Apparatus for vaporizing nanogens suitable for in vivo treatment and an apparatus including the same

Abstract

The present invention relates to a device (1) for vaporizing a nano-pharmaceutical (E) having a therapeutic or diagnostic effect, or both a therapeutic and diagnostic effect, at a specific target site (V) in the body, and to a device (10) constituting the device (1). The assembly (1) comprises at least one first magnetic element (2) configured to generate a first magnetic field (MF1) in a first direction and at least one second magnetic element (3) configured to generate a second magnetic field (MF2) in a direction substantially opposite to the first direction, at least one third magnetic element (4) configured to generate a variable magnetic field (MF3) for exciting magnetic nanoparticles (B) located in a magnetic field free region (MFFR), where the first magnetic field (MF1) and the second magnetic field (MF2) are oriented in opposite directions and suppress the effect of each other, at least one receiving coil (5) configured to measure the magnetization of the magnetic nanoparticles (B) to which the variable magnetic field (MF3) is applied, and at least one first ultrasonic transducer (6) configured to apply ultrasonic energy by transmitting acoustic waves (AW) to a nano-reagent (E) located in the magnetic field free region (MFFR).

Description

Technical Field

[0001] The present invention relates to an apparatus for vaporizing a nanoagent having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, at a specific target site in the body, and an apparatus including the apparatus.

Background Art

[0002] The development of micro- and nano-scale theranostic (therapy-diagnosis) agents provides an individualized platform for treating various diseases at the microbial and cellular levels and monitoring treatment outcomes. For example, cancer cells can be targeted using drug-containing nanoparticles to which antibodies that recognize overexpression of cancer-related factors are added.

[0003] Nanoparticles can release drugs in response to stimuli such as pH, temperature, light, and pressure, and can also be used for hyperthermia treatment. Ideally, it is desirable that the therapeutic agent is effective only at the lesion (e.g., tumor) and does not damage healthy tissues. Monitoring the dosage of the drug applied to the affected area during treatment also enhances the effectiveness of the treatment.

[0004] Microbubbles are microscale particles filled with gas that can undergo volume changes under the pressure wave (acoustic wave) of ultrasonic waves. Since these particles scatter and return ultrasonic signals with a high probability, they are used as a contrast agent for imaging blood vessels with high contrast in ultrasonic imaging diagnosis after intravenous injection into the body. The volume expansion and contraction (cavitation) of microbubbles widen the space between endothelial cells of capillaries and open the blood-organ barrier. An example of such an application is to temporarily open the blood-brain barrier (a structure around the capillaries of the brain that protects the brain by preventing large molecules from passing through). This blood-brain barrier can potentially impede the transport of therapeutic drugs and agents to the brain in the treatment of brain diseases. As described as a known technique in US Patent Document US6514221, by applying ultrasonic energy to a site in the body where microbubbles are present, the blood-organ barrier can be opened and therapeutic drugs can be released extravascularly. The contraction and expansion of microbubbles without disturbing their structure is called stable cavitation. When the output of ultrasonic waves is relatively high, microbubbles may expand and suddenly collapse. During this process, high energy is generated, and accordingly, the temperature becomes extremely high in a very small volume, generating free radicals. This phenomenon is called inertial cavitation. In order to open the blood-brain barrier using microbubbles, it is necessary to achieve stable cavitation by applying sufficiently high ultrasonic energy. However, in order to prevent inertial cavitation, it is necessary to keep the absolute pressure of the applied acoustic wave below a certain threshold. To achieve this, cavitation activity is continuously monitored, for example, by an acoustic sensor. When inertial cavitation is detected during this monitoring process, the ultrasonic energy applied to the microbubbles, that is, the absolute pressure of the acoustic wave, is reduced. The inertial cavitation threshold (the ultrasonic output required for inertial cavitation) depends on the absolute pressure of the applied ultrasonic wave and decreases as the applied ultrasonic frequency decreases. Since the attenuation effect of the skull increases as the frequency increases, intracranial ultrasonic applications can be performed at relatively low frequencies (<1 MHz). As a result, the probability of inertial cavitation occurring in intracranial treatment is relatively high.Therefore, there is a high possibility that healthy tissues will be damaged during treatment.

[0005] In the known technical field, research has been conducted on using the inertial cavitation effect of microbubbles for treatment. For example, inertial cavitation occurs at the diseased site in the body, damaging the blood vessels supplying the diseased cells. In the research conducted for this purpose, microbubbles in the region focused by ultrasonic waves in the brains of monkeys were subjected to inertial cavitation with ultrasonic energy to damage the tissue. (C. D. Arvanitis, N. Vykhodtseva, F. Jolesz, M. Livingstone ve N. MacDannold, “Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model” J. Neurosurgery 9, 1-10 (2015)). However, during that procedure, tissue damage also occurred in areas outside the focus, and it was also observed that the blood-brain barrier was opened. Due to these side effects, a safer method for health is required to perform the above-mentioned procedure.

[0006] In order to ensure that the above-mentioned technique is safe for health, it is necessary to ensure that microbubbles are only effective at the diseased site. On the other hand, outside the focus of the ultrasonic beam, there is a possibility of cavitation, especially due to reflections from the skull and bones, resulting in an increase in ultrasonic energy in unnecessary areas. Since microbubbles are present systemically in all blood vessels, current techniques have significant safety problems with any treatment method based on stable cavitation and inertial cavitation.

[0007] Today, due to the rapid development of nanotechnology, the surface of nanoparticles can be coated with antibodies or imaging components that can bind to the molecules at the disease site. Elements such as drugs, viruses, and nucleic acids are added to the nanoparticles, enabling the treatment of diseases. It is possible to sensitize the nanoparticles to external stimuli and enhance the effect in the target area. Current technologies have proposed nanoagents that release therapeutic charges into the medium under optical, electromagnetic, or acoustic energy. Magnetic nanoparticles can be heated under a variable magnetic field. In US Patent Document No. US2005 / 0090732, magnetic particles coated with antibodies and drugs are proposed as a known technology, aiming to obtain a therapeutic effect by applying a uniform magnetic field to the region including the disease site. Identifying the position and determining the number of therapeutic nanoparticles by imaging are important for controlling the dosage of treatment. Therefore, not only the therapeutic effect of the nanoagent but also visualization must be possible. Since magnetic nanoparticles are used as contrast agents for magnetic resonance imaging, they are suitable for both treatment and imaging diagnosis. In addition, by utilizing an external magnetic field, they can be accumulated in specific parts of the body.

[0008] US Patent Document No. US20130204181, which is a known technology, describes microbubbles containing a hydrophobic gas and carrying a hydrophobic drug and lipophilic superparamagnetic nanoparticles on their surface. The microbubbles in question can be imaged by ultrasound because they contain gas and can also be imaged by magnetic resonance because they contain superparamagnetic nanoparticles. In addition to these, high-frequency and low-intensity ultrasound are applied to destroy the microbubbles in question and release the drug into the environment. However, as described above, especially in hard tissues such as bone and skull, the ultrasound beam weakens or reflects, so it can only be applied to limited regions in the body.

[0009] In the publicly known U.S. Patent Document No. US2015 / 0231282, examples include nanobubbles containing a hydrophobic liquid such as perfluorocarbon that becomes a gas when heated, and nanoparticles containing different types of nanoparticles such as metals, magnetic materials, ferroelectrics, and semiconductors. The liquid in question can increase the diameter of the bubbles by vaporizing with ultrasonic energy or raising the temperature. This process is called acoustic droplet evaporation. Since the evaporation of acoustic droplets occurs relatively quickly, the therapeutic load is vigorously released into the tissue during evaporation and can reach deep into the cells. The vaporized nanobubbles can be visualized with ultrasound. If the acoustic droplet evaporation process can be performed at the focus of the tissue, microbubbles are formed only in the focal region, so the above-described therapeutic effect by microbubbles can be achieved without damaging healthy tissue. However, to achieve the vaporization of droplets by ultrasound, high-frequency (above 1 MHz) and high-power ultrasonic energy far exceeding the safety limits defined for imaging are required. Therefore, when such high-power ultrasonic energy is generated in the tissue, it may damage healthy tissue. In addition, as already described, high-frequency ultrasound cannot be effectively applied to all parts of the body (for example, in the application to the brain, the frequency of ultrasound that should be effectively applied must be lower than 1 MHz). For this reason, nanobubbles cannot be vaporized at specific sites including the brain, and as a result, the desired treatment cannot be performed at the corresponding sites.

[0010] An object of the present invention is to provide an apparatus for vaporizing a nanoagent having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, in a focused region with a low-frequency and low-power acoustic wave below the safety limit, which can pass through hard tissues such as the skull in order to provide these effects, and an apparatus including the apparatus.

[0011] Preferably, an apparatus for vaporizing a nano reagent comprising a vaporizable liquid to be intravenously administered into the body, a core composed of magnetic nanoparticles disposed in the liquid, and a surface surrounding the core and separating the core from the external environment, having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, the apparatus defined in claim 1 and the dependent claims of the present invention; At least one first magnetic element configured to generate at least a first magnetic field in a first direction, and at least one second magnetic element configured to generate at least a second magnetic field in a direction substantially opposite to the first direction, and at least one third magnetic element configured to generate a variable magnetic field for exciting the magnetic nanoparticles; At least one receiving coil configured to measure the magnetization of the magnetic nanoparticles under the influence of the variable magnetic field, and at least one first ultrasonic transducer configured to apply an acoustic wave having a specific ultrasonic frequency at an absolute pressure lower than a predetermined minimum absolute pressure that causes inertial cavitation in the tissue at the ultrasonic frequency, particularly during vaporization of the nano reagent.

[0012] Nanopharmaceuticals that vaporize in the body through an aggregate to produce a therapeutic effect, a diagnostic effect, or both a therapeutic effect and a diagnostic effect should be stable in the liquid phase after being administered into the body and should be vaporizable with the applied energy. The boiling temperature of the liquid in the core is relatively high to prevent the direct vaporization of the nanoreagent without applying energy after it is introduced into the body. In a preferred embodiment, perfluorocarbon is used as the liquid. The boiling point of perfluorocarbon is higher inside the nanoreagent than outside the nanoreagent because the internal pressure of the nanoreagent is greater than the atmospheric pressure due to the Laplace pressure. The boiling points of perfluorocarbon in a 200-nm-diameter nanoreagent are approximately 35 °C, 79 °C, 117 °C, and 152 °C for octafluoropropane, decafluorobutane, dodecafluoropentane, and perfluorohexane, respectively. In the device according to the present invention, the first magnetic field generated by the first magnetic element and the second magnetic field generated by the second magnetic element are substantially opposite to each other and cancel each other out at a certain point in the body. The point where this magnetic field becomes zero and its vicinity can be called a magnetic field-free region. The magnetic field-free region is arranged at the affected part to be treated during treatment. The position of the magnetic free region can be arbitrarily obtained according to the characteristics of the first magnetic field and the second magnetic field, and the position and diameter of the magnetic free region can be arbitrarily adjusted by the positions of the first magnetic element and the second magnetic element and / or the current applied to the first magnetic element and the second magnetic element. When the nanopharmaceutical administered into the body is in the magnetic field-free region, the magnetic nanoparticles in the nanopharmaceutical are in a free state, that is, they are not in a state where they can react even when another external magnetic field is applied. Outside the magnetic field-free region, there is a magnetic field with an amplitude sufficient for the magnetic nanoparticles in the nanoreagent to reach magnetic saturation (saturation state). Therefore, the nanoreagent located outside the magnetic field-free zone is not in a free state. In other words, it can react even when another external magnetic field is applied. Therefore, when a variable magnetic field is generated by a tertiary magnetic element in the region where no magnetic field is generated and its periphery, only the magnetic nanoparticles in the nanoreagent located in the region where no magnetic field is generated are magnetized.In a preferred embodiment, a variable magnetic field in the frequency range from 100 kHz to 500 kHz is generated by a third magnetic element, thereby locally heating the magnetic nanoparticles and thus the core and nanoagar. Thus, the variable magnetic field generated by the third magnetic element contributes to the vaporization of the nano reagent in the desired region within the body. The receiving coil within the assembly receives the magnetization signal generated by the variable magnetic field on the magnetic nanoparticles. By processing the magnetization signal received by the receiving coil, for example by a computer, the amount and temperature of the nano reagent within the demagnetized zone can be determined. The effectiveness of the treatment can also be judged by measuring the amount and temperature of the nanoagent in the portion without the magnetic field. The magnetic nanoparticles in the region without the magnetic field evaporate the nano reagent by cavitation nucleation by the ultrasonic energy supplied by the acoustic wave from the first ultrasonic transducer. In a preferred embodiment of the present invention, an ultrasonic frequency of less than 1 MHz is applied by the first ultrasonic transducer, and with an ultrasonic frequency of less than 1 MHz, a targeted nanoagent can be vaporized in any desired region of the body, including hard tissues such as the skull. With the device of the present invention, the nano reagent is locally heated by the variable magnetic field supplied from the third magnetic element and vaporized by the ultrasonic energy supplied from the first ultrasonic transducer, and the diameter of the nano reagent increases rapidly due to vaporization. In this way, drugs and similar therapeutic agents within the structure of the nano reagent are released into the environment with high momentum, ensuring that the therapeutic agent penetrates deep tissues and enhances the therapeutic effect. The device for achieving the object of the present invention and the instruments constituting the device are shown in the accompanying drawings.

Brief Description of the Drawings

[0013]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

[0014] Each component in the figure is numbered, and the corresponding ones are shown below.

Description of Reference Signs

[0015] 1. Device 2. Primary magnetic element 3. Secondary magnetic body 4. Tertiary magnetic element 5. Receiving coil 6. First ultrasonic oscillator 7. Second ultrasonic oscillator 8. Coupling device 9. Control device 10. Device 11. Main body A. Liquid B. Magnetic nanoparticles C. Core D. Surface E. Nanojar F. Molecule MF1. First magnetic field MF2. Second magnetic field MF3. Variable magnetic field MFFR Magnetic field free zone AW Acoustic wave V: Body

[0016] For vaporizing the nano-drug (E) (Figure 1) having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect AssemblyComprising: a vaporizable liquid (A); a core (C) containing magnetic nanoparticles (B) disposed in the liquid (A); and a surface (D) surrounding the core (C) and separating the core (C) from the external environment , previously introduced into the body (V) For vaporizing a nano-drug (E) (Figure 1) Assembly (1) wherein At least one first magnetic element (2) configured to generate a first magnetic field (MF1) in a first direction, and at least one second magnetic element (3) configured to generate a second magnetic field (MF2) in a direction substantially opposite to the first direction the first magnetic field (MF1) and the second magnetic field (MF2) are directed in opposite directions and suppress each other's effects At least one third magnetic configured to generate a variable magnetic field (MF3) for exciting magnetic nanoparticles (B) located in a magnetic field free region (MFFR) element (4) and And at least one receiving coil (5) configured to measure the magnetization of the magnetic nanoparticles (B) to which the variable magnetic field (MF3) is applied Assembly(1) vaporizes within the body (V) to produce a therapeutic effect, a diagnostic effect, or both a therapeutic and a diagnostic effect. The core (C) of the nanoagent (E) consists of a vaporizable liquid (A) and preferably a plurality of magnetic nanoparticles (B) in the liquid (A) (Figure 2). The magnetic nanoparticles (B) are preferably iron oxide having a diameter in the range of 5 nm to 50 nm. To prevent the magnetic nanoparticles (B) from aggregating and localizing with each other in the liquid (A), the magnetic nanoparticles (B) are preferably coated with a polymer such as chitosan or other materials having similar properties. The kernel (C) may also contain additional agents such as agents that produce a therapeutic effect. In one embodiment, the core (C) has a diameter in the range of 10 nm to 1000 nm. In one embodiment, the surface (D) that separates the core (C) from the external environment surrounds the core (C) such that a space filled with air remains between the cores (C). The surface (D) preferably has a monolayer or bilayer lipid structure. In one embodiment, the surface (D) contains at least one antibody that can directly bind to a protein that is present in large amounts in diseased cells or in regions where diseased cells are present. Also, the surface (D) may contain various molecules (F) such as agents that produce a therapeutic effect, viruses, nucleic acids, etc. In an alternative embodiment, the surface (D) may contain excess magnetic nanoparticles (B). In the device (1) for vaporizing the nanoagent (E), the first magnetic element The first magnetic field (MF1) generated by (2) and the second magnetic element The second magnetic field (MF2) generated by (3) are opposed to each other, so body It is zeroed at a point within (V). The point where this magnetic field becomes zero and its vicinity magnetic field free region Can be called (MFFR). This magnetic field free region (MFFR) is placed on the affected part to be treated. magnetic field free region (MFFR) 's position is the first magnetic field of (MF1) and the second magnetic field of (MF2) depends on the characteristics of, magnetic field free region The position (MFFR) and diameter of are the first magnetic element of (2) and the second magnetic element of Can be appropriately adjusted by the current applied to (3). In the magnetic field free region (MFFR) and its vicinity,third magnetic element (4) generates a variable magnetic field (MF3), and only the magnetic nanoparticles (B) located in the magnetic field free region (MFFR) are magnetized. In a preferred embodiment, a variable magnetic field (MF3) having a frequency between 100 kHz and 500 kHz magnetizes the magnetic nanoparticles (B), and thus the core (C) and drug (E) to locally heat them. nanodrug (E) is generated by third magnetic element (4). Thus, third magnetic element (4) generates a variable magnetic field (MF3) that contributes to the vaporization of the nanoagent (E) in the desired region within body (V). In a preferred embodiment, third magnetic element (4) also generates a variable magnetic field with a frequency range from 1 kHz to 150 kHz such that the magnetic nanoparticles generate a measurable magnetization signal. The receiving coil (5) within the assembly (1) receives the magnetization signal generated by the variable magnetic field (MF3) on the magnetic nanoparticles (B). By processing the magnetization signal received by the receiving coil (5) with, for example, a computer, the amount of the nano medicine agent (E) and magnetic field free region (MFFR) temperature can be calculated. The effectiveness of the treatment can be determined by magnetic field free region calculating the amount (E) and temperature of the nanoagent in the (MFFR). Assembly (1)'s first magnetic element (2) and second magnetic element (3) can be selected as natural magnets or electromagnets, but third magnetic element (4) needs to form a variable magnetic field (MF3) and is preferably selected as an electromagnet.

[0017] The apparatus (1) of the present invention comprises at least one first ultrasonic transducer (6) configured to transmit an acoustic wave (AW) having an ultrasonic frequency and an absolute pressure lower than a predetermined minimum absolute pressure sufficient to cause inertial cavitation in tissue at the ultrasonic frequency during vaporization of the nanoagent (E) (Fig. 5). By the apparatus (1) of the present invention, the nanoagent (E) is locally heated by a variable magnetic field (MF3) provided by the three-dimensional magnetic element (4) and vaporized by ultrasonic energy provided by the first ultrasonic transducer (6), so that the diameter of the nanoagent (E) rapidly increases due to vaporization. In this way, the nanoagent (E) releases the drug and similar therapeutic agents in its structure into the environment with high momentum, ensuring that the therapeutic agents penetrate deep tissue and enhance the therapeutic effect. The first ultrasonic transducer (6) supplies the acoustic wave (AW) at an absolute pressure lower than the minimum absolute pressure sufficient to cause inertial cavitation of the nanoagent (E), thereby preventing damage to the tissue caused by the ultrasonic energy applied when vaporizing the nanoagent (E) and enhancing the health safety during treatment. Furthermore, stable cavitation is formed by exciting the nanosheet (E) vaporized by the low-power ultrasonic wave supplied from the first ultrasonic transducer (6). Stable cavitation opens the capillary wall, discharges the drug-like therapeutic agent in the blood vessel to the outside of the blood vessel, and at the same time acts as a pump to promote the diffusion of the therapeutic agent. In addition to these, stable cavitation brings a heating effect to the affected area and weakens the diseased cells.

[0018] In one embodiment of the present invention, the first ultrasonic transducer (6) is configured to apply ultrasonic energy by transmitting an acoustic wave (AW) having a frequency of less than 1 MHz to the nanoparticles (E) within the magnetic field free region (MFFR). The ultrasonic energy supplied from the first ultrasonic transducer (6) by the acoustic wave (AW) causes a pressure change in the environment where the nanoagent (E) is disposed, enabling vaporization of the nanoagent (E).

[0019] By applying a frequency of less than 1 MHz with the first ultrasonic transducer (6), the targeted nanoagent (E) can be vaporized in any desired region of the body (V) including hard tissues such as the skull.

[0020] In one embodiment of the present invention, the tertiary magnetic element (4) is configured to generate a variable magnetic field (MF3) having a frequency of less than 150 kHz. In the present application, the magnetic relaxation of the magnetic nanoparticles (B) in the magnetic field free region (MFFR) is performed by the variable magnetic field (MF3) generated at a frequency lower than 150 kHz in the magnetic field free region (MFFR). By receiving the magnetization signal of these magnetic nanoparticles (B) with the receiving coil (5), the magnetic relaxation of the magnetic nanoparticles (B) can be measured. In other words, the amount of the magnetic nanoparticles (B) in the magnetic field free region (MFFR), and thus the amount of the nanoagent (E), can be quantitatively measured by the measured magnetic relaxation. Since the relaxation characteristics of the magnetic nanoparticles (B) change with temperature, the temperature of the nanoagent (E) in the magnetic field free region (MFFR), and thus the temperature of the magnetic field free region (MFFR), can be calculated at least approximately according to the magnetization signal received from these magnetic nanoparticles (B).

[0021] In one embodiment of the present invention, the first ultrasonic transducer (6) is configured to transmit an acoustic wave (AW) having an absolute pressure sufficient to induce the vaporized nanoagent (E) in the magnetic field free region (MFFR) into an inertial cavitation state. The absolute ultrasonic pressure required for the vaporized nanoparticles (E) to enter the inertial cavitation state is much lower than the absolute ultrasonic pressure required for the non-vaporized nanoparticles (E) to enter the inertial cavitation state. Therefore, inertial cavitation is achieved only in the magnetic field free region (MFFR). As a result, the vaporized nanoagent (E) disintegrates rapidly by itself, forming a locally very high temperature, and free radicals are formed by the diffusion of the radicals contained in the structure of the nanoagent (E) into the environment. Since this occurs in diseased cells and tissues, the therapeutic effect is further enhanced.

[0022] In one embodiment of the present invention, the apparatus (1) further comprises at least a second ultrasonic transducer (7) configured to image the vaporized nano reagent (E). By imaging the evaporating nano reagent (E), the amount of the evaporated nano reagent (E) can be measured. In an embodiment of the present invention in which the vaporized nano reagent (E) is subjected to inertial cavitation by the ultrasonic energy applied by the first ultrasonic transducer (6), broadband acoustic radiation is generated during inertial cavitation, and the second ultrasonic transducer (7) collects the acoustic radiation and enables monitoring of the inertial cavitation process. By monitoring this process, the amount (E) of the nanoagent causing inertial cavitation can be estimated, and the effect of the applied treatment can be monitored instantaneously.

[0023] In one embodiment of the present invention, the apparatus (1) further comprises at least one coupling element (8) configured to provide low-loss transmission of acoustic waves (AW) between the first ultrasonic transducer (6) and / or the second ultrasonic transducer (7) and the body (V).

[0024] The coupling element (8) is adapted to use a material close to the acoustic impedance of the body (V) so as to provide acoustic impedance matching between the first ultrasonic transducer (6) and / or the second ultrasonic transducer (7) and the body (V) when the first ultrasonic transducer (6) and / or the second ultrasonic transducer (7) cannot be in direct contact with the body (V).

[0025] In one embodiment of the present invention, the first ultrasonic transducer (6), the second ultrasonic transducer (7) and the coupling element (8) are combined with each other and arranged to have a monolithic structure (FIG. 6). In this way, the number of manufacturing and assembly steps, labor, and time of the assembly (1) are reduced, and manufacturing and assembly advantages are obtained.

[0026] In one embodiment of the present invention, the assembly (1) further comprises a plurality of imaging magnetic elements (not shown) configured to generate a magnetic field in two directions perpendicular to the direction of the variable magnetic field (MF3) generated by the tertiary magnetic element (4), and an imaging receiving coil (not shown) configured to receive the magnetization signals of the magnetic nanoparticles (B) in these directions. In this application, the magnetization signals received by the imaging receiving coil are processed, for example, by a computer, enabling two-dimensional or three-dimensional imaging of the magnetic nanoparticles (B) and thus the nano-drug (E) in the zero magnetic field region (MFFR).

[0027] The present invention also relates to an apparatus (10) comprising an apparatus (1) of the type described above and at least one control unit (9) configured to drive the apparatus (1) in a controlled manner and to control its operation (FIG. 7). In one embodiment of the present invention, the primary magnetic element (2), the secondary magnetic element (3), the tertiary magnetic element (4), the receiving coil (5), the first ultrasonic transducer (6), the second ultrasonic transducer (7) and the coupling element (8) are housed in a body (11) which can also be called a head, and in an alternative embodiment of the present invention, at least some of said elements (2, 3, 4, 5, 6, 7, 8) can be arranged independently of each other so as to be arranged around the body (V). In one embodiment of the present invention, the apparatus (10) is controlled by a control unit (9) and further comprises at least a first power supply and drive circuit (not shown) configured to supply the first magnetic element (2) with the current necessary to generate a first magnetic field (MF1). In one embodiment of the present invention, the apparatus (10) is controlled by a control unit (9) and further comprises at least a second power supply and drive circuit (not shown) configured to supply the second magnetic element (3) with the current necessary to generate a second magnetic field (MF2). In one embodiment of the present invention, the apparatus (10) further comprises at least one waveform generator, power amplifier and drive circuit (not shown) controlled by the control unit (9) to supply the tertiary magnetic element (4) with the current necessary to generate a variable magnetic field (MF3). In one embodiment of the present invention, the apparatus (10) is controlled by a control unit (9) and further comprises at least one acoustic wave (AW) generator, power amplifier and drive circuit (not shown) configured to supply the signal necessary for the first ultrasonic transducer (6) to emit an appropriate acoustic wave (AW). By controlling and driving the primary magnetic element (2) and the secondary magnetic element (3) independently of each other, it is possible to form a magnetic field free region (MFFR) at a location suitable for treatment, i.e. at the affected part or size of the body (V) to be treated. By controlling and driving the third magnetic element (4) and the first ultrasonic oscillator (6) independently of each other, the magnetic field strength and ultrasonic energy applied for the vaporization of the nanomedicine (E) located in the magnetic field free zone (MFFR) can be adjusted as desired, providing an effective treatment.In one embodiment of the invention, the device (10) further comprises at least one sensor (not shown) configured to detect a marking (not shown) disposed on the body (V) that coincides with the site where the diseased tissue is located and thus where treatment is required. In this way, a magnetic field free zone (MFFR) is automatically created at the location of the signal detected by the sensor.

[0028] The invention also relates to a method of vaporizing a nanomedicine (E) having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, the method comprising a vaporizable liquid (A) previously introduced into the body (V), a core (C) consisting of magnetic nanoparticles (B) disposed in the liquid (A), and a surface (D) surrounding the core (C) and separating the core (C) from the external environment; As a result of generating a first magnetic field (MF1) and a second magnetic field (MF2), a magnetic field free zone (MFFR) is generated in the diseased area in the body (V) that requires treatment, Excitation and / or heating of magnetic nanoparticles (B) contained in the nanoreagent (E) located in the magnetic field free zone (MFFR) by a variable magnetic field (MF3) specially generated to cover the magnetic field free zone (MFFR), Vaporizing a nano-reagent (E) located in a magnetic field free region (MFFR) by applying an acoustic wave (AW) having a specific ultrasonic frequency and an absolute pressure lower than a predetermined minimum absolute pressure sufficient to cause inertial cavitation in tissue at the ultrasonic frequency. In the method of the present invention, as a result of generating a first magnetic field (MF1) by a first magnetic element (2) and a second magnetic field (MF2) by a second magnetic element (3), a magnetic field free zone (MFFR) is formed in a target region within the body (V). Thereafter, a variable magnetic field (MF3) is generated by a third magnetic element (4) to excite and / or heat magnetic nanoparticles (B) within the nano-agent (E) located in the magnetic field free region (MFFR). Further, an acoustic wave (AW) is applied by a first ultrasonic transducer (6) at an acoustic frequency and at an absolute pressure value lower than a predetermined minimum absolute pressure value sufficient to cause inertial cavitation of the nano-agent (A) at the applied frequency, thereby vaporizing the nano-agent (E) located in the magnetic field free region (MFFR). In a preferred embodiment of the present invention, the first ultrasonic transducer (6) preferably transmits an acoustic wave having a frequency lower than 1 MHz to the nano-reagent (E) located in the magnetic field free region (MFFR). By applying a frequency of less than 1 MHz by the first ultrasonic transducer (6), the target nano-agent (E) can be vaporized in any desired region of the body (V) including hard tissues such as the skull.

[0029] With the device (1) of the present invention, a therapeutically effective nanoagent (E) pre-administered to the body (V) is vaporized by an acoustic wave (AW) having a frequency preferably lower than 1 MHz and has two different effects. A variable magnetic field (MF3) provided at a frequency in the range of 100 kHz to 500 kHz by the cubic magnetic element (4) in the assembly (1) heats the core (C) of the nanoagent (E) and assists in the vaporization of the nanoagent (E). Secondly, the magnetic nanoparticles (B) in the nanoagent (E), particularly the magnetic nanoparticles (B) in the core (C), act as cavitation nuclei by an acoustic wave (AW) having a frequency of less than 1 MHz supplied by the first ultrasonic transducer (6) and can initiate vaporization with low ultrasonic energy. These nanoagents (E) change into microbubbles after vaporization, and a therapeutic effect based on stable inertial cavitation is obtained in a magnetic field-free region (MFFR) formed in the affected part (V) of the body without being affected by the ultrasonic beam. For this reason, regions other than the affected part, in other words, regions other than the magnetic field-free region (MFFR), are not affected by the applied ultrasonic energy. Furthermore, stable cavitation is formed by exciting the nanosheet (E) vaporized by the low-power ultrasonic waves supplied from the first ultrasonic transducer (6). Stable cavitation opens the capillary walls, discharges the drug-like therapeutic agent in the blood vessels to the outside of the blood vessels, and at the same time promotes the diffusion of the therapeutic agent by acting as a pump. In addition to these, stable cavitation brings a heating effect to the affected part and weakens the diseased cells.

Claims

**Claim 1**: An assembly (1) having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, enabling vaporization of a nanomedicine (E) previously introduced into a body (V), comprising: a vaporizable liquid (A); a core (C) containing magnetic nanoparticles (B) inside the vaporizable liquid (A); a surface (D) surrounding the core (C) outside the vaporizable liquid (A) and separating the core (C) from the external environment; at least one first magnetic element (2) configured to generate a first magnetic field (MF1) in a first direction; at least one second magnetic element (3) configured to generate a second magnetic field (MF2) in a direction substantially opposite to the first direction; at least one third magnetic element (4) configured to generate a variable magnetic field (MF3) for exciting magnetic nanoparticles (B) located in a magnetic field free region (MFFR) where the first magnetic field (MF1) and the second magnetic field (MF2) in opposite directions suppress each other's effects; at least one receiving coil (5) configured to measure the magnetization of the magnetic nanoparticles (B) to which the variable magnetic field (MF3) is applied; and at least one first ultrasonic transducer (6) configured to transmit an acoustic wave (AW) having an absolute pressure lower than a predetermined minimum absolute pressure sufficient to generate inertial cavitation in tissue at a predetermined ultrasonic frequency and for vaporization of the nanomedicine (E). **Claim 2**: The assembly (1) according to claim 1, wherein the first ultrasonic transducer (6) is configured to apply ultrasonic energy by transmitting the acoustic wave (AW) having a frequency of less than 1 MHz to the nanomedicine (E) located in the magnetic field free region (MFFR). **Claim 3**: The assembly (1) according to claim 1, wherein the third magnetic element (4) is configured to generate the variable magnetic field (MF3) having a frequency of less than 150 kHz. **Claim 4**: The assembly (1) according to claim 1, wherein the third magnetic element (4) is configured to generate the variable magnetic field (MF3) having a frequency between 100 kHz and 500 kHz.

5. The assembly (1) according to claim 1, characterized in that the first ultrasonic transducer (6) is configured to transmit an acoustic wave (AW) having an absolute pressure sufficient to induce the vaporized nanoagent (E) in the magnetic field free region (MFFR) only into an inertial cavitation state.

6. The assembly (1) according to claim 1, characterized in that at least one second ultrasonic transducer (7) is configured to image the vaporized nanoagent (E).

7. The assembly (1) according to claim 6, characterized by at least one coupling element (8) configured to provide transmission of the acoustic wave (AW) between the first ultrasonic transducer (6) and / or the second ultrasonic transducer (7) and the body (V).

8. The assembly (1) according to claim 7, characterized in that the first ultrasonic transducer (6), the second ultrasonic transducer (7) and the coupling element (8) are appropriately arranged to form a monolithic structure.

9. The assembly (1) according to claim 1, characterized by a plurality of imaging magnetic elements configured to generate a magnetic field in two directions perpendicular to the direction of the variable magnetic field (MF3) generated by the third magnetic element (4), and a receiving coil configured to receive a signal of the magnetization of the magnetic nanoparticles (B) in the direction.

10. An apparatus (10) comprising the assembly (1) according to any one of claims 1 to 9, and at least one control unit (9) configured to controllably drive the assembly (1) and control its operation.

11. A method for enabling vaporization of a nanoagent (E) introduced in advance into a body (V), comprising a vaporizable liquid (A) having a therapeutic effect or a diagnostic effect, or both a therapeutic effect and a diagnostic effect, a core (C) containing magnetic nanoparticles (B) inside the vaporizable liquid (A), and a surface (D) surrounding the core (C) outside the vaporizable liquid (A) and separating the core (C) from the external environment, wherein the method comprises Generating a magnetic field-free region (MFFR) over a diseased part in a body (V) (excluding the human body) that requires treatment by suppressing the effects of a first magnetic field (MF1) in a first direction and a second magnetic field (MF2) in a direction substantially opposite to the first direction through generation; Exciting and / or heating magnetic nanoparticles (B) in a nano-drug (E) located in the magnetic field-free region (MFFR) by a specially generated variable magnetic field (MF3) that covers the magnetic field-free region (MFFR); Vaporizing the nano-drug (E) located in the magnetic field-free region (MFFR) by applying an acoustic wave (AW) having a predetermined ultrasonic frequency and an absolute pressure lower than a predetermined minimum absolute pressure sufficient to cause inertial cavitation in tissue at the ultrasonic frequency. A method comprising the steps of:

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