked with * indicate a p-value (Student's t-test) less than 0.01 compared to data at 37°C at the corresponding time point, and data marked with + indicate a p-value less than 0.01 compared to data at 5 minutes at the same temperature for the data at 10 and 20 minutes.

[0137] Figure 20 Experimental data demonstrating the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), stigmataecarpa (“PT”), and their combinations on AsPC1 cells are presented. For TTF data, the TT field was applied at 200 kHz for 240 minutes (from minute 0 to minute 240) with a field strength of 1.5 μT. For HT data, hyperthermia was applied at 52°C for 20 minutes (from minute 120 to minute 140). For PT data, 20 μM stigmataecarpa was applied from minute 0 to minute 240. The data show the mean viable cell count across 5 experiments, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #.

[0138] Figures 21B to 21HMicroscopic images of in vitro AsPC1 cell cultures after exposure to different external treatments are shown. Figure 21A Microscopic images of control in vitro AsPC1 cell cultures that have not been exposed to any external treatment and have been maintained at the optimal temperature for AsPC1. Figure 21B Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz for 0 to 240 minutes are shown. Figure 21C This shows cell cultures exposed to 52°C for 20 minutes from minute 120 to minute 140. Figure 21D Cell cultures exposed to 20 μM styrax from minute 0 to minute 240 are shown. Figure 21E Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes and those exposed to heating at 52 °C for 20 minutes from 120 to 140 minutes are shown. Figure 21F Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes and exposed to 20 μM argentide from minute 0 to minute 240 are shown. Figure 21G Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes, to heating at 52 °C for 20 minutes from 120 to 140 minutes, and to 20 μM styrax (PT) from 0 to 240 minutes are shown. Figure 21H This shows the effect of maintaining cultured cells at 37°C without any treatment for 24 hours. Figure 21G Cell cultures. In Figure 21G 24 hours after the combined treatment, the growing cells did not appear to recover.

[0139] Figure 22 Experimental data demonstrating the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), gemcitabine (“GEM”), pterostilbene (“PT”), and their combinations on AsPC1 cells are presented. For TTF data, the TT field was applied at 200 kHz for 240 minutes (from minute 0 to minute 240) with a field strength of 1.5 μT. For HT data, hyperthermia was applied at 52 °C for 20 minutes (from minute 120 to minute 140). For GEM data, 25 μM gemcitabine was applied from minute 0 to minute 240. For PT data, 20 μM pterostilbene was applied from minute 0 to minute 240. Data show the mean number of viable cells in 5 experiments for each experimental condition, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #. The combined application of all four treatments eliminated AsPC1 cells.

[0140] Figure 23 In vitro experimental data on the effects of exposure to different oscillating magnetic fields on cell viability of A2058 (melanoma, ATCC) cells are presented. Different cell cultures were exposed to one of the following magnetic fields: 2 μT at 100 kHz; 1.5 μT at 200 kHz; 0.7 μT at 300 kHz; or 0.5 μT at 400 kHz. Cell viability was measured at each frequency for each cell culture at 1, 2, 3, 4, and 5 hours. Five independent experiments were performed at each frequency and time point. Data for each frequency show the mean cell viability and standard deviation over time (from left to right, 1 hour to 5 hours) for the five corresponding experiments. Comparisons between different groups were performed using two-way ANOVA. It can be seen that cell viability decreased for all frequencies below 300 kHz. Data were assigned letters “a” and “b” according to the statistical tests applied to the data. Data with the same letter were considered statistically similar, while data with different letters were considered significantly different (P < 0.01).

[0141] Figure 24 In vitro experimental data on the effect of heat exposure on the cell viability of A2058 cells are presented. Different cell cultures were heated to temperatures of 37°C, 42°C, 47°C, or 52°C. Five independent experiments were performed at each temperature and time point. Data for each temperature show the mean cell viability and standard deviation of the five corresponding experiments after exposure to that temperature for 5, 10, and 20 minutes. Heating to 52°C significantly reduced the viability of A2058 cells. Data marked with * indicate a p-value (Student's t-test) less than 0.01 compared to data at the corresponding time point of 37°C, and data marked with + indicate a p-value less than 0.01 compared to data at 5 minutes at the same temperature for the data at 10 and 20 minutes.

[0142] Figure 25 Experimental data showing the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), stigmatae (“PT”), and their combinations on A2058 cells are presented. For TTF data, the TT field was applied at 200 kHz for 240 minutes (from minute 0 to minute 240) with a field strength of 1.5 μT. For HT data, hyperthermia was applied at 52°C for 20 minutes (from minute 120 to minute 140). For PT data, 20 μM stigmatae was applied from minute 0 to minute 240. The data show the mean viable cell count for five experiments under each experimental condition, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #. The application of all four treatments significantly reduced cell viability compared to TTF+HT.

[0143] Compare Figure 12 , Figure 20 and Figure 25 Data suggests that using higher magnetic flux densities (approximately 8 μT or above) allows tissue to be heated to lower temperatures while still maintaining or even enhancing therapeutic efficacy. This higher magnetic flux density, combined with heating to temperatures above 42°C and the application of styrax, may be sufficient to eliminate tumors. This is particularly important for body areas where limited heating can be applied, such as the brain. For example... Figure 22 Data suggests that even with a lower magnetic field, combining tumor treatment fields and heating with one or more of styrax and another anticancer drug can reduce or even eliminate cancer cells.

[0144] Figures 26B to 26H Microscopic images of in vitro A2058 cell cultures after exposure to different external treatments are shown. Figure 26A Microscopic images showing control AsPC1 cell cultures in vitro that were not exposed to any external treatment and maintained at a physiological internal temperature of 37°C. Figure 26B Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz for 0 to 240 minutes are shown. Figure 26C This shows cell cultures exposed to 52°C for 20 minutes from minute 120 to minute 140. Figure 26D Cell cultures exposed to 20 μM styrax from minute 0 to minute 240 are shown. Figure 26E Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes and exposed to 20 μM argentide from minute 0 to minute 240 are shown. Figure 26F Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes and those exposed to heating at 52 °C for 20 minutes from 120 to 140 minutes are shown. Figure 26G Cell cultures exposed to an electromagnetic field with a magnetic flux density of approximately 1.5 μT at 200 kHz from 0 to 240 minutes, to heating at 52 °C for 20 minutes from 120 to 140 minutes, and to 20 μM styrax (PT) from 0 to 240 minutes are shown. Figure 26H This shows the effect of maintaining cultured cells at 37°C without any treatment for 24 hours. Figure 26G Cell cultures. In Figure 26G 24 hours after the combined treatment, the growing cells did not appear to recover.

[0145] Figure 27Experimental data showing the in vitro effects of TT field (“TTF”), hyperthermia (“HT”), paclitaxel (“PAC”), and their combinations on A2058 cells are presented. For TTF data, a TT field of 200 kHz was applied for 240 minutes (from minute 0 to minute 240) at a field strength of 1.5 μT. For HT data, hyperthermia was applied at 52 °C for 20 minutes (from minute 120 to minute 140). For PAC data, 10 μM paclitaxel was applied from minute 0 to minute 240. The data show the mean number of viable cells in 5 experiments for each experimental condition, where P < 0.01 compared to control was marked as *, P < 0.01 compared to TTF was marked as +, and P < 0.01 compared to TTF+HT was marked as #. Cell elimination occurred with the application of all three treatments.

[0146] Table 1 shows data examining the effect of GSH consumption on the in vitro cell viability of U87MG, AsPC1, and A2058 cells. For rows containing "TTF," a TT field was applied at 200 kHz for 240 minutes (from minute 0 to minute 240) with a field strength of 1.5 μT. For rows containing "HT," hyperthermia was applied to U87MG at 42°C and to AsPC1 and A2058 at 52°C for 20 minutes (from minute 120 to minute 140). For rows containing "BSO," 1 mM butylcysteine ​​sulfinamide (a specific inhibitor of GSH synthesis) was added to the cell culture medium at the time of cell seeding. When HT and TTF were administered in combination with BSO, HT and TTF were administered 24 hours post-seeding. Data show the mean and standard deviation of five independent experiments. Data marked with * have a p-value less than 0.01 compared to control data (Student's t-test). Data marked with a + sign have a p-value less than 0.01 compared to TTF+HT data (Student's t-test). Therefore, the data indicate that GSH consumption enhances the anticancer effects of electromagnetic radiation and heat.

[0147] Table 1

[0148]

[0149] Therefore, the use of the device disclosed herein, combined with the administration of pterostilbene, provides a highly effective method for treating cancerous sites and can even completely eliminate cancer cells. Thus, in one aspect, the anticancer composition comprises (i) pterostilbene, pterostilbene phosphate, or a pharmaceutically acceptable salt thereof. Alternatively, the anticancer composition may be provided in the form of cocrystals, water-soluble prodrugs, nanoparticles, nanodots, nanorods, nanospikes, nanorods, nanoclusters, nanoceramics, liposomes, or exogenous formulations, or may be provided in an implantable device configured to release the anticancer composition upon implantation in vivo. Note that the anticancer composition may comprise any antioxidant composition. In this sense, the anticancer composition may comprise any arsenic compound suitable as an anticancer agent other than pterostilbene, such as resveratrol.

[0150] (i) Pterostilbene and Pterostilbene phosphate

[0151] The terms "Pter" or "trans-3,5-dimethoxy-4'-hydroxypyrrolizin" refer to compounds of the following formula:

[0152]

[0153] The term "Pterocarpus santalinus phosphate" refers to a compound with the following formula:

[0154]

[0155] The term "pharmaceuticalally acceptable salt" means any salt of pterostilbene or pterostilbene phosphate that, when administered to a recipient, can (directly or indirectly) provide the compound described herein. Preferably, as used herein, the term "pharmaceuticalally acceptable salt" means a salt approved by a federal or state regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, and more particularly for human use. Salts can be prepared by methods known in the art. Exemplary, non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannins, pantothenates, hydrogen tartrates, ascorbic acid salts, succinates, maleates, gentianates, fumarates, gluconates, glucurons, sucrose salts, formates, benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and dihydroxynaphthaleneates. Pharmaceutically acceptable salts of stigmacandra or stigmacandra phosphate are preferably prepared from polyphenolic compounds having acidic functional groups and acceptable inorganic or organic bases. Suitable bases include, but are not limited to, hydroxides of alkali metals (e.g., sodium, potassium, and lithium); hydroxides of alkaline earth metals (e.g., calcium and magnesium); hydroxides of other metals (e.g., aluminum and zinc); ammonia and organic amines, such as unsubstituted or hydroxylated mono-, bis-, or tri-alkylamines, dicyclohexylamine; tributylamine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tri-(2-hydroxysubstituted lower alkylamines), such as mono-; bis- or tri-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tri-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxylower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-O-glucosamine; and amino acids, such as arginine, lysine, etc. The term "pharmaceutically acceptable salt" also includes hydrates of polyphenolic compounds. In the specific implementation plan, the pharmaceutically acceptable salt is the disodium salt.

[0156] Further exemplary non-limiting examples of cancer chemotherapeutic agents according to the present invention include: alkylating agents, such as nitrogen mustard / oxygen-nitrogen-phosphorus cyclohexane (e.g., cyclophosphamide, ifosfamide), nitrosoureas (e.g., carmustine), triazines (e.g., temozolamide), and alkyl sulfonates (e.g., busulfan); antimetabolites (e.g., 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, or pemetrexed); anthracycline antibiotics such as doxorubicin and daunorubicin; and taxanes such as paclitaxel.TMAnd docetaxel, vinca alkaloids such as vincristine and vinca alkaloid, 5-fluorouracil (5-FU), leucovorin, irinotecan, idarubicin, mitomycin C, oxaliplatin, raltitrexed, pemetrexed, tamoxifen, cisplatin, carboplatin, methotrexate, actinomycin D, mitoxantrone, blenoxane, mithramycin, paclitaxel, 2-methoxyestradiol, prinomastat, batimastat, BAY 12-9566, carboxytriazole, CC-1088, dextromethorphan acetate, dimethylxanthrone acetate, endostatin, IM-862, marimastat, penicillamine, PTK787 / ZK222584, RPI.4610, Squalamine Lactate, SU5416, Thalidomide, Combretastatin, COL-3, Neovastatin, BMS-275291, SU6668, Anti-VEGF Antibody, Medi-522 (Vitaxin II), CAI, Interleukin-12, IM862, Amiloride, Angiostatin, Angiostatin Kl-3, Angiostatin Kl-5, Captopril (captopril), DL-α-difluoromethylornithine, DL-α-difluoromethylornithine HCl, endostatin, fumonisin, chlorhexidine A, 4-hydroxyphenyl retinoic acid, juglone, laminin, laminin hexapeptide, laminin pentapeptide, fumonisin A, medroxyprogesterone, minocycline, placental ribonuclease inhibitor, suramin, thromboretin, antibodies targeting angiogenesis factors (e.g., bevacizumab) Cetuximab, panitumumab, trastuzumab; topoisomerase inhibitors; antimicrotubule agents; low molecular weight tyrosine kinase inhibitors of angiogenic growth factors (e.g., erlotinib, sorafenib, sunitinib, gefitinib); GTPase inhibitors; histone deacetylase inhibitors; AKT kinase or ATPase inhibitors; Wnt signaling inhibitors; E2F transcription factor inhibitors; mTOR inhibitors (e.g., temsirolimus); α, β, and γ interferons, IL-12, matrix metalloproteinase inhibitors (e.g., COL3, mamasitol, balmasitol); ZD6474, SUl1248, vitaxin; PDGFR inhibitors (e.g., imatinib); NM3 and 2-ME2; cyclic peptides such as cilengitide. Other suitable chemotherapeutic agents are described in detail in The Merck Index, 13th edition, on CD-ROM. In a preferred embodiment of the invention, the chemotherapeutic agent is selected from docetaxel. Cisplatin, Pemetrexed, Gemcitabine, and Irinotecan.

[0157] In specific embodiments, the cancer chemotherapeutic agent is a taxane, preferably comprising or composed of paclitaxel. As used herein, the term "paclitaxel" refers to a compound with the chemical name (2α,4α,5β,7β,10β,13α)-4,10-bis(acetoxy)-13-{[(2R,3S)-3(benzoylamino)-2-hydroxy-3-phenylpropionyl]oxy}-1,7-dihydroxy-9-oxy-5,20-epoxytax-11-en-2-ylbenzoate, having the following chemical formula:

[0158]

[0159] In a more specific embodiment, paclitaxel is protein-bound paclitaxel. As used herein, the terms “protein-bound paclitaxel” or “nab-paclitaxel” or “nanoparticle albumin-bound paclitaxel” refer to formulations in which paclitaxel is bound to albumin, which serves as a delivery carrier.

[0160] The cancer chemotherapy agents will vary depending on the type of cancer to be treated with the combination therapy of the present invention. Those skilled in the art can easily determine which cancer chemotherapy agent is more suitable for treating a particular type of cancer.

[0161] Optionally, in step S4, in addition to the anticancer compound, a glutathione (GSH) consumable is also provided to the target site. The GSH consumable can be administered by any suitable method, such as oral or intravenous. It should be noted that the GSH consumable can be provided before or simultaneously with steps S1, S2, and S3, or at a predetermined time after steps S1, S2, or S3, preferably at a predetermined time after step S3. The provided GSH consumable can be any GSH consumable disclosed herein, including those related to… Figures 12 to 27 Or the GSH consumables listed in Table 1.

[0162] As used herein, the term "glutathione depleting agent" refers to a substance that reduces or eliminates glutathione from cells that have been exposed to it. Those skilled in the art can determine whether a particular molecule is a glutathione depleting agent, for example, by comparing the effect of a particular molecule to that of butylcysteine ​​(BSO) (a specific inhibitor of γ-glutamyl-cysteine ​​ligase) using methods described for in vitro and in vivo conditions (Terradez P et al, Biochem J 1993, 292(Pt 2):477-83). In specific embodiments, a molecule is a glutathione depleting agent if it has at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, 100%, or more of the glutathione-depleting effect of butylcysteine. An illustrative, non-limiting example of a glutathione depleting agent is:

[0163] a) Bcl-2 antisense oligodeoxynucleotides, i.e., oligodeoxynucleotides complementary to the RNA sequence of the Bcl-2 gene, as described in Ortega, et al., Cancers (Basel) 2011, 3, 1285-1310. Non-limiting examples of Bcl-2 antisense oligodeoxynucleotides are described in US5734033, WO2003040182A1, and US5831066A. Assays used to determine whether a particular compound is a Bcl-2 antisense oligodeoxynucleotide are, for example, assays based on the compound’s effect on Bcl-2 mRNA levels or Bcl-2 protein levels, as described in Mena et al., Clinical Cancer Research 2007, 13(9):2658-66.

[0164] b) Inhibitors of multidrug resistance protein 1 (MRP1). As described above by Ortega et al.

[0165] As used herein, the term "MRP1 inhibitor" refers to a compound that inhibits the activity of MRP1. The term inhibitor includes, but is not limited to, MRP1 antagonists, anti-MRP1 antibodies, compounds that prevent MRP1 expression, and compounds that reduce the mRNA or protein levels of MRP1. Non-limiting examples of MRP1 inhibitors are verapamil and MK-571. Assays used to determine whether a particular compound is an MRP1 inhibitor are, for example, the methods described in Olson DP et al., Cytometry 2001, 46(2):105-13.

[0166] c) Inhibitors of gamma-glutamyl transferase or gamma-glutamyl transferase (GGTP or GGT), such as those described in Silber et al., Anal Biochem 1986, 158(1):68-71.

[0167] As used herein, the term "GGTP inhibitor" refers to a compound that inhibits the activity of GGTP, an enzyme that catalyzes the transfer of the γ-glutamyl moiety of glutathione to its receptor. The term inhibitor includes, but is not limited to, GGTP antagonists, anti-GGTP antibodies, compounds that prevent GGTP expression, and compounds that reduce GGTP mRNA or protein levels. GGTP inhibitors include both selective and non-selective inhibitors (which also affect asparagine synthase). Non-limiting examples of GGTP inhibitors are acividin and 2-amino-4-{[3-(carboxymethyl)phenyl](methyl)phosphonoyl}butyrate (GGsTop). TM Assays used to determine whether a particular compound is a GGTP inhibitor include, for example, those described by Silver et al., Anal Biochem 1986, 158(1):68-71.

[0168] d) Cystine uptake inhibitors, as described in Obrador et al., Hepatology 2002, 35, 74-81.

[0169] The term "cystine uptake inhibitor" refers to compounds that inhibit the transport of extracellular cystine into the cell, including sodium-independent X. c - The system and sodium-dependent XAG system (McBean GJand Flynn J., Biochem Soc Trans. 2001, 29(Pt6):712-22). The term inhibitor includes competitive and non-competitive inhibitors. Non-limiting examples of cysteine ​​uptake inhibitors are acivicin, L-glutamate, L-serine O-sulfate, L-cysteine ​​sulfinate, L-cysteine, L-trans-pyrrolidine-2,4-dicarboxylate, and potassium magnesium sulfate. The assay used to determine whether a particular compound is a cysteine ​​uptake inhibitor is, for example, based on determining... 35 Determination of S-labeled cysteine ​​uptake.

[0170] e) Glutathione disulfide (NOV-002) or its disodium salt, disodium glutathione disulfide, wherein glutathione disulfide (NOV-002) is a compound having the following formula:

[0171]

[0172] As described in Gumireddy et al., J Carcinog Mutagen 2013 (2013).

[0173] f) Phenethyl isothiocyanate is a compound having the following formula:

[0174]

[0175] As described in Trachootham, et al., Cancer Cell 2006, 10:241-252.

[0176] g) Glucocorticoid receptor antagonists, as described in Min, et al., J Mol Med (Berl) 2012, 90:309-319.

[0177] The term "glucocorticoid receptor antagonist" refers to a compound that binds to glucocorticoid receptors but lacks any substantial ability to activate the receptors themselves. The term "glucocorticoid receptor antagonist" includes neutral antagonists and inverse antagonists. A "neutral antagonist" is a compound that blocks the action of an agonist but has no effect on intrinsic or spontaneous receptor activity. An "inverse antagonist" blocks the action of an agonist on the receptor and attenuates the receptor's constituent activity. The term "antagonist" also includes competitive antagonists, which are drugs that bind to the same site as a natural ligand; non-competitive antagonists, which bind to receptor sites different from natural ligands; reversible antagonists, which bind and dissociate from the receptor at a rate determined by receptor-ligand kinetics; and irreversible antagonists, which permanently bind to the receptor by forming a covalent bond with the active site or simply by binding so tightly that the dissociation rate is practically zero. Non-limiting examples of glucocorticoid receptor antagonists are RU-486 (mifepristone), RU-43044, octahydrophenanthrene, spirocyclodihydropyridine, triphenylmethane and diaryl ethers, chromene, dibenzylaniline, dihydroisoquinoline, pyrimidinide, azadecahydronaphthalene, arylpyrazolozadecahydronaphthalene, 11-monoaryl steroids, phenanthrene, diphenyl[2.2.2]cyclooctane and its derivatives, dibenzocycloheptane and its derivatives, dibenzylamine benzenesulfonamide and its derivatives, di(aryl)pentanol, chromene derivatives, azadecahydronaphthalene, aryl Quinolones, 11,21-bisaryl steroids, and 11-aryl and 16-hydroxy steroids, as well as dual antagonist-agonist agents such as beclomethasone, betamethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone, and triamcinolone. Whether a specific compound is a glucocorticoid receptor antagonist can be determined, for example, by commercial kits such as the Glucocorticoid Receptor Pathway Reporter Kit (BPS BIOSCIENCE, SAN DIEGO, CA, USA).

[0178] h) Anti-IL-6 agents, as described in Obrador et al. J Biol Chem 2011, 286: 15716-15727.

[0179] The term "anti-IL-6 agent" refers to a compound that reduces IL-6 activity by lowering IL-6 levels, by completely or partially blocking binding to the IL-6 receptor, or by completely or partially inhibiting IL-6 receptor activity. The term "anti-IL-6 agent" includes inhibitory antibodies against IL-6, i.e., antibodies that bind to IL-6 and thus prevent IL-6 from binding to its receptor (such as isilimomab and siltuximab), and inhibitors of the IL-6 receptor (such as tocilizumab). Assays used to determine whether a particular compound is an anti-IL-6 agent include, for example, ELISA kits for determining IL-6 levels, such as those from Life Technologies, Carlsbad, CA, USA, or assays for determining intracellular signaling derived from the binding of IL-6 to its receptor, such as the Quiagen (Valencia, CA, USA) IL6 / STAT3 signaling pathway Plus PCR array.

[0180] i) Butyrosine sulfinamide (BSO), which is a compound having the following formula:

[0181]

[0182] Terradez P. et al., Biochem J. 1993, 292: 477-483 has described the glutathione-depleting effect of BSO.

[0183] j) Diethyl maleate or DEM, which is a compound having the following formula:

[0184]

[0185] The glutathione-depleting effect of DEM has been described in Estrela JMet al.,Nat Med 1995,1(1):84-88.

[0186] k)NPD926, a compound having the following formula:

[0187]

[0188] The glutathione-depleting effect of NPD926 has been described in Biochem J 2014, 463:53-63.

[0189] l) Trichoderma lactone, a compound having the following formula:

[0190]

[0191] Pei S. et al., J Biol Chem 2013, 288(47):33542-58 has described the glutathione-depleting effect of NPD926.

[0192] m) Compounds having the following formula:

[0193]

[0194] Wherein A is C(O) or S(O)2; where n = 0, 1, 2 or 3; where the ortho carbon of the benzene ring is unsubstituted or substituted by a halogen; where R1 is selected from hydrogen, halogen, C≡C-alkyl, C≡C-cycloalkyl, C≡C-cycloalkyl halide, C≡C-aryl, C≡C-aryl halide and aryl; where R2 is selected from hydrogen, alkyl, alkenyl and aryl; where R3 is selected from hydrogen, alkyl, alkenyl and aryl; and where R4, R5 and R6 are each independently selected from hydrogen, bromine, chlorine, fluorine, ketone, hydroxyl, alkyl, alkenyl, alkoxy, methoxy, aminoalkyl, aminoalkenyl and aminoalkoxy.

[0195] Specifically, long pepperamide is a compound having the following formula:

[0196]

[0197] Pei S. et al., mentioned above, have described the glutathione-depleting effect of piperazine.

[0198] n) Inhibitors of proteins from the bromodomain and terminal extradomain families, as described in Shao Q. et al., Cancer Research 2014, 74(23):7090-102.

[0199] The term "inhibitor of proteins from the bromodomain and terminal extra-terminal (BET) domain family" or "BET inhibitor" refers to a compound that binds to the bromodomain and terminal extra-terminal (BET) domain of the proteins BRD2, BRD3, BRD4, and BRDT, thereby preventing protein-protein interactions between BET proteins and acetylated histones and transcription factors. The term "BET inhibitor" includes inhibitors targeting any of BRD2, BRD3, BRD4, and BRDT. Non-limiting examples of BET inhibitors are JQ1, GSK525762A, and OTX-015. Assays used to determine whether a particular compound is a BET inhibitor are, for example, the Homogeneous Proximity Assay for screening BRD4 inhibitors from BioTek (Winooski, VT, USA).

[0200] In specific embodiments, the glutathione consumables of the present invention are selected from: a) Bcl-2 antisense oligodeoxynucleotides; b) multidrug resistance protein 1 inhibitors; c) γ-glutamyl transpeptidase inhibitors; d) cystine uptake inhibitors; e) disodium glutathione disulfide; f) phenethyl isothiocyanate; g) glucocorticoid receptor antagonists; h) anti-IL-6 agents; i) butylcysteine ​​sulfinamide; j) diethyl maleate; k) NPD926; l) parthenolide; m) long peppermint; and n) inhibitors of proteins from the bromine domain and terminal extradomain families, particularly GSK525762A or I-BET762.

[0201] In a more specific implementation, the inhibitor of multidrug resistance protein 1 is verapamil, which is a compound having the following formula:

[0202]

[0203] In a more specific implementation, the inhibitor of gamma-glutamyl transpeptidase is azithromycin, which is a compound having the following formula:

[0204]

[0205] In a more specific implementation, the cystine uptake inhibitor is sulfasalazine, which is a compound having the following formula:

[0206]

[0207] In a more specific implementation, the glucocorticoid receptor antagonist is RU-486 or mifepristone, which is a compound having the following formula:

[0208]

[0209] In a more specific implementation, the anti-IL-6 agent is an inhibitory antibody against IL-6 or an inhibitor of the IL-6 receptor. In even more specific implementations, the anti-IL-6 agent is selected from tocilizumab, islimomab, and cetuximab. The term "tocilizumab" refers to a humanized monoclonal antibody against the IL-6 receptor. The term "islimomab" refers to a mouse monoclonal antibody against IL-6. The term "cetuximab" or "CNTO328" refers to a chimeric monoclonal antibody against IL-6.

[0210] In a more specific implementation, the inhibitors of proteins from the bromine domain and terminal extradomain families are selected from JQ1, GSK525762A, and OTX-015. The term "JQ1" refers to a compound with the following formula:

[0211]

[0212] The term "GSK525762A" refers to a compound with the following formula:

[0213]

[0214] The term "OTX-015" refers to a compound with the following formula:

[0215]

[0216] The term "CPI-0610" refers to the compound mentioned in CAT#:206117, as marked by MedKoo Biosciencies Inc.

[0217] In the specific implementation plan, the glutathione consumable is diethyl maleate, GSK525762A (I-BET762), or piperazine.

[0218] In step S5, direct heating is stopped, and in step S6, the non-ionizing alternating electric field is stopped. It should be noted that steps S5 and S6 can occur simultaneously, or direct heating can be stopped before the non-ionizing alternating electromagnetic field is stopped, so that only the non-ionizing alternating electromagnetic field is applied for a predetermined time after direct heating is stopped.

[0219] It should be noted that Figure 11 The sequence of steps shown does not require steps S1 through S5 to be in any chronological order. For example, steps S3 and / or S4 (depending on whether one or both are implemented in the method) may be implemented simultaneously with the start of step S1, or at a predetermined time after the start of step S1 but before the start of step S2, or simultaneously with the start of step S2, or at a predetermined time after the start of step S2. Further, in the example of implementing both steps S3 and S4, they may be implemented at the same or different times. For example, regardless of when (or whether) step S4 is implemented, step S3 may be implemented simultaneously with the start of step S1, or at a predetermined time after the start of step S1 but before the start of step S2, or simultaneously with the start of step S2, or at a predetermined time after the start of step S2. Similarly, regardless of when (or whether) step S3 is implemented, step S4 may be implemented simultaneously with the start of step S1, or at a predetermined time after the start of step S1 but before the start of step S2, or simultaneously with the start of step S2, or at a predetermined time after the start of step S2. Furthermore, step S1 may apply a first duration, step S2 may apply a second duration, and the second duration may partially or completely overlap with the first duration, or the second duration may begin when the first duration ends.

[0220] For example, a non-ionizing alternating electromagnetic field (e.g., at 300 kHz) can be provided simultaneously with an anticancer composition and a GSH consumable (e.g., pterostilbene and gemcitabine). The alternating electromagnetic field is applied for two hours, and heating (e.g., heating the target site to 52°C for 10 minutes) is applied during these two hours. In another example, a non-ionizing alternating electromagnetic field (e.g., at 300 kHz) can be provided first for a first time period (e.g., 2 hours), and heating (e.g., pterostilbene, simultaneously heating to 47°C for 2 hours) can be applied at the end of the first time period in combination with the anticancer composition and / or a GSH consumable.

[0221] In this method, the non-ionizing alternating electromagnetic field can have a frequency of 10 kHz to 500 kHz, provide a magnetic flux density of 0.1 pT to 1 mT, or 0.1 pT to 100 μT, or 100 μT to 1 mT, and / or a corresponding electric field strength amplitude of 1 V / cm to 3 V / cm, depending on the tissue impedance, and can be applied for a period of 1 minute to 24 hours.

[0222] Direct heating preferably involves heating the target area to a temperature of at least 42°C, more preferably between 42°C and 57°C.

[0223] Heating the target area using a tumor treatment field

[0224] The mechanism by which the oscillating magnetic field of a tumor therapy field heats tissue is through the induction of Foucault currents (or "eddy currents") within the tissue. These currents rotate around the magnetic field lines in the tissue and heat tumor cells via the Joule effect. This is due to the electrical conductivity σ of living tissue. The electrical conductivity of tumor tissue increases with increasing oscillating magnetic field frequency, reaching approximately 0.15 Siemens / m at 300 kHz. This conductivity provides a path for tiny eddy currents flowing along circular paths. The power P per unit mass heating these cells is given by the following equation:

[0225] P = π 2 B 2 d 2 f 2 / (6.ρ.D)

[0226] Where B is the magnetic flux density, d is the tissue depth to which the magnetic field is provided, f is the field frequency, ρ is the tissue resistivity (the reciprocal of conductivity), and D is the tissue mass density.

[0227] The electrical conductivity of tumor tissue can be five times that of healthy tissue, approximately 0.15 Siemens / m at 100-300 kHz. The conductivity (D) of biological tissue is variable (900 kg / m). 3 Up to 1050kg / m 3 However, it can be approximated by the water's D, i.e., 1000 kg / m³. 3The highest magnetic flux density of the tumor therapy field was 1 mT. The highest frequency was 300 kHz. In in vitro experiments, the thickness of the culture flask was approximately 1 mm, i.e., the value of d. This yielded a P value of 20 pW / kg. This is an extremely low value. Therefore, the mechanism of the TT field is not due to heating. Cell death is likely a result of the disruption of mitochondrial charge. Due to the higher conductivity of tumor tissue, this effect is stronger in tumor tissue, approximately 5 times higher than in healthy cells. The synergistic effect with thermotherapy can be attributed to the increase in conductivity associated with increased mobility of charged molecules.

[0228] All of the foregoing is entirely within the scope of this disclosure and is considered to form the basis for alternative implementations that apply one or more combinations of the foregoing features, but is not limited to the specific combinations disclosed above.

[0229] In view of this, there will be many alternatives to implementing the teachings of this disclosure. It is anticipated that those skilled in the art will be able to modify and adapt the above disclosure within the scope of this disclosure to suit their own circumstances and requirements, while retaining some or all of the same technical effects disclosed in accordance with common general knowledge in the art or which can be deduced from the foregoing. All such equivalents, modifications or adaptations fall within the scope of this disclosure.

Claims

1. A device for treating a cancerous target site, comprising: An electromagnetic transmitter comprising one or more electrodes having an electrically insulating coating for preventing electrical contact between the electrodes and the target site, the electromagnetic transmitter being configured to provide a tumor therapeutic field at the target site via the one or more electrodes, the tumor therapeutic field being a non-ionizing alternating electromagnetic field having a frequency of 10 kHz to 300 kHz; and the tumor therapeutic field also having a magnetic flux density of 0.1 pT to 1 mT; A heat source configured to provide heating at the target site to induce hyperthermia at the target site; and An electronic controller is used to electronically control the electromagnetic transmitter and the heat source; The device is configured to independently apply a non-ionizing alternating electromagnetic field and heating.

2. The apparatus of claim 1, wherein the apparatus is configured to provide the non-ionizing alternating electromagnetic field at the target location for a first time period and to provide direct heating at the target location for a second time period.

3. The apparatus of claim 1, wherein the apparatus is configured to provide the non-ionizing alternating electromagnetic field at the target site for a first time period of 1 minute to 24 hours.

4. The apparatus of claim 1, wherein the apparatus is configured to provide the heating at the target site for a second time period of 1 minute to 360 minutes.

5. The apparatus of claim 4, wherein the heating is simultaneously applied to the non-ionizing alternating electromagnetic field for a third time period.

6. The apparatus of claim 1, wherein the electromagnetic transmitter is configured to provide an alternating electromagnetic field having a magnetic flux density of 0.1 pT to 100 μT at the target location.

7. The apparatus of claim 1, wherein the electromagnetic transmitter is configured to provide an alternating electromagnetic field having a magnetic flux density of 0.5 µT to 1 mT at the target location.

8. The apparatus of claim 1, wherein the electromagnetic transmitter is configured to provide an alternating electromagnetic field having a magnetic flux density of 8µT to 1mT at the target location.

9. The apparatus of claim 1, wherein the electromagnetic transmitter is configured to provide an alternating electromagnetic field having a frequency of 100 kHz to 300 kHz.

10. The apparatus of claim 1, wherein the heat source is configured to heat the target portion to a temperature of 42°C or higher.

11. The apparatus of claim 10, wherein the heat source is configured to heat the target portion to a temperature of 42°C to 57°C.

12. The apparatus of claim 1, wherein the heat source comprises an ultrasonic transmitter configured to provide ultrasonic irradiation to the target site.

13. The apparatus of claim 12, wherein the ultrasonic irradiation has one or more focused regions in the target site.

14. The apparatus according to claim 1, wherein the heat source includes an electromagnetic transmitter configured to provide electromagnetic radiation to the target site.

15. The apparatus of claim 1, wherein the heat source comprises a fluid pump configured to pump fluid to the target location and a heater configured to heat the fluid before the fluid reaches the target location.

16. The apparatus of claim 1, wherein the heat source comprises a conductive heat emitter configured to provide heat to the target site via thermal conduction.

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