Nanoparticles sequentially exposed to low intensity acoustic waves for medical or cosmetic applications

Abstract

To provide a system for acoustic wave treatment of a body part of an individual, wherein nanoparticles are administered to the body part of the individual and an acoustic wave is applied to the body part.SOLUTION: Provided is a system comprising a composition including nanoparticles and a device E that generates non-focused thermal radiation.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to nanoparticles that are sequentially exposed to low intensity acoustic waves for medical treatment. [Background technology]

[0002] Diseases such as cancer, e.g., prostate cancer, can currently be treated with ultrasound, typically using high-intensity focused ultrasound (HIFU). However, this treatment has several drawbacks. To be effective, HIFU typically requires heating cancerous tissue to relatively high temperatures, which can also damage healthy tissue. Using HIFU requires heating the tumor at several sites to eradicate it. To overcome these drawbacks, low-intensity ultrasound (LIU) may be used instead of HIFU. In this invention, we propose a method to make LIU effective in medical treatment. This is based on using nanoparticles located at the pathological site and sequentially exposing it to low-intensity sound waves (Non-Patent Reference 1). (References) (Non-Patent Document 1) Nature Reviews Cancer, V.5, p.321 (2005) Detailed Description of the Invention

[0003] The present invention also relates to nanoparticles for use in ultrasonic treatment of a body part of an individual, wherein the nanoparticles are administered to the body part of the individual and ultrasonic waves are applied to the body part, wherein—the ultrasonic waves are applied to the body part sequentially, and / or—the nanoparticles are magnetosomes.

[0004] The present invention also relates to nanoparticles for use in radiotherapy of a body part of an individual, wherein the nanoparticles are administered to the body part of the individual and radiation is applied to the body part, wherein: - radiation is applied to the body part sequentially, and / or - the nanoparticles are magnetosomes.

[0005] The present invention also relates to nanoparticles for use in radiation or ultrasound therapy of a body part of an individual, wherein the nanoparticles are administered to the body part of the individual and radiation or ultrasound is applied to the body part, wherein: - the radiation or ultrasound is applied to the body part sequentially, and / or - the nanoparticles are synthesized in living tissue, in particular inside or outside living tissue.

[0006] The present invention also relates to magnetosomes for use in sonic or radiation treatment of a body part of an individual, wherein the magnetosomes are administered to the body part of the individual and the body part is exposed to sonic waves or radiation. In some cases, the magnetosomes are administered to the body part of the individual and the body part is exposed to sonic waves or radiation.

[0007] The present invention also relates to nanoparticles for use in sonic or radiation treatment of a body part of an individual, wherein the nanoparticles are administered to the body part of the individual and sonic or radiation is applied to the nanoparticles and / or the body part, particularly sequentially.

[0008] The present invention relates to a method of treating a body part of an individual, which comprises administering to said body part an effective amount of nanoparticles and, particularly sequentially, applying to said body part effective sound waves or radiation, wherein said nanoparticles are particularly magnetosomes.

[0009] In some cases, the nanoparticles are administered to the body part of the individual and the body part is exposed to sound waves or radiation, particularly sequentially.

[0010] In some cases, saying that acoustic waves are applied to a nanoparticle or body part is equivalent to saying that the nanoparticle or body part is exposed to acoustic waves or radiation.

[0011] In some embodiments, the nanoparticles are 1, 10, 10 2 , 10 3 , 10 5 , 10 10 or 10 50It refers to one or more nanoparticles or a collection of nanoparticles.

[0012] In other embodiments, the nanoparticles are 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10 2 , 50, 10, 5, 2 or 1 nanoparticle or collection of nanoparticles.

[0013] In one embodiment of the present invention, a nanoparticle region is i) a portion of the body part that contains nanoparticles, ii) a mass of the body part that is occupied by nanoparticles, or iii) a mass outside of the body part that is occupied by nanoparticles.

[0014] The present invention relates to nanoparticles used according to the invention, wherein the acoustic waves have at least one of the following characteristics: i1) a power or power density of less than 1000 W (Watts); i2) per cm; 2 per cm 3 i) per cm of body part, with a power or power density of 1000 W or less per cm of body part 2 per, or body part cm 3 i4) per cm of transducer, with a power or power density of 1000W or less per cm of transducer 2 per cm of transducer 3 i) have a power or power density of 1000 W or less per gram of nanoparticles; ii) have a power or power density of 1000 W or less per gram of nanoparticles; 5 ii) per cm, cm 2 per, or cm 3 10 per 5 ii) per cm of body part, cm of body part, with a power or power density of less than or equal to W·sec 2 per, or body part cm 3 10 per 5ii4) per cm of transducer, with a power or power density of W·sec or less; 2 per cm of transducer 3 10 per 5 with a power or power density of less than or equal to W·sec, ii5)10 5 ii6) per cm, cm 2 per cm 3 10 per 5 ii7) having a power or power density of J or less per cm of body part, cm of body part 2 per, or body part cm 3 10 per 5 ii8) with a power or power density of J or less per cm of transducer, cm of transducer 2 per cm of transducer 3 10 per 5 ii9) have a power or power density of 10 J or less per gram of nanoparticles; 5 iii) have a power or power density of 10 J or less; 5 MHz or less, iv) 10 -5 cm or greater penetration depth, v) is not focused, and / or vi) is not focused or high intensity ultrasound.

[0015] In one embodiment of the present invention, sound waves or radiation are irradiated and / or applied to the body part and / or nanoparticles, which means that the sound waves or radiation are applied to the body part and / or nanoparticles or at least 10 -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75 or 80% of the body part or nanoparticles to be covered, targeted, reached and located therein, or to the body part or nanoparticles or at least 10 -100 , 10 -50 , 10 -10 , 10 -9 , 10 -7 , 10 -5, 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75, or 80% of the body part or nanoparticles are exposed to the sound waves or radiation. In some instances, the sound waves or radiation can cover, target, reach, and locate the body part or nanoparticles, especially when the sound waves or radiation are of a power or energy that is sufficiently low or does not induce toxicity.

[0016] In one embodiment of the invention, the excitation of the nanoparticles with radiation or sound waves or the irradiation of the body part or nanoparticles with sound waves or radiation or the application of the nanoparticles or body part to the nanoparticles or body part occurs or occurs in less than 100%, 90%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, 1% or 0.1% of the body part, particularly on the nanoparticles or body part.

[0017] In one embodiment of the invention, when a body part or nanoparticle is irradiated or exposed to sound waves or radiation, the body part or nanoparticle receives or absorbs the energy or power of the sound waves or radiation. In some cases, the body part or nanoparticle receives or absorbs at least 10 times the energy or power of the sound waves or radiation. -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1, 1, 5, 10, 25, 50, 75, or 80% of the energy or power of the sound waves or radiation. This is when the concentration of nanoparticles in the body part and / or the sound waves or radiation applied to the body part or nanoparticles is large. In some cases, the body part or nanoparticle receives or absorbs 80, 70, 50, 60, 10, 5, or 1% or less of the energy or power of the sound waves or radiation. This is when the concentration of nanoparticles in the body part and / or the sound waves or radiation applied to the body part or nanoparticles is small. In some cases, this percentage is i) the ratio of the power or energy of the sound waves or radiation absorbed or received by the body part or nanoparticle divided by the power or energy of the sound waves or radiation applied to the body part or nanoparticle, or ii) the ratio of the power or energy of the sound waves or radiation absorbed or received by the body part or nanoparticle divided by the power or energy of the sound waves or radiation generated by the sound wave or radiation generating device.

[0018] For the purposes of this invention, acoustic waves are: i) mechanical waves that specifically induce mechanical perturbations or disturbances in a medium or a body part through which the medium passes, such as compression and / or expansion of the medium; ii) elastic waves; iii) waves that cannot propagate or exist in empty space; or iv) waves that induce or are associated with the movement or vibration of matter, atoms, ions, or nanoparticles with non-zero mass or weight. Acoustic waves are not typically electromagnetic waves. However, in some cases, they may generate or produce electromagnetic waves, for example, when the charge of matter moving / vibrating in response to the acoustic waves is non-zero. An example of radiation generated from, caused by, or associated with acoustic waves may be acoustic radiation force.

[0019] The term "sonic" may designate sonic energy, sonic power, sonic intensity, or sonic frequency. In some cases, sonic intensity may have the same meaning as sonic power or sonic energy. In other cases, sonic power may have the same meaning as sonic energy. Sound waves are absorbed, reflected, or transmitted by nanoparticles or body parts. Sound waves can have a frequency, energy, power, or intensity, which may be designated as the frequency, energy, power, or intensity of the sound wave, respectively. Sound waves can be 1, 10, 10 2 , 10 3 , 10 5 , 10 10 or 10 20 The assembly of these sound waves can be specified. Sonic energy can be expressed as the power of the sound wave multiplied by the time the sound wave is applied. It can be expressed as a unit of power, such as watts, multiplied by a unit of time, such as seconds.

[0020] The energy density of a sound wave is measured per unit length, such as cm 2 per unit surface area, such as cm 3 The energy of a sound wave per unit volume, such as 1 / 2, can be expressed in units of power, such as watts. The sound power density is proportional to the sound energy per unit of length, such as cm. 2 per unit surface area, such as cm 3 The sound power per unit volume can be expressed as cm 2 It is proportional to the sound power per unit surface area, such as watts. 2 In some cases, unit length, unit surface area, and unit volume can represent the length, surface area, and volume of a nanoparticle, respectively.

[0021] In one embodiment of the present invention, sound waves are associated with, linked to, directing, generating, originating, resulting from, causing, or producing the movement or vibration or oscillation of a substance or collection of substances, which substance has: i) in some cases 10-20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 5 or 10 7 Grams or cm of larger body parts 3 10 gram per gram or grams of nanoparticles, ii) 10 gram per gram or grams of nanoparticles in other cases 9 , 10 7 , 10 5 , 10 3 , 10 2 , 10, 1, 10 -2 , 10 -5 , 10 -7 , 10 -9 , 10 -20 or 10 -50 Grams or cm for smaller body parts 3 iii) mass in grams per gram or grams of nanoparticles, 0 and 10 20 , 10 -20 and 10 20 , 10 -10 and 10 10 , or 10 -10 and 10 grams or cm of body parts 3 mass in grams per nanoparticle or grams of nanoparticles, iv) in some cases a positive charge, v) in other cases a negative charge, and / or vi) in still other cases a neutral charge.

[0022] In one embodiment of the present invention, the substance is a nanoparticle.

[0023] In some cases, the sound waves are 2, 5, 10, 10 5 , 10 10 or 10 20 The movement of more than 10 nanoparticles 10 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -2 or 10 -5 Within minutes, especially 1.1, 2, 5, 10, 10 5 , 10 10 or 10 20These changes in nanoparticle movement or concentration can be attributed to changes in nanoparticle concentration by factors of greater than or equal to 100,000, particularly in parts of the body.

[0024] In one embodiment of the present invention, the movement, vibration or oscillation of the substance is periodic or is periodically repeated. In this case, the movement, vibration or oscillation of the substance is particularly 3 , 10 6 or 10 9 The motion, vibration, or sway of the material may be repeated one or more times, and at least one property associated with the motion, vibration, or sway of the material may be repeated, and the property may be the material's velocity or change in velocity through time or space, its displacement or change in displacement through time or space, or its acceleration or change in acceleration through time or space.

[0025] For purposes of the present invention, sound waves are defined as or can be infrasound, sound, ultrasound, or hypersound.

[0026] In the present invention, the sound waves are in particular ultrasound waves, in particular: i) 10 -2 Between 10 and 100 MHz -1 and / or ii) cm 2 10 per -2 and 10 2 Between W, cm 2 10 per -1 Between 10W and 10cm 2 They have a power between 1 and 5W per

[0027] In particular, infrasound can be defined as sound waves with low frequencies. In some cases, infrasound frequencies are 2, 20, 200, 2000 or 10 5 In some other cases, the infrasonic frequencies are 10 -100 , 10 -50 , or 10 -10 Hz. Most notably, infrasound has frequencies below 20 Hz.

[0028] In particular, sound can be defined as sound with the following frequencies: i) 2·10 -3 , 2·10 -1 , 2, 20 or 200 Hz. ii) In some other cases, 2, 20, 200 or 2·10 5 kHz or less. Most specifically, the frequency of sound is between 16Hz and 16kHz.

[0029] In particular, ultrasound can be defined as sound with a frequency of: i)2·10 -3 , 2, 20, or even greater than 200 kHz; ii) 0.1, 1, 10, or 10 5 It can also have frequencies below GHz. Most notably, ultrasonic frequencies are between 16 kHz and 10 MHz.

[0030] In particular, hypersound can be defined as sound with a large frequency. In some cases, the frequency of hypersound is 10 -10 , 10 -3 , 10 -2 , 10 -1 , 1 or 10 GHz. In other cases, the frequency of hypersonic waves is 10 1000 , 10 100 , 10 10 or 10 5 It may be lower than GHz. Most preferred is that the hypersonic frequency is above 10 MHz.

[0031] In some cases, sound waves, infrasound, sound, ultrasound, or hypersound are waves, especially longitudinal waves, especially 10 -100 and 10 100 It may be a wave with a frequency between 100 Hz and 200 Hz.

[0032] In some cases, as a sound wave passes through a medium and its frequency increases while passing through this medium, the sound wave may reach a large value of frequency.

[0033] In other cases, a sound wave may reach a lower value of frequency as it passes through a medium and its frequency decreases while passing through this medium.

[0034] In one embodiment of the present invention, ultrasound has a frequency greater than sound, and hypersound has a frequency greater than ultrasound, both of which are particularly so by the following factors: i) possibly 1.001, 1.1, 2, 5, 10 or 10 3 ii) In some other cases, 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 5, or 2 or less, or iii) in some other cases 1.00001 to 10 50 It is between.

[0035] According to the present invention, the form of radiation can be waves, such as electromagnetic waves, sound or acoustic waves, or particle waves, where the particles have: i) in some cases weight or mass, ii) in other cases no weight or mass, iii) in some cases motion, or iv) in other cases no motion.

[0036] In another embodiment of the invention, the radiation is a wave that causes, relates to, connects, induces, generates, results, causes, or produces a motion, vibration, or oscillation of a substance or collection of substances, where the substance has: i) zero mass, or ii) 1.111, 1.5, 2, 5, 10, 10 less than the mass of the substance that is associated with, connected to, induced, generated, or results from the sound wave. 3 , or 10 5 Less mass by a factor of more than.

[0037] According to the present invention, the form of radiation can be electromagnetic radiation.

[0038] According to the present invention, the radiation may in some cases be acoustic radiation force, radiation force, or radiation pressure.

[0039] According to the invention, the radiation is in particular a sonic irradiation of the body part.

[0040] Preferably, the radiation source is selected from the group consisting of i) a magnetic or electric field, ii) laser light, iii) light produced by a lamp, iv) light emitted at a single wavelength, v) light emitted at multiple wavelengths, vi) ionizing radiation, vii) microwaves, viii) radio frequency, and ix) sound waves.

[0041] In some cases, the radiation may be selected from the group consisting of alpha, beta, gamma, x-ray, neutron, proton, electron, ion, neutrino, muon, meson, and photon particles or radiation.

[0042] Preferably, the radiation may optionally be selected from the group consisting of sonic, infrasonic, sound, ultrasonic, and hypersonic.

[0043] Preferably, the radiation is, generates, results in, causes, or induces a magnetic or electromagnetic field. In some cases, the strength of the magnetic or electromagnetic field is greater than 1 μT, 10 μT, 100 μT, 1 mT, 10 mT, 100 mT, 1 T, 5 T, 10 T, or 100 T. In other cases, the strength of the magnetic or electromagnetic field is greater than 10 20 , 10 5 , 10 2 , 10, 1, 10 -1 , 10 -3 or 10 -9 It is below T.

[0044] In some cases, the radiation according to the invention may be 10 per cm3 of body part. -10 , 10 -5 , 10 -3 , 0.01, 0.1, 1, 10, 10 2 , 10 3 , 10 5 or 10 7 It can have an output of more than Gy or Gy per gram of body part or greater than Gy per gram of nanoparticles.

[0045] In some other cases, radiation according to the present invention may be 100 , 10 50 , 1010 , 10 5 , 10 2 , 10, 1, 10 -3 or 10 -5 May have outputs of the following: Gy or Gy per cm3 of body part or Gy per gram of body part or Gy per cm3 of nanoparticles or Gy per gram of nanoparticles.

[0046] In another embodiment of the invention, the sound wave is not at least one radiation selected from the group consisting of: i) electromagnetic radiation, ii) magnetic field, iii) electric field, iv) alternating electric or magnetic field, v) laser or laser light, vi) lamp or light produced by a lamp, vii) light emitted at a single wavelength, viii) light emitted at multiple wavelengths, ix) ionizing radiation, x) microwave, xi) radio frequency, xii) photon, xiii) alpha, beta, gamma, x-ray, neutron, proton, electron, ion, neutrino, muon, meson, photon particle or radiation, and xiv) particle, matter, or photon radiation originating from an atom or molecule.

[0047] In some cases, the sound waves are acoustic radiation or can be replaced by acoustic radiation.

[0048] In some cases, sound waves or radiation may be 1, 5, 10, 10 3 , 10 5 , 10 10 , 10 20 or 10 50 In other cases, the sound waves or radiation may be or represent a collection of more than 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 5, or may represent a collection of two or fewer sound waves or forms of radiation.

[0049] In the present invention, the radiation or sound waves may be radiation or sound waves generated or produced by a device or apparatus that specifically generates or produces the radiation or sound waves before, during, or after the radiation or sound waves reach, cover, or target the body part or nanoparticles. In some cases, the device or apparatus is different from the nanoparticles and is specifically manufactured by a human.

[0050] In some cases, the device that generates the sound waves is or includes a transducer that specifically converts an electrical signal into sound waves.

[0051] In the present invention, the radiation or sound waves may be radiation or sound waves generated by nanoparticles in some cases. In this case, the radiation or sound waves may be due to changes in the organization of nanoparticles, particularly before and after the administration of nanoparticles to a body part or an individual. For example, nanoparticles may be organized into chains before administration to an individual, and then gradually decompose after administration to an individual, for example, by lysosomes, resulting in a change, particularly an increase, in the distance between nanoparticles, and thus a change in the interaction between nanoparticles may cause sound waves or radiation.

[0052] In one embodiment of the present invention, the intensity, power, energy, or frequency of a sound wave or radiation is the intensity or frequency of a sound wave generated by a sound wave or radiation generating device or transducer. It can be the intensity, power, energy, or frequency of a sound wave or radiation measured immediately after the sound wave or radiation exits the sound wave or radiation generating device or the transducer. It can also be the intensity, power, energy, or frequency of a sound wave or radiation measured after the sound wave or radiation exits the sound wave or radiation generating device or the transducer and passes through another medium (liquid, gas, solid), such as a body part.

[0053] In some cases, the device for detecting sound waves may include a sound wave sensor, in particular comprising a transducer, in particular converting the power or energy of the sound waves into an electrical signal.

[0054] In some cases, the intensity, strength, or power of the sound waves or radiation may be undetectable because it is too small or undetectable for available sound wave or radiation detectors. In these cases, the presence of the sound waves or radiation may be revealed by the movement, vibration, or changes in size, texture, composition, or charge of the substance that produces the sound waves, such as nanoparticles.

[0055] The present invention also relates to nanoparticles for use according to the present invention, wherein the intensity, power or power density of the acoustic waves or radiation is less than: i) 10 100 , 10 50 , 10 20 , 10 10 , 10 9 , 10 6 , 10 5 , 10 3 , 10 2 , 100, 50, 10, 5, 3, 1, 10 -1 10 -2 , 10 -3 , 10 -5 or 10 -7 W (Watts), ii) 10 100 , 10 50 , 10 20 , 10 10 , 10 9 , 10 6 , 10 5 , 10 3 , 10 2 , 100, 50, 10, 5, 3, 1, 10 -1 10 -2 , 10 -3 , 10 -5 or 10 -7 W / cm, W / cm², or W / cm 3 iii)10 100 , 10 50 , 10 20 , 10 10 , 10 9 , 10 6 , 10 5 , 10 3 , 10 2 , 100, 50, 10, 5, 3, 1, 10 -1 10 -2 , 10 -3, 10 -5 or 10 -7 W per cm of body part, cm of body part 2 W per, or cm of body part 3 per Wiv)10 100 , 10 50 , 10 20 , 10 10 , 10 9 , 10 6 , 10 5 , 10 3 , 10 2 , 100, 50, 10, 5, 3, 1, 10 -1 10 -2 , 10 -3 , 10 -5 or 10 -7 W per cm of transducer, cm of transducer 2 per W or cm of transducer 3 per Wv)10 100 , 10 50 , 10 20 , 10 10 , 10 9 , 10 6 , 10 5 , 10 3 , 10 2 , 100, 50, 10, 5, 3, 1, 10 -1 10 -2 , 10 -3 , 10 -5 or 10 -7 W per gram of nanoparticles.

[0056] In some cases, 1 cm 3 , 1cm 2 , and 1cm are 1cm, respectively. 3 body part, 1cm 2 body parts of 1 cm and body parts of 1 cm.

[0057] In other cases, 1 cm 3 , 1cm 2 , and 1cm are 1cm, respectively. 3 transducer, 1cm 2 transducer, and 1 cm transducer.

[0058] In some cases, a transducer may designate the part of the transducer that produces sound waves.

[0059] In other cases, the 1 gram of nanoparticles can be 1 gram of nanoparticles that are exposed to sound waves or radiation, or 1 gram of nanoparticles to which sound waves are applied.

[0060] The present invention also relates to nanoparticles for use according to the present invention, wherein the intensity, power or power density of the acoustic waves or radiation is greater than: i) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 5, 10, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 W (Watts), ii) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 5, 10, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 W / cm, W / cm 2 , or W / cm 3 , iii)10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 5, 10, 10 2 , 103 , 10 5 , 10 7 or 10 9 , per cm of body part W, cm of body part 2 W per, or cm of body part 3 per W, iv) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 5, 10, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 W per cm of transducer, 1 cm of transducer 2 per W, or 1 cm of transducer 3 per W, v) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 5, 10, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 W per gram of nanoparticles.

[0061] The present invention also relates to nanoparticles for use according to the present invention, wherein the intensity, power or power density of the acoustic waves or radiation is between: i) 0 and 10 100 , 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 and 10 W (Watts), ii) between 0 and 10 100 , 10 -100and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 Between 10 and 10 W / cm, W / cm 2 , or W / cm 3 iii) 0 and 10 100 , 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 W per cm of body part between and 10 cm of body part 2 W per, or cm of body part 3 W per, iv) 0 and 10 100 , 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 and 10 W per cm of transducer, cm of transducer 2 per W or cm of transducer 3 per W, v) 0 and 10 100 , 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 Between 10 and 10 W per gram of nanoparticles

[0062] The present invention also relates to nanoparticles for use according to the present invention, in which the energy or energy density of the sound waves or radiation is less than: i) 10 9 , 10 6 , 105 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 W·sec, ii)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 W sec / cm, W sec / cm 2 , or W·sec / cm 3 , iii)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 W·sec per cm of body part, cm of body part 2 per W·sec, or cm of body part 3 per W·sec, iv)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 W·sec / cm per transducer, W·sec per transducer / cm2, or W·sec / cm per transducer 3 , v)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 per J (joule), vi) 10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 J / cm, J / cm 2 , or J / cm 3 vii)109 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 J per cm of body part, cm of body part 2 per J, or cm of body part 3 per J, viii)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 J per transducer cm, transducer cm 2 per J, or transducer cm 3 per J, or ix)10 9 , 10 6 , 10 5 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 , or 10 -5 J per gram of nanoparticles,

[0063] In some cases, the power of the sound waves is low and / or the duration of sound application is shorter than 24, 12, 6, 3, 2, or 1 hour, or shorter than 50, 30, 15, 10, 5, 2, or 1 minute, or shorter than 50, 30, 20, 10, 5, 2, 1, 10-1, 10 -3 , 10 -6 or 10 -9 When shorter than a second, sound waves can have low energy.

[0064] The present invention also relates to nanoparticles for use according to the present invention, wherein the energy or energy density of the acoustic waves or radiation is greater than: i) 10 -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 W·sec, ii)10-50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 W sec / cm, W sec / cm 2 , or W·sec / cm 3 , iii) per 1 cm of body part, per 1 cm of body part 2 per, or body part cm 3 10 per -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 W·sec, iv) per cm of transducer, cm of transducer 2 per, or cm of transducer 3 10 per -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 W·sec, v)10 -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 J (joule), vi) 10 -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 J / cm, J / cm 2 or J / cm 3 vii) per cm of body, cm of body 2 per or body cm 3 10 per -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1, 1, 10, 10 2 , or 10 5 J, viii) per transducer cm, transducer cm 2 per transducer, or cm 3 10 per -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 J, or ix) 10 per gram of nanoparticles -50 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 2 , or 10 5 J

[0065] In some cases, the power of the sound waves is high and / or the duration of the sound application is particularly long. -50 , 10 -10 , 10 -1 , 1, 5, 10, 10 5 or 10 10 For periods longer than a minute, sound waves can have a lot of energy.

[0066] The present invention also relates to nanoparticles for use according to the present invention, wherein the energy or energy density of the acoustic waves or radiation is between: i) 10 -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 W·sec, ii)10 -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 W sec / cm, W sec / cm2 , or W·sec / cm 3 , iii) per cm of body part, cm of body part 2 per or body part cm 3 10 per -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 W·sec between, iv) per cm of transducer, cm 2 per or cm 3 10 per -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 W·sec between v)10 -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 Between J (Joule), vi) 10 -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 Between J / cm, J / cm2 or J / cm 3 , vii) per cm of body part, cm 2 per or cm 3 10 per -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5, or 1 and 10 4 between J, viii) per transducer cm, cm 2 per or cm 3 10 per -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 J between, or ix) 10 per gram of nanoparticles -50 and 10 50 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 5 , or 1 and 10 4 J in between.

[0067] In some cases, the power of the sound waves or radiation may be equal to 0 watts or 0 gray, particularly before, at the beginning, at the end, or after a sound treatment or a radiation treatment, or during some specific treatments or methods described in the present invention, such as the treatment of anemia.

[0068] In other cases, the power of the sound waves or radiation may be greater than 0 watts or 0 grays, particularly during ultrasound or radiation therapy.

[0069] The present invention also relates to nanoparticles for use according to the invention, in which the frequency of the sound waves or radiation is 10 5 MHz or less. In some cases, the frequency of the sound waves or radiation is 100 , 10 50 , 10 30 , 10 20 , 10 10 , 10 5 , 10 3 , 10 2 , 10, 1, 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10-6 , 10 -7 , 10 -8 , 10 -10 or 10 -15 It can be MHz or even kHz.

[0070] In some other cases, the radiation or sound waves according to the present invention are -100 , 10 -50 , 10 -20 , 10 -10 , 10 -8 , 10 -7 , 10 -6 , 10 -5 , 10 -4 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 3 , 10 5 or 10 10 It can be kHz or MHz or higher.

[0071] In still other cases, the radiation or sound waves according to the present invention may have a frequency between: 10 -15 and 10 15 MHz, 10 -13 and 10 13 MHz, 10 -11 and 10 11 MHz, 10 -9 and 10 9 MHz, 10 -7 and 10 7 MHz, 10 -5 and 10 5 MHz, 10 -3 and 10 3 MHz, or 10 -1 and 10MHz

[0072] In some cases, the frequency of the sound waves or radiation may be the frequency of vibration of the sound waves or radiation.

[0073] The present invention also relates to nanoparticles used in which sound waves or radiation are transmitted to the body, particularly in the form of 10 -10 , 10 -5 , 10 -3 , 10 -1, having a penetration depth of greater than 1, 5, 10, 20, 50 or 500 cm.

[0074] The present invention also relates to nanoparticles for use, wherein the sound waves or radiation are 10 , 10 5 , 10 3 , 50, 50, 20, 10, 5, 1, 0.1 or 0.001 cm.

[0075] In some cases, sound waves or radiation may be present, especially at 10 -10 and 10 10 , 10 -5 and 10 3 , 10 -3 and 10 3 , 10 -3 and 100, 10 -2 and 10, or 10 -2 and has a penetration depth of between 10cm.

[0076] Depth of penetration refers to the depth of penetration, particularly through or within a body part or nanoparticle region, or -3 , 10 -9 or 10 -20 % penetration depth of sound waves or radiation through or within a nanoparticle region or within or within the region separating the device generating the sound waves or radiation from the body part or nanoparticle region.

[0077] In one embodiment, the intensity, energy, power, frequency of the sound waves or radiation may be, among others, 1.1, 1.2, 1.5, 2, 3, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 The penetration depth of sound or radiation is reduced by a factor of more than 1.1, 1.2, 1.5, 2, 3, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 It decreases by a factor of 1 or more.

[0078] In one embodiment of the present invention, the penetration depth of the sound waves or radiation is inversely proportional to the frequency of the sound waves or radiation. 2 , 10 3 , 10 5 or 10 10 To increase the frequency of the sound waves or radiation by a factor of 1.1, 1.2, 1.5, 2, 3, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 It can be reduced by more than double.

[0079] In one embodiment of the present invention, unfocused acoustic waves or radiation are applied to a body part, which consists of or includes nanoparticle-containing regions and / or nanoparticle-free regions, and which also includes or consists of diseased cells and / or healthy cells.

[0080] In one embodiment of the present invention, a sonic volume or acoustic volume is defined as a volume that is exposed to, receives sonic energy, or is affected by sonic waves.

[0081] In one embodiment of the present invention, the volume of radiation is defined as the volume exposed to radiation, subjected to radiation energy, or affected by radiation.

[0082] The present invention also relates to nanoparticles for use according to the present invention, wherein the acoustic waves or radiation are not focused.

[0083] In some cases, unfocused acoustic waves or radiation can be applied to a wave volume or radiation volume that includes the nanoparticle region or body part, or a portion of the nanoparticle region or body part.

[0084] In some cases, unfocused acoustic waves or radiation can be applied to a wave volume or radiation volume, which can be: i) 10 -10 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 102 , 10 3 , 10 5 or 10 10 cm 3 ii) greater than the nanoparticle region or body part or healthy or pathological site, particularly 1.1, 1.5, 2, 5, 10, 10 3 or 10 5 Greater than or equal to a factor greater than or equal to 1, 10, 10 3 , 10 5 or 10 10 cm 3 or iii) is greater than the acoustic volume or radiation volume reached or present by the focused acoustic waves or radiation or produced by applying the focused acoustic waves or radiation, in particular by 1.1, 1.5, 2, 5, 10, 10 3 or 10 5 By a factor greater than or equal to 1, 10, 10 3 , 10 5 or 10 10 cm 3 Only bigger.

[0085] In some cases, this situation can occur when unfocused sound waves or radiation are applied to an area containing healthy cells without damaging or destroying the healthy cells, particularly because i) the healthy cells are not in contact with or mixed with the nanoparticles, and application of sound waves or radiation to both the healthy cells and the nanoparticles is particularly necessary to induce pathological cell destruction, or ii) the healthy cells are less sensitive to or less likely to be destroyed by sound waves or radiation than the pathological cells. In other cases, this situation can occur when treating large, young areas.

[0086] In other cases, unfocused sound waves or radiation may be applied to a sound volume or radiation volume. 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -1, 10 -3 or 10 -5 cm 3 ii) smaller than nanoparticle regions or body parts or healthy or pathological sites, especially 1.1, 1.5, 2, 5, 10, 10 3 or 10 5 by a factor of 1, 10, 10 3 , 10 5 or 10 10 cm 3 In some cases, this situation may occur when: i) unfocused sound waves or radiation are applied to an area or volume that is not too large, especially to avoid toxicity that may be caused by applying large amounts of sound waves or radiation, ii) to treat body parts of small size, or iii) to avoid the need to use equipment that generates the sound waves or radiation that is too large, too expensive, or too energy-consuming.

[0087] In other cases, unfocused sound waves or radiation may be applied to a sound wave or radiation volume, the volume being i) 10 -100 and 10 100 cm 3 ,10 -50 and 10 50 cm 3 , or 10 -10 and 10 10 or ii) between 10 and 10% of the body part, nanoparticle region, pathological site, and / or healthy site. 100 , 10 10 , 10 5 , 10 3 , 10, 5, or 2 times smaller volumes and 2, 5, 10, 10 than body parts, nanoparticle regions, pathological sites, and / or healthy sites. 3 , 10 5 , 10 10 or 10 100 Between large volumes.

[0088] In other cases, unfocused sound waves or radiation may be applied beyond the sound wave or radiation volume, which is larger than the sound wave or radiation volume of the focused sound waves or radiation by the following factors: i) 0 and 10 50 cm 3 , 0 and 10 3 cm 3 , 0 and 10cm 3 , 10 -50 and 10 50 cm 3 , or 10 -3 and 10 3 cm 3 , or ,ii) between 1 and 10 50 , 1 and 10 5 , 1.1 and 10 50 , or 1.1 and 10 5 Between.

[0089] The present invention also relates to nanoparticles for use according to the present invention, wherein the sound waves or radiation are focused. In this case, the sound waves or radiation are focused at a rate of 0.001, 0.1, 1, 10, 10 2 , 10 3 , 10 5 or 10 10 cm 3 This applies to acoustic or radiation volumes contained especially in body parts smaller than 1000 mW.

[0090] In one embodiment of the present invention, the focused sound waves or radiation are applied to 10 of the body part. -5 , 10 -3 , 10 -1 , 1, 10, 10 3 or 10 5 % or less to 10 3 , 10 2 , 10, 5, 2 or 1 application or application spot can be used to cover.

[0091] In some cases, the acoustic volume of focused acoustic waves can be a volume exposed to focused ultrasound, or focused ultrasound, particularly high intensity focused ultrasound (HIFU). In some cases, the acoustic volume can be a focal region of the acoustic waves. In the case of HIFU, a typical focal region is, in particular, a spot, i) an ellipsoid or ellipsoid volume 15 mm along the beam axis and 1.5 mm in diameter, or ii) a 10 5 , 10 3 , 100, 75 or 50mm 3 It may be a smaller volume.

[0092] In some cases, the focused sound or ultrasound waves may be high intensity focused ultrasound (HIFU).

[0093] In one embodiment of the present invention, the acoustic waves are not focused acoustic waves or HIFU.

[0094] In one embodiment of the present invention, the radiation or sound waves have an intensity, power, intensity, wavelength, or frequency that does not vary as a function of time and / or space.

[0095] In another embodiment of the invention, the radiation has an intensity, power, intensity, wavelength, or frequency that varies as a function of time and / or space.

[0096] In one embodiment of the present invention, the radiation or sound waves have a spatially varying intensity, power, or frequency. In some cases, the intensity, power, or frequency of the radiation is expressed in μT per cm of nanoparticles, cm 2 per μT, or cm 3 µT per gram or µT per gram, or watts per cm, cm 2 Watts per cm 3 Watts per gram or watts per cm of nanoparticles 2 per Hz or cm 3 10 of Hz per cm or Hz per gram or Hz per gram -50 , 10 -20 , 10 -10 , 10 -5 , 10-2 , 1, 10, 10 2 , 10 3 , 10 5 or 10 10 It changes by twofold.

[0097] In other cases, variations in the intensity, power, or frequency of the radiation may be as high as 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 1, 10, 10 -2 , 10 -3 , 10 -5 or 10 -10 μT or cm per cm of nanoparticles below 2 per μT or cm 3 μT per gram or μT per watt or cm of nanoparticles 2 Watts per cm 3 Watts per gram or Watts per gram or Hz per cm of nanoparticles or cm 2 per Hz or cm 3 The units are Hz per unit mass or Hz per gram.

[0098] In some cases, cm, cm 2 , and cm 3 and cm of body part and cm of body part respectively. 2 , and cm of body part 3 You can specify that or they can be.

[0099] In some cases, 1 cm 3 A body part of a gram can be specified as a body part of a gram or it can be a gram.

[0100] In some cases, the radiation or sound waves are of sufficient power, intensity, and / or frequency to specifically heat the nanoparticles or induce the generation of radicals or reactive species by the nanoparticles, particularly in the range of 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10-3 , 10 -2 , 10 -1 , intensities greater than 1 or 10 mT, especially 10 -100 , 10 -3 , 10 -2 , 10 -1 , 10, 50, 100 or 200 KHz, and or frequencies greater than 10 -100 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 or 10 10 Watts per cm or cm of a body part 2 per W or cm 3 W per or W per gram, or W per gram of nanoparticles, or Gy per cm of body part, or Gy per cm of body part 2 per Gy or cm 3 It may have a power greater than Gy per gram or Gy per gram of nanoparticles.

[0101] In some other cases, the radiation or sound waves may have a power, intensity, and / or frequency that is kept below a certain threshold to specifically avoid toxicity induced by Foucault currents or excessive heating, or excessive production of radicals or reactive species induced or generated outside the body part. 100 , 10 50 , 10 10 , 10 5 , 10, 1, 10 -1 or 10 -5 The radiation or sound frequency may be lowered or kept lower than 10 100 , 10 50 , 10 10 , 10 5 , 10 3 , 10, 1 or 10 -3 The radiation or sound power may be lowered or kept lower than 10 100 , 10 50 , 10 20 , 10 10, 10 5 , 10 3 , 10, 1, 10 -1 , 10 -3 or 10 -6 W or cm per cm of body part 2 per W or cm 3 per W or per gram, W per gram of nanoparticles, or Gy per cm or Gy per cm2 of body part 3 The dose may be kept lower, or even lower, than the dose of Gy per gram or Gy per gram of nanoparticles.

[0102] In one embodiment of the present invention, the excitation of the nanoparticles by radiation or sound waves, or the application of radiation or sound waves to the nanoparticles or body part in particular, is continuous. In some cases, the continuous application of radiation or sound waves is continuous, for example, for 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -6 , 10 -3 , 10 -1 , 1 or 10 3 The application of radiation or sound waves without stopping during the course of a time period exceeding t1, especially t1, is considered to be a time period exceeding 10 seconds. 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 1, 10 -1 or 10 -5 It is the application of radiation that does not cease during the passage of a time shorter than seconds, hours, days, months, or years.

[0103] In some other cases, the nanoparticles may be nanoparticles that are exposed to radiation or sound waves.

[0104] In one embodiment of the present invention, the nanoparticles are or belong to or are included in the group of nanoparticles selected from ...spheres, nanocapsules, dendrimers, carbon nanotubes, lipid / solid nanoparticles, lipid or protein or DNA or RNA based nanoparticles, in particular nanoparticles with an internal aqueous environment surrounded by a stabilizing layer, most in particular a phospholipid layer, multi-layer nanoparticles, polymeric nanoparticles, quantum dots, metal nanoparticles, polymeric micelles or nanoparticles, carbon-based nanostructures, nanobubbles, nanosomes, drug cells, niosomes, nanopores, microorganisms, liposomes, in particular recombinant viruses, herbal nanoparticles, antibodies, and vesicles.

[0105] In one embodiment of the present invention, the nanoparticle is not or does not belong to or is not included in the group of nanoparticles selected from the following: nanospheres, nanocapsules, dendrimers, carbon nanotubes, lipid / solid nanoparticles, lipid or protein or DNA or RNA based nanoparticles, in particular nanoparticles with an internal aqueous environment surrounded by a stabilizing layer, most in particular a phospholipid layer, multi-layer nanoparticles, polymeric nanoparticles, quantum dots, metal nanoparticles, polymeric micelles or nanoparticles, carbon-based nanostructures, nanobubbles, nanosomes, drug cells, niosomes, nanopores, microorganisms, liposomes, in particular recombinant viruses, herbal nanoparticles, antibodies, and vesicles.

[0106] In some cases, the nanoparticles may be in a liquid, gaseous, or solid state, particularly before, during, or after their presence or administration to the body part.

[0107] In other cases, the nanoparticle may not be in one or two states, particularly liquid, gas, or solid, before, during, or after its presence or administration in a body part.

[0108] In still other cases, nanoparticles may be assimilated or included in ferrofluids, chemical or biological ferrofluids, where chemical and biological ferrofluids are fluids containing iron, specifically forming nanoparticles, which are produced by chemical or biological synthesis, respectively.

[0109] In still other cases, the ferrofluid or nanoparticle assembly may include nanoparticles and an excipient, solvent, matrix, gel, which allows for the nanoparticles to be specifically administered to an individual or body part.

[0110] In still other cases, the nanoparticles may include synthetic and / or biological and / or inorganic and / or organic materials.

[0111] In one embodiment of the present invention, the nanoparticles are or are designated as: i) a suspension of nanoparticles, ii) a composition comprising nanoparticles, iii) an aggregate of nanoparticles, iv) a nanoparticle domain, v) a mineral portion of a nanoparticle, vi) an organic portion of a nanoparticle, vii) an inorganic portion of a nanoparticle, viii) or a coating of a nanoparticle.

[0112] In one embodiment of the present invention, the nanoparticles or nanoparticles of the present invention are -100 , 10 -50 , 10 -10 , 10 -5 , 10 -1 , 1, 10, 10 2 , 10 3 , 10 5 , 10 10 , 10 20 or 10 50 or more nanoparticles or mg of nanoparticles or mg of iron contained in nanoparticles or cm 3 per mg of nanoparticles or cm of body part 3 per mg of nanoparticles or cm 3 Iron contained in nanoparticles per mg or cm of body part 3 In some cases, an assembly or suspension or composition containing a large number of nanoparticles may be used to induce or generate temperature elevation, radicals or reactive species, or dissociation of compounds from the nanoparticles.

[0113] In one embodiment of the present invention, the nanoparticles or nanoparticles of the present invention are -100 , 10 -50 , 10 -10 , 10 -5 , 10 -1 , 1, 10, 10 2 , 10 3 , 10 5 , 10 10 , 10 20 or 10 50 The following nanoparticles or mg of nanoparticles or mg of iron contained in nanoparticles or cm 3 per mg of nanoparticles or cm of body part 3 per mg of nanoparticles or cm 3 Iron contained in nanoparticles per mg or cm of body part 3 The term "nanoparticle aggregate" refers to or is a nanoparticle aggregate, suspension, or composition containing iron per mg of nanoparticles. In some cases, nanoparticle aggregates, suspensions, or compositions containing a small number of nanoparticles may be used to prevent toxicity.

[0114] In one embodiment of the present invention, a nanoparticle or nanoparticle or nanoparticle aggregate of the present invention may represent or be and be designated as the area, volume, surface, or length of the nanoparticle that contains or in which the nanoparticle is located. In some cases, the volume of the area occupied by the nanoparticle in a body part is designated as the nanoparticle area.

[0115] In some cases, the nanoparticle region can be the volume occupied by a collection of nanoparticles in a body part, where the nanoparticles are particularly 9 , 10 6 , 10 3 Or separated by 10 nm or less.

[0116] In some cases, nanoparticle assemblies are a more general term than nanoparticle regions and may designate any type of nanoparticle assembly before, during, or after nanoparticle administration to a body part.

[0117] In some cases, the separation distance between nanoparticles within a nanoparticle assembly or nanoparticle region may correspond to the average or maximum distance separating the nanoparticles within the assembly.

[0118] In some cases, the distribution of separation distances between nanoparticles can be as small as 50, 10, 1, 10 of the total number of nanoparticles in a single individual. -2 or 10 -5 % of nanoparticles, especially at small separation distances, i.e., 10 9 , 10 6 , 10 3 or separation distances less than 10 nm, or separation distances greater than 10 nm, i.e., 9 , 10 6 , 10 3 or by a separation distance greater than 10 nm, in which case the presence of this small number of nanoparticles is not specifically taken into account for estimating the average or maximum separation distance between nanoparticles.

[0119] The present invention also relates to nanoparticles for use according to the invention, wherein the nanoparticles are crystallized or metallic or magnetic.

[0120] In one embodiment of the present invention, the nanoparticles are crystallized. In this case, they are particularly visible under an electron microscope. 2 , 10 3 , 10 6 or 10 9 It has at least that many crystal planes or regular atomic arrangements.

[0121] In one embodiment of the present invention, the nanoparticles are metallic. In this case, they are at least 1, 10, 10 3 , 10 5 or 10 9 The nanoparticles, particularly metal oxide nanoparticles, contain at least 1, 10, 50, 75, or 90% of the metal atoms, where the percentage is the number or mass of the metal atoms in the nanoparticle divided by the total number or mass of all atoms in the nanoparticle. 3, 10 5 or 10 9 The nanoparticle may contain at least 1, 10, 50, 75, or 90% oxygen atoms, where the percentage is the ratio of the number or mass of oxygen atoms in the nanoparticle divided by the total number or mass of all atoms in the nanoparticle.

[0122] In another embodiment of the invention, the metal or metal atom is selected from the list consisting of lithium, beryllium, sodium, magnesium, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, gallium, rubidium, strontium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, indium, tin, cesium, barium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, hafnium, rutherfordium, dubnium, seaborgium, bohrium, hassium, meitnerium, darmstadtium, roentgenium, copernicium, nihonium, flerovium, moscovium, and livermorium or livermorium atoms.

[0123] In another embodiment of the present invention, the nanoparticles are 3 , 10 5 or 10 9 or containing 1, 10, 50, 75, or 90% or less of metal atoms, where the percentage is the ratio of the number or mass of metal atoms in the nanoparticle divided by the total number or mass of all atoms in the nanoparticle, and which is 1, 10, 10, 105 , 10 9 The nanoparticle may contain no more than 1, 10, 50, 75, or 90% or less oxygen atoms, where the percentage is the number or mass of oxygen atoms in the nanoparticle divided by the total number or mass of all atoms in the nanoparticle.

[0124] In one embodiment of the present invention, a nanoparticle is magnetic if it has magnetic behavior or properties, in particular magnetic behavior or properties selected from the group consisting of diamagnetic, superparamagnetic, paramagnetic, ferromagnetic, and ferrimagnetic behavior or properties.

[0125] In some cases, magnetic behavior or properties may be observed or present at temperatures below: i) 10 5 , 10 3 , 500, 350, 200, 100, 50, 20, 10, 1, 0.5 or 1 K (Kelvin), ii) the Curie temperature, or iii) the blocking temperature.

[0126] In other cases, magnetic behavior or properties may be observed or present at temperatures greater than the following: i) 0.5, 1, 10, 20, 50, 100, 200, 350, 500, 10 3 or 10 5 K, ii) Curie temperature, or iii) blocking temperature.

[0127] In still other cases, 10 -20 and 10 20 K, or between 0.1 and 1000 K, magnetic behavior or properties may be observed or present.

[0128] In one embodiment of the present invention, the nanoparticles have or are characterized by at least one of the following properties: i) the presence of a core, in particular magnetic, in particular mineral, in particular comprising a metal oxide such as iron oxide, most particularly maghemite or magnetic iron, or an intermediate composition between maghemite and magnetite; ii) the presence of a coating surrounding the core and in particular preventing aggregation of the nanoparticles, in particular allowing administration of the nanoparticles to an organism or body part, or stabilizing the nanoparticle core, wherein the thickness of the coating is between 0.1 nm and 10 μm, 0.1 nm and 1 μm, 0.1 nm and 100 nm, 0.1 nm and 10 nm, or 1 nm and 5 nm; iii) magnetic properties resulting in diamagnetic, paramagnetic, superparamagnetic, ferromagnetic, or ferrimagnetic behavior; iv) a thickness of 0.01, 0.1, 1, 10, 100, 10 3 , 10 4 , 10 5 , 10 9 or 10 20 v) a ratio of remanence to saturation magnetization greater than 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 0.9, or 0.99; vi) a saturation magnetization greater than 0.1, 1, 5, 10, or 50 emu / g; vii) magnetic properties such as coercivity, remanence, and saturation magnetization that are specifically measured or observed at temperatures greater than 0.1K, 1K, 10K, 20K, 50K, 100K, 200K, 300K, 350K, or 3000K; viii) a degree of crystallinity, i.e., at least 1, 2, 5, 10, or 100 crystal planes. and specifically observable or measurable by electron microscopy; ix) the presence of a single domain; x) a size greater than 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 50, 60, 70, 80, 100, 120, 150 or 200 nm; xi) a size of 0.1 nm to 10 μm, 0.1 nm to 1 μm, 0.1 nm to 100 nm, 1 nm to 100 nm, or 5 nm to 80 nm; xii) non-pyrogenic or pyrogenic, which means that the nanoparticles are ... 20, 10,000, 1,000, 100, 50, 10, 5, 2, or 1 EU (endotoxin unit), or that the nanoparticles do not cause fever or an increase in whole body temperature of more than 100, 50, 6.6, 5, 3, 2, or 1°C after administration to a living organism or body part. xiii) synthesis by a synthesizing organism, particularly bacterial synthesis; xiv) chemical synthesis; xv) the presence of 50, 25, 15, 10, 5, 2 or 1% or less of organic or carbonaceous material derived from the synthesizing organism; xv) the presence of more than 99, 95, 80, 70, 60, 50 or 25% of mineral material derived from the synthesizing organism; or xvi) a specific absorption rate (SAR) of more than 1, 10, 1000 or 104 watts per gram of nanoparticles, particularly as measured under the application of an alternating magnetic field of strength greater than 0.1, 1, 10 or 100 mT and / or under the application of a frequency greater than 1, 10, 100 or 1000 KHz, or under the application of sound waves, or under the application of radiation such as electromagnetic acoustic or optical radiation.

[0129] In some cases, the synthesizing organisms may be magnetotactic bacteria, other types of bacteria, particularly Mycobacterium paratuberculosis, Shewanella oneidensi, Geothrixfermentans, enzymes from certain bacteria that synthesize nanoparticles extracellularly, ants, fungi, or various plants.

[0130] In another embodiment of the present invention, the nanoparticles have or are characterized by at least one of the following properties: i) 0.01, 0.1, 1, 10, 100, 10 3 , 10 4 , 10 5 , 10 9 or 10 20ii) a coercivity of less than Oe; ii) a ratio of remanence to saturation magnetization of 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.75, 0.9, or 0.99 or less; iii) a saturation magnetization of 0.1, 1, 5, 10, 50, 200, 1000, or 5000 emu / g or less; iv) magnetic properties specifically measured or observed at temperatures of 0.1K, 1K, 10K, 20K, 50K, 100K, 200K, 300K, 350K, or 3000K or less; v) 0.1, a size smaller than 0.5, 1.5, 10, 15, 20, 25, 30, 50, 60, 70, 80, 100, 120, 150, or 200 nm; vi) the presence of 50, 25, 15, 10, 5, 2, or 1% or more organic or carbonaceous material derived from living organisms during synthesis; vii) the presence of 99, 95, 80, 70, 60, 50, or 25% or less mineral material derived from living organisms during synthesis; or viii) the presence of 1, 10, 1000, or 10 nanoparticles per gram. 4 Specific Absorption Rate (SAR) in watts or less, specifically 0.1, 1, 10, or 100, 200, 500, 10 3 or 10 5 of intensity below mT, and / or especially 1, 10, 100, 10 3 , 10 5 or 10 9 It is particularly measured under the application of an alternating magnetic field of a frequency below KHz, alternatively particularly under the application of sound waves, alternatively under the application of electromagnetic, acoustic or other radiation, or optical radiation.

[0131] In some cases, the mineral may be part of a nanoparticle or magnetosome that is free of organic material or has a low percentage of organic material by weight, particularly 100, 99, 50, 20, 10, 5, 1, 10-1, or 10-2 percent or less by weight of organic material. The mineral is particularly the core of the nanoparticle.

[0132] In some other cases, the mineral is present in a range of 0, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 100, 200, 300, 400, 500, 600, 700, 800, 900, 10 ... -50 , 10 -10 , 10 -2 , 10 -1Or it may contain a percent or percent by weight of organic matter greater than 1. This may be the case if the purification step fails to remove the organic matter, or if organic matter is added to the mineral after the purification step.

[0133] In some cases, nanoparticles may be surrounded by a coating. The coating may be synthetic, organic, inorganic, or contain a functional group selected from the group consisting of carboxylic acids, phosphoric acids, sulfonic acids, esters, amides, ketones, alcohols, phenols, thiols, amines, ethers, sulfides, acid anhydrides, acyl halides, amidines, amides, nitriles, hydroperoxides, imines, aldehydes, and peroxides. In some cases, the coating may be made of carboxymethyldextran, citric acid, phosphatidylcholine (DOPC), or oleic acid. In some cases, the coating may enable the nanoparticles to be dispersed in a matrix or solvent, such as water, particularly without aggregation or precipitation of the nanoparticles. In some cases, the coating may enable the internalization of the nanoparticles within cells. In other cases, the coating may i) specifically link two or more nanoparticles into chains, ii) prevent aggregation of the nanoparticles, and / or iii) achieve a uniform nanoparticle distribution.

[0134] In one embodiment of the present invention, the nanoparticles are non-pyrogenic. Non-pyrogenic nanoparticles are particularly: i) 10 100 , 10 50 , 10 20 , 10 8 , 10 5 , 10 3 , or 10 EU (endotoxin units) or less or cm of a body part 3 per EU or mg of nanoparticles per EU or cm of body part 3 containing EU per mg or EU per mg of nanoparticles, or ii) 10 mg before, after or without application of sound waves or radiation to nanoparticles, especially at or above body temperature. 5 , 10 3 , 10 2, induce a temperature increase in an individual or body part of 50, 10, 5, 5, 4, 3, 2 or 1°C or less.

[0135] In one embodiment of the present invention, the nanoparticles or compounds are composed of or comprise chemical elements from a family selected from the group consisting of metals (alkali metals, alkaline earth metals, transition metals), metalloids, nonmetals (halogens, noble gases), chalcogens, lanthanides, and actinides.

[0136] In another embodiment of the invention, the nanoparticles or compounds are composed of or contain a chemical element selected from the following group: hydrogen, lithium, sodium, potassium, rubidium, cesium, francium, beryllium, magnesium, calcium, strontium, barium, radium, scandium, yttrium, lanthanides, actinides, titanium, zirconium, hafnium, rutherfordium, vanadium, niobium, tantalum, dubnium, chromium, molybdenum, tungsten, seaborgium, manganese, technetium, rhenium, bohrium, iron, ruthenium, osmium, hesium, cobalt, rhodium, iridium, magnesium, nickel, palladium, platinum, darmstadtium, copper, silver, gold, renthenium, zinc, cadmium, mercury, copernicium, boron, aluminum, gallium, indium The elements are: thallium, thallium, ununtrium, carbon, silicon, germanium, tin, lead, phleobium, nitrogen, phosphorus, arsenic, antimony, bismuth, ununpentium, oxygen, sulfur, selenium, tellurium, polonium, hepatomolium, fluorine, chlorine, bromine, iodine, astatine, unseptium, helium, neon, argon, krypton, xenon, radon, ununoctium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, actinium, thorium, proctactinium, uranium, neptunium, plutonium, americium, curium, berkelium, californium, einsteinium, fermium, mendelevium, nobelium, and lawrencium.

[0137] In some cases, the nanoparticles or compounds may be composed of or include alloys, mixtures, or oxides of the above chemical elements.

[0138] In some cases, the nanoparticles or compounds are -50 , 10 -20 , 10 -10 , 10 -5 , 10 -2 , 1, 5, 10, 50, 75, 80, 90, 95, or 99% of one or more of the above elements. This percentage may represent the mass or number of the above chemical elements contained in the nanoparticle or compound divided by the total mass or number of all chemical elements contained in the nanoparticle or compound, or the total mass of the nanoparticle or compound.

[0139] In some other cases, the nanoparticles or compounds are 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -2 , may consist of or contain up to 1, 5, 10, 50, 75, 80, 90, 95 or 99% of one or more of the above chemical elements.

[0140] In still other cases, the one or more chemical elements are contained within the nanoparticle or compound, on the surface of the nanoparticle or compound, in the mineral or core of the nanoparticle or compound, or in the coating of the nanoparticle or compound.

[0141] In one embodiment of the present invention, the nanoparticles or compounds do not consist of or contain at least one chemical element belonging to a family selected from the group of metals (alkali metals, alkaline earth metals, transition metals), metalloids, nonmetals (halogens, noble gases), chalcogens, lanthanides, actinides.

[0142] In another embodiment of the invention, the nanoparticles or compounds lack or do not contain at least one chemical element selected from the group consisting of: hydrogen, lithium, sodium, potassium, rubidium, cesium, francium, beryllium, magnesium, calcium, strontium, barium, radium, scandium, yttrium, lanthanides, actinides, titanium, zirconium, hafnium, rutherfordium, vanadium, niobium, tantalum, dubnium, chromium, molybdenum, tungsten, seaborgium, manganese, technetium, rhenium, bohrium, iron, ruthenium, osmium, hesium, cobalt, rhodium, iridium, magnesium, nickel, palladium, platinum, darmstadtium, copper, silver, gold, renthenium, zinc, cadmium, mercury, copernicium, boron, aluminum, gallium. , indium, thallium, ununtrium, carbon, silicon, germanium, tin, lead, phleobium, nitrogen, phosphorus, arsenic, antimony, bismuth, ununpentium, oxygen, sulfur, selenium, tellurium, polonium, hepatomolium, fluorine, chlorine, bromine, iodine, astatine, unseptium, helium, neon, argon, krypton, xenon, radon, ununoctium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, lutetium, actinium, thorium, proctactinium, uranium, neptunium, plutonium, americium, curium, berkelium, californium, einsteinium, fermium, mendelevium, nobelium, and lawrencium.

[0143] In another embodiment of the invention, the nanoparticles or compounds do not consist of or contain alloys, mixtures or oxides of this(these) chemical elements.

[0144] In one embodiment of the present invention, the nanoparticles have a size of 10 -1Nanoparticles are defined as particles larger than 1, 2, 5, 10, 20, 50, 70, 100, 200, or 500 nm. Larger nanoparticles have greater coercivity and / or remanence than smaller nanoparticles, and / or can absorb the energy or power of sound waves more strongly or more efficiently. In some cases, nanoparticle sizes are categorized as 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 10 3 , 10 5 , or 10 7 By increasing the amount of energy or power absorbed by the nanoparticles by a factor of more than 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 10 3 , 10 5 or 10 7 double increase.

[0145] In another embodiment of the invention, the nanoparticles have a size of 10 4 , 10 3 , 10 2 , 10, 1 or 10 -1 Nanoparticles are defined as particles of less than 1 nm in size. Their small size makes them easier to administer, for example, intravenously, and also avoids toxic effects such as embolism.

[0146] In yet another embodiment of the present invention, the nanoparticle size is 10 -2 and 10 20 Between,,10 -2 and 10 4 nm, 10 -1 and 10 3 Between nm, or 1 and 10 2 nm, where the nanoparticles or nanoparticle aggregates have a well-defined, particularly narrow size distribution.

[0147] In yet another embodiment of the invention, the nanoparticle size distribution is less than or equal to 1000, 100, 75, 50, 25, 10, 5, 2, or 1 nm. A narrow nanoparticle size distribution may be desirable to prevent aggregation or to promote organization of nanoparticle chains.

[0148] In yet another embodiment of the invention, the nanoparticle size distribution is greater than 1000, 100, 75, 50, 25, 10, 5, 2, or 1 nm. A larger size distribution of nanoparticles may allow for more rapid removal of the nanoparticles.

[0149] In another embodiment of the invention, the surface charge of the nanoparticles is greater than −200, −100, −50, −10, −5, 0.1, 1, 2, 5, 10, 50, or 100 mV, particularly at a pH of less than or equal to 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. In particular, nanoparticles can have a large surface charge at low pH if they are surrounded by a coating that allows them to reach such a charge without being destroyed.

[0150] In another embodiment of the invention, the nanoparticles preferably have a surface charge of less than −200, −100, −50, −10, −5, 0.1, 1, 2, 5, 10, 50, or 100 mV, and particularly have a pH greater than 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14. Nanoparticles can have a low surface charge at high pH if they are surrounded by a coating that allows them to reach such a charge without being destroyed.

[0151] In yet another embodiment of the invention, the nanoparticles have a surface charge between +200 and -200mV, +100 and -100mV, +50 and -50mV, +40 et -40mV, +20 and -20, +10 and -10mV, or +5 and -5mV, particularly at a pH of 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or less.

[0152] In yet another embodiment of the invention, the nanoparticles have a surface charge between +200 and -200mV, +100 and -100mV, +50 and -50mV, +40 et -40mV, +20 and -20, +10 and -10mV, or +5 and -5mV, particularly at a pH greater than 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.

[0153] In another embodiment of the invention, the nanoparticles have a weight or mass, particularly expressed in units such as grams (g), kilograms (kg), or milligrams (mg). A gram of nanoparticles can be a gram of metal, such as iron, contained in the nanoparticles. The mass or weight of the nanoparticles can correspond to the mass or weight of a single nanoparticle or the mass or weight of a collection of nanoparticles.

[0154] In one embodiment, the mass of the nanoparticles is 10 -20 , 10 -10 , 10 -5 , 10 -2 , 1, 10, 10 3 , 10 9 or 10 20 Larger than a gram. In some cases, a large nanoparticle mass may be desirable to increase the amount of acoustic energy absorbed by the nanoparticle.

[0155] In some embodiments, the mass of the nanoparticles is 10 -20 , 10 -10 , 10 -5 , 10 -2 , 1, 10, 10 3 , 10 9 or 10 20 In some cases, it may be desirable to reduce the mass of the nanoparticles to prevent or minimize toxicity of the nanoparticles.

[0156] In one embodiment of the present invention, the nanoparticles, suspensions, compositions or aggregates of nanoparticles are particularly stable over time, and in particular have a stability period of 10 -10 , 5, 10, 10 50 or 10 100In some cases, the nanoparticles, suspension, composition, or nanoparticle ensemble may be stable at a concentration of greater than 1, 5, 10, 50, 100, 200, 500, or 1000 mg of nanoparticles per mL of solvent, matrix, or body part surrounding or containing the nanoparticles. In some cases, the nanoparticles, suspension, composition, or nanoparticle ensemble may be stable if: i) the nanoparticles have not degraded or partially or completely lost their coating and can be administered to the body part; or ii) the optical density of the nanoparticles, suspension, composition, or nanoparticle ensemble is greater than 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 50, 60, 70, 80, 90, 100, 150, 200, 35, 40, 50, 60, 70, 80, 100, 150, 250, 300, 450, 500, or 1000 mg of nanoparticles per mL of solvent, matrix, or body part surrounding or containing the nanoparticles. 3 , 10 7 or 10 20 Within seconds, 1, 5, 10, 50, 75, or 90% or more of the specific measurement at 480 nm or another fixed wavelength, or 10 -10 , 10 -3 , 10 -1 , and does not decrease above 0.5 or 0.7. This ratio (OD B -OD A ) / OD B or OD A / OD B is equal to OD B is the optical density of a nanoparticle, suspension, composition, or assembly of nanoparticles measured before homogenization or mixing, or an optical density or absorbance measurement of a nanoparticle, suspension, composition, or assembly of nanoparticles, and OD A is the optical density of the nanoparticles, suspension, composition, or collection of nanoparticles measured after homogenization or mixing, or an optical density or absorbance measurement of the nanoparticles, suspension, composition, or collection of nanoparticles.

[0157] In some cases, the nanoparticles are suspended in a liquid or dispersed in a matrix or body part to obtain a uniform nanoparticle dispersion or a highly stable nanoparticle composition or suspension.

[0158] In one embodiment of the invention, the nanoparticles are arranged in chains comprising more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35 or 40 nanoparticles.

[0159] In another embodiment of the invention, the nanoparticles are arranged in chains as follows: i) 2·10 10 , 2·10 5 , 2·10 3 or 2·10 2 nm or shorter, or ii) 2, 5, 10, 10 2 or 10 3 The number of nanoparticles in each smaller chain. In some cases, short chains of nanoparticles are desired or obtained, for example, to facilitate internalization of the nanoparticles within a cell, or after partial or complete disruption of long chains.

[0160] In another embodiment of the present invention, the nanoparticles are arranged in chains, which have: i) 10 -1 , 1, 5, 10, 2·10 2 , 2·10 3 or 2·10 5 longer lengths, or ii) 2, 5, 10, 10 2 or 10 3 The number of nanoparticles in each chain is larger.

[0161] In yet another embodiment of the present invention, the nanoparticles are arranged in a chain and have: i) 10 -1 and 10 10 nm, between 1 and 10 5 nm in length, or ii) between 2 and 10 5 , 2 and 10 3 , 2 and 10 2 , or the number of nanoparticles in each chain between 2 and 50.

[0162] In yet another embodiment of the present invention, nanoparticles are arranged in a chain when they are bonded or linked to one another or when the crystallographic directions of two adjacent nanoparticles in the chain are aligned, such alignment being particularly characterized by an angle between two crystallographic directions belonging to two adjacent nanoparticles in the chain of 90, 80, 70, 60, 50, 20, 10, 3, or 2° (degrees) or less.

[0163] When nanoparticles are biologically synthesized, they can be arranged in chains, i) in particular, before or after extraction or isolation from the organism, and ii) outside the organism, in particular, before or after extraction or isolation from the organism.

[0164] In one embodiment of the present invention, the nanoparticles are not arranged in chains.

[0165] In another embodiment of the invention, nanoparticles are chemically synthesized or not synthesized by a living organism when 1, 2, 5, 10, or 100 or fewer steps of their production, such as iron oxide crystallization, stabilization of iron oxide mineral, and nanoparticle organization, involve or result from a living organism. In some cases, chemical synthesis can be defined as synthesis that includes a majority of steps, 1, 2, 5, or 10 or more steps, or 1, 2, 5, 25, 50, 75, or 90% or more steps involving chemical reactions that occur without the involvement of a living organism or parts of a living organism, such as DNA, RNA, proteins, enzymes, or lipids.

[0166] In another embodiment of the present invention, chemical synthesis can be used to generate chemicals or compounds that mimic, copy, or replicate compartments, organelles, or other biological materials, where the chemical synthesis or chemicals can be used or result in the production of nanoparticles. In some cases, the compartments, organelles, or other biological materials can be lysosomes, endosomes, vesicles, or other biological materials that have the ability or function to either dissolve or convert crystallized iron to free iron or convert free iron to crystallized iron. In some cases, this conversion is partial, resulting in the destruction or formation of partially crystallized aggregates of iron atoms or iron, or a mixture of crystallized and amorphous iron. In some cases, crystallized iron can be defined as an aggregate of iron atoms or ions that results in the presence of crystalline planes, particularly observable using techniques such as transmission or scanning electron microscopy, and free iron can be defined as one of several iron atoms or ions that does not result in the presence of crystalline planes, particularly highlighted by the absence of a diffraction pattern, for example, using transmission or scanning electron microscopy.

[0167] In one embodiment of the present invention, the nanoparticles are particularly at least 1, 2, 5, 10, 10 3 , 10 6 or 10 9 Biologically or biologically synthesized by organisms, called synthetic organisms, consisting of or composed of eukaryotic cells, prokaryotic cells, or parts of these cells. In some cases, the parts of the eukaryotic or prokaryotic cells can be biological substances that originate in or are produced in the cell, such as RNA, DNA, organelles, nucleoli, nuclei, ribosomes, vesicles, rough endoplasmic reticulum, Golgi apparatus, cytoskeleton, smooth endoplasmic reticulum, mitochondria, vacuoles, cytosol, lysosomes, centrosomes, cell membranes, etc. In some cases, biological synthesis can be at least 1, 2, 10, 10 3 , 10 6 or 10 9It may be defined as a synthesis that includes the majority of steps, more than 1, 2, 5, or 10 steps, or more than 1, 2, 5, 25, 50, 75, or 90% of the steps, involving chemical reactions occurring involving living organisms or parts of living organisms such as DNA, RNA, proteins, enzymes, or lipids.

[0168] In yet another embodiment of the present invention, the nanoparticles are synthesized or produced or crystallized or assembled or converted into nanoparticles by compartments, organelles, or other biological materials such as proteins, lipids, enzymes, DNA, or RNA, particularly those produced by or derived from eukaryotic or prokaryotic cells.

[0169] In another embodiment of the invention, the nanoparticles are synthesized by or in at least one eukaryotic cell, prokaryotic cell, or part of a cell.

[0170] In another embodiment of the invention, the nanoparticles are synthesized by or within i) a matrix, medium or environment located outside at least one eukaryotic cell, prokaryotic cell, or part of this cell, or ii) an extracellular matrix.

[0171] In one embodiment of the present invention, the nanoparticles are synthesized by a living organism when at least 1, 2, 5, 10 or 100 steps of their production, such as iron oxide crystallization, stabilization of the iron oxide mineral, organization of the nanoparticles in, for example, chains or aggregates, involve or are synthesized by a living organism.

[0172] The present invention also relates to nanoparticles for use, wherein the nanoparticles are magnetosomes synthesized by, originating from, extracted or isolated from magnetotactic bacteria.

[0173] In one embodiment of the present invention, magnetosomes are synthesized, produced, derived, extracted or isolated by magnetotactic bacteria.

[0174] In one embodiment of the present invention, the magnetotactic bacterium is selected from the following group: Magnetospirillum magnetum strain AMB-1, Magnetotactic Coccus MC-1, three facultative anaerobic Vibrio strains MV-1, MV-2, and MV-4, Magnetospirillum magnetotactic strain MS-1, Magnetospirillum gryphiswaldense strain MSR-1, facultative anaerobic magnetotactic spirillum, Magnetospirillum magnetotactic strain MGT-1, and obligate anaerobes, and Desulfovibriomagneticus RS-1.

[0175] In one embodiment of the present invention, magnetotactic bacteria are defined as bacteria capable of synthesizing magnetosomes, these magnetosomes being characterized in particular by at least one of the following properties: i) they are produced intracellularly, ii) they are magnetic, iii) they contain minerals, iv) the core is composed of metal oxides, in particular iron oxide, v) the core is surrounded by biological material, such as lipids, proteins, endotoxins, etc., which can in particular be removed, vi) they are arranged in chains, vii) they generate heat under the application of an alternating magnetic field.

[0176] In one embodiment of the present invention, magnetosomes have one or several properties in common with nanoparticles, such as at least one magnetic, size, composition, chain sequence, charge, core, mineral, coating, or crystallinity property.

[0177] In one embodiment of the present invention, the magnetosomes specifically comprise the mineral portion synthesized by magnetotactic bacteria, i.e., the crystallized iron oxide produced by these bacteria, in which case the magnetosomes or magnetosome mineral portion are free of proteins, lipids, endotoxins, or carbon-containing biological materials, or contain less than or equal to 0.1, 1, 10, 30, 50, or 75% or more percentages by mass of the carbon produced by these bacteria.

[0178] The present invention also relates to the use of nanoparticles, in which the nanoparticles are or are assimilated to chemical analogues of magnetosomes, such as Sigma Nanoparticles (Reference Number: 637106-25G), SPION20 (nanomag®-D-spio20, Reference Number: 79-02-201), SPION50 (synomag-D50, Reference Number: 104-000-501), SPION100 (nanomag®-D-spio100, Reference Number: 79-00-102), or nanoparticles synthesized using methods similar to these nanoparticles but offering improved or additional properties, such as chain arrangement. In some cases, the chemical analogues of magnetosomes can be chemically synthesized and / or are not synthesized by magnetotactic bacteria.

[0179] In some cases, the chemical analog of a magnetosome has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 properties in common with magnetosomes, particularly at temperatures greater than 0, 5, 10, 50, 100, 200, 300, 500, or 1000 K. -50 , 10 -10 , 10 -2 , a coercivity greater than 1, 5, 10 or 100 Oe; a large size, particularly greater than 1, 5, 10, 20, 50 or 70 nm; and / or a chain arrangement, particularly an arrangement of more than 1, 2, 5 or 10 nanoparticles in a chain.

[0180] In one embodiment of the present invention, the nanoparticles or magnetosomes are purified to remove endotoxins and / or other biological materials, such as proteins or lipids derived from synthetic or magnetotactic bacteria, in amounts greater than 10, 50, or 90 percent by mass. In other cases, the nanoparticles or magnetosomes are purified to remove no more than 100, 99.9, 99, 95, or 90 percent endotoxins and other biological materials. This purification step produces specifically purified nanoparticles or magnetosomes. In some cases, this ratio can be equal to [QBP-QAP] / QBP or QAP / QBP, where QBP and QAP are the amounts of endotoxins, biological materials, proteins, or lipids before and after the purification step, respectively.

[0181] In some cases, the purification step may consist in using methods or detergents such as NaOH and / or KOH, which are mixed in particular with the synthetic organisms or magnetotactic bacteria or bacterial debris, thereby in particular removing organic matter or separating organic matter from inorganic matter contained in the nanoparticles or magnetosomes, and in particular recovering minerals of the nanoparticles or magnetosomes, in particular contained in the nanoparticles or magnetosomes.

[0182] In some cases, the purified nanoparticles or magnetosomes are nanoparticle or magnetosome minerals.

[0183] In one embodiment of the present invention, the nanoparticles according to the invention are a drug, a medical device, a cosmetic, a biological product, a product used for research purposes, or a product used to determine the properties of biological samples.

[0184] In one embodiment of the present invention, the nanoparticles are ultrasound sensitizers, particularly for use in sonodynamic therapy.

[0185] In one embodiment of the present invention, the ultrasound sensitizer is a substance that enhances the effect of sound waves, i.e., biological material, in particular dead, destroyed, degenerated or inactivated pathological cells, in particular by 1.2, 1.5, 2, 5, 10, 10 3 or 10 5 1.2, 1.5, 2, 5, 10, 10 fold increase in the number of healthy cells, and / or particularly those that are dead, destroyed, degenerated, or inactivated. 3 or 10 5 A sonosensitizer may also be defined as a substance that causes a temperature increase under the application of sound waves, the temperature increase being greater in the presence of the sonosensitizer than in its absence, i.e., the temperature increase is particularly greater than 10 -100 , 10 -50 , 10 -10 , 10 -5 , 0.1, 1, 2, 5, 10, 20, or 50°C greater in the presence than in the absence of sonosensitizer, where the concentration of sonosensitizer is mL or cm of a particular body region. 3 10 per -50 , 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 100 or 10 3 Larger than mg.

[0186] In another embodiment of the present invention, the nanoparticles, nanoparticle suspension or aggregate or composition is in liters (l), milliliters (ml), cm of nanoparticles, metals, metallic chemical elements, iron, iron oxide, maghemite, magnetite. 3 , m 3 It has a concentration particularly expressed in units such as grams (g), kilograms (kg), or milligrams (mg) per unit volume, or per unit surface area, or per unit length, etc. It particularly has a concentration before or after administration to a body part, where the volume, surface area, or length is the volume, surface area, or length of a suspension, assembly, or composition of nanoparticles before or after administration to a body part, or the volume, surface area, or length of a body part.

[0187] The present invention also relates to nanoparticles for use according to the invention, wherein the concentration of nanoparticles located in particular in a body part or nanoparticle region, which is particularly exposed to sound waves or radiation or to which sound waves or radiation is applied, is less than 10 ... 3 in g of nanoparticles per cm of body part 3 The nanoparticles contain less than 10 g of iron per cm. In some cases, the nanoparticle concentration is 3 Per or body part cm 3 Nanoparticles measured per cm 3 Per or body part cm 3 10 grams (g) of nanoparticles measured per 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10 2 , 10, 5, 2, 1, 10 -3 , 10 -6 or 10 -9 In some cases, low concentrations of nanoparticles may be necessary or desirable to prevent toxicity that can occur with high concentrations of nanoparticles.

[0188] The present invention also relates to nanoparticles for use according to the present invention, wherein the concentration of nanoparticles located in particular in a part of the body or in a nanoparticle region that is particularly exposed to sound waves or radiation or to which sound waves or radiation are applied is greater than or equal to cm 3 Per or body part cm 3 Nanoparticles measured per cm 3 Per or body part cm 3 10 grams (g) of nanoparticles measured per -50 , 10 -20 , 10 -10 , 10 -9 , 10 -6 , 10 -3 , 1, 2, 5, 10, 10 2 , 10 5 , 10 10 , 10 20 or 10 50A high concentration of nanoparticles may be required to produce the effects of applying acoustic waves to nanoparticles, such as increasing the temperature or dissociating compounds from the nanoparticles. In some cases, the nanoparticle concentration is the concentration of at least one substance contained in the nanoparticles, such as iron, an oxide, an iron oxide, or a metal other than iron.

[0189] The present invention also relates to nanoparticles for use according to the invention, wherein the concentration of nanoparticles located in particular in the part of the body or in the nanoparticle area that is particularly exposed to sound waves or radiation or to which sound waves or radiation are applied is greater than or equal to cm 3 Per or body part cm 3 Nanoparticles measured per cm 3 Per or body part cm 3 10 grams (g) of nanoparticles measured per -50 and 10 50 , 10 -20 and 10 20 , 10 -3 and 10 3 , 0 and 10 50 , 1 and 10 100 , 1 and 10 20 , or 1 and 10 5 It is between.

[0190] In yet another embodiment of the invention, the nanoparticle concentration is comprised between a minimum value and a maximum value. In some cases, the minimum value is large enough to allow the generation of heat by the nanoparticles or dissociation of compounds from the nanoparticles, especially under application of laser radiation. In other cases, the maximum value is small enough to allow imaging of the body part.

[0191] The present invention also relates to nanoparticles for use according to the invention, which have or result in at least one of the following properties: i) per gram of nanoparticles or cm of body part 3 10 per second when measured per gram of nanoparticles per cm3 of body part -9 or 10 -50 ii) Generation of a gradient of initial temperature change, especially increasing over °C. ii) Per gram of nanoparticles or cm of body part3 10 in watts per -9 a specific absorption rate greater than Watt, and / or iii) a specific absorption rate that increases with increasing power of the acoustic waves applied to the nanoparticles at a rate that can increase with decreasing nanoparticle concentration.

[0192] In some cases, by applying sound waves to the nanoparticles or body part, the gradient of the initial, particularly increasing, change in temperature with time can be measured or obtained.

[0193] In some cases, (ΔT / δt) (N) can be the initial variation of temperature over time of the body part containing the nanoparticles.

[0194] In some cases, (ΔT / δt) (WN) can be the initial variation of temperature over time of a body part that does not contain nanoparticles.

[0195] In some cases, the abbreviation N for nanoparticles may be replaced with the abbreviation M for magnetosomes.

[0196] In some cases, (ΔT / δt) real , (ΔT / δt) (N) , or (ΔT / δt) (WN) is the time of initial application of sound or radiation (t i (specified as 1, 5, 10, 50, 75, 10) 2 or 10 3 %, which may represent a temperature change greater than t i The temperature change reached during the measurement can be the ratio of the temperature change reached during the measurement to the initial temperature just before the application of the sound waves or radiation.

[0197] In some cases, (ΔT / δt) real is (ΔT / δt) (N) -(ΔT / δt) (WN) is equal to

[0198] In some cases, (ΔT / δt) real , (ΔT / δt) (N) , and / or (ΔT / δt) (WN)can be the slope of the initial temperature fluctuation with respect to the measured time: i) the first 10°C of the application of the acoustic wave; -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , or 10 5 ii) 10 minutes 3 , 10 2 , 10, 1, 10 -2 , 10 -3 , 10 -6 or 10 -9 seconds or less, especially after the start of application of sound waves or radiation; iii) when the temperature changes linearly, i.e., proportionally with time; iv) before the saturation temperature is reached; v) during the initial period of heating or heating step that is not more than 1, 5, 10, 25, 50, 75, 80, 90, 95, or 99% of the total duration of the heating or heating step.

[0199] In one embodiment of the present invention, (ΔT / δt) (N) , (ΔT / δt) (WN) , and or (ΔT / δt) real The value is 10 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -7 , 10 -6 , 10 -5 , 10 -3 , 10 -1 , 1, 10 3 , 10 5 , 10 6 or 10 9 °C / sec. In some cases, if the heating power of the nanoparticles is large, or if the acoustic or radiation power applied to the nanoparticles is large, (ΔT / δt) (N) and or (ΔT / δt) real is big.

[0200] In another embodiment of the present invention, (ΔT / δt) (N) , (ΔT / δt) (WN) , and or (ΔT / δt) real The value is 10 100 , 10 50 , 1020 , 10 9 , 10 6 , 10 3 , 1, 10 -1 , 10 -3 , 10 -6 or 10 -9 Less than °C / sec. In some cases, (ΔT / powert) (N) and / or (ΔT / δt) real is small when the heating power of the nanoparticles is low or when the power of the acoustic or radiation applied to the nanoparticles is low.

[0201] In yet another embodiment of the present invention, the value of (ΔT / δt)(N), (ΔT / δt)(WN), and / or (ΔT / δt)real is 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , or 10 -5 and 10, 10 -5 and °C / sec.

[0202] In some cases, the unit °C / sec is used to express the mass of a gram of nanoparticles, a gram of body part, or a cm of nanoparticles. 3 , cm of nanoparticles 2 , cm of nanoparticles, cm of body part 3 Per, cm of body part 2 may be replaced by °C / sec measured per cm or per cm of body part.

[0203] In one embodiment of the present invention, (ΔT / δt) (N) is (ΔT / δt) (WN) greater than by a factor a, where a is: i) 1.00001, 1.1, 1.2, 1.5, 2, 5, 10, 10 3 , 10 5 or 10 9 Greater than or equal to 10 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -6 , 10 -3 , 10 -1, 1, 10 3 , 10 6 or 10 9 °C / sec or greater, ii) 10 5 , 10 3 , 10 2 , 5, 2 or less than 1.1, or 10 100 , 10 50 , 10 5 , 10 2 , 5, 2 or 1.5, or iii) in yet another case 10 -100 and 10 100 , 10 -5 and 10 5 , 10 -1 and 10, or 10 -100 and 10 100 °C / sec, or 10 -10 and 10 5 °C / sec.

[0204] In one embodiment of the present invention, (ΔT / δt) (M) Suitable values ​​for are between 0.09°C / sec and 0.7°C / sec. The lowest value of this range (0.09°C / sec) is the maximum value for the cm of tissue. 3 45 μg of magnetosomes or nanoparticles per 0.5 W / cm 2 In some cases, this minimum was estimated by exposing the magnetosomes or nanoparticles to concentrations of 1.5, 2, 5, 10, 50, and 10 2 , 10 5 , 10 7 , 10 9 or 10 20 or by reducing the intensity, power, or frequency of the sound waves by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 , or 10 20 By reducing by the above factors, 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 , or 10 20The maximum value of this range (0.7°C / sec) was estimated by exposing 100 μg of magnetosomes mixed in 100 μL of water to 1.5 W / cm2 of sound. In some cases, this maximum value can be reduced by increasing the magnetosome or nanoparticle concentration, particularly by increasing the concentration of magnetosomes or nanoparticles to 1.5, 2, 5, 10, 50, or 10. 2 , 10 5 , 10 7 , 10 9 or 10 20 Increase the intensity, power, or frequency of the sound waves by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By increasing by the above factors, 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 It can be increased by a factor of 1 or more.

[0205] In another embodiment of the present invention, (ΔT / δt) (WM) The range of suitable values ​​for is between 0.063°C / sec and 0.645°C / sec. The minimum value of this range (0.063°C / sec) was estimated by applying 0.5 W / cm2 of sound to the tissue slice. In some cases, this minimum value can be achieved by increasing the sound intensity, power, or frequency by 1.5, 2, 5, 10, 50, or 10 2 , 10 5 , 10 7 , 10 9 , or 10 20 By reducing by a factor of more than 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 , or 10 20 The maximum value of this range (0.645°C / sec) is 1.5 W / cm in aqueous solution. 2 In some cases, this maximum was estimated by applying sound waves of 1.5, 2, 5, 10, 50, 102 , 10 5 , 10 7 , 10 9 , or 10 20 By increasing the frequency by a factor of 1.5, 2, 5, 10, 50, 10 or more, or by using body parts that absorb less sound waves, 2 , 10 5 , 10 7 , 10 9 , or 10 20 It can be increased by a factor of 1 or more.

[0206] In one embodiment of the present invention, the Specific Absorption Rate (SAR) of a nanoparticle, also referred to as SAR, is the specific absorption rate of a nanoparticle contained in, mixed with, or inserted into a body part. It can be calculated by dividing a unit of power, such as watts, by a unit of mass, such as grams, or by dividing a unit of power by cm, cm 2 ,cm 3 It can be expressed by dividing it by a length, surface area, or volume unit such as:

[0207] In particular, the SAR is measured under the application of sound waves or radiation that specifically causes a temperature increase in the presence of nanoparticles. In some cases, such radiation or sound waves may have: i) 10 -9 , 10 -5 , 10 -3 , 10 -1 , 1, 10 or 10 3 W / cm, W / cm 2 , or W / cm 3 , ii)10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 or 10 6 Frequencies greater than MHz.

[0208] In some other cases, such radiation may be an alternating magnetic field, in particular: i) at a frequency greater than 10-9, 10-6, 10-3, 1, 103, 106, or 109 kHz, and / or ii) in a container or tube containing the nanoparticles and outside this container or tube.

[0209] In particular, heat exchange is minimized when a temperature drop of 75, 60, 50, 25, 10, 5, 2, 1 or 0.1°C or less occurs.

[0210] In one embodiment of the present invention, the SAR is estimated by exposing nanoparticles, particularly those contained in a body part, to sound waves or radiation. In some cases, the SAR may be equal to or proportional to the specific heat capacity of the medium surrounding the nanoparticles, particularly the time resulting from the application of sound waves or radiation multiplied by the initial gradient of the temperature change, particularly divided by the concentration of the nanoparticles.

[0211] In another embodiment of the invention, the SAR does not correspond to, is not related to, or is not a SAR estimated by exposing the nanoparticles to an alternating magnetic field or sound waves or another excitation source other than radiation.

[0212] The present invention also relates to nanoparticles for use according to the present invention, wherein the nanoparticles have a specific absorption rate (SAR) measured specifically in a body part, which is 0.01 W / g nano ), cm of nanoparticles 3 per (W / cm 3 nano ), per gram of body part (W) / g bp ), or cm of body part 3 per (W / cm 3 bp ) measured at 10 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -6 , 10 -3 , 1, 10 3 , 10 6 or 10 9 W (Watts) or greater. In some cases, large SAR values ​​may be obtained under certain conditions, for example, by using high power or frequency sound waves or radiation, by using high nanoparticle concentrations, or by combining the application of sound waves with the application of another energy source or with the application of different types of sound waves or radiation.

[0213] The present invention also relates to nanoparticles for use according to the present invention, which have a specific absorption rate (SAR) measured specifically in a body part, which is expressed as W / g nanoparticles. nano ), cm of nanoparticles 3 per (W / cm 3 nano ), per gram of body part (W) / g bp ), or cm of body part 3 per (W / cm 3 bp ) measured at 10 100 , 10 50 , 10 20 , 10 -9 , 10 -6 , 10 -3 , 1, 10 3 , 10 6 or 10 9 Lower than watts.

[0214] The present invention also relates to nanoparticles for use according to the present invention, which have a specific absorption rate (SAR) measured specifically in a body part, which is expressed as W / g nanoparticles. nano ), cm of nanoparticles 3 per (W / cm 3 nano ), per gram of body part (W) / g bp ), or cm of body part 3 per (W / cm 3 bp ) measured at 10 -100 and 10 100 , 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -3 and 10 3 , 0 and 10 100 , 10 and 10 10 , 10 and 10 4 It's W.

[0215] In one embodiment of the present invention, a suitable range of nanoparticle SAR, particularly measured under the application of acoustic waves, is between 1.2 watts per gram of nanoparticles, particularly in iron, and 424 watts per gram of nanoparticles, particularly in iron. In some cases, the minimum value of this range (1.2 W / gM) may decrease, e.g., 1.5, 2, 5, 10, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 1 3 , 10 5 , 10 7 or 10 9 In some other cases, the maximum value of this range (424 W / gM) can increase by, for example, a factor of 1.5, 2, 5, 10, 10, 10, 10, or 10 or more when the viscosity of the body part decreases, the thermal diffusion of the body part increases, the nanoparticle concentration in the body part increases, the power of the acoustic waves increases, or the heat generated by the acoustic waves in the absence of nanoparticles decreases.

[0216] In another embodiment of the present invention, the lowest SAR value is determined as the SAR value decreases with decreasing nanoparticle concentration or number of nanoparticles, particularly as the nanoparticle concentration or number of nanoparticles decreases from 1.1, 2, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 When it decreases by a factor greater than 1.1, 2, 5, 10, or 10 2 , 10 3 , 10 5 or 10 10 This can be justified by the fact that it can be reduced by a factor of 10 or more. 7 For nanoparticles, a SAR of 1 W per gram of nanoparticles is equivalent to a SAR of 10 W per gram of nanoparticles for a single nanoparticle. -7 This behavior can be explained by a collective effect, where the SAR values ​​of the individual nanoparticles add up to produce the SAR of the nanoparticle ensemble, which is the sum of or proportional to the SAR values ​​of the single nanoparticles.

[0217] In yet another embodiment of the invention, small nanoparticles, particularly those smaller than 1, 10, 20, 50, 100, 200 or 500 nm in size, have no SAR or do not exceed 10 per gram of nanoparticles. 5 , 10 3 , 10, 1, 10 -1 , 10 -3 , 10 -6 or 10 -9 In yet another embodiment of the invention, large nanoparticles, particularly those having a size greater than 1, 10, 20, 50, 100, 200 or 500 nm, have a SAR of less than 10 per gram of nanoparticles. -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 or 10 5 It has a larger SAR than

[0218] The present invention also relates to nanoparticles for use according to the present invention, wherein the nanoparticles have an SAR that increases with increasing power of the acoustic waves applied to the nanoparticles at a rate that may increase with decreasing nanoparticle concentration.

[0219] In some cases, the SAR is determined by the power of the sound waves or radiation applied to the nanoparticles, particularly when the nanoparticle concentration is 1.01, 1.1, 2, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 Rates increase by factors of 1.01, 1.1, 2, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 When it decreases by a factor of 1.01, 1.1, 2, 5, 10, 10 2 , 10 3 , 10 5 or 10 10 Increasing by these factors, especially 1.01, 1.1, 2, 5, 10, and 10 2 , 10 3 , 10 5 or 10 10To meet this characteristic, nanoparticle concentrations must be measured specifically per mL or cm of the body part. 3 10 per -9 and 10 9 , 10 -5 and 10 5 , 10 -2 and 10 2 , or 10 -1 It should contain between 10 and 10 mg of nanoparticles.

[0220] In one embodiment of the present invention, the rate of SAR increase with increasing sound wave or radiation intensity corresponds to the percentage SAR increase, i.e., (SARI2-SARI1) / SARI1, where SARI1 and SARI2 are the SAR measured at two different sound wave or radiation intensities I1 and I2, and where I2>I1, specifically divided by I2 / I1.

[0221] In yet another embodiment of the present invention, the SAR of nanoparticles is 10 between different nanoparticle concentrations. 5 , 500, 90, 70, 50, 25, 10, 5, or 2%, and this percentage may represent C2-C1 / C1, where C1 and C2 are concentrations of two different nanoparticles. In some cases, this situation may occur when the nanoparticle concentration is 10 -6 and 10 6 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -2 and 10 2 Between mg / mL or cm of body part 3 In some other cases, nanoparticle concentrations are measured at mg per 1000, 100, 10, 1, 0.1, or 0.01 ml or cm of the body part. 3 This situation occurs when the nanoparticle concentration is less than mg per 1000, 100, 10, 1, 0.1, or 0.01 mL or cm of the body part. 3 This situation occurs when the mass is greater than mg per unit mass.

[0222] In one embodiment of the invention, the nanoparticles have an SAR that increases with decreasing nanoparticle concentration. 2 , 10 3 , 10 5 or 10 10 The SAR of nanoparticles is reduced by a factor of 1.1, 2, 5, 10, and 10. 2 , 10 3 , 10 5 or 10 10 To meet this requirement, the nanoparticle concentration must be increased by a factor of 10 per mL of nanoparticles. -9 and 10 9 , 10 -5 and 10 5 , 10 -2 and 10 2 , or 10 -1 and 10 mg, or a nanoparticle concentration of 10 per mL of nanoparticles -9 , 10 -7 , 10 -5 , 10 -2 , 10 -1 , 1, 10 or 100 mg or less. This behavior is interesting because it is the opposite of the behavior observed when the SAR is measured with an applied alternating magnetic field.

[0223] In some cases, SARs are (SARs) (real) can be specified.

[0224] In some cases (SAR) (real) may be the SAR of the nanoparticle, taking into account the initial gradient of temperature change in the body part with and without the nanoparticle.

[0225] In one embodiment of the present invention, a suitable range for the SAR increase with increasing acoustic power is between 15% and 440%, with the minimum and maximum values ​​of this range being the SAR values ​​shown in Tables 2 and 1, respectively. real In some cases, the minimum value of this range was increased by lowering the sound wave intensity or by changing the maximum concentration in the body part, specifically to values ​​of 2, 5, 10, and 10. 3 or 105 It can be reduced by twofold.

[0226] In some cases, the SAR can be calculated using the following formula: (real) SAR (real) =a real [(ΔT / δt) (real) ] where a real is C v / C nano where C v The SAR, C of the body parts, tissues, and water that make up the nanoparticles nano is the concentration or amount or number of nanoparticles contained in a particular body part.

[0227] In another embodiment of the present invention, a suitable range of SAR(actual) values ​​is between 5 W / g and 427 W / g. The lowest value of this range (5 W / g) is the maximum SAR(actual) value per cm of tissue. 3 1W / cm for 45μg of magnetosomes 2 In some cases, this minimum was estimated by applying sound intensity, power, or frequency of 1.5, 2, 5, 10, 50, or 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By reducing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 The maximum value of this range (427 W / g) is obtained by mixing 100 μl of magnetosomes in 100 μl of water with a 1 W / cm 2 In some cases, this maximum was estimated by applying sound waves of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 or by using body parts that absorb less sound waves.2 , 10 5 , 10 7 , 10 9 or 10 20 It can be increased by a factor of 1 or more.

[0228] In other cases, the SAR (N) It may be equal to .

[0229] In some cases, SAR (N) =aN(ΔT / δt) (N) where aN is C v / C mag The lowest value in this range (37 W / g) is equivalent to 1 cm of tissue. 3 0.5W / cm for 45μg of magnetosomes 2 In some cases, this minimum value (37 W / g) was estimated by applying sound waves of 1.5, 2, 5, 10, 50, 10, and 20 W / g. 2 , 10 5 , 10 7 , 10 9 , or 10 20 By reducing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 , or 10 20 The maximum value of this range (3124 W / g) is 1.5 W / cm for an aqueous solution of 100 μg of magnetosomes in 100 μl of water. 2 In some cases, this maximum was estimated by applying sound waves of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 , or 10 20 By increasing the frequency by a factor of 1.5, 2, 5, 10, 50, 10 or more, or by using body parts that absorb less sound waves, 2 , 10 5 , 10 7 , 10 9 , or 1020 It can be increased by a factor of 1 or more.

[0230] In yet another embodiment of the present invention, a N and / or a WN The value of -9 , 10 -6 , 10 -3 , 1, 10 3 , 10 6 or 10 9 (sec / ℃)·(W / g nano ) or (sec / °C) (W / g bp ) or (sec / °C) (W / cm 3 bp ) or (sec / °C)·(W / cm 3 nano ) is smaller than

[0231] In yet another embodiment of the present invention, a N and / or a WN The value is 10 -9 , 10 -6 , 10 -3 , 1, 10 3 , 10 6 or 10 9 (sec / ℃)·(W / g nano ) or (sec / °C)·(W / g bp ) or (sec / °C)·(W / cm 3 bp ) or (sec / °C)·(W / cm 3 nano ) is greater than

[0232] In still other cases, SAR is AW This is the SAR measured by applying sound waves to the nanoparticles. AW is SAR AMF This may differ from the SAR measured by applying an alternating magnetic field called the SAR. AW is SAR AMF and at least 10 -9 , 10 -7 , 10 -5 , 10-3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 % difference. This percentage is (SAR AW -SAR AMF ) / SAR AW This percentage is measured specifically for a given nanoparticle concentration, which may be equal to i) cm of the body part, as the case may be 3 or cm 3 nanoparticles measured per 10 9 , 10 7 , 10 5 , 10 3 , 10, 1, 10 -3 , 10 -5 , 10 -7 or 10 -9 smaller than mg, ii) in some other cases, cm 3 Per centimeter or body part 3 Nanoparticles measured per 10 9 , 10 7 , 10 5 , 10 3 , 10, 1, 10 -3 , 10 -5 , 10 -7 or 10 -9 greater than mg, or iii) cm 3 or cm of body part 3 10 per -9 and 10 9 , 10 -7 and 10 7 , 10 -5 and 10 5 , 10 -3 and 10 3 , or 10 -1 and 10 mg of nanoparticles.

[0233] In one embodiment of the present invention, the SAR is not measured in the presence of a magnetic or alternating magnetic field applied to the nanoparticles, and in some cases, the SAR is not due to, among other things, hysteresis loss, Brownian motion, Neel relaxation, movement of the nanoparticles under application of acoustic waves, or reversal of the magnetic moment of the nanoparticles under application of acoustic waves, or coupling of the magnetic moment of the nanoparticles with acoustic waves.

[0234] In another embodiment of the present invention, the SAR is not due to, or is not solely or primarily caused by, Brownian motion, Neel relaxation, or hysteresis losses. AW is due in particular, partially or mainly, to the absorption of sound waves by nanoparticles or body parts containing nanoparticles. AW is due in particular partly or mainly to absorption of sound waves by body parts that do not contain or do not contain nanoparticles, followed in particular by thermal diffusion between body parts without or without nanoparticles and body parts with or containing nanoparticles.

[0235] In one embodiment of the present invention, the body part is divided between a portion of the body part that contains nanoparticles and a portion of the body part that does not contain nanoparticles.

[0236] In one embodiment of the invention, the portion of the body part that contains the nanoparticles is a nanoparticle region or a portion of the body part to which the nanoparticles, nanoparticle aggregates, or nanoparticle suspensions are or have been administered.

[0237] In another embodiment of the invention, the portion of the body part that is free of nanoparticles is a portion of the body part to which nanoparticles, nanoparticle aggregates, or nanoparticle suspensions are not or have not been administered, e.g., a portion of the body part prior to nanoparticle administration or outside the nanoparticle region.

[0238] In some cases, the portion of the body part containing the nanoparticles absorbs sound or radiation energy at a rate of 10 -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1, 1, 5, 10, 25, 50, 75 or 80% or more of the energy of the sound waves or radiation, and the body parts that do not contain nanoparticles can absorb 10% or more of the energy of the sound waves or radiation. -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 In some other cases, the body part containing the nanoparticles can absorb up to 10% of the sound or radiation energy. -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75, or 80% or less of the sound or radiation energy, and that part of the body that does not contain nanoparticles -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75 or 80% or more of the energy can be absorbed. The percentages referred to in this and the previous embodiment are the energy of the sound or radiation applied to the nanoparticles divided by the energy of the sound or radiation or sonic energy applied to the body part, or the energy of the radiation applied to the nanoparticles or body part divided by the energy of the sound or radiation generated by the sound or radiation generating device.

[0239] In some cases, body part may refer to a portion of a body part or a portion of a body part that includes nanoparticles.

[0240] In some other cases, a body part may refer to a portion of a body part or a portion of a body part that does not include nanoparticles.

[0241] In still other cases, body part may refer to both portions of the body part that include nanoparticles or nanoparticle regions and portions of the body part that do not include nanoparticles or nanoparticle regions.

[0242] In some cases, the body part may be i) especially mm 3 Per or body part cm 3 per, or per pathological or healthy cell -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 mg or more of nanoparticles, or ii) particularly mm 3 Per or body part cm 3 10 per -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 mg or more of pathological or healthy cells.

[0243] In some other cases, the body part is i) specifically mm 3 Per or body part cm 3 per, or per pathological or healthy cell -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 mg or less nanoparticles, or ii) 1 mm 3 or 1 cm 3 10 per -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 It may contain up to mg of diseased or healthy cells.

[0244] The present invention also relates to nanoparticles for use according to the invention, in which the concentration of the nanoparticles administered is less than 10 ... 3 10 per -3 mg. In some cases, the concentration of nanoparticles can be as high as mm 3 per mL of suspension containing nanoparticles, or per mm of matrix or (biological or non-biological) 3 Measured around 10 -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 Grams or milligrams or more.

[0245] In one embodiment of the present invention, a suitable range of nanoparticle concentration in a body part is determined based on the concentration of nanoparticles in the body part mm 3 per 1 ng of nanoparticles, especially in iron, and mm of body parts 3 The range is between 1 g of nanoparticles, especially iron, per 1 g of magnetosome or nanoparticle suspension. The minimum value of this range (1 ng / mm3) was estimated by calculating the lowest concentration of magnetosome or nanoparticle suspension that can be administered to a body part, i.e., the lowest concentration of magnetosomes or nanoparticles that can normally be detected. In some cases, this minimum value is reduced if more sensitive detection methods are used or developed to detect the presence of magnetosomes or nanoparticles, or if some of the magnetosomes or nanoparticles diffuse away from the body part after administration to the body part. The maximum value of this range (1 g / mm3) was estimated by calculating the maximum magnetosome or nanoparticle concentration that produces a stable suspension. This maximum value can be reduced, for example, if the magnetosomes or nanoparticles are inserted into a matrix or solvent that is solid, semi-solid, or more viscous than water, or if the magnetosomes are concentrated in the body part after administration, resulting in a greater concentration in the body part than the magnetosome or nanoparticle suspension used for injection, e.g., 10, 10 3 , 106 or 10 9 The maximum value of this range (1g / mm 3 ) was estimated by calculating the maximum magnetosome or nanoparticle concentration that produces a stable suspension. This maximum value can be reached, for example, when the magnetosomes or nanoparticles are inserted into a matrix or solvent that is solid, semi-solid, or more viscous than water, or when the magnetosomes are concentrated in the body part after administration, resulting in a greater concentration in the body part than the magnetosome or nanoparticle suspension used for injection, e.g., 10, 10 3 , 10 6 or 10 9 It could be twice as big.

[0246] In another embodiment of the invention, the nanoparticles are administered at a concentration of 1, 2, 5, 10, 20, 50, 100, 10 3 or 10 4 During sequences or sessions exceeding 1, 2, 5, 10, 50, 100 or 10 3 In another embodiment of the invention, the nanoparticles remain in the body part for a period of time during the treatment, particularly for 1, 2, 5, 10, 20, 50, 100, 10, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 3 3 or 10 4 During the following sequences or sessions, specifically 1, 2, 5, 10, 50, 100 or 10 3 It remains for days, especially on the body.

[0247] In some cases, the nanoparticles may be 10 times smaller in size than the nanoparticles before administration to the body part or before treatment begins. -4 , 10 -1 , 1, 10, 20, 50, 100, 500, 10 3 or 10 4 % remain in the body part during treatment without being reduced by more than 100%. In some cases, this percentage can be equal to the ratio between the location of the nanoparticles after administration to the body part and the size of the nanoparticles before administration to the body part.

[0248] In some cases, the body part is a body part that is exposed to radiation or sound waves.

[0249] In the present invention, the body part or nanoparticles exposed to sound waves or radiation are those that are present in, in or on the target, or in particular at least 10% of the body part or nanoparticles, as defined by the present invention. -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75, or 80%. This percentage can represent the number or volume of nanoparticles or body parts exposed to sound waves or radiation divided by the total number or volume of nanoparticles or body parts. In some cases, sound waves or radiation can be applied, present, applied, or located outside, on, or inside of a body part or nanoparticle so as not to induce toxicity, especially if these sound waves or radiation are not of sufficiently low power or energy.

[0250] Additionally, in some cases, a body part or nanoparticle may be exposed to sound waves or radiation when sound waves or radiation are applied to the body part or nanoparticle, or when sound waves are applied to the body part or nanoparticle, or when the body part or nanoparticle may be exposed to sound waves or radiation, or when the body part or nanoparticle is subjected to sound waves or radiation, or when the body part or nanoparticle is affected by sound waves or radiation, or when the body part or nanoparticle is subjected to disturbances caused by sound waves or radiation, or when the body part or nanoparticle is subjected to disturbances from sound waves or radiation.

[0251] In one embodiment of the present invention, the body part is or relates to i) a body part that is exposed to sound waves or radiation, or ii) a body part that receives sound wave or radiation energy or power, or iii) a body part that absorbs sound wave or radiation energy or power.

[0252] In some cases, a body part may also be or relate to: i) a body part that is not exposed to sound or radiation, or ii) a body part that is not subject to sound or radiation energy or power, or iii) a body part that does not absorb sound or radiation energy or power.

[0253] The present invention also relates to nanoparticles for use according to the invention, wherein the application of sound waves or radiation to a body part is preferably within 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10 or 10 3 This results in an increase in body temperature of more than °C.

[0254] In some cases, the temperature increase is at least 10°C higher in the presence of nanoparticles than in the absence of nanoparticles. -10 , 10 -5 , 10 -1 , 1, 2, 5, 10, 50, 75, or 80% greater than the temperature rise in the body part. In some cases, this percentage may be the ratio of the temperature rise in the body part without the nanoparticles to the temperature rise in the body part with the nanoparticles.

[0255] The present invention also relates to nanoparticles for use according to the invention, wherein an increase in temperature of a body part, a decrease in temperature of a body part, or dissociation of the compound from the nanoparticles results in 10 minutes of heating of the body part. 20 , 10 10 , 10 5 , 10 3 , 500, 200, 90, 70, 50%, 10 or 1% or less.

[0256] In some other cases, the temperature increase in the body part, the temperature decrease in the body part, or the dissociation of the compound from the nanoparticles occurs within 10 minutes of the body part. -10 , 10 -5 , 10 -1 , 1, 10, 50, 70, 90, 200, 500, 10 3 , 10 5 or 10 20 Occurs at % or more.

[0257] The present invention also relates to nanoparticles for use according to the invention, wherein the temperature increase in the body part, the temperature decrease in the body part, or the dissociation of the compound from the nanoparticles is less than 10% of the volume occupied by the nanoparticles in the body part. -10 , 10 -5 , 10 -1 , 1, 10, 50, 70, 90, 200, 500, 10 3 , 10 5 , 10 10 or 10 20 % or more. This percentage can be the ratio of the volume in which the temperature increase in the body part, the temperature decrease in the body part, or the dissociation of the compound from the nanoparticle occurs to the total volume occupied by the nanoparticles in the body part.

[0258] In some other cases, the temperature increase in the body part, the temperature decrease in the body part, or the dissociation of the compound from the nanoparticles is greater than 10% of the volume occupied by the nanoparticles in the body part. 20 , 10 10 , 10 5 , 10 3 , 500, 200, 90, 70, 50%, 10 or 1% or less.

[0259] In one embodiment of the present invention, a body part includes one or more, two, five, ten, or one hundred or more similar or different organisms, devices, organs, tissues, cells, or biomolecules. In some cases, a body part may be all or part of a head, neck, shoulder, arm, leg, knee, foot, hand, ankle, elbow, torso, lower limb, or upper limb. In some other cases, a body part may be or belong to an organ, musculoskeletal, muscular, digestive, respiratory, urinary, female reproductive, male reproductive, circulatory, cardiovascular, endocrine, circulatory, lymphatic, nervous system (peripheral or non-peripheral), or cardiac, enteric, sensory, or integumentary system, reproductive organ (internal or external), sensory organ, or endocrine gland. Organs or body parts include the human skeleton, joints, ligaments, tendons, mouth, teeth, tongue, salivary glands, parotid glands, submandibular glands, sublingual glands, pharynx, esophagus, stomach, small intestine, duodenum, jejunum, ileum, large intestine, liver, gallbladder, mesentery, pancreas, nasal cavity, pharynx, larynx, trachea, bronchi, lungs, diaphragm, kidneys, ureters, bladder, urethra, ovaries, fallopian tubes, uterus, vagina, vulva, clitoris, placenta, testes, epididymis, vas deferens, seminal vesicles, prostate, urethral glands, penis, scrotum, pituitary gland, pineal gland, thyroid gland, parathyroid gland, The body part or organ may be the thyroid gland, adrenal gland, pancreas, heart, artery, vein, capillary, lymphatic vessel, lymph node, bone marrow, thymus, spleen, gut-associated lymphoid tissue, tonsils, brain, cerebrum, cerebral hemisphere, diencephalon, brainstem, midbrain, pons, medulla, oblongata, cerebellum, spinal cord, choroid plexus, nerve, cranial nerve, spinal nerve, ganglion, eye, cornea, iris, ciliary body, lens, retina, ear, outer ear, earlobe, tympanic membrane, middle ear, ossicles, inner ear, cochlea, vestibule, semicircular canal, olfactory epithelium, tongue, taste buds, mammary gland, or skin. The body part or organ may belong to the blood circulation or circulatory system.

[0260] In some cases, the body part may be or contain at least one tumor, cancer, virus, bacteria, or pathological cell.

[0261] In one embodiment of the invention, the body part is or comprises water, an excipient, a solution, a suspension, at least one chemical element, an organic material, or a gel, which may be synthetic or biologically produced.

[0262] Preferably, an individual body part, also designated as body part, represents or is part of an individual or a whole individual, where an individual is in particular a human being, an animal or a living organism, in particular a living, inactivated or dead organism, comprising at least one prokaryotic or eukaryotic cell.

[0263] In one embodiment of the present invention, the body part is a living (or non-living) tissue, water, medium, substance, cell, organelle, organ protein, lipid, DNA, RNA, biological material, particularly localized to a particular area of ​​an individual, particularly originating from or extracted from such a site.

[0264] In one embodiment of the present invention, the body part comprises a pathological site, a healthy site, and / or a nanoparticle region.

[0265] In some cases, a pathological site may be defined as an unhealthy site, or a site in a state that differs from a site in a healthy individual, or a site in an unhealthy individual.

[0266] It can include pathological cells, such as tumor cells, bacteria, eukaryotic or prokaryotic cells, as well as viruses or other pathological agents. Pathological cells can be cells that: i) are not organized or functioning as they normally do in a healthy individual; ii) divide more rapidly than healthy cells; iii) are transformed or modified healthy cells; iv) sometimes die due to the presence of a virus or other organism; or v) are exposed to or interact with a foreign substance, such as a virus that does not belong to the individual, allowing the virus to invade, colonize, or replicate within these cells. In some cases, pathological cells may be assimilated by a virus or other organism, colonize, destroy, use, or interact with cells, particularly target cells, enabling their own reproduction, growth, survival, or death. In some cases, pathological sites may contain healthy cells, but are significantly less numerous, active, or proliferating than pathological cells.

[0267] In one embodiment of the invention, the body part is or comprises a healthy site or healthy cells. In some cases, a healthy site can be defined as a site or area that comprises healthy cells, and a healthy cell can be defined as a cell that belongs to a healthy individual or a body part of a healthy individual.

[0268] In some cases, healthy areas are 1, 10 mm away from diseased areas. -1 , 10 -3 , 10 -6 or 10 -9 If it is at a distance of less than m, it may surround the pathological area.

[0269] In some cases, the number of pathological or healthy cells specifically contained in the body part or volume exposed to sound waves or radiation may be increased, especially in the cm 3 10 per 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10, 5, 2 or 1 cell.

[0270] In some other cases, the number of pathological or healthy cells specifically contained in the body part or volume exposed to sound waves or radiation is determined, especially in the cm 3 1, 10, 10 per 3 , 10 5 , 10 7 , 10 9 , 10 20 , 10 50 or 10 100 There may be more than one cell in the

[0271] In still other cases, the ratio between the number of pathological cells and the number of healthy cells in the body part or volume exposed to sound waves or radiation is 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10 2 , 10, 5, 2 or 1 or less.

[0272] In still other cases, the ratio between the number of pathological cells and the number of healthy cells in the body part or volume specifically exposed to sound waves or radiation is 1, 2, 5, 10, 10 3 , 10 5 , 10 20 or 10 100 It can be bigger.

[0273] In another embodiment of the present invention, the body site, healthy or pathological site, or nanoparticle region may be m, m 2 , or m 3 Measured at 10 3 , 1, 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , or 10 -9 or 10 -20 has a length, surface area, or volume greater than

[0274] In another embodiment of the present invention, the body site, healthy or pathological site, or nanoparticle region may be m, m 2 , or m 3 Measured at 10 3 , 1, 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 , 10 -7 , 10 -8 , or 10 -9 has a length, surface area, or volume smaller than

[0275] In one embodiment of the present invention, the nanoparticles are administered either directly to the body part or in the vicinity of the body part, particularly within 10 minutes from the body part. -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10-6 or 10 -9 When administered at or below 1 μm, the nanoparticles may be administered to or into a body part, in which case the nanoparticles may not need to transport or diffuse from the site where they are administered to the body part.

[0276] In another embodiment of the invention, the nanoparticles are located far from the body part, in particular 1, 10 -1 , 10 -2 , 10 -3 , 10 -4 , 10 -5 , 10 -6 or 10 -9 When administered more than m apart, the nanoparticles are administered to or at a body part, in which case they can be transported or diffused into the body part from the site where they are administered.

[0277] In another embodiment of the invention, the nanoparticles are administered to or on a body part when injected, mixed, introduced, or inserted into or on a body part.

[0278] In another embodiment of the present invention, the nanoparticles are capable of being absorbed into the body by the body part. -9 , 10 -7 , 10 -5 , 10 -3 The nanoparticles are administered to a body part or a body region when the nanoparticles occupy 1, 10, 25, 50, or 75% or more of the body part or region. This percentage may be the ratio between the volume of the region occupied by the nanoparticles within the body part or nanoparticle region and the volume of the body part. This occupancy may be greater than or equal to 10% after nanoparticle administration. -5 , 10 -3 , 10 -1 , 1, 10, 10 3 or 10 5 This may correspond to occupancy measured in minutes.

[0279] In another embodiment of the invention, the nanoparticles are administered to or into a body part according to at least one of the following routes of administration: topical, enteral, gastrointestinal, parenteral, local, oral, inhalation, intramuscular, subcutaneous, intratumoral, intraorgan, intravenous, intraarterial, intrablood, or intratissue.

[0280] In one embodiment of the present invention, the thermal conductivity or density of a body part, the speed of sound, the attenuation of sound, the absorption of sound, the elasticity of sound, or the acoustic impedance of sound is at least 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 50, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 1109, 1110, 1120, 1121, 1130, 1131, 1140, 1150, 1160, 1170, 1180, 1190, 1211, 1220, 1222, 1230, 1231, 1240, 1250 2 , 10 3 or 10 5 It's even bigger.

[0281] In one embodiment of the present invention, the thermal conductivity or density, sound wave speed, sound wave attenuation, sound wave absorption, sound wave elasticity, or sound wave acoustic impedance of the body part is at least 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 50, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 1109, 1110, 1120, 1121, 1130, 1131, 1140, 1141, 1150, 1151, 1160, 1162, 1170, 1172, 1180, 1182, 1190, 1200, 1211, 121 2 , 10 3 or 10 5 small.

[0282] In one embodiment of the present invention, the thermal conductivity of the body part is at least 10% higher in the body part containing nanoparticles than in the body part not containing nanoparticles. 20 , 10 10 , 10 5 , 10 3 , 10 2 , 50, 10, 5, 2, 1, 10 -1 , 10 -2 , 10 -3 , 10 -5 , 10 -10 or 10 -20 W / m·K (Watt / meter·kelvin) increases.

[0283] In one embodiment of the present invention, the thermal conductivity of the body part is at least 10% higher in the portion of the body part that includes nanoparticles than in the portion of the body part that does not include nanoparticles. 20 , 10 10 , 10 5 , 10 3 , 10 2 , 50, 10, 5, 2, 1, 10 -1 , 10 -2 , 10-3 , 10 -5 , 10 -10 or 10 -20 W / m·K (Watts per meter·Kelvin) will be lower.

[0284] In one embodiment of the present invention, the density of the body part is at least 10% higher in the body part containing nanoparticles than in the part of the body part not containing nanoparticles. -9 , 10 -6 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 3 or 10 6 g / cm 3 Only bigger.

[0285] In one embodiment of the invention, the density of the portion of the body part containing nanoparticles is at least 10 times higher than the portion of the body part not containing nanoparticles. -9 , 10 -6 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 3 or 10 6 g / cm 3 Only lower.

[0286] In one embodiment of the present invention, the speed of the acoustic waves is at least 10 -5 , 10 -3 , 10 -1 ,1,10,100,1000,1500,2000,3000,5000,10 4 or 10 6 The area of ​​the body part containing nanoparticles is larger than the area of ​​the body part not containing nanoparticles by m / s.

[0287] In one embodiment of the present invention, the speed of the acoustic waves is at least 10 -5 , 10 -3 , 10 -1 ,1,10,100,1000,1500,2000,3000,5000,10 4 or 10 6 m / s is lower for the portion of the body part containing nanoparticles than for the portion of the body part not containing nanoparticles.

[0288] In one embodiment of the present invention, the attenuation of the sound waves is at least 10 -5 , 10 -3 , 10 -1 , 1, 10, 100, 10 3 or 10 5 dB / cm is greater for the area of ​​the body part containing nanoparticles than for the area of ​​the body part without nanoparticles.

[0289] In one embodiment of the present invention, the attenuation of the acoustic waves is at least 10 in a portion of the body part. -5 , 10 -3 , 10 -1 , 1, 10, 100, 10 3 or 10 5 dB / cm lower in the body part containing nanoparticles than in the body part without nanoparticles.

[0290] In one embodiment of the present invention, the acoustic impedance of the sound wave is at least 10 -3 , 10 -2 , 10 -1 , 0.5, 1, 1.5, 2, 5, 10, 10 2 , 10 4 , 10 6 , 10 9 or 10 20 MRayl or Kg·m -2 s -1 is greater in the portion of the body part containing nanoparticles than in the portion of the body part not containing nanoparticles.

[0291] In one embodiment of the present invention, the acoustic impedance of the sound wave is at least 10 -3 , 10 -2 , 10 -1 , 0.5, 1, 1.5, 2, 5, 10, 10 2 , 10 4 , 10 6 , 10 9 or 10 20 MRayl or Kg·m -2 s -1 only lower in the body-parts containing nanoparticles than in the body-parts not containing nanoparticles.

[0292] In another embodiment of the present invention, the increase, decrease, or variation in thermal conductivity or density of the body part, speed of sound waves, attenuation of sound waves, absorption of sound waves, elasticity of sound waves, or acoustic impedance of sound waves between a portion of the body part that does not contain nanoparticles and a portion of the body part that contains nanoparticles is due to at least one of the following properties: i) the nanoparticle density of the body part; 3 per, or body part cm 3 particle concentration per -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 mg, ii) nanoparticle size is 10 -6 , 10 -3 , 10 -1 , 1, 20, 50, 10 3 or 10 6 nm or larger, iii) chain arrangements of nanoparticles, or iv) nanoparticles forming aggregates.

[0293] In another embodiment of the present invention, the increase, decrease, or variation in thermal conductivity or density, sound velocity, sound attenuation, sound absorption, sound elasticity, or sound acoustic impedance of a body part between a body part that does not contain nanoparticles and a body part that contains nanoparticles is due to at least one of the following properties: i) mm 3 per, or body part cm 3 10 per -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 ii) nanoparticle concentrations in body parts lower than 10 mg; -6 , 10 -3 , 10 -1 , 1, 20, 50, 10 3 or 106 Nanoparticle size of less than nm.

[0294] In one embodiment of the present invention, sonic treatment refers to a medical treatment or therapy. In some cases, the treatment uses or is due to the intensity or power of sonic energy specifically applied to nanoparticles or body parts. In some cases, the treatment may involve, be due to, or result from sonic waves specifically applied to nanoparticles. In some cases, the treatment produces a medical, pharmaceutical, immunological, metabolic, diagnostic, medical device, drug, biological, or cosmetic effect. In some cases, the medical treatment may be the treatment of a disease, such as an infection, cancer, or therapeutic treatment. It may be the treatment of a disease due to the dysfunction of an organ or body part. This may be due to the dysfunction of an individual's body part. In some cases, it may be a diagnosis of a disease or a cosmetic treatment. In some cases, it may be the treatment of at least 10, ... 3 , 10 6 , or 10 9 It can induce the death, destruction, denaturation, or inactivation of biological material. Cell death can occur via apoptosis or necrosis, particularly apoptosis.

[0295] The present invention also relates to nanoparticles for use according to the present invention, wherein the medical treatment is the treatment of a disease or disorder selected from the group consisting of diseases associated with the proliferation of cells different from cell proliferation in healthy individuals: diseases associated with the presence of pathological cells in an individual or body part, diseases associated with the presence of pathological sites in an individual or body part, diseases or disorders or dysfunctions of body parts, diseases associated with the presence, radioresistant or acoustically resistant cells, infectious diseases, autoimmune diseases, neuropathologies, cancers, tumors, diseases containing or caused by at least one cancer or tumor cell, skin diseases, endocrine diseases, eye diseases or disorders, intestinal diseases, communication disorders, genetic disorders, neurological disorders, voice disorders, vulvovaginal disorders, liver failure, cardiac disorders, heating disorders, mood disorders, anemia, in particular iron anemia, and personality disorders.

[0296] In some cases, the disease or disorder may be a disease or disorder of or pertaining to an individual or body part, or a disease or disorder from which an individual is afflicted.

[0297] In one embodiment of the present invention, the cancer or tumor is selected from the following group: cancer of an organ, cancer of the blood, cancer of a biological system, adrenal cancer, anal cancer, bile duct cancer, bladder cancer. Cancerous diseases such as bone cancer, brain cancer, breast cancer, cervical cancer, colon / rectum cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, heart cancer, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma cancer, ovarian cancer, pancreatic cancer, pancreatic-penile cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine cancer, uterine sarcoma cancer, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia Wilms tumor, Castleman's disease Ewing tumor, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, myelodysplastic syndrome pituitary tumor, and gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, malignant mesothelioma.

[0298] In one embodiment, the disorder or dysfunction of a body part is associated with dysfunction of cells, for example, dividing more rapidly or entering a state of apoptosis or necrosis, or dysfunction of the immune system or immune cells.

[0299] In one embodiment of the present invention, the medical treatment is or includes the detection or diagnosis of a disease as described in the previous embodiments.

[0300] In one embodiment of the present invention, the medical treatment is the treatment of anemia, and the nanoparticles are used to treat anemia, preferably anemia of a substance contained in a body part or compound, particularly anemia of iron or a substance contained in the core and / or coating of the nanoparticle. In some cases, anemia can be defined as the concentration of a substance contained in an individual, which is 1.001, 1.01, 1.1, 2, 5, 10, 10 in an affected individual, than in a healthy individual. 2 , 10 5, 10 10 or 10 20 More than twice as low.

[0301] In some cases, anemia of a substance contained in a body part is defined as the concentration of a substance contained in a nanoparticle or compound, such as iron or oxide, in a body part before or without nanoparticle administration that is higher than that after or with nanoparticle administration, specifically 1.001, 1.01, 1.1, 2, 5, 10, 10. 2 , 10 5 , 10 10 or 10 20 Twice as low.

[0302] The present invention also relates to a method for the treatment of anemia or an anemic disease, or to nanoparticles, in particular magnetosomes, for use in the treatment of an anemic disease, in particular iron-anemic disease, wherein the magnetosomes are administered to a body part of an individual, in particular to reduce or stop the anemia.

[0303] The present invention also relates to a method for treating an anemic disorder, the disorder being selected from the group consisting of iron deficiency anemia, vitamin deficiency anemia, anemia of chronic disease, aplastic anemia, anemia associated with bone marrow disease, hemolytic anemia, sickle cell anemia, thalassemia, pernicious anemia, Fanconi anemia, sideroblastic anemia, congenital erythroblastic anemia (CDA), Diamond-Blackfan anemia, and megaloblastic anemia. In some cases, the anemia is a decrease in the total amount of red blood cells (RBCs) or hemoglobin in the blood, or a decrease in the oxygen-carrying capacity of the blood.

[0304] The present invention also relates to a method for treating anemia or an anemic disorder, wherein the treatment results from, involves, or is caused by the release or dissociation of iron or free iron from nanoparticles, particularly magnetosomes. In some cases, the percentage of iron released by the nanoparticles, particularly magnetosomes, is greater than or equal to 10 -5 , 10 -3 , 10 -1, 1, 5, 10, 50, 75, 90, or 99%. In other cases, the percentage of iron released by nanoparticles, particularly magnetosomes, is 100, 99, 90, 75, 50, 10, 5, 1, or 1% or less. In some cases, this percentage is the ratio QFI / QIM, where QFI is the amount of free iron released by nanoparticles, particularly magnetosomes, and QIM is the total amount of iron contained in the nanoparticles, particularly magnetosomes. In some other cases, this percentage is the ratio SMFI / SM, where SMFI is the size of the nanoparticles, particularly magnetosomes, measured after free iron has been released from the nanoparticles, particularly magnetosomes, and SM is the size of the nanoparticles, particularly magnetosomes, measured before free iron has been released from the nanoparticles, particularly magnetosomes.

[0305] The present invention also relates to a method for treating anemia or an anemic disorder in which the amount of free iron dissociated or released from nanoparticles, particularly magnetosomes, is greater than the amount of iron contained in the body part of an individual. In some cases, the amount of free iron dissociated or released from nanoparticles, particularly magnetosomes, is greater than the amount of iron contained in the body part by a factor of 1.00001, 1.1, 2, 5, 10, or 50 or more. In other cases, the amount of free iron dissociated or released from nanoparticles, particularly magnetosomes, is greater than the amount of iron contained in the body part of an individual, particularly before treatment is initiated, by a factor of 1.00001, 1.1, 2, 5, 10, or 50 or more. In other cases, the amount of free iron dissociated or released from nanoparticles, particularly magnetosomes, is greater than the amount of iron contained in the body part of an individual, particularly before treatment is initiated. -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -2 , 10 -1 , 1, 10 or 10 3 Nanoparticles, especially magnetosomes, per gram, or nanoparticles, especially magnetosomes, per gram, or cm of a body part that specifically contains nanoparticles, especially magnetosomes 3 Per gram.

[0306] The present invention also relates to a method for treating anemia or an anemic disease, in which the amount of free iron dissociated or released from nanoparticles, particularly magnetosomes, is determined in grams of free iron per nanoparticle, particularly magnetosome, or per gram of nanoparticle, particularly magnetosome, or cm of a body part particularly comprising nanoparticles, particularly magnetosomes. 3 10 in grams per 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 1, 10 -1 , 10 -5 , 10 -10 or 10 -50 The following is the result.

[0307] The present invention also relates to methods for the treatment of anemia or anemic disorders, wherein the treatment is due to, resulting from, or caused by: i) internalization of nanoparticles within cells, ii) externalization of nanoparticles from cells, iii) alteration of the structure, shape, composition, size, size distribution, surface charge of the nanoparticles, and or iv) application of radiation or sound waves to the nanoparticles.

[0308] In some cases, the change in nanoparticle properties can be as large as 10 -50 , 10 -10 , 1, 5, 10, or 50% variation, where the nanoparticle property can be nanoparticle structure, geometry, composition, size, size distribution, or surface charge. In other cases, the change in a nanoparticle property is no more than 100, 99, 90, 80, 70, 50, 25, 10, or 5% variation in this property. In some cases, this ratio may be equal to PAT / PBT, where PAT and PBT are the values ​​of this property before and after anemia treatment, respectively.

[0309] The present invention also relates to a method for treating anemia or an anemic disorder, wherein the radiation is selected from the group consisting of x-rays, light waves, microwaves, radio waves, and sound waves. In some cases, irradiating the nanoparticles increases the amount of free iron dissociated or released from the nanoparticles, particularly by a factor of 1.0001, 1.1, 2, 5, 10, 10, 10, or 10, where this factor is equal to QFIR / QFI, where QFIR and QFI are the amounts of free iron released or dissociated from the nanoparticles after and before irradiating the nanoparticles, respectively.

[0310] The present invention also relates to a method for the treatment of anemia or anemia disease, wherein the output of radiation is 10 times that of a body part. -10 and 10 10 Between watts or cm 3 per watt or body part cm 3 The unit is watts per cell or watts per cell.

[0311] The present invention also relates to a method for treating anemia or anemia diseases, in which radiation is applied to nanoparticles sequentially, the sequence comprising the following steps: i) at time t1: during application of radiation ii) during time t2: no application of radiation or application of radiation of lower power than at t1.

[0312] In some cases, sequential application of radiation to nanoparticles or magnetosomes results in the amount of free iron dissociated or released from the nanoparticles or magnetosomes exceeding 1.0001, 1.1, 2, 5, 10, 10 3 , 10 5 or 10 10 , or a factor equal to or greater than 1, where this factor is equal to QFISR / QFIR, where QFISR and QFIR are the amounts of free iron released or dissociated from the nanoparticles or magnetosomes after continuous and discontinuous irradiation of the nanoparticles or magnetosomes, respectively.

[0313] In one embodiment of the present invention, the treatment according to the present invention is sonodynamic therapy.

[0314] In some cases, sonodynamic therapy can be defined as a therapy that induces therapeutic activity by i) applying low-intensity sound waves to nanoparticles or body parts, or ii) using nanoparticles as ultrasound sensitizers. In some cases, sonodynamic therapy can induce therapeutic activity by increasing the temperature by 10 50 , 10 5 , 10 3 , 500, 200, 100, 50, 25, 10, 5, 2, or 1 °C below, and or the rate of dissociation of the compound is 10 -5 , 10 -2 , 10 -1 , 1, 10, 10 3 or 10 7 % or more of treatment.

[0315] In some cases, the percentage of compound dissociation or the percentage of dissociated compounds can be defined as the ratio of i) the number or mass of compounds that are not linked to, or bound to, or dissociated from nanoparticles, particularly following application of sound waves or radiation, and ii) the number or mass of compounds that are not bound to or dissociated from nanoparticles, particularly before or without application of sound waves or radiation.

[0316] In some other cases, sonodynamic therapy has been shown to increase the temperature by 10 5 , 10 3 , 500, 200, 100, 50, 25, 10, 5, 2 or 1 °C or higher, and / or the dissociation rate of the compound is 10 -5 , 10 -2 , 10 -1 , 1, 10, 10 3 or 10 7 % or less.

[0317] The present invention also relates to nanoparticles for use according to the present invention, wherein the application of sound waves or radiation to the nanoparticles or to a body part induces a temperature increase in the body part or nanoparticles, which increases by 10 -10 and 10 10 , 10 -5 and 10 5 , 10 -1 and 10 4°C, or between 1 and 30 (degrees Celsius). In some cases, the temperature of the body part or nanoparticles may be 10 -10 and 10 10 , 10 -5 and 10 5 , or 10 -1 and 10 4 The temperature rises between 100°C and 120°F.

[0318] In some other cases, the temperature is on the nanoscale, i.e., 2, 5, 10, 10 3 , 10 5 or 10 9 The following nanoparticle scales may be measured: i) 1, 2, 5, 10, 10 3 , 10 5 or 10 9 nanoparticles or ii) 10 5 , 10 3 , 10 2 , 10 or 1 nm.

[0319] In some cases, the temperature may be measured on a macroscopic scale, i.e., on the following scales: i) at least 1.001, 1.1, 1.2, 1.5, 5, 10, 10 below the nanoscale; 3 or 10 5 times larger, ii) 1, 10, 10 3 , 10 5 or 10 9 nanoparticle sizes, or iii) 2, 5, 10, 10 3 , 10 5 or 10 9 The nanoparticles include at least one nanoparticle.

[0320] In one embodiment of the present invention, the temperature rise ΔT of a body part or nanoparticle exposed to acoustic waves is above physiological temperature or above the temperature of the body part of the nanoparticles reached before the application of acoustic waves or radiation. In some cases, ΔT = TNPBP - TBP, where TNPBP is the temperature or temperature rise of a body part containing nanoparticles exposed to acoustic waves or radiation, and TBP is i) the temperature or temperature rise of a body part not containing nanoparticles exposed to acoustic waves or radiation, or ii) the temperature or temperature rise of a body part not containing nanoparticles that has not been exposed to acoustic waves or radiation. In other cases, ΔT may be generated or measured: i) in a body part containing nanoparticles, ii) in a nanoparticle region, iii) in a body part without nanoparticles, iv) in a body part without nanoparticles and in a nanoparticle region, or v) in a nanoparticle region but not in a body part without nanoparticles. It may be preferable to have a greater temperature rise in a body part or nanoparticle region containing nanoparticles than in a body part without nanoparticles.

[0321] In some cases, the temperature rise ΔT will be the difference between the temperature measured or generated for sequentially applied acoustic waves or radiation to the nanoparticles and the temperature measured or generated for sequentially applied acoustic waves or radiation to the nanoparticles.

[0322] The invention also relates to nanoparticles for use in accordance with the invention, wherein application of sound waves or radiation to the nanoparticle or body part induces a temperature increase in the body part or nanoparticle of greater than 0.01, 0.1, 1, 2, 5, 10, 30, 50, 100, or 1000° C. In some cases, application of sound waves or radiation to the nanoparticle or body part increases the temperature of the nanoparticle by more than 0.01, 0.1, 1, 2, 5, 10, 30, 50, 100, or 1000° C.

[0323] In one embodiment of the present invention, the sound waves or radiation, preferably the sound waves or radiation frequency, is thermal. In this case, the sound waves or radiation cause an increase in temperature, in particular 0.1, 1, 2, 5, 10, 10 2 or 103 °C. The frequency of the thermosonic waves is especially -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 10 or 10 20 It will be greater than Hz.

[0324] The present invention also relates to nanoparticles for use according to the invention, wherein the application of sound waves or radiation to the nanoparticles or to a body part induces a temperature increase in the body part or nanoparticles, which increases by 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10 2 , 50, 30, 10, 5, 2, 1, 0.1, or 0.01°C or less. In some cases, when sound waves or radiation are applied to the nanoparticle or body part, the temperature of the body part or nanoparticle increases by 10 3 , 10 2 , the temperature rises by no more than 50, 30, 10, 5, 2, 1 or 0.1°C.

[0325] In one embodiment of the present invention, the frequency of the sound waves or radiation is non-thermal, meaning that the frequency of the sound waves or radiation does not cause an increase in temperature or 3 , 10 2 , causing a temperature rise of less than 10, 5, 2, 1 or 0.1°C. In this case, the frequency of the sound waves or radiation is particularly 20 , 10 10 , 10 5 , 10 3 , 10 1 , 1, 10, 10 -3 , 10 -5 , 10 -10 or 10 -20 Lower than Hz.

[0326] In one embodiment of the present invention, a suitable range of temperature increase ΔT is between 3° C. and 28° C. The minimum value of this range (3° C.) was estimated by mixing 100 μg of magnetosomes in 100 μl of water and exposing them to 1.5 W / cm of sound. In some cases, this minimum value can be achieved by increasing the sound intensity, power, or frequency by 1.5, 2, 5, 10, 50, 10, 25, 30, 40, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 280, 300, 320, 360, 380, 400, 420, 440, 460, 480, 500, 52 2 , 10 5 , 10 7 , 10 9 or 10 20 Reduce nanoparticle concentrations in body parts by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 The maximum value of this range (28°C) is the tissue cm 3 This maximum was estimated by exposing 45 μg of magnetosomes per sample to 1.5 W / cm2 of sound. In some cases, this maximum was reached by increasing the sound intensity, power, or frequency by 1.5, 2, 5, 10, 50, or 10. 2 , 10 5 , 10 7 , 10 9 or 10 20 or by increasing the nanoparticle concentration in the body part by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By increasing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 It can be increased by a factor of 1 or more.

[0327] In another embodiment of the invention, a suitable range for TNPBP is between 18° C. and 56° C. The lower end of this range (18° C.) corresponds to a suspension of 100 μg of magnetosomes in 100 μl of water at 0.5 W / cm 2In another embodiment, this minimum value is estimated by exposing the subject to an acoustic wave of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 or by reducing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By reducing the nanoparticle concentration in the body part by a factor of more than 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 The maximum value of this range (56°C) is 3 This maximum was estimated by exposing 45 μg of magnetosomes per sample to 1.5 W / cm2 of sound. In some cases, this maximum was reached by increasing the sound intensity, power, or frequency by 1.5, 2, 5, 10, 50, or 10. 2 , 10 5 , 10 7 , 10 9 or 10 20 or by increasing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By increasing the nanoparticle concentration in the body part by a factor exceeding 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 can be increased by more than two times.

[0328] In yet another embodiment of the present invention, a suitable range for TBP is between 13°C and 32°C. The minimum value of this range (13°C) was estimated by exposing the aqueous solution to sound waves at 0.5 W / cm2. In some cases, this minimum value can be determined by increasing the sound wave intensity, power, or frequency by 1.5, 2, 5, 10, 50, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 410, 420, 430, 2 , 10 5 , 10 7 , 10 9 or 10 20 By reducing by a factor of more than 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 The above coefficients are 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 The maximum value of this range (32°C) is 1 W / cm², which can reduce the tissue 2 In some cases, this maximum was estimated by increasing the sound intensity, power, or frequency by 1.5, 2, 5, 10, 50, or 10 2 , 10 5 , 10 7 , 10 9 or 10 20 By increasing by a factor of 1.5, 2, 5, 10, 50, 10 2 , 10 5 , 10 7 , 10 9 or 10 20 can be increased by a factor of .

[0329] In one embodiment of the present invention, the application of sound waves or radiation to the nanoparticles brings them to a saturation temperature (ST), or sound waves or radiation is applied to the nanoparticles until ST is reached. In some cases, the saturation temperature may be the desired temperature.

[0330] In one embodiment of the present invention, as soon as the saturation temperature is reached, the application of sound waves or radiation is stopped, in particular to avoid overheating.

[0331] In particular, the saturation temperature is the highest temperature that can be reached during the application of sound waves or radiation, or during the application time of sound waves or radiation, designated as ts or t1 or t3, 1, 5, 10, 50, 75, 10 2 or 10 3 represents the temperature that does not change by more than %.

[0332] Time. t s , t1, t3 follow in particular time t1, which is the first time that sound waves or radiation begin to be applied. s is smaller than t1. In some other cases, t1 / (t1+t s ) is 10 -9 , 10 -7 , 10 -5 , 10 -4 , 10 -3 , 10 -2 , 10 -1 , 0.5, 0.75, or greater than 0.9. In some other cases, t s / t1 is 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 or 10 9 In some other cases, t s / t1 is 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 or 10 9 Smaller than.

[0333] In another embodiment of the present invention, t1=t i +t s is.

[0334] In some cases, ST is: i) -270, -200, -100, -50, 0, 1, 10, 10 3 , or 10 5or ii) at least 1.00001, 1.1, 1.2, 1.5, 2, 5, 10, 10 °C greater in the presence of nanoparticles than in the absence of nanoparticles. 3 , 10 5 or 10 9 is larger by a factor of .

[0335] In other cases, ST is: i) 10 20 , 10 5 , 10 3 , 10, 1, -100 or -200°C lower, or ii) at least 1.00001, 1.1, 1.2, 1.5, 2, 5, 10, 10 in the presence of nanoparticles than in their absence. 3 , 10 5 or 10 9 and goes down.

[0336] In still other cases, the ST is between -270 and 10 50 , -100 and 10 20 , 0 and 10 10 , 10 and 10 5 , 37 and 10 3 , or 41 and 10 3 °C.

[0337] In one embodiment of the present invention, a suitable range of ST values ​​is (37±4)°C to (73±4)°C, as estimated from Table 2, considering the initial temperature to be physiological. In some cases, the minimum value of this range (37±4)°C may be reduced, e.g., by 1, 5, 10, 20, 50, or 100°C or more, when the temperature of the body part is reduced, e.g., by using a device or substance such as ice that reduces the temperature of the body part, by reducing the intensity, power, or frequency of the sound waves, or by reducing the concentration of nanoparticles. In some other cases, the maximum value of this range (73±4)°C may be increased, e.g., by 1, 5, 10, 20, 50, or 100°C or more, when the temperature of the body part is increased, e.g., by using a device or substance that increases the temperature of the body part, by increasing the intensity, power, or frequency of the sound waves, or by increasing the concentration of nanoparticles.

[0338] In one embodiment of the present invention, the compound to be administered to the body part is bound or attached to the nanoparticles, especially before or without applying sound waves or radiation to the nanoparticles.

[0339] In one embodiment of the present invention, a compound is attached to or does not dissociate from a nanoparticle if: i) the compound is removed from the nanoparticle; 5 , 10 3 , 100 or 10 nm; ii) when bound or linked to the nanoparticle, especially via hydrogen, van der Wall, London, covalent, metallic, or ionic bonds; iii) the compound cannot be magnetically separated from the nanoparticle; iv) when bound or linked to the nanoparticle, or 10, 1, 10 -1 , 10 -3 , 10 -6 or 10 -9 The percentage of compounds within a distance of 0.5 cm or less is greater than 99, 90, 75, 50, 30, 20, 10, 5, 2, or 1%, which percentage can be the ratio of the number or mass of compounds bound or associated with the nanoparticles before magnetic separation to the number or mass of compounds linked or associated with the nanoparticles after magnetic separation.

[0340] The present invention also relates to nanoparticles for use according to the invention, wherein a compound is attached to the nanoparticle and the application of acoustic waves to the nanoparticles induces dissociation of the compound from the nanoparticles.

[0341] In some cases, a compound may not be linked or bound to a nanoparticle or may dissociate from the nanoparticle if: i) it is not attached to or bound to the nanoparticle or to the surface of the nanoparticle or the coating of the nanoparticle; -3 , 10 -1 , 1, 5, 10, 100, 10 3 or 10 5 nm or greater than 1 and 10 10ii) are not bound or linked to the nanoparticles via hydrogen, van der Wall, London, covalent, metallic, or ionic bonds; iii) the nanoparticles can be magnetically separated from the compound using a magnet that specifically attracts the nanoparticles; iv) are associated or linked to the nanoparticles or are within 10, 1, 10, 10 -1 , 10 -3 , 10 -6 or 10 -9 The proportion of compounds at a distance of 99, 90, 75, 50, 30, 20, 10, 5, 2, or 1% or less is within a distance of 1 cm.

[0342] In some cases, magnetic separation involves applying a magnetic field of spatially varying strength to the nanoparticles, particularly strengths of 10, 1, 10 -1 , 10 -3 or 10 -9 It is possible to separate the compounds from the nanoparticles by using a magnet below T. This intensity is measured specifically near the surface or magnet and decreases with distance from the magnet.

[0343] In other cases, the compound may bind or attach to the nanoparticle but not dissociate from the nanoparticle. In this case, the compound may be released from the nanoparticle or the surface of the nanoparticle or the coating of the nanoparticle. 100 , 10 50 , 10 10 , 10 5 , 10 2 , 10, 5, 2 or 1 nm or less, or 10 -3 The distance between the electrodes can be 1 nm and 1 nm.

[0344] In particular, the compounds attach to the nanoparticles without the application of sound waves or radiation and dissociate from the nanoparticles under the application of sound waves or radiation.

[0345] In one embodiment of the present invention, the acoustic waves or radiation are associated with, coupled to, induce, generate, result in, are responsible for, or create the movement, vibration, or oscillation of the compound, particularly after dissociation of the compound from the nanoparticle.

[0346] In one embodiment of the present invention, the compound is a therapeutic, immunogenic, metabolic, luminescent, fluorescent, radioactive, diagnostic, biological, or chemical compound. 2 , 10 3 , 10 5 , 10 7 , 10 10 , 10 20 or 10 50 The compound may be or represent an aggregate of more than 10 nanoparticles. Specifically linked or bound to the nanoparticles. In some cases, under the application of sound waves or radiation, the compound may dissociate from the nanoparticles. In some cases, the compound may be more than 10 nanoparticles. -5 , 10 -3 , 10 -1 , 1, 5, 10, 25, 50, 75, 85, or greater than 90% of the compound dissociates from the nanoparticle. This percentage is the ratio of the amount of compound dissociated from the nanoparticle after or during application of sound waves or radiation to the amount of compound bound or attached to the nanoparticle before or during application of sound waves or radiation. In some cases, the number of compounds linked or attached to a single nanoparticle is 1, 2, 5, 10, 10 3 , 10 5 or 10 10 In other cases, the number of compounds linked or attached to a single nanoparticle can exceed 2, 5, 10, 10 3 , 10 5 or 10 10 In still other cases, the fraction of compound that dissociates is at least 1.01, 1.1, 2, 5, 7, 10, 10 or less between before and after application of sound or radiation to the nanoparticles. 2 or 10 5 double increase.

[0347] In one embodiment of the present invention, the compound is part of a nanoparticle, in which case it may in particular be in ionic form, free iron or free oxygen, which in particular dissociates or leaks or diffuses out of the nanoparticle during or after application of sound waves or radiation to the nanoparticle or to a body part, in particular after dissolution or decomposition of the nanoparticle, in particular after administration of the nanoparticle to a body part.

[0348] In another embodiment of the present invention, the ratio between the mass, number, or weight of the compound specifically bound to a single nanoparticle and the mass, number, or weight of the single nanoparticle is 10 20 , 10 9 , 10 5 , 10 2 , 2, 1, 10 -2 , 10 -5 , 10 -9 or 10 -20 is smaller than.

[0349] In another embodiment of the present invention, the ratio of the mass, number, or weight of the compound specifically bound to a single nanoparticle to the mass, number, or weight of the single nanoparticle is 10 20 , 10 9 , 10 5 , 10 2 , 1, 10 -2 , 10 -5 , 10 -9 or 10 -20 is greater than.

[0350] In one embodiment of the present invention, a suitable range of values ​​for the number of compounds specifically bound to a single nanoparticle is 1 to 178, with the minimum value of 1 corresponding to the minimum number of compounds that can be bound to a single nanoparticle, and the maximum value of 178 corresponding to the number of RhB molecules that can be linked to and at least partially dissociated from a single magnetosome according to the incorporated by reference patent WO2017 / 068252. In some cases, this maximum value of 178 can be, depending on the situation, in particular, 5, 10, 10 3 , 10 7 , 10 10 , or 10 20 i) The size or mass of the compound bound to the nanoparticle can be increased by a factor of 1.1, 2, 5, 10, 10, or more, among others. 3 , 10 7 , 10 10 , or 10 20 ii) changing the type of bond between the compound and the nanoparticle; or iii) changing the method of bonding or binding the compound to the nanoparticle.

[0351] In an important embodiment of the present invention, the sequential application of sound waves or radiation is used or allows, in particular during at least one sequence, to reach a lower or maximum temperature than the maximum temperature reached by using continuous application of sound waves or radiation. On the one hand, heating at a lower temperature compared to continuous application of sound waves or radiation may result in less toxicity. On the other hand, creating a temperature gradient or a gradient in the velocity or movement of nanoparticles during at least one sequence can result in a higher efficiency, particularly an antitumor or anticancer effect, than continuous application of sound waves or radiation, which is at least one mechanism of treatment disclosed in the present invention.

[0352] The present invention also relates to the use of nanoparticles according to the present invention, wherein the sequential application of sound waves or radiation on a body part or nanoparticle induces: i) a series of temperature increases of the body part or nanoparticle followed by a temperature decrease of the body part or nanoparticle, and or ii) a series of dissociation of a compound from the nanoparticle followed by a non-dissociation of the compound from the nanoparticle.

[0353] In one embodiment of the present invention, sound waves or radiation are applied sequentially, particularly to a body part or nanoparticle, if: i) they are not applied consecutively over time, ii) they are not applied at consecutive powers, intensities, or frequencies over time, or iii) they create, associate, or generate at least one sequence.

[0354] In some cases, the time t1 is the period of application of the sound wave or radiation.

[0355] In some other cases, time t2 is a period of non-application of sound waves or radiation.

[0356] In still other cases, time t3 is a period of application of sound waves or radiation, the intensity, energy, power, or frequency of which is lower than that applied to the nanoparticles during times t1 or t2.

[0357] In some cases, the sequence may correspond to the application of sound or radiation for a time t1, followed by the non-application of sound or radiation for a time t2.

[0358] In some other cases, the sequence may apply sound waves or radiation during time t1, followed by another sound wave or radiation during time t3, where the sound waves or radiation applied during time t3 are of lower intensity, power, energy, or frequency than the sound waves or radiation applied during time t1.

[0359] In one embodiment of the present invention, time t1 is the duration of the heating step.

[0360] In one embodiment of the present invention, the heating step is one in which the temperature of the body part or the nanoparticles is increased.

[0361] In one embodiment of the present invention, the temperature increase in the heating step has at least one of the following properties: i) is greater in the presence of nanoparticles than in their absence; ii) t1 is greater than t2 or t3; iii) is greater than 10 -20 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 25, 50, 100, 200, 500, 10 3 , 10 5 or 10 9 °C or greater; iv) Leading to or characterized by an initial temperature rise, also called the initial slope of the temperature rise with time, ΔT / δt, 10 -40 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 2 , 10 3 or 10 5 °C / sec measured per gram of nanoparticle or body part, or cm of nanoparticle or body part 3v) The maximum temperature reached during the heating step is 25, 30, 37, 39, 41, 45, 50, 100, 10 °C / s or greater. 3 , 10 5 , 10 9 or 10 11 °C or less, or vi) at least 10 °C less than the temperature increase achieved by applying sound waves or radiation in the absence of nanoparticles. -5 , 10 -3 , 10 -1 , 1, 2, 5, or 10, 10 3 , 10 5 , or 10 9 °C or more.

[0362] In another embodiment of the invention, the temperature rise of the heating step has at least one of the following characteristics: i) is less than or equal to 10 50 , 10 9 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -1 , 10 -3 or 10 -5 °C or less, ii) 10 50 , 10 20 , 10 10 , 10 3 , 10 2 , 10, 5, 2, 1, 10 -1 , 10 -3 , 10 -5 , 10 -7 , 10 -10 , 10 -20 or 10 -40 Measured in °C / sec or per gram of nanoparticles or body part °C / sec or cm of nanoparticles or body part 3 iii) the maximum temperature reached during the heating step is less than 10°C / s; 11 , 10 9 , 10 5 , 10 3, 100, 50, 45, 41, 39, 37, 30, 25, 10, 5, 0, -100, -200 or -273°C or less; iv) the temperature rise is at least 10°C higher than that achieved by applying sound waves or radiation in the absence of nanoparticles. -50 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, or 10, 10 3 , 10 5 , or 10 9 °C lower, or v)10 100 , 10 40 , 10 20 , 10 5 , 10 3 , 10 2 , 10, 5, 2, 1, 10 -1 , 10 -3 , 10 -5 , 10 -7 , 10 -20 or 10 -40 °C / sec measured per gram of nanoparticle or body part, or cm of nanoparticle or body part 3 Become or be characterized by a ΔT / δt value less than 0.05°C / sec, measured per °C / sec.

[0363] In one embodiment of the present invention, the temperature rise or the initial gradient of this rise, in particular of the heating step, is measured or generated at: i) physiological temperature, ii) the temperature of the individual or body part during the heating step, iii) the cooling step, or iv) the temperature rise reached by applying sound waves or radiation to the body part without nanoparticles.

[0364] In one embodiment of the present invention, the temperature increase that is specifically generated or measured during the heating step is the temperature difference between the temperatures measured: i) after and before the application of the sound waves or radiation, ii) at the start and end of t1.

[0365] In some cases, the temperature rise specifically generated or measured during the heating step is 10 -20 , 10 -3 , 10 -2 , 10 -1, 1, 10, 10 2 , 10 3 or 10 5 °C.

[0366] In some other cases, the temperature rise specifically generated or measured during the heating step is greater than 10 20 , 10 5 , 10 3 , 10 2 , 10, 1, 10 -1 , 10 -2 or 10 -3 °C.

[0367] In still other cases, the temperature rise specifically generated or measured during the heating step is greater than 10 -50 and 10 50 , 10 -5 and 10 50 , 10 -1 and 10 10 , 10 -5 and 10 3 , or 10 -2 and 10 3 °C.

[0368] In still other cases, the temperature increase specifically generated or measured during the heating step is 10 times greater in the presence of nanoparticles than in their absence. -50 , 10 -20 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 2 , 10 3 or 10 5 °C higher.

[0369] In one embodiment of the present invention, a suitable range of magnitude of temperature increase is between 0°C and 36°C, as inferred from Table 2. In some cases, the maximum of this range (36°C) may be increased by, for example, 1, 5, 10, 20, 50, or 100°C or more, particularly when the temperature of the body part is increased, for example, by using devices or substances that increase the temperature of the body part, by increasing the intensity, power, or frequency of the sound waves, or by increasing the concentration of nanoparticles.

[0370] In one embodiment of the present invention, t2 and / or t3 = 0 seconds in the case of continuous application of sound waves or radiation.

[0371] In some cases, t1, t2, and / or t3 are selected so as to reach a temperature at the end of a total period n·(t1+t2) or n·(t1+t3) that is at least a factor of 1.00001, 1.1, 2, or 5 lower than the temperature reached at the end of the continuous application of sound waves or radiation of a duration n·t1, in particular, where the heating time of sound waves or radiation is the same for the sequential and continuous applications, and n is between 1 and 10. 100 is an integer.

[0372] The present invention also relates to nanoparticles for use according to the present invention, wherein the application of sound waves or radiation to the nanoparticles or to the body part preferably induces a temperature increase during at least one heating step, which is i) at the pathological site, -10 , 10 -5 , 10 -3 , 10 -1 , 1, 5 or 10°C, and / or ii) 10°C or more in healthy areas, especially surrounding the pathological area. 10 , 10 5 , 10 3 , 100, 50, 20, 10, 5, 2, 1, 10 -1 , 10 -5 or 10 -10 °C or less.

[0373] In another embodiment of the invention, the time t2 or t3 is the duration of the cooling step.

[0374] In one embodiment of the invention, the cooling step is a step in which the temperature of the body part is reduced. In some cases, the temperature reduction of the cooling step can be the magnitude or absolute value of this reduction.

[0375] In one embodiment of the present invention, the temperature drop in the cooling step has at least one of the following properties: i) is greater in the presence of nanoparticles than in their absence; ii) is greater between t2 or t3 than between t1; iii) is greater than 10 -20 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 25, 50, 100, 200, 500, 10 3 , 10 5 or 10 9 °C or greater, leading to or characterized by an initial temperature drop, also known as the initial slope of temperature drop with time, ΔT / δt, expressed in °C / sec, or °C / sec nanoparticle, or cm of body part. 3 When measured in °C / sec per 10 -40 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 2 , 10 3 or 10 5 v) The minimum temperature reached during the cooling step is -273, -150, -100, -75, -50, -30, -10, 0, 5, 10, 25, 30, 37, 39, 41, 45, 50, 100, 10 3 , 10 5 , 10 9 or 10 11 °C or higher, and vi) the temperature drop is at least 10°C lower than that achieved by non-application of acoustic waves in the absence of nanoparticles. -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 3 , 10 5 or 10 9°C greater, or vii) it is characterized by a ΔT / δt value, the value of which is °C / sec or °C / sec per gram of nanoparticle or body part, or cm of nanoparticle or body part. 3 Measured in °C / sec per 10 -40 , 10 -20 , 10 -10 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 2 , 10 3 or 10 5 Greater than.

[0376] In another embodiment of the invention, the temperature of the cooling step has at least one of the following properties: i) is lower in the presence of nanoparticles than in their absence; ii) is lower than 10 50 , 10 9 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -1 , 10 -3 or 10 -5 °C or less, iii) this is characterized by or results in a value of ΔT / δt, the value of which is expressed in °C / sec or °C / sec per gram of nanoparticle or body part, or cm of nanoparticle or body part. 3 Measured in °C / sec per 10 50 , 10 20 , 10 10 , 10 3 , 10 2 , 10, 5, 2, 1, 10 -1 , 10 -3 , 10 -5 , 10 -7 , 10 -10 , 10 -20 or 10 -40 iv) the minimum temperature reached during the cooling step is 10 11 , 10 9 , 10 5 , 10 3, 100, 50, 45, 41, 39, 37, 30, 25, 10, 5, 0, -100, -200 or -273°C or less; v) temperature drop at least 10°C less than that reached in the absence of nanoparticles. -50 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, or 10, 10 3 , 10 5 , or 10 9 °C lower, or vi) this will be or be characterized by a value of ΔT / δt, the value of which is in °C / sec or °C / sec per gram of nanoparticle or body part, or cm of nanoparticle or body part. 3 Measured in °C / sec per 10 100 , 10 40 , 10 20 , 10 5 , 10 3 , 10 2 , 10, 5, 2, 1, 10 -1 , 10 -3 , 10 -5 , 10 -7 , 10 -20 or 10 -40 Lower,

[0377] In one embodiment of the present invention, the temperature decrease, in particular the initial slope of the temperature decrease of the cooling step, is measured or generated by: i) the temperature of the individual or body part without the cooling step, before and after the cooling step, or ii) the temperature of the individual or body part during the heating step.

[0378] In one embodiment of the present invention, the temperature drop that is specifically generated or measured during the cooling step is the temperature difference between the temperatures measured between the start and end of t2 or t3.

[0379] In some cases, the temperature drop that occurs or is measured specifically during the cooling step is 10 -20 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 2 , 10 3 or 10 5It may be greater than °C.

[0380] In some other cases, the temperature drop that occurs or is measured specifically during the cooling step is 10 20 , 10 5 , 10 3 , 10 2 , 10, 1, 10 -1 , 10 -2 or 10 -3 It may be lower than °C.

[0381] In still other cases, the temperature drop that occurs or is measured specifically during the cooling step is 10 -50 and 10 50 , 10 -5 and 10 50 , 10 -1 and 10 10 , 10 -5 and 10 3 , or 10 -2 and 10 3 °C.

[0382] In still other cases, the temperature drop that occurs or is measured specifically during the cooling step may be: i) a temperature drop that is sometimes 10 times lower in the presence of nanoparticles than in the absence of nanoparticles; -50 , 10 -20 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 2 , 10 3 or 10 5 °C greater, and / or ii) in some other cases 10 °C greater in the presence of nanoparticles than in their absence. -50 , 10 -20 , 10 -5 , 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 2 , 10 3 or 10 5 °C lower.

[0383] In one embodiment of the present invention, the time t1 is the duration of the dissociation step, which is the step in which the compound dissociates from the nanoparticles.

[0384] In some cases, greater than 0.01, 0.1, 1, 5, 10, 25, 50, 75, 80 or 90% of the compound is or becomes dissociated from the nanoparticles, particularly during the dissociation step.

[0385] In other cases, no more than 100, 99, 90, 80, 75, 50, 20, 10, 5, 2, 1 or 0.1% of the compound is or becomes dissociated from the nanoparticles, particularly during the dissociation step.

[0386] In still other cases, particularly during the dissociation step, -1 Between 1 and 100, 1 and 99, 1 and 50, or 2 and 10% of the compound is or becomes dissociated from the nanoparticles.

[0387] This percentage is equal to the ratio of the number, concentration, or mass of compounds dissociated from the nanoparticles divided by the total number, concentration, or mass of compounds that have not dissociated from the nanoparticles and / or that have not attached to the nanoparticles.

[0388] In another embodiment of the invention, time t2 or t3 is the duration of a non-dissociation step, a step in which the compound does not dissociate from the nanoparticle.

[0389] In some cases, the percentage of compound dissociated or dissociated from the nanoparticles is greater than or equal to 1.00001, 1.1, 1.2, 1.5, 2, 5, 10, 10's ... 5 or 10 10 If the coefficient of dissociation is low, the compound does not dissociate from the nanoparticles.

[0390] In some cases, the value of t2 may be the same as the value of t1.

[0391] In one embodiment of the present invention, the time t1, t2, or t3 is 10 -3 , 10-2 , 10 -1 , 1, 10, 10 2 or 10 3 , 10 5 , 10 20 , 10 100 or 10 1000 In some cases, t1, t2, or t3 may be less than 10 minutes. -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 It will be less than a second.

[0392] In yet another embodiment of the present invention, the time t1, t2, or t3 is 10 -3 , 10 -2 , 10 -1 , 1, 10, 10 2 , or 10 3 longer than 10 minutes. In some cases, t1, t2, or t3 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -7 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 5 , 10 7 or 10 9 longer than a second.

[0393] In one embodiment of the present invention, the time t1, t2, or t3 is preferably at least 1.1, 1.5, 2, 5, 10, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000 times longer than the time of the pulse. 2 , 10 3 , 10 5 , 10 7 , 10 9 , 10 12 , 10 15 or 10 20 It is shorter by a factor of .

[0394] In yet another embodiment of the invention, the time t1, t2 or t3 is at least 1.1, 1.5, 2, 5, 10, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000 times longer than the time of the pulse. 2 , 10 3 , 10 5 , 10 7 , 10 9 , 10 12 , 10 15 or 10 20 It is long by a factor of .

[0395] In yet another embodiment of the invention, the pulse is an acoustic wave or radiation, in particular 10 6 , 10 3 , 1, 10 -3 , 10 -6 or 10 -9 It is defined as the application of power, energy, or intensity of sound waves or radiation to a nanoparticle or body part for a period of time shorter than 100 s.i.m.

[0396] In one embodiment of the present invention, the ratio t1 / t3 or t2 / t3 is 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 , 10 20 , 10 50 or 10 100 Smaller than.

[0397] In yet another embodiment of the present invention, the ratio t1 / t3 or t2 / t3 is 10 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 or 10 9 Greater than.

[0398] In one embodiment of the present invention, the acoustic or radiation intensity, energy, power, or frequency applied during t3 is at least 1.1, 1.3, 1.5, 2, 5, 10, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 1109, 1110, 1120, 1130, 2 , 10 3 , 10 5 , 10 7 or 10 9 low.

[0399] In one embodiment of the present invention, suitable ranges of values ​​are between 0.2 and 0.43 minutes for t1 and between 0.2 and 0.36 minutes for t2. The minimum and maximum values ​​of this range were predicted by sequentially exposing 500 μg of magnetosomes mixed in 100 μl of water to 1.5 W / cm2 sound waves at a frequency of 3 MHz and predicting the minimum and maximum values ​​of t1 and t2 between two different sequences, as described in Example 1(c).

[0400] In another embodiment of the present invention, the minimum value of the range of t1 or t2 values ​​may be, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This can reduce the amount of nanoparticles in a body part by a factor of, for example, 1.5, 2, 5, 10, 10 or more. 3 , 10 6 or 10 9 This can be achieved by reducing the diffusion of nanoparticles away from the body part or the decomposition of nanoparticles between different sequences by reducing the power, intensity, or frequency of the acoustic waves by a factor of, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This can also be achieved by increasing the absorption by a factor equal to or greater than the nanoparticle absorption factor. This can be achieved by reducing the absorption in the body parts that do not contain the nanoparticles, and in particular by reducing the temperature fluctuations that result from this absorption. For t1 and t2, this can be achieved by using devices, materials, in particular compounds or nanoparticles, that heat the body part (to determine the effect on t1) or cool the body part (to determine the effect on t2).

[0401] In another embodiment of the present invention, the maximum value of the range of values ​​of t1 or t2 may be, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This means that the amount of nanoparticles in the body part can be increased by a factor of, for example, 1.5, 2, 5, 10, 10 or more due to increased nanoparticle diffusion from the body part or increased nanoparticle degradation between different sequences. 3 , 10 6 or 10 9 This is achieved by reducing the power, intensity, or frequency of the sound waves by a factor of, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This can also be achieved by increasing the absorption in parts of the body that do not contain the nanoparticles, and in particular by increasing the temperature change that results from this absorption. In the case of t1 and t2, this can be achieved by using a device or substance that heats (to determine the effect on t1) or cools (to determine the effect on t2) a body part that is specifically different from the compound or nanoparticles.

[0402] In some cases, the sequence of heating, cooling, dissociating, or non-dissociating steps, in particular of duration t1, t2, or t3, in particular of duration t1+t2 or t1+t3, may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 250, 500, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 Can be repeated more than once.

[0403] In some cases, the treatment is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 250, 500, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 The above sequences may be included.

[0404] In some other cases, the treatment is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 250, 500, 10 2 , 10 3 , 10 5 , 10 7 or 10 9 It may include the following sequence:

[0405] In one embodiment of the present invention, the time t1, t2, or t3 is 99.9, 99, 90, 75, 50, 25, 10, or 10 seconds between the two sequences. -1 In some cases, this percentage variation can be estimated as (t1 - t1') / t1, the absolute value of (t2 - t2') / t2, or (t3 - t3') / t3, where t1 and t1', t2 and t2', or t3 and t3' are the durations of two different heating / dissociation or cooling / dedissociation steps belonging to two different sequences.

[0406] In one embodiment of the present invention, the suitable ratio of (t1-t1') / t1 ranges from 5% to 43%, and the suitable ratio of (t2-t2') / t2 ranges from 5% to 44%. The minimum and maximum values ​​of these ranges are determined by the minimum and maximum values ​​of the magnetosomes at 1.5 W / cm2 for 500 μg of magnetosomes mixed in 100 μl of water, as described in Example 1(c). 2 and frequency 3 MHz, and the minimum and maximum variations in t1 and t2 values ​​between two different sequences are predicted.

[0407] In one embodiment of the present invention, the duration (t1+t2) or (t1+t3) is 99.9, 99, 90, 75, 50, 25, 10 or 10 between two different sequences. -1 In some cases, this percentage variation can be estimated as the absolute value of [(t1+t2)-(t1+t2)'] / (t1+t2), or [(t1+t3)-(t1+t3)'] / (t1+t3), where (t1+t2) and (t1+t2)', or (t1+t3) and (t1+t3)', are the durations of two different sequences.

[0408] In one embodiment of the present invention, a suitable range for the percentage [(t1 + t2) - (t1 + t2)'] / (t1 + t2) is between 2% and 35%. The minimum and maximum values ​​of this range can be estimated by sequentially exposing 500 μg of magnetosomes in 100 μl of water to acoustic waves of 1.5 W / cm2 and a frequency of 3 MHz, as described in Example 1(c), and determining the minimum and maximum variation in the (t1 + t2) values ​​between two different sequences.

[0409] In another embodiment of the invention, the values ​​(t1-t1') / t1, (t2-t2') / t2, [(t1+t2)-(t1+t2)'] / (t1+t2) are, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This can be achieved by reducing the amount of magnetosomes in the body part by a factor of, for example, 1.5, 2, 5, 10, 10, or 10, by decreasing the diffusion of nanoparticles from the body part or the degradation of nanoparticles between different sequences. 3 , 10 6 or 10 9 This can be achieved by increasing the power, intensity, or frequency of the sound waves by a factor of 1.5, 2, 5, 10, 10 or more. 3 , 10 6 or 10 9 This can be achieved by reducing absorption in parts of the body that do not contain nanoparticles, and in particular by reducing the temperature rise that results from this absorption.

[0410] In another embodiment of the invention, the maximum value of the range given by the values ​​of (t1-t1') / t1, (t2-t2') / t2, [(t1+t2)-(t1+t2)'] / (t1+t2) can be increased, for example, to 50, 70, 80, 90, 95, 99 or 99.9%, which allows for the reduction of the amount of nanoparticles, for example, 1.5, 2, 5, 10, 10% by reducing the diffusion of nanoparticles away from the body part or the degradation of nanoparticles between different sequences. 3 , 10 6 or 10 9This can be achieved by reducing the power, intensity, or frequency of the sound waves by a factor of, for example, 1.5, 2, 5, 10, 10 3 , 10 6 or 10 9 This can be achieved by increasing the absorption in the body parts that do not contain nanoparticles, and in particular by increasing the temperature rise that results from this absorption.

[0411] In one embodiment of the invention, the treatment is 1, 2, 5, 10 or 10 3 The present invention can include more than one session, including: i) 1, 5, 10, or more than 100 sequences; ii) a series of heating or dissociation steps followed by a cooling or non-dissociation step.

[0412] In some cases, sessions are 1, 5, 10, 20, 50, 10 2 , 10 3 or 10 5 It can last for more than a minute.

[0413] Otherwise, the session is 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , may last for 10, 5, 2 or 1 minute or less.

[0414] In still other cases, each session is 1, 5, 10, 10 2 , 10 3 , 10 5 , 10 10 or 10 50 They can be separated over the course of minutes or more.

[0415] In still other cases, each session is 50 , 10 10 , 10 5 , 10 3 , 10 3 , 10 2 , 10, 5, or 1 minute or less.

[0416] The time lapse separating the two sessions is more important than times t1, t2, t3, t1+t2, or t1+t3, especially at 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 20, 50, 100, 10 3 , 10 5 or 10 9 It is long by the above factor.

[0417] The present invention also relates to an acoustic or radiation treatment, in which acoustic waves or radiation are applied to a nanoparticle or a body part, in particular sequentially, in particular spatially sequentially, in which: i) the acoustic waves or radiation are applied to a volume V1; ii) the nanoparticle or body part is contained in a volume V2, V2 being smaller than V1. In some cases, volume V2 is 1.0001, 1.1, 1.2, 2, 5, 10 ... 3 , 10 5 or 10 20 with a factor a greater than or equal to 10 -5 , 10 -1 , 1, 5, 10, 10 3 or 10 5 nm 3 or cm 3 It may be smaller by a larger factor or volume. In some other cases, the volume V2 is smaller than V1 by 10 20 , 10 5 , 10, 5 or 2 with a factor a smaller than 10 100 , 10 50 , 10 10 , 10 5 , 10 3 , 10, 1 or 10 -5 nm 3 or cm 3 a smaller factor or 10 100 , 10 50 , 10 10 , 10 5 , 10 3 , 10, 1 or 10 -5 nm 3 or cm 3 In some other cases, the volume V2 can be smaller than V1 by 1.0001 and 10.20 , 1.2 and 10 10 , or 2 and 10 5 or 10 with a coefficient a between -5 and 10 100 , 10 -1 and 10 10 , or 1 and 10 5 nm 3 or cm 3 The volume between the two can be smaller.

[0418] In one embodiment of the present invention, sound waves or radiation are applied to the nanoparticles or body parts, in particular, when or where: - First, the sound waves or radiation are applied within an area, volume, surface or length that is larger than the area, volume, surface or length containing the nanoparticles; - Second, the area, volume, surface or length containing the nanoparticles absorbs the sound waves or radiation, causing a temperature increase or resulting in anti-tumor activity or destruction of the body part, pathological cells or tumor cells within the area, volume surface or length that does not contain the nanoparticles.

[0419] In yet another embodiment of the present invention, the heating, cooling, dissociation or de-dissociation step is particularly advantageous in that the nanoparticle region is within 10 of the acoustic or radiating volume. 20 , 10 10 , 10 5 , 10 3 , 90, 70, 50, 20, 10, or 1% or less of the sound wave or radiating volume 20 , 10 10 , 10 5 , 10 3 , 90, 70, 50, 20, 10 or 1% or less. These percentages are the ratios of i) the volume in which the heating, cooling, dissociation or de-dissociation step occurs to the sonic volume, or ii) the volume containing the nanoparticles to the sonic or radiating volume.

[0420] The present invention also relates to an acoustic or radiation treatment, in which acoustic waves or radiation are applied to nanoparticles or body parts in a sequential, in particular spatially sequential manner, where i) the acoustic waves or radiation are applied to a volume V1, and ii) the nanoparticles or body parts are contained in a volume V2, V2 being larger than V1. In some cases, volume V2 is 1.0001, 1.1, 1.2, 2, 5, 10 ... 3 , 10 5 or 10 20 with a factor a greater than or equal to 10 -5 , 10 -1 , 1, 5, 10, 10 3 or 10 5 nm 3 or cm 3 In some other cases, the volume V2 may be larger than V1 by a factor of 10 or more. 20 , 10 5 , 10, 5 or 2 with a factor a smaller than 10 100 , 10 50 , 10 10 , 10 5 , 10 3 , 10, 1 or 10 -5 nm 3 or cm 3 It may be larger by a smaller factor or volume. In some other cases, the volume V2 is 1.0001 and 10 times larger than V1. 20 , 1.2 and 10 10 , or 2 and 10 5 or 10 with a coefficient a between -5 and 10 100 , 10 -1 and 10 10 , or 1 and 10 5 nm 3 or cm 3 It can be larger by a factor or volume between .

[0421] In another embodiment of the invention, sound waves or radiation are sequentially applied to nanoparticles or body parts in the following cases or locations: - first, within an area, volume, surface, or length that is smaller than the area, volume, surface, or length containing the nanoparticles; - second, within an area, volume, surface, or length containing the nanoparticles that is not exposed or irradiated with sound waves, causing a temperature increase or resulting in anti-tumor activity or destruction of the body part, pathological or tumor cells, whereby the effects induced by the application of sound waves to nanoparticles, such as cavitation, nanoparticle movement, temperature increase, etc., are transmitted via mechanisms from the nanoparticles exposed to sound waves to the nanoparticles that are not exposed to sound waves.

[0422] In another embodiment of the present invention, in particular, the nanoparticle region is 10 1 / 2 of the acoustic wave volume. -10 , 10 -5 , 10 -1 , 1, 10, 20, 50, 70, 90, 10 3 , 10 5 , 10 10 or 10 20 % or more, the heating, cooling, dissociation, or de-dissociation steps are particularly -10 , 10 -5 , 10 -1 , 1, 10, 20, 50, 70, 90, 10 3 , 10 5 , 10 10 or 10 20 This is done at % or more.

[0423] The present invention also relates to an acoustic or radiation treatment, in which acoustic waves or radiation are applied to a nanoparticle or a body part in a continuous, in particular spatially continuous manner, i) the acoustic waves or radiation are applied to a volume V1, ii) the nanoparticle or the body part is contained in a volume V2, and V2 is equal to or is identical to V1. In some cases, volume V2 is 1.0001, 1.1, 1.2, 2, 5, 10, 10's or 10's away from V1. 3 , 10 5 or 10 20 It can be similar to or equal to V1 by a factor a greater than or not changed by a factor of 10. -5, 10 -1 , 1, 5, 10, 10 3 or 10 5 nm 3 or cm 3 It is a much larger volume.

[0424] In one embodiment of the present invention, the heating, cooling, dissociation, or de-dissociation step is performed within the nanoparticle region or within 10 of the nanoparticle region. -9 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 20, 50, 70, 10 9 , 90 or 99% or more, and notably not occurring outside this region. This percentage is the ratio of the volume in which the heating, cooling, dissociation, or non-dissociation steps occur to the volume of the nanoparticle region.

[0425] In one embodiment of the present invention, when sound waves or radiation are applied to the nanoparticles or the body part, the generation or generation of heat, radicals or reactive species, bubbles, cavitation, or cavitation bubbles by the nanoparticles occurs, in particular, in volume V2 and in particular not in volume V1, or in particular in volume V2 rather than volume V1, in particular with the following coefficients a: i) 1.0000001, 1.1, 1.2, 1.5, 2, 5, 10, 10 3 or 10 5 ii) greater than 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 10, 5, 2, 1.2 or 1.000001, iii) 1.000001 and 10 100 , or 1.1 and 10 5 Yet other cases between.

[0426] As the case may be, the volumes V2 and / or V1 are assimilated and replaced by i) the surfaces S2 and / or S1, or ii) the lengths L2 and / or L1, respectively.

[0427] In one embodiment of the present invention, the sonic intensity, sonic power, sonic power density, sonic energy, sonic energy density, radiant energy, radiant energy density, radiant intensity, radiant power, or radiant power density applied during t1 or t3 in particular is 10 100 , 10 50 , 10 20 , 10 9 , 10 6 , 10 3 , 100, 10, 1, 10 -1 , 10 -2 or 10 -5 W or W / cm or W / cm 2 or W / cm 3 or W·sec or W·sec / cm or W·sec / cm 2 or W·sec / cm 3 Lower.

[0428] In one embodiment of the present invention, the sonic intensity, sonic power, sonic power density, sonic energy, sonic energy density, radiant energy, radiant energy density, radiant intensity, radiant power, or radiant power density applied during t1 or t3 in particular is 10 -100 , 10 -50 , 10 -20 , 10 -9 , 10 -6 , 10 -2 , 1, 10, 110 2 or 10 5 W or W / cm or W / cm 2 or W / cm 3 or W·sec or W·sec / cm or W·sec / cm2 or W·sec / cm 3 Greater than

[0429] In one embodiment of the present invention, the frequency of the sound waves or radiation applied during t1 or t3 is 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 1, 10 -3 , 10 -6 , 10 -9 or 10-20 Lower than GHz.

[0430] In another embodiment of the invention, the frequency of the sound waves or radiation applied during t1 or t3 is 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 10 3 , 10 6 , 10 9 or 10 20 Higher than GHz.

[0431] In some cases, the sound waves or radiation are measured per cell or mm of the body part. 3 on a per 10 basis -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 or 10 20 The following applies to nanoparticles or mg of nanoparticles:

[0432] In some other cases, sound waves or radiation are measured cell by cell or mm of body part. 3 10 per -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 , or 10 20 Applies to nanoparticles or mg of nanoparticles.

[0433] In another embodiment of the invention, when sound waves or radiation are applied to the nanoparticles or the body part, it results in: i) an increase in the temperature of the nanoparticles or the body part, ii) dissociation of compounds from the nanoparticles, iii) destruction or growth inhibition of cells particularly belonging to the body part, in particular pathological or tumor cells, iv) death, destruction, denaturation, reduction or inactivation of biological material particularly belonging to the pathological site or body part, v) movement or vibration of the nanoparticles, vi) pressure exerted on the body part or nanoparticles, vii) absorption of the sound waves or radiation by the nanoparticles, or viii) internalization of the nanoparticles in cells.

[0434] In one embodiment of the present invention, cells, preferably mm of a body part, are 3 or cm 3 1, 10, 10 per 3 , 10 6 , 10 9 or 10 20 Destruction or growth inhibition of more than one cell is possible by adapting or adjusting the frequency, intensity, energy, or power of the sound waves or radiation.

[0435] In one embodiment of the present invention, the acoustic waves or radiation induces movement or vibration of the nanoparticles when the mass of the nanoparticles is: i) 10 per nanoparticle; -50 , 10 -5 , 10 -1 or greater than 1 μg, or ii) 10 per nanoparticle. 20 , 10 10 , 10 5 , 10 3 , 10 2 , 1, 10 -3 , or 10 -5 In other cases smaller than μg, the acoustic waves may induce greater or lesser movement or vibration in the nanoparticles than other substances, atoms, ions that are not located or aggregated within the nanoparticles, particularly surrounding the nanoparticles.

[0436] In one embodiment of the present invention, the sound waves or radiation exert pressure on the nanoparticles or body parts, which may be i) in particular on the body part cm 3 10 per -9, 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 or 10 9 may be greater than MPa, or ii) particularly in body parts cm 3 10 per -9 , 10 -5 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 or 10 9 It may be below MPa.

[0437] In one embodiment of the present invention, the acoustic energy is absorbed by the nanoparticles, particularly by a factor of at least 1.1, 2, 5, 10, 25, 50 or 100, more than by other substances, atoms, ions that are not disposed or assembled on or contained in the nanoparticles, particularly surrounding the nanoparticles or belonging to the body part, and in some cases by a factor of at least 10, more than by other substances or regions outside the nanoparticle region. -9 , 10 -6 , 10 -3 , 1, 2, 5, 10 or even 20°C greater temperature increases may occur.

[0438] In one embodiment of the present invention, the internalization of nanoparticles into cells, particularly per cell or mm of a body part, is 3 10 per -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 , or 10 20 Cellular internalization of more than one nanoparticle or mg is possible by adapting or adjusting the frequency, intensity, energy, application time or power values ​​of the sound waves or radiation.

[0439] In one embodiment of the present invention, the internalization of nanoparticles into cells, per cell or mm of a body part is 3 Around 10, especially -6 , 10-3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 or 10 20 Internalization of more than 10 nanoparticles or mg of nanoparticles is prevented by adapting or adjusting the frequency, intensity, energy, application time, or power of the sound waves or radiation to values ​​different from those in the previous embodiment.

[0440] In another embodiment of the present invention, the sound waves or radiation when applied to the nanoparticles or body part does not result in destruction or growth inhibition of cells, especially healthy cells.

[0441] In one embodiment of the present invention, cells, preferably healthy cells, preferably 1, 10, 10 of these cells 3 , 10 6 , 10 9 or 10 20 Destruction or growth inhibition of cells beyond this range is prevented by adapting or adjusting the frequency, intensity, energy, application time, or power of the sound waves or radiation.

[0442] In one embodiment of the present invention, the acoustic treatment or its effectiveness, or the destruction or treatment or volume reduction of a tumor, body part, or pathological site, is due to or associated with a treatment mechanism, particularly a treatment mechanism, which in some cases specifically occurs when acoustic waves or radiation are applied to the nanoparticles or body part, and specifically does not occur when acoustic waves or radiation are not applied to the nanoparticles or body part.

[0443] In one embodiment of the present invention, the mechanism of treatment, and in particular the onset or initiation of this mechanism, includes, results from, or is associated with: i) preferential temperature increase of a body part or nanoparticle, ii) generation or production of radicals or reactive species by the nanoparticle, in particular radical oxygen species (ROS), iii) dissociation of the compound from the nanoparticle, iv) preferential pharmaceutical effect of the compound, v) metabolic effect, or vi) cavitation.

[0444] In one embodiment of the present invention, cavitation involves the generation of gas bubbles. In some cases, cavitation induces mechanical stress on cells, particularly cell membranes, leading to cell death. In the presence of nanoparticles, the size and number of gas bubbles can be altered. They can be 1.5, 2, 10, 100, 10 3 or 10 9 In some cases, the size and number of bubbles tend to be close to the size and number of nanoparticles exposed to the sound waves or radiation, and / or the size and number of these nanoparticles may be greater than or less than 10 9 , 10 5 , 10 3 , 10 2 or differ by a factor of 10 or less.

[0445] In another embodiment of the invention, the mechanism that specifically follows or results from the initiation or initiation of this treatment mechanism is involved in or results from or is related to: i) activation of the immune system or such system preferentially on body parts, ii) preferential apoptotic mechanisms of pathological cells, iii) indirect mechanisms, or stander effects. In some cases, it is 1, 5, 10, 10's from the beginning or initiation of this mechanism. 3 , 10 5 or 10 10 occurs after more than a second.

[0446] In some cases, indirect mechanisms or stander effects may involve, result from, or be associated with the destruction of pathological cells located distant from the nanoparticle or nanoparticle region: i) 5, 2, 1, 10 -1 , 10 -3 , 10 -3 , 10 -6 or 10 -9 closer than m, ii) 10 -1 , 1, 5, 10, 10 3 or 10 5 nm, or iii) in some other cases 10 -1 and 10 20 nm, or 1 and 10 10nm, or 1 and 10 5 Between nm.

[0447] In some cases, the mechanism of treatment may involve, result from, or be related to the direct effects of the nanoparticles, particularly immune or bystander effects, or to specifically exclude some effects that may induce destruction of pathological or tumor cells, or at a distance from the nanoparticles, such as 1, 10, 10's of nanoparticles. 3 , 10 5 , 10 10 , 10 20 , 10 50 or 10 100 At distances especially greater than nm, the volume of the body part decreases.

[0448] In one embodiment of the present invention, the treatment mechanism, particularly during at least one session or sequence, is: i) activated by an initial application of sound waves or radiation, ii) reactivated by reapplication of sound waves or radiation, or iii) deactivated by ceasing application of sound waves or radiation following activation or reactivation.

[0449] In one embodiment of the present invention, the radiation, sound waves, and nanoparticle parameters are: i) power, intensity, strength, frequency, energy of the sound waves or radiation, ii) volume or body part exposed to the sound waves or radiation, iii) time of application of the sound waves or radiation, iv) time t1, t2, or t3, v) duration of the sequence or session, vi) time separating two sequences or sessions, and or vii) nanoparticle characteristics such as concentration, tissue, distribution, size, composition of the nanoparticles.

[0450] In other cases, the radiation, acoustic, or nanoparticle parameters are adjusted, fixed, optimized, long enough or large, small enough or low, or set to specific values ​​selected to achieve at least one of the following treatment parameters, particularly the desired treatment parameters: i) the mechanism of treatment, ii) the desired or specific level of cavitation, iii) the desired or specific level or concentration of radicals or reactive species such as radical oxygen species (ROS), iv) the desired or specific level of apoptosis or apoptotic cells, v) the desired or specific temperature during the heating step, vi) the desired or specific proportion of dissociated compound during the dissociation step, vii) the desired or specific temperature during the cooling step, viii) the desired or specific proportion of dissociated compound during the non-dissociation step.

[0451] In one embodiment of the present invention, the desired treatment parameters are those treatment parameters that one wishes to reach during treatment. -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 50, 100, 10 4 , 10 5 or 10 10 In some other cases, the treatment parameters are different from those achieved by applying nanoparticles or body parts at 10% or less. -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 5, 10, 50, 100, 10 4 , 10 5 or 10 10 % or more different from the treatment parameters achieved by applying sound waves or radiation. In still other cases, the percentage may be the ratio between the desired treatment parameters and the treatment parameters achieved by applying sound waves or radiation to the nanoparticles or body part.

[0452] In some cases, at least one treatment parameter is, in particular, at least 1, 1.2, 1.5, 2, 5, 10, 10 2 , 10 3 , 10 5 , 10 9 or 10 20 may be higher or larger during t1 than during t2 or t3 by a factor equal to

[0453] In some cases, the cavitation can result in bubbles or cavitation bubbles. In some other cases, the radicals or reactive species or bubbles are associated with or can be compounds.

[0454] In other cases, the radical or reactive species or bubble is not a compound.

[0455] In some cases, the desired temperatures during the heating step are 0, 5, 10, 25, 30, 37, 39, 41, 45, 50, 100, 10 3 or 10 5 °C or higher.

[0456] In some cases, the desired temperature during the heating step is 10 5 , 10 3 , 100, 50, 45, 41, 39, 37, 30, 25, 30 or lower than 37°C.

[0457] In still other cases, the desired temperatures during the heating step are between -273 and 10 10 , 0 and 10 3 , or between 10 and 100°C.

[0458] In one embodiment of the present invention, a suitable range of desired temperature values ​​is between 41°C and 100°C, with 41°C being the minimum value capable of eliciting therapeutic effects, particularly antitumor activity, and 100°C being the boiling temperature of water, which constitutes the majority of the body part. In some cases, the minimum value of this range (41°C) can decrease by 1, 5, 10, 50, 100, 150, 200, or 250°C or more, for example, when the body part cools. In some other cases, the maximum value of this range (100°C) can increase, for example, when the body part does not contain primarily water, or when the body part is heated, when the intensity or frequency of the acoustic waves increases, or when the concentration of magnetosomes or nanoparticles increases.

[0459] In some cases, the desired percentage of dissociated compound during the dissociation step can be 0.1, 1, 5, 10, 25, 50, 75, or 90% or more.

[0460] In some other cases, the desired percentage of dissociating compound during the dissociation step may be lower than 100, 90, 75, 50, 25, 10, 5, 1 or 0.1%.

[0461] In still other cases, the desired percentage of dissociated compound during the dissociation step may be between 0 and 100%, 0.1 and 99%, or 5 and 75%.

[0462] In some cases, the desired temperature during the cooling step is 10°C lower than the temperature of the heating step. -5 , 1, 5, 10 3 or 10 5 °C or more lower.

[0463] In some other cases, the desired temperature during the cooling step is 10°C lower than the temperature of the heating step. 5 , 10 3 , 5, 1 or 10 -5 Low below °C.

[0464] In some cases, the desired rate of dissociation of the compound is 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 75, 80, 90, or 99% or more lower during the non-dissociation step than the dissociation step.

[0465] In still other cases, the desired rate of dissociation of the compound is no more than 100, 90, 80, 75, 50, 25, 10, 5, 2, 1, 0.1, 0.01, or 0.001% lower during the non-dissociation step than during the dissociation step.

[0466] In one embodiment of the present invention, in order to reach a desired temperature during the heating step or a desired level of dissociated compounds during the dissociation step, the following may be increased, particularly by a factor b, particularly between time t2 or t3 and time t1: i) the power, intensity, strength, frequency, energy of the sound waves or radiation; ii) the volume or body part exposed to the sound waves or radiation; iii) the application time of the sound waves or radiation; and / or iv) the nanoparticle concentration.

[0467] In one embodiment of the present invention, in order to reach a desired temperature during the cooling step or a desired level of dissociated compound during the non-dissociation step, the following may be reduced, particularly by a factor b, particularly between time t1 and time t2 or t3: i) the power, intensity, strength, frequency, energy of the sound waves or radiation, ii) the volume or body part exposed to the sound waves or radiation, and or iii) the time of application of the sound waves or radiation.

[0468] In some cases, b is 1.00001, 1.0001, 1.001, 1.01, 1.1, 1.2, 1.5, 2, 5, 10, 10 3 , 10 5 , 10 10 , 10 20 or 10 40 It can be bigger.

[0469] Otherwise, b is 10 50 , 10 20 , 10 10 , 10 5 , 10 3, 10, 5, 2, 1.5, 1.2, 1.1, 1.01, 1.001, 1.000 or 1.00001.

[0470] In still other cases, b is between 1.00001 and 10 50 , 1.1 and 10 5 , or 1.2 and 10 3 It can be between.

[0471] The present invention also relates to nanoparticles for use in sonic or radiation treatment or treatment of a body part of an individual, the treatment involving or comprising at least one of the following steps: - preparation of a suspension or composition of nanoparticles, preferably of a stability and concentration great enough to allow treatment of the body part (step 1), - administration of the nanoparticles to the body part or individual (step 2), - targeting the nanoparticles to the body part (step 3), - detection or imaging of the nanoparticles (step 4), - detection or imaging of the body part, in particular containing the nanoparticles (step 5), - application of sound waves or radiation to the nanoparticles (step 6), - removal of the body part, in particular by surgery (step 7), - treatment of the body part using a therapy other than sonic or radiation treatment, for example using surgery or chemotherapy (step 8).

[0472] In one embodiment of the present invention, the temperature, preferably the temperature of the body part or the nanoparticles, is measured during steps 1 to 8, preferably during, before or after step 6.

[0473] In one embodiment of the present invention, some of steps 1 through 8 follow each other in the order shown or in any other order.

[0474] In one embodiment of the present invention, the treatment method, particularly step 4 or 5, uses imaging of the body part, particularly using imaging techniques such as magnetic resonance imaging (MRI), computed tomography (CT), scanners, positron emission tomography (PET), X-rays, or ultrasound, to track the evolution or growth of the body part, particularly after treatment. In some cases, the concentration of nanoparticles is too large to allow efficient imaging of the body part. In some cases, the nanoparticles may act like a screen or obscure the body part, preventing efficient imaging of the body part. In some cases, the composition of the nanoparticles is adjusted or modified to enable imaging of the body part. To enable imaging of the body part or treatment, the following actions may be performed: i) the iron oxide composition may be replaced by a compound containing other substances selected from the following: lithium, beryllium, scandium, titanium, vanadium, chromium, manganese, iron, nickel, copper, zinc, boron, carbon, nitrogen, oxygen, fluorine, or helium group, or alkali metals, or alkaline earth metals, or hard metals, or triels, or tetraels, or penteles, or pnictogens, or chalcogens, or halogens, or noble gases, or ii) the concentration of nanoparticles is, in particular, 10 -20 , 10 -9 , 10 -6 , 10 -3 , 10 -1 , 1, 10, 10 3 , 10 6 , 10 9 or 10 20 cm 3 per mg or cm of body part 3 It is reduced to less than mg per unit weight.

[0475] Preferably, the radiation or sound waves according to the present invention generate radicals or reactive species, especially when they are applied to nanoparticles or magnetosomes.

[0476] The present invention also relates to nanoparticles for use in preventing the sequential application of sound waves or radiation to a body part or nanoparticle from reducing the temperature of the body part or nanoparticle.

[0477] In one embodiment of the present invention, when sound waves or radiation are applied to a body part or nanoparticles, preferably under conditions relating to nanoparticle concentration, frequency, power, and / or energy of the applied sound waves, sequential application of sound waves or radiation that prevents temperature reduction will prevent temperature reduction, while continuous application of sound waves or radiation will not prevent such temperature reduction.

[0478] In some cases, the magnitude of the temperature drop prevented is cm of body part per minute. 3 0, 10 measured per gram of nanoparticles or per gram of nanoparticles -50 , 10 -20 , 10 -10 , 10 -5 , 10 -1 , 1, 5, 10 or 10 2 It can be greater than °C.

[0479] In some other cases, the magnitude of the temperature drop prevented is particularly significant, especially in minutes and cm of body parts. 3 per gram of nanoparticles, or 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 10, 5, 2, 1, 10 -1 or 10 -2 °C.

[0480] In still other cases, the magnitude of the temperature drop prevented is particularly 3 per gram of nanoparticles, or 10 -50 and 10 50 , 10 -20 and 10 20 , 10 -10 and 10 10 , or 10 -3 and 10 3 The temperature may be between 100°C and 200°F.

[0481] The optimum temperature drop is approximately 2°C for a magnetosome concentration of 500 μg / mL and sonication at 100 W / cm for 12 min. 2 A greater increase in temperature drop can be achieved by increasing i) magnetosome concentration above 500 μg / mL, ii) acoustic frequency above 1 MHz, and / or iii) 100 mW / cm 2 Sonic power exceeding.

[0482] The present invention also relates to the use of nanoparticles according to the invention, wherein the application of sound waves or radiation to the nanoparticles generates or produces radicals or reactive species.

[0483] The present invention also relates to a method for generating reactive species or radicals by nanoparticle or sonic treatment, wherein: i) radioactive or sonic waves are sequentially applied to nanoparticles, ii) the nanoparticles are degraded, and / or iii) the nanoparticles are magnetosomes.

[0484] In some cases, the nanoparticles are degraded by cells, body parts, organelles, or lysosomes, particularly when dissolved, degraded, and / or decrystallized.

[0485] The present invention also relates to sonic or radiation treatment according to the invention for the generation of reactive species or radicals by nanoparticles.

[0486] In some cases, sonication or radiation treatment can be a method for or include the generation of reactive species or radicals by nanoparticles.

[0487] In one embodiment of the present invention, the reactive species or radicals are superoxide, oxygen radical, hydroxyl, alkoxy radical, peroxy radical, nitric oxide, nitric oxide, and nitrogen dioxide.

[0488] In one embodiment of the present invention, the reactive species or radicals are associated with, derived from, extracted from, or generated by HO. In some cases, the reactive species or radicals may be a derivative of HO, or the result of a transformation of HO, or the result of a chemical reaction involving HO.

[0489] In one embodiment of the present invention, the radicals or reactive species are free when dissociated or dissociated from the nanoparticles. In some cases, the radicals or reactive species are compounds that specifically dissociate from the nanoparticles upon application of radiation or sound waves to the nanoparticles or body part.

[0490] In one embodiment of the present invention, the production or generation of radicals or reactive species, particularly by nanoparticles, is related to or leads to or produces: i) the effectiveness of the sonic treatment, ii) is related to or leads to the destruction of a body part, and / or iii) a reduction in the volume of a body part.

[0491] In one embodiment of the present invention, the generation or production of reactive species or radicals, especially by nanoparticles, especially when radiation or sound waves are applied to the nanoparticles, is caused by or associated with: i) degradation of the nanoparticles, especially by biological materials, cells, organelles; ii) degradation of the nanoparticles, especially by biological materials, cells, organelles; -5 , 10 -3 , 1, 5, 10, 50, or 75%, or more, where this percentage is the ratio between the size of the nanoparticles following sonication and the size of the nanoparticles before sonication, in particular from a size of greater than 1, 5, 10, 50, 75, or 100 nm before sonication to a size of greater than 10, 5, 10, 50, 75, or 100 nm after sonication. 5 , 10 3 , 10 2 , to a size smaller than 50, 20, 10, 5, 2 or 1 nm, or iii) the generation or release or dissociation from the nanoparticles of compounds or free ions such as free oxygen, nitrogen, iron, etc.

[0492] The present invention also relates to a method for generating reactive species or radicals, or sonomedical treatment, or radiomedical treatment, for: i) treating a disease involving radio- or sonoresistant cells, ii) destroying or killing at least one radio- or sonoresistant cell specifically contained in a body part, or iii) reducing the volume of a body part.

[0493] In some cases, radioresistant cells may be cells that are not destroyed when irradiated in the absence of nanoparticles, but are destroyed when irradiated in the presence of nanoparticles. Similar radiation, radiation output, radiation intensity, and / or radiation frequency may be applied to a particular nanoparticle or body part, allowing for comparison of cell destruction or death in the presence and absence of the particular nanoparticle.

[0494] In some cases, sonoresistant cells may be cells that are not destroyed when sound waves are applied to them in the absence of nanoparticles, but are destroyed when sound waves are applied to them in the presence of nanoparticles. The same or similar sound waves, sound power, sound intensity, and / or sound frequency are applied to a particular nanoparticle or body part, particularly allowing for a comparison of cell destruction in the presence and absence of nanoparticles.

[0495] The present invention also relates to a method for generating radicals or reactive species, or sonication, which radicals or reactive species: i) destroy pathological cells, tumor cells, bacteria, viruses, or pathological sites, and / or ii) do not destroy healthy cells, non-pathological cells, non-tumor cells, healthy sites, or cells belonging to healthy individuals.

[0496] The invention also relates to the use of nanoparticles according to the invention, which induce the destruction of a pathological site in a body part without the destruction of healthy sites particularly surrounding the pathological site.

[0497] In some cases, the nanoparticles are 1, 10, 10 3 , 10 6 , 10 9 or 10 15Destruction of more than 1, 10, 10 pathological cells, and / or 3 , 10 6 , 10 9 or 10 15 It can cause the destruction of healthy cells by: In some cases, radicals or reactive species generate oxidative stress, leading to the destruction or death of cells, especially pathological cells, especially tumor cells, bacteria, or viruses.

[0498] The present invention also relates to a method for generating radicals or reactive species or sonic treatment, wherein the amount or concentration of radicals or reactive species produced or generated, particularly by nanoparticles, is higher when the radiation or sonic waves are applied to the nanoparticles or body part sequentially than when the radiation or sonic waves are applied to the nanoparticles or body part continuously, particularly by a factor a. In some cases, the factor a is greater than or equal to: i) 1.0001, 1.1, 1.2, 1.5, 2, 5, 10, or 10 3 or more, or ii) 1, 2, 5, 10, 10 3 , 10 5 , 10 10 or 10 50 cm of radicals or reactive species or body parts 3 radicals or reactive species per gram of nanoparticles, or iii) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 3 , 10 5 , 10 10 or 10 50 μM reactive species or radicals. This may be the case if the application of radiation or sound waves to the nanoparticles does not more gently alter or increase the amount of radicals or reactive species produced or generated by the nanoparticles.

[0499] In another embodiment of the invention, the amount or concentration of radicals or reactive species, particularly generated or produced by the nanoparticles, is lower when the radiation or sound waves are applied sequentially to the nanoparticles or body part than when the radiation or sound waves are applied sequentially to the nanoparticles or body part, particularly by a factor a. In some cases, the factor a can be greater than or equal to the following values: i) 1.0001, 1.1, 1.2, 1.5, 2, 5, 10, or 10 3 , or ii) 1, 2, 5, 10, 10 3 , 10 5 , 10 10 or 10 50 Radicals or reactive species, or bioparticles 1cm 3 radicals or reactive species per gram of nanoparticles, or iii) 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -3 , 10 -1 , 1, 2, 5, 10, 10 3 , 10 5 , 10 10 or 10 50 μM of reactive species or radicals. This is the case when the amount of radicals or reactive species due to the application of radiation or sound waves is significantly reduced by preventing the dissociation or detachment of ions or radicals or reactive species from nanoparticles, such as iron or oxygen ions. In some other cases, the coefficient a can be equal to or less than: i) 10 100 , 10 10 , 10 5 , 10 3 , 10, 5, 3 or 2, or ii) 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 10 or 5 radicals or reactive species or body parts cm 3 radicals or reactive species per gram of nanoparticles, or iii) 10 100 , 10 50, 10 20 , 10 10 , 10 5 , 10, 10 -5 or 10 -10 μM of radicals or reactive species, if the application of radiation or sound waves to the nanoparticles does not more slowly change or decrease the amount of radicals or reactive species produced or generated by the nanoparticles.

[0500] The present invention also relates to a method for generating radicals or reactive species or sonication, wherein the nanoparticles have at least one of the following properties: i) 10 -50 nm -1 a larger surface / volume ratio; ii) a composition or chemical formula comprising: a) atoms with at least two different stoichiometric coefficients or oxidation or reduction states, such as Fe2 and Fe3; b) ions with different numbers of charges or oxidation states or reduction states, such as Fe2+; and c) atoms forming at least two types of ions with different numbers of charges, oxidation states or reduction states, such as Fe2+ and Fe3+; iii) a composition and / or size and / or surface / volume ratio that allows or leads to a Fenton or Haber-Weiss reaction; iv) dissolution, decomposition, or amorphization, especially those that promote reactions of free ions originating from or dissociated from the nanoparticles; v) a chain-like arrangement; and / or vi) 1 cm 3 per 1 mg or per cell or cm of body part 3 and a concentration of 1 mg or less per nanoparticle, wherein at least one of these properties is less than that produced in the absence of radiation or sound waves in the presence of radiation or sound waves applied to the nanoparticles, particularly 1.0001, 1.1, 1.5, 2, 5, 10, 10 3 or 10 5 This leads to the amount or concentration of radicals or reactive species being produced in greater amounts by a factor of two or more.

[0501] In one embodiment of the present invention, the surface / volume ratio of the nanoparticles is particularly 10 -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -3, 10 -1 , 1, 5, 10 or 100 nm -1 More than that.

[0502] If the surface / volume ratio of the nanoparticles is large enough, a large number of atoms on the surface of the nanoparticles can be exposed to radiation or sound waves, and these atoms can specifically react to form free radicals or reactive species.

[0503] In particular, atoms located at or within the nanoparticle are more difficult to generate free radicals or reactive species from than atoms located at the surface of the nanoparticle.

[0504] In another embodiment of the invention, the surface / volume ratio of the nanoparticles is low, in particular 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -5 , 10 -10 , 10 -20 or 10 -50 nm -1 The surface-to-volume ratio of a nanoparticle is small enough to allow the nanoparticle to maintain a three-dimensional volume or geometry, and / or to prevent the nanoparticle from switching from a three-dimensional to a two-dimensional system, and / or to allow the nanoparticle to absorb or interact with radiation or sound waves, where the absorption or interaction with radiation or sound waves is more pronounced in three dimensions than in two-dimensional systems.

[0505] In yet another embodiment of the present invention, the surface / volume ratio of the nanoparticles is 10 -5 nm -1 and 10 3 nm -1 or 10 -2 nm -1 and 1 nm -1 is included between.

[0506] In one embodiment of the present invention, the composition of the chemical formula of the nanoparticles is determined by the presence of at least one atom A, which allows for at least two different values ​​of its coefficient or stoichiometric coefficient a. a where a can be an integer or decimal number equal to 0, 1, 2, 3, 4, 5, 67, 8, 9, 10, 11, 12, 13, 14, 15.

[0507] In one embodiment of the present invention, the nanoparticles effect the Fenton reaction, which in some cases can be written as: i) Fe2 + H2O2 ---> Fe3+ OH + OH - , and or, ii) Fe3+H2O2---->Fe2+·OOH+H + In some cases, the Fenton reaction occurs as follows: i) iron(II) is oxidized by hydrogen peroxide to iron(III), forming a hydroxyl radical and hydroxide ion in the process, and / or ii) iron(III) is reduced by another molecule of hydrogen peroxide back to iron(II), forming a hydroperoxyl radical and a proton. In some cases, the Fenton reaction is favored, increased, or effective when: i) the nanoparticle or nanoparticle's chemical formula contains Fe2, Fe2+, Fe3, and / or Fe3+ ions or atoms; ii) the nanoparticle contains maghemite and magnetite; or iii) radiation or sound waves are applied to the nanoparticle or body part. In other cases, the Fenton reaction generates radicals or reactive species.

[0508] In one embodiment of the present invention, the nanoparticles undergo or undergo a Heber-Weiss reaction, which in some cases can be written as follows: Fe 3+ +·O2 - →Fe 2+ +O2,Fe 2+ +H2O2→Fe 3+ +OH - + OH and or O2 - +H2O2→·OH+OH - +O2.

[0509] In some cases, the Haber-Weiss or Fenton reaction produces H2O2 (hydrogen peroxide) and / or superoxide (·O2 - ) to generate ·OH (hydroxyl radical) and / or ·OOH (hydroperoxy radical). In some cases, this reaction is catalyzed by nanoparticles or iron contained in or derived from the nanoparticles.

[0510] In one embodiment of the present invention, dissolution of the nanoparticles is a partial or total loss of mass of the nanoparticles, in particular a loss of mass of the nanoparticles of 10 -50 , 10 -10 , 10 -1 , 1, 5, 10, 50, 75 or greater than 90%, where the percentage is the ratio of the mass of the nanoparticles after dissolution to the mass of the nanoparticles before dissolution.

[0511] In another embodiment of the present invention, the degradation of nanoparticles is achieved by a partial or total change in the composition of the nanoparticles, in particular by a change in the -50 , 10 -10 , 10 -1 A change in the composition of a nanoparticle of greater than 1, 5, 10, 50, 75 or 90%. This percentage is the ratio of the volume or number of atoms in the nanoparticle where the composition change occurs to the total volume or number of all atoms in the nanoparticle.

[0512] In one embodiment of the present invention, decrystallization of a nanoparticle is the partial or total loss of crystallinity or crystalline planes or ordered atomic arrangement of the nanoparticle, or the transition from a crystalline structure to an amorphous structure of the nanoparticle, particularly the loss of crystallinity within the nanoparticle. 3 or 10 5 In some cases, the loss of at least one crystal plane can be observed using an electron microscope or an instrument capable of obtaining similar information.

[0513] The present invention also relates to a method for generating radicals or reactive species, or a sonic or radiation treatment, in which: i) first: radiation or sonic waves are applied to nanoparticles (step 1) until a certain amount of radicals is reached (time 1); second: radiation or sonic waves are not applied to the nanoparticles for a time t2 (step 2) to reduce the amount of radicals or reactive species generated compared to step 1; third: steps 1 and 2 are optionally repeated two or more times; and / or ii) radiation or sonic waves applied to nanoparticles or a body part locally produce or generate radicals or reactive species around the nanoparticles. This local production or generation of radicals or reactive species can in particular be achieved using: a) low concentration nanoparticles, within 1 cm of a body part. 3 Especially 10 per 50 , 10 20 , 10 5 , 10 3 , 10, 5, 2, 1, 10 -2 or 10 -5 gram or less nanoparticles, or b) using nanoparticles that occupy parts of the body or cells such as lysosomes that are capable of generating nanoparticle reactive or radicals.

[0514] The present invention also relates to a method for generating radicals or reactive species, or sonication or radiation treatment, wherein the amount of radicals or reactive species produced or generated in particular by nanoparticles is greater than: i) 1, 2, 5, 10, 10 3 , 10 5 , 10 10 or 10 50 Radicals or reactive species per nanoparticle, or radicals or reactive species per gram of nanoparticle, or cm of body 3 Radicals or reactive species per cm of body 3 ii) parts per gram of nanoparticles or radicals or reactive species or radicals or reactive species per atom specifically contained on the surface or nanoparticle; -50 , 10 -20 , 10 -10 , 10 -5 , 1, 5, 10, 10 3 , 10 5 or 1010 Nanomoles (nM) or micromoles (μM) of radicals or reactive species, or nM or μM of radicals or reactive species per gram of nanoparticles, cm of body part 3 μM of radicals or reactive species per cm of body part 3 nM or μM of radicals or reactive species per gram of nanoparticles per 10 -50 , 10 -20 , 10 -10 , 10 -5 , 1, 5, 10, 10 3 , 10 5 or 10 10 nM or μM of radicals or reactive species per watt, or cm of body part per watt 3 nM or μM of radicals or reactive species per watt, or nM or μM of radicals or reactive species per Gy, or Gy per cm of body part 3 nM or μM of radicals or reactive species per gram of nanoparticles per Gy, or nM or μM of radicals or reactive species per gram of nanoparticles per Gy. In some cases, the production of radicals or reactive species can be large, especially if the nanoparticles can be dissolved into free ions, if Fenton or Heber-Weiss reactions occur, or if the surface of the nanoparticles is large enough and / or reactive to result in the production of these species.

[0515] In some cases, the reactive species or radical may be H2O2.

[0516] The present invention also relates to a method for generating radicals or reactive species or a sonication or radiation treatment, in which the amount or concentration of radicals or reactive species produced or generated in particular by nanoparticles is lower than: i) 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3, 10, 5, 2, or 1 radical or reactive species per nanoparticle, or per gram of nanoparticle, or cm of body part 3 per radical or reactive species, or per gram of nanoparticles per cm of body part 3 per radical or reactive species, in particular per atom contained on or within a nanoparticle; ii) 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 2 , 10, 5, 2, 1, 10 -1 , 10 -3 or 10 -5 nM or μM of radicals or reactive species, or nM or μM of reactive species per gram of nanoparticles, or nM or μM of radicals or reactive species per cm3 of body part, or nM or μM of radicals or reactive species per gram of nanoparticles per cm3 of body part, or iii) 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10 3 , 10, 5, 2, 1 or 10 -3 nM or μM of radicals or reactive species per watt, or cm of body 3 nM or μM of radicals or reactive species per watt, or nM or μM of radicals or reactive species per watt per gram of nanoparticles, or nM or μM of radicals or reactive species per Gy, or cm of body part 3 nM or μM of radicals or reactive species per Gy, or nM or μM of radicals or reactive species per Gy per gram of nanoparticles. In some cases, production of radicals or reactive species can be low if the nanoparticles cannot dissolve into free ions, if the Fenton or Heber-Weiss reaction does not occur, or if the surface of the nanoparticles is not large and / or reactive enough to result in the production of these species.

[0517] In one embodiment of the present invention, the amount or concentration of radicals or reactive species specifically produced or generated by the nanoparticles will be in the following range: i) between 1 and 10 100 , 10 and 10 50 , or 10 3 and 10 20 radicals or reactive species per nanoparticle between, or radicals or reactive species per gram of nanoparticles, or cm of body part 3 per radical or reactive species, or per gram of nanoparticles per cm of body part 3 radicals or reactive species per atom, radicals or reactive species per atom specifically contained on the surface or nanoparticle, or ii) 10 -100 and 10 100 , 10 -50 and 10 50 , 10 -10 and 10 10 , 1 and 10 10 , or 1 and 10 5 nM or μM of radicals or reactive species per gram of nanoparticles or cm of body part 3 nM or μM of radicals or reactive species per cm of body part 3 nM or μM of radicals or reactive species per gram of nanoparticles, or iii) 10 -100 and 10 100 , 10 -50 and 10 50 , 10 -10 and 10 10 , 1 and 10 10 , or 1 and 10 5 nM or μM radicals or reactive species per watt, or watts per cm of body part 3 nM or μM radicals or reactive species per watt per gram of nanoparticles, or nM or μM radicals or reactive species per Gy, or nM or μM radicals or reactive species per Gy per gram of nanoparticles.

[0518] In one embodiment of the present invention, the amount or concentration of radicals or reactive species is measured, which is either i) the same as or similar to the actual amount or concentration of radicals or reactive species produced or generated by the nanoparticles in the first case, or ii) different from the actual amount or concentration of radicals or reactive species produced or generated by the nanoparticles in the second case, where the reactive species or radicals are short-lived, reactive, and in a location that cannot be detected, or are too few or too many to be detected, have reacted with, interacted with, or absorbed by some compound.

[0519] The present invention also relates to a method for generating radicals, or for sonic or radiotherapy, by: i) increasing the temperature of the nanoparticles or the body part, in some cases, especially by 10 -10 , 10 -5 , 10 -1 , 1, 5, 10, 100 or 10 3 °C (degrees Celsius) or more, or in some other cases, especially 10 10 , 10 5 , 10 3 , 10 2 ii) Increase the movement of nanoparticles, which in some cases may be particularly -100 , 10 -50 , 10 -20 , 10 -10 , 10 -5 , 10 -1 , 1, 5, 10, 10 2 , 10 3 or 10 5 nm / sec or more, and in other cases 10 100 , 10 50 , 10 20 , 10 10 , 10 5 , 10, 5, 2, 1, 10 -1 , 10 -3 or 10 -5 nm / sec or less, and 10 in other cases -100 and 10 100 , 10 -50 and 10 50 , 10 -5 and 10 5, 10 -1 and 10 3 , or 10 -1 and 10 nm / sec, and / or iv) dissociation of the compound from the nanoparticles.

[0520] The present invention also relates to a method for generating radical or reactive species by applying sound waves or radiation to nanoparticles or sound waves or radiation treatment, wherein the radical oxygen species specifically destroy at least one pathological cell without destroying at least one healthy cell.

[0521] The present invention also relates to a composition, in particular a pharmaceutical composition, comprising at least one nanoparticle as defined in the present invention, optionally in association with a pharmaceutically acceptable excipient (vehicle).

[0522] In one embodiment, the excipient is a chemical compound.

[0523] The present invention also relates to pharmaceutical compositions in which the pharmaceutically acceptable excipient is a compound.

[0524] The present invention also relates to a diagnostic composition comprising at least one nanoparticle as defined in the present invention.

[0525] The present invention also relates to a medical device comprising at least one nanoparticle as defined in the present invention.

[0526] The present invention also relates to a medical device comprising at least one nanoparticle associated or bound to a compound.

[0527] The present invention also relates to compositions, medical devices, drugs, or cosmetic compositions comprising the nanoparticles of the present invention, optionally associated or bound to a compound.

[0528] The present invention also relates to magnetosomes for use in the treatment of anemia, preferably iron anemia.

[0529] The present invention also relates to sonication or radiation treatment for or as a method for generating reactive or radical compounds.

[0530] The present invention also relates to sonication or radiation treatment as a method of: i) reducing the cell density of a body part or tumor, and / or ii) reducing the volume of a body part, wherein this method makes it possible to administer nanoparticles to the body part in particular.

[0531] In yet another embodiment of the present invention, the properties or characteristics of the nanoparticles or methods or treatments described in individual embodiments or sections or sentences of this patent application may be combined to become properties or characteristics of a particular combination of nanoparticles or methods or treatments.

[0532] In yet another embodiment of the present invention, if an entity such as a compound, substance, nanoparticle, radiation, etc. has a property with a value of P1 that is higher, longer, or larger by a factor a than a property with a value of P2, then it means P1=a·P2 (a>1) or P1=a+P2.

[0533] In yet another embodiment of the invention, if an entity such as a compound, substance, nanoparticle, radiation, etc. has a property with a value of P1 that is lower, smaller, or shorter by a factor a than a property with a value of P2, then P1=a·P2(a<1), P1=P2 / a(a>1), P1=P2-a, or P1=a-P2.

[0534] The invention is further illustrated by the following non-limiting figures and examples. [Brief explanation of the drawings]

[0535] [Figure 1](a) For 210 μg of iron nanoparticles (magnetosomes or sigma) inserted into 4.6 cm3 of tissue exposed to ultrasound at a frequency of 3 MHz and a power of 0.5 W / cm2, ΔT specifies the temperature difference between the temperature measured for the tissue or body part containing the nanoparticles and the temperature measured for the tissue or body part without the nanoparticles as a function of ultrasound duration (time in minutes), (b) same as (a) but with an ultrasound power of 1 W / cm2, (c) same as (a) but with an ultrasound power of 1.5 W / cm2.

[0536] [Figure 2](a) For 100 μg of magnetosomal iron dispersed in 100 μl of water exposed to ultrasound at a frequency of 3 MHz and powers of 0.5 W / cm2, 1 W / cm2, or 1.5 W / cm2, ΔT is the temperature difference measured between the magnetosomes dispersed in water and the water without magnetosomes as a function of ultrasound application time (in minutes). (b) For 100 μg of sigma nanoparticles dispersed in 100 μl of water exposed to ultrasound at a frequency of 3 MHz and powers of 0.5 W / cm2, 1 W / cm2, or 1.5 W / cm2, ΔT is the temperature difference measured between the sigma nanoparticles dispersed in 100 μl of water and the water without sigma nanoparticles as a function of ultrasound application time (in minutes). (c) 100 μl of water containing 100 μg of SPION50 iron nanoparticles dispersed therein was exposed to ultrasound at a frequency of 3 MHz and a power of 0.5 W / cm², 1 W / cm², or 1.5 W / cm². ΔT is the temperature difference measured for the SPION50 nanoparticles dispersed in 100 μl of water compared to the temperature measured for the 100 μl of water containing no SPION50 nanoparticles, as a function of ultrasound application time (in minutes). (d) 100 μl of water containing 100 μg of SPION100 iron nanoparticles dispersed therein was exposed to ultrasound at a frequency of 3 MHz and a power of 0.5 W / cm², 1 W / cm², or 1.5 W / cm². ΔT is the temperature difference measured for the SPION100 nanoparticles dispersed in 100 μl of water compared to the temperature measured for the 100 μl of water containing no SPION100 nanoparticles, as a function of ultrasound application time (in minutes). (e) For 100 μg of iron in SPION20 nanoparticles dispersed in 100 μl of water exposed to ultrasound at a frequency of 3 MHz and a power of 0.5 W / cm2, 1 W / cm2, or 1.5 W / cm2, ΔT specifies the temperature difference between the temperature measured in the SPION20 nanoparticles dispersed in 100 μl of water and the temperature measured in 100 μl of water without SPION20 nanoparticles as a function of the duration of ultrasound application (in minutes).

[0537] [Figure 3](a) 100 μl of water containing 800 μg of magnetosomal iron (magnetosomes) and 100 μl of water without magnetosomes (water) were subjected to a heating step of duration t1 in which they were exposed to ultrasound at a frequency of 3 MHz and a power of 1.5 W / cm2, and a cooling step of duration t2 in which they were not exposed to ultrasound. The different values ​​of heating and cooling times (t1 and t2) during sequences 1 to 13 (SQ1 to SQ13) are shown in Table 3. (b) Differences in the temperature of magnetosomes dispersed in water (magnetosomes in (a)) and water without magnetosomes (water in (b)) as a function of the duration of ultrasound application during the different sequences.

[0538] [Figure 4] Variation of the SAR, expressed in watts per gram of iron contained in the nanoparticles, as a function of the iron concentration contained in the BNF-starch, for a 100 μl suspension of BNF-starch nanoparticles (see Micromod: 10-00102) mixed in water and subjected to an alternating magnetic field with an average strength of 30 mT and a frequency of 196 kHz. BNF-starch are ferrimagnetic iron oxide nanoparticles of various sequences with an average size of 18 nm.

[0539] [Figure 5](a) Histogram showing the percentage of viable U87-MG cells resulting from the following treatments: 2.5 105 viable U105-MG cells were placed in three concentrations of magnetosomes (0, 100, and 500 μg iron magnetosomes per ml of medium and cells) and exposed for 5 min continuously to 100 mW / cm2 ultrasound (middle column with ascending and descending lines and filled black circles) or 500 mW / cm2 ultrasound (right column with downward lines and filled black squares) or no ultrasound exposure (left column with no hatching and gray). (b) 2.5·105 U87-MG cells exposed to three different concentrations of magnetosomal iron: 0 mg / mL (solid black line and filled black circles), 100 μg / mL (dashed line touching white squares), and 500 μg / mL (half solid line and black diamonds). The cells were continuously exposed to ultrasound at a power of 100 mW / cm2 for 5 min. The temperature change was measured with an infrared camera and shown as a function of the continuous ultrasound exposure time. (c) 2.5·105 U87-MG cells exposed to three different concentrations of magnetosomal iron: 0 mg / mL (solid black line and filled black circles), 100 μg / mL (dashed line and white squares), and 500 μg / mL (half solid line and black diamonds). The cells were continuously exposed to ultrasound at a power of 500 mW / cm2 for 5 min. The temperature change was measured with an infrared camera and shown as a function of the continuous ultrasound exposure time.

[0540] [Figure 6](a) Histogram showing the percentage of viable U87-MG cells after the following treatments: 2.5·105 live U87-MG cells were contacted with three concentrations of magnetosomes (0, 100, and 500 μg of magnetosomal iron per mL) and sequentially exposed to ultrasound. The sequence details are as follows: 1 minute of ultrasound exposure followed by 1 minute of no ultrasound exposure; 2nd period: 1 minute 24 seconds of ultrasound exposure followed by 1 minute 24 seconds of no ultrasound exposure; 3rd period: 1 minute of ultrasound exposure followed by 1 minute 30 seconds of no ultrasound exposure; 4th period: 1 minute of ultrasound exposure followed by 1 minute 18 seconds of no ultrasound exposure; 5th period: 1 minute 12 seconds of ultrasound exposure followed by 1 minute 18 seconds of no ultrasound exposure. During ultrasound exposure, the ultrasound power was set at 100 mW / cm² (center column with solid black circles and ascending and descending lines) or 500 mW / cm² (right column with solid black squares and descending lines). The percentage of viable cells obtained in the no ultrasound exposure treatment is shown in the left gray column without hatching. (b) Three different concentrations of magnetosomes, namely, 0 mg / ml (solid black dots), 100 μg / ml (dashed line and white squares), and 500 μg / ml (half of the solid line and black diamonds), were sequentially exposed to ultrasound at a power of 100 mW / cm (details of the sequence are given in the legend of Figure 6(a)). Temperature fluctuations were measured during the treatment. (c) 2.5 10 U87-MG cells were contacted with three concentrations of magnetosomes, namely, 0 mg / ml (solid black dots), 100 μg / ml (dashed line and white squares), and 500 μg / ml (half of the solid line and black diamonds). They were sequentially exposed to ultrasound at a power of 500 mW / cm (details of the sequence are given in the legend of Figure 6(a)). Temperature fluctuations were measured during the treatment.

[0541] [Figure 7](a) Percentage of surviving cells after the following treatments: U87-MG cells in contact with 1 mg / mL of magnetosomal iron, no contact with magnetosomes (0 mg / mL), no exposure to laser (W / oL), or continuous irradiation with laser at an average power of 3 W / cm for 6 min (continuous L). (b) Variation in temperature as a function of time for U87-MG cells in contact with 0 mg / mL and 1 mg / mL magnetosomes and continuously irradiated with laser at an average power of 3 W / cm for 6 min. (c) Variation in temperature as a function of time for U87-MG cells in contact with 0 mg / mL and 1 mg / mL magnetosomes and sequentially irradiated with laser at an average power of 3 W / cm for 6 min. (The sequence details are as follows: First sequence: i) laser application at an average power of 3 W / cm2 for 60 seconds until the temperature reached 45°C, ii) no laser application for 18 seconds, resulting in a temperature drop from 45°C to 37°C; second sequence: i) laser application at an average power of 3 W / cm2 for 17.5 seconds, resulting in a temperature increase from 37°C to 45°C, ii) no laser application, resulting in a temperature drop from 45°C to 37°C in 24 seconds; third sequence: i) laser application at an average power of 3 W / cm2 for 17.5 seconds, resulting in a temperature increase from 37°C to 45°C, ii) no laser application, resulting in a temperature drop from 45°C to 37°C in 20 seconds. Fourth sequence: i) application of a laser with an average power of 3 W / cm2 over 15.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 20.5 seconds. Fifth sequence: i) application of a laser with an average power of 3 W / cm2 over 15 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 21.5 seconds. Sixth sequence: i) application of a laser with an average power of 3 W / cm2 over 14.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 21.5 seconds.Seventh sequence: i) application of a laser with an average power of 3 W / cm2 over 15 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 20 seconds. Eighth sequence: i) application of a laser with an average power of 3 W / cm2 over 13.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 22 seconds. Ninth sequence: i) application of a laser with an average power of 3 W / cm2 over 13 seconds resulted in a temperature increase from 37°C to 45°C, ii) removal of the laser, resulting in a temperature decrease from 45°C to 37°C over 21 seconds. Sequence 10: i) Laser application at an average power of 3 W / cm2 over 15 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 23 seconds. Sequence 11: i) Laser application at an average power of 3 W / cm2 over 14.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 20 seconds. Sequence 12: i) Laser application at an average power of 3 W / cm2 over 15 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 25 seconds. Sequence 13: i) Laser application at an average power of 3 W / cm2 over 14.5 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 20 seconds. Sequence 14: i) Laser application at an average power of 3 W / cm2 over 12.5 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 24 seconds. Sequence 15: i) Laser application at an average power of 3 W / cm2 over 12.5 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 18.5 seconds. Sequence 16: i) application of a laser with an average power of 3 W / cm2 during 15 seconds resulted in a temperature increase from 37°C to 45°C, and ii) removal of the laser resulted in a temperature decrease from 45°C to 37°C during 23 seconds.Sequence 17: i) Laser application at an average power of 3 W / cm2 over 12.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 22.5 seconds. Sequence 18: i) Laser application at an average power of 3 W / cm2 over 13.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 24 seconds. Sequence 19: i) Laser application at an average power of 3 W / cm2 over 13.5 seconds resulted in a temperature increase from 37°C to 45°C, ii) the laser was removed, resulting in a temperature decrease from 45°C to 37°C over 21.5 seconds. Sequence 20: i) Laser application at an average power of 3 W / cm² for 14 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 21 seconds. Sequence 21: i) Laser application at an average power of 3 W / cm² for 14.5 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 23 seconds. Sequence 22: i) Laser application at an average power of 3 W / cm² for 14 seconds resulted in a temperature increase from 37°C to 45°C; ii) Laser removal resulted in a temperature decrease from 45°C to 37°C over 16 seconds. Total laser exposure time was 6 minutes and 2 seconds.

[0542] [Figure 8](a) Percentage of viable cells after the following treatments: 3T3 cells were exposed to 1 mg / mL of magnetosomal iron, or not exposed to magnetosomes (0 mg / mL), and not exposed to laser (W / oL), or sequentially exposed to laser at an average power of 3 W / cm for 6 min (continuous L), the sequence details of which are shown in the legend of Figure 8(c) (sequential L). Or sequentially exposed to laser at an average power of 3 W / cm for 6 min (continuous L). Figure 8: (a) Percentage of viable cells after the following treatments: 3T3 cells were exposed to 1 mg / mL of magnetosomal iron, or not exposed to magnetosomes (0 mg / mL), or not exposed to laser (W / oL), and sequentially exposed to laser at an average power of 3 W / cm for 6 min (continuous L). (b) Variation in temperature as a function of time of 3T3 cells in contact with 0 mg / mL and 1 mg / mL magnetosomes and sequentially irradiated with a laser at an average power of 3 W / cm for 6 minutes. (c) Variation in temperature as a function of time of 3T3 cells in contact with 0 mg / mL and 1 mg / mL magnetosomes and sequentially irradiated with a laser at an average power of 3 W / cm. The sequence details are as follows: First sequence: i) 90 seconds of laser irradiation at an average power of 3 W / cm until the temperature reached 45°C, ii) 21 seconds without laser irradiation, during which the temperature decreased from 45°C to 37°C; Second sequence: i) 17.5 seconds of laser irradiation with an average power of 3 W / cm, during which the temperature increased from 37°C to 45°C, ii) 22 seconds without laser irradiation, during which the temperature decreased from 45°C to 37°C. Third sequence: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C, ii) When the laser was not applied for 20.5 seconds, the temperature fell from 45°C to 37°C. Fourth sequence: i) When a laser with an average power of 3 W / cm2 was applied for 14.5 seconds, the temperature rose from 37°C to 45°C, ii) When the laser was not applied for 20.5 seconds, the temperature fell from 45°C to 37°C.Fifth sequence: i) Irradiation with a laser with an average power of 3 W / cm2 for 15.5 seconds raised the temperature from 37°C to 45°C, ii) 19 seconds without laser irradiation reduced the temperature from 45°C to 37°C. Sixth sequence: i) Irradiation with a laser with an average power of 3 W / cm2 for 15.5 seconds raised the temperature from 37°C to 45°C, ii) 19.5 seconds without laser irradiation reduced the temperature from 45°C to 37°C. Seventh sequence: i) Irradiation with a laser with an average power of 3 W / cm2 for 18.5 seconds raised the temperature from 37°C to 45°C, ii) 20 seconds without laser irradiation reduced the temperature from 45°C to 37°C. Eighth sequence: i) Irradiation with a laser with an average power of 3 W / cm2 for 18.5 seconds raised the temperature from 37°C to 45°C, ii) 21 seconds without laser irradiation reduced the temperature from 45°C to 37°C. Ninth sequence: i) When a laser with an average power of 3 W / cm2 was applied for 20 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 20 seconds, the temperature dropped from 45°C to 37°C. Tenth sequence: i) When a laser with an average power of 3 W / cm2 was applied for 18.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 19.5 seconds, the temperature dropped from 45°C to 37°C. Eleventh sequence: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 18.5 seconds, the temperature dropped from 45°C to 37°C. Sequence 12: i) When a laser with an average power of 3 W / cm2 was applied for 15.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 19.5 seconds, the temperature dropped from 45°C to 37°C. Sequence 13: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 18.5 seconds, the temperature dropped from 45°C to 37°C. Sequence 14: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 18.5 seconds, the temperature dropped from 45°C to 37°C.Sequence 15: i) When a laser with an average power of 3 W / cm2 was applied for 19.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 21.5 seconds, the temperature dropped from 45°C to 37°C. Sequence 16: i) When a laser with an average power of 3 W / cm2 was applied for 18 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 19.5 seconds, the temperature dropped from 45°C to 37°C. Sequence 17: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C; ii) When the laser was not applied for 19.5 seconds, the temperature dropped from 45°C to 37°C. 18th sequence: i) When a laser with an average power of 3 W / cm2 was applied for 17.5 seconds, the temperature rose from 37°C to 45°C, ii) When the laser was not applied for 20 seconds, the temperature dropped from 45°C to 37°C. 19th sequence: i) When a laser with an average power of 3 W / cm2 was applied for 19 seconds, the temperature rose from 37°C to 45°C, ii) When the laser was not applied for 18.5 seconds, the temperature dropped from 45°C to 37°C.

[0543] [Figure 9] (a) ROS generation rates after the following treatments: 3T3 cells were exposed to 1 mg / mL of magnetosomal iron (M-CMD), or not exposed to magnetosomes (0 mg / mL), and not exposed to laser (W / oL), continuously exposed to laser at an average power of 3 W / cm for 6 min, or sequentially exposed to laser at an average power of 3 W / cm. The sequence is shown in the legend of Figure 7(c). (b) ROS generation rates after the following treatments: U87-MG cells were exposed to 1 mg / mL of magnetosomal iron, or not exposed to magnetosomes (0 mg / mL), or not exposed to laser (W / oL), continuously exposed to laser at an average power of 3 W / cm for 6 min, or sequentially exposed to laser at an average power of 3 W / cm. The sequence is shown in Figure 8(c).

[0544] [Figure 10](a) ROS generation rate after the following treatments: 3T3 cells were exposed to 1 mg / mL magnetosomal iron, no magnetosomes (0 mg / mL), no AMF (alternating magnetic field) (with or without AMF), continuous exposure to AMF at 34-47 mT and 198 kHz for 30 minutes, or sequential exposure to AMF at 34-47 mT and 198 kHz. The sequence details are as follows: First sequence: i) AMF at 34-47 mT and 198 kHz for 5 minutes until the temperature reaches 45°C; ii) no AMF for 2.2 minutes, resulting in a decrease in temperature from 45°C to 37°C. Second sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 3.7 minutes until the temperature reached 45°C, ii) no AMF applied for 2.7 minutes, resulting in a temperature drop from 45°C to 37°C. Third sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 3.1 minutes until the temperature reached 45°C, ii) no AMF applied for 2.3 minutes, resulting in a temperature drop from 45°C to 37°C. Fourth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.3 minutes until the temperature reached 45°C, ii) no AMF applied for 2.5 minutes, resulting in a temperature drop from 45°C to 37°C. Fifth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 1.8 minutes until the temperature reached 45°C, ii) no AMF applied for 1.5 minutes, resulting in a temperature drop from 45°C to 37°C. Sixth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.2 minutes until the temperature reached 45°C, ii) no AMF applied for 2.6 minutes, resulting in a temperature drop from 45°C to 37°C. Seventh sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.4 minutes until the temperature reached 45°C, ii) no AMF applied for 2.9 minutes, resulting in a temperature drop from 45°C to 37°C. Eighth sequence: i) application of AMF with intensity 34-47 mT and frequency 198 KHz for 2.8 min until the temperature reached 45°C, ii) non-application of AMF for 2.7 min resulting in a decrease in temperature from 45°C to 37°C.Ninth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.4 minutes until the temperature reached 45°C, ii) no AMF applied for 2.4 minutes, resulting in a temperature drop from 45°C to 37°C. Tenth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.1 minutes until the temperature reached 45°C, ii) no AMF applied for 2.7 minutes, resulting in a temperature drop from 45°C to 37°C. (b) ROS generation rate after the following treatments: U87-MG cells were exposed to 1 mg / mL of magnetosomal iron, or not exposed to magnetosomes (0 mg / mL), or not exposed to AMF (with or without AMF), or continuously exposed to AMF at intensities of 34-47 mT and a frequency of 198 kHz for 30 min, or sequentially exposed to AMF at intensities of 34-47 mT and a frequency of 198 kHz for 30 min, with the following sequence details: First sequence: i) AMF at intensities of 34-47 mT and a frequency of 198 kHz was applied for 5 min until the temperature reached 45°C; ii) no AMF was applied for 2.2 min, resulting in a decrease in temperature from 45°C to 37°C. First sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 3.7 minutes until the temperature reached 45°C, ii) no AMF applied for 2.7 minutes, resulting in a temperature drop from 45°C to 37°C. Third sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 3.1 minutes until the temperature reached 45°C, ii) no AMF applied for 2.2 minutes, resulting in a temperature drop from 45°C to 37°C. Fourth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.3 minutes until the temperature reached 45°C, ii) no AMF applied for 2.5 minutes, resulting in a temperature drop from 45°C to 37°C. Fifth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 1.8 minutes until the temperature reached 45°C, ii) no AMF applied for 1.5 minutes, resulting in a temperature drop from 45°C to 37°C. Sixth sequence: i) AMF applied at an intensity of 34-47mT and a frequency of 198KHz for 2.2 minutes until the temperature reached 45°C, ii) no AMF applied for 2.6 minutes, resulting in a temperature drop from 45°C to 37°C.Seventh sequence: i) AMF of 34-47mT intensity and 198KHz frequency was applied for 2.4 minutes until the temperature reached 45°C, ii) no AMF was applied for 2.9 minutes, resulting in a temperature decrease from 45°C to 37°C. Eighth sequence: i) AMF of 34-47mT intensity and 198KHz frequency was applied for 2.8 minutes until the temperature reached 45°C, ii) no AMF was applied for 2.7 minutes, resulting in a temperature decrease from 45°C to 37°C. Ninth sequence: i) AMF of 34-47mT intensity and 198KHz frequency was applied for 2.4 minutes until the temperature reached 45°C, ii) no AMF was applied for 2.4 minutes, resulting in a temperature decrease from 45°C to 37°C. Tenth sequence: i) application of AMF with an intensity of 34-47 mT and a frequency of 198 KHz for 2.1 min until the temperature reached 45°C, ii) non-application of AMF for 2.7 min resulting in a decrease in temperature from 45°C to 37°C.

[0545] [Figure 11] (a) Percentage of viable cells after treatment: 3T3 cells exposed to magnetosomal iron at 1000, 500, 250, or 16 μg / mL, no magnetosomes (0 mg / mL) and no gamma radiation (control), or different doses of gamma radiation (5, 10, 20, 40, or 80 Gy. (b) ROS generation rate after treatment: 3T3 cells exposed to magnetosomal iron at 1000, 500, 250, or 16 μg / mL, no magnetosomes (0 mg / mL) and no gamma radiation (control), or different doses of gamma radiation (5, 10, 20, 40, or 80 Gy).

[0546] [Figure 12](a) Percentage of viable cells after the following treatments: CAL-33 cells were contacted with 1000, 500, 250, or 16 μg / mL of magnetosomes, or no magnetosomes (0 mg / mL) and no gamma radiation (control), or different doses of gamma radiation of 5, 10, 20, 40, or 80 Gy. (b) ROS production rate after the following treatments: CAL-33 cells were contacted with 1000, 500, 250, or 16 μg / mL of magnetosomal iron, or no magnetosomes (0 mg / mL) and no gamma radiation (control), or different doses of gamma radiation of 5, 10, 20, 40, or 80 Gy. (Example 1)

[0547] Materials and Methods

[0548] Nanoparticles: Magnetosomes extracted from magnetotactic bacteria and further purified to remove most organic material from the bacteria were used. They consist of: i) a maghemite core or mineral with a mass percentage of 0.3% organic material derived from magnetotactic bacteria, and ii) a carboxymethyl dextran coating surrounding the core. The magnetosomes form chains and were prepared using an adapted and improved protocol described in patent PCT / FR2016 / 000095 (publication number WO2016 / 203121A1), incorporated by reference (Example 8). These magnetosomes are referred to as M-CMD. Also used were: i) nanoparticles containing iron oxide, 35 × 13 nm in size, purchased from Sigma, designated as Sigma Nanoparticles (Reference: 637106-25G, Lot #MKBK2270V); ii) superparamagnetic nanoparticles consisting of 20 nm iron oxide, purchased from Micromod, SPION20 (nanomag®-D-spio20, Ref: 79-02-201); iii) superparamagnetic nanoparticles consisting of 50 nm iron oxide, designated as SPION50 from Micromod (synomag-D50, Ref: 104-000-501); iv) superparamagnetic nanoparticles consisting of 100 nm iron oxide, purchased from Micromod, designated as SPION100 (nanomag®-D-spio100, Ref: 79-00-102).

[0549] Preparation of samples containing nanoparticles inserted into tissue or dispersed in water For tissue heating experiments, 10 μl of a suspension containing 204 μg of water alone or nanoparticle iron (magnetosomes and Sigma or Sigma nanoparticles) was added to a 4.5 cm 3 The nanoparticles were uniformly inserted into the liver tissue, resulting in a concentration of 45 μg of iron nanoparticles per cm3 of liver tissue. For heating experiments under aqueous conditions, 100 μl of water alone or 100 μg of water mixed with 100 μg of iron nanoparticles (magnetosomes, Sigma, SPION20, SPION50, SPION100) was dispersed in a 200 μl Eppendorf flask.

[0550] A heating device that generates ultrasound waves: Samples made of tissue with or without nanoparticles or water with or without nanoparticles were measured at intensities of 0.5, 1, or 1.5 W / cm 3 The subject was exposed to 3 MHz ultrasound for 10 minutes. The intensity corresponds to the red color on the device, and there may be a difference between the ultrasound intensity of the body part and the ultrasound intensity displayed by the Phyaction 190i.

[0551] Temperature measurement During the experiment, an infrared camera (EasIRTM-2, Optophase) placed 13 cm above the transducer was used to measure the spatial distribution of temperature as a function of time. The temperature distribution was measured at the following time points: 0 s, 30 s, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, and 10 min. Only the maximum temperature recorded at each time point was considered.

[0552] Results and Discussion:

[0553] a) Non-sequential heating experiments on tissues Figure 1 shows the temperature difference, ΔT, between tissue containing nanoparticles and tissue without nanoparticles measured at each time point, at an ultrasound power of 0.5 W / cm. 2 (Fig. 1(a)), 1 W / cm 2 (Fig. 1(b)), and 1.5 W / cm 2 (Fig. 1(c)). At the three different powers tested, ΔT was positive, indicating a larger temperature rise in tissue with nanoparticles than in tissue without nanoparticles. 2 At the lowest power of 1.5 W / cm, sigma nanoparticles generate more heat than magnetosomes. 2 In , the opposite phenomenon was observed, with magnetosomes producing more heat than sigma nanoparticles.

[0554] mixed into the tissue and applied at 0.5, 1, or 1.5 W / cm 2 For magnetosomes exposed to different ultrasound powers, ΔT 10minreal(M) We also estimated the value of ΔT 10min(M) -ΔT 10min(W) where ΔT 10min(M) and ΔT 10min(W)is the temperature increase observed after 10 minutes of ultrasound application to samples containing magnetosome-containing tissue and tissue without magnetosomes, respectively. minreal(M) is 0.5W / cm 2 6°C to 1.5W / cm 2 It was observed that the temperature increased to 28°C (Table 1). (M) ) and Temperaturerise (M) =(ΔT 10min(M) / ΔT 10min(W) -1) × 100. 0.5W / cm 2 37% to 1.5W / cm 2 The SAR real(M) =Slope real(M) xCv / C nano to calculate the watts per gram of iron contained in magnetosomes (W / g Fe ) is the specific absorption rate (SAR) of the magnetosomes inserted into the tissue. real(M) The value of was estimated. Here, Slope real(M) =Slope (M) -Slope (W) , Slope (M) and Slope (W) represents the initial gradient of the temperature change estimated from the plot in Fig. 1(a). v =4.2JK -1 g -1 is the specific heat of water, and C nano is the nanoparticle concentration in grams of nanoparticles per mL of water. real(M) is 0.5-1W / cm 2 5-12W / g Fe to 1.5 W / cm 2 This increases to 71 W / gFe (Table 1). (M) =[(Slope (M) / Slope (W) )-1] × 100 (M) was also estimated at 0.5-1W / cm 2 9-47% to 1.5W / cm 2increases to 124%.

[0555] mixed into the tissue and applied at 0.5, 1, or 1.5 W / cm 2 For sigma nanoparticles exposed to different ultrasonic powers of ΔT 10minreal(S) We also estimated the value of ΔT 10min(S) -ΔT 10min(W) , where ΔT 10min(S) and ΔT 10min(W) are the temperature increases observed after 10 min of ultrasound exposure in samples containing tissue with and without sigma nanoparticles, respectively. 10minreal(S) is 0.5W / cm 2 At 14°C from 1-1.5W / cm 2 A decrease of 6-7°C at 0.5 W / cm was observed (Table 1). The rate of temperature rise (S) was estimated using the formula: Temperature rise (S) = (ΔT10min(S) / ΔT10min(W)-1) × 100. 2 90% at 1-1.5W / cm 2 The SAR real(S) =Slope real(S) ×C v / C nano Specific absorption rate values ​​of Sigma nanoparticles inserted into tissues using SAR real(S) of sigma nanoparticles in iron (W / g Fe ) where Slope real(S) represents the initial gradient of the temperature change estimated from the plots in Figures 1(a) to 1(c) for the sigma nanoparticles, and C v =4.2JK -1 g -1 is water and C nano is the nanoparticle concentration in grams of sigma nanoparticles per mL of water. real(S) is 0.5~1.5W / cm 2 Between 16 and 28 W / g Fe The formula Sloperise(S) = (Slope (S) / Slope (W)Sloperise, the rate of slope rise, expressed using (-1) × 100 (S) was also estimated at 0.5W / cm 2 118% to 1-1.5W / cm 2 This reduces to 30-36% of the original value.

[0556] b) Non-sequential heating experiments in water :

[0557] Figures 2(a), 2(b), 2(c), 2(d), and 2(e) show ΔT, the difference between the temperature of suspensions containing different nanoparticles dispersed in water and the water temperature. The different suspensions without nanoparticles were subjected to 0.5, 1, or 1.5 W / cm for 10 minutes. 2 When exposed to ultrasound at 1000 W / s, Figures 2(a), 2(b), 2(c), 2(d), and 2(e) show ΔT as a function of time for magnetosomes, sigma, SPION50, SPION100, and SPION20, respectively. For different nanoparticles and the three different test powers, ΔT is positive, indicating a larger temperature increase for nanoparticles dispersed in water compared to water alone.

[0558] Mixed in water, 0.5, 1, or 1.5 W / cm 2 ΔT10 for magnetosomes exposed to different ultrasound powers minreal(M) The value of ΔT 10min(M) -ΔT 10min(W) where ΔT 10min(M) and ΔT 10min(W) is the temperature increase observed after 10 min of ultrasound exposure in samples containing magnetosome-containing tissue and magnetosome-free tissue, respectively. WT 10minreal(M) is 0.5W / cm 2 to 1.5 W / cm 2 (Table 2) 2 This is smaller than the values ​​observed in tissues (Table 1) (Table 2). (M) =(ΔT 10min(M) / ΔT 10min(W) -1) × 100(M) ) was estimated to be 0.5-1 W / cm 2 37-43% to 1.5W / cm 2 (Table 2) and 1.5 W / cm 2 Temperature rise measured in tissue at (M) (Table 1) is smaller than the formula SAR real(M) =Slope real(M) ×C v / C nano to calculate the watts per gram of magnetosomes in iron (W / g Fe ) is the specific absorption rate (SAR) of magnetosomes dispersed in water. real(M) The value of was estimated. Here, Slope real(M) represents the initial gradient of the temperature change with time estimated from the plot in Fig. 2(a), and C v =4.2JK -1 g -1 is the specific heat of water, and C nano is the magnetosome concentration in grams of magnetosomes per mL of water. SAR real(M) is 0.5W / cm 2 294W / g Fe to 1.5 W / cm 2 424W / g Fe (Table 2), which is higher than the values ​​measured in tissue (Table 1). The slope rise rate (M) was also estimated using the formula Sloperise(M) = (Slope(M) / Slope(W)-1) x 100. 0.5-1.5 W / cm 2 The efficiency was only 16-24% at 1.5 W / cm (Table 2). 2 This is smaller than the 124% estimated for tissue (Table 1).

[0559] Dispersible in water, 0.5, 1, or 1.5 W / cm 2 For sigma nanoparticles exposed to different ultrasonic powers of ΔT 10minreal(S) We also estimated the value of ΔT 10min(S) -ΔT 10min(W) where ΔT is equal to 10min(S) and ΔT 10min(W)are the temperature increases observed after 10 min of ultrasonic irradiation for water samples with and without dispersed sigma nanoparticles, respectively. 2 For ultrasonic energy of ΔT 10minreal(S) The temperature remained at 6 to 12°C (Table 2). (S) =(ΔT 10min(S) / ΔT 10min(W) -1) × 100 (S) ) was estimated to be 0.5-1.5W / cm 2 At power levels above 1000 W, the SAR remains at 31-60% (Table 2). Also, the SAR values ​​of Sigma nanoparticles inserted into tissues are real(S) The formula SAR real(S) =Slope real(S) ×C v / C nano The watts per gram (W / g) of sigma nanoparticles in iron was calculated using Fe ) estimated by real(S) represents the initial gradient of the temperature change estimated from the plot in Figure 2(b) for the sigma nanoparticles, and C v =4.2JK -1 g -1 is the specific heat capacity of water, C nano is the nanoparticle concentration in grams of sigma nanoparticles in iron per mL of water. real(S) is 0.5W / cm 2 0W / g at Fe to 1.5 W / cm 2 2686W / g Fe (Table 2). (S) =(Slope (S) / Slope (W) The gradient rise rate (S) was also estimated using the gradient rise rate (S) expressed as 0.5-1 W / cm. 2 from 0-8% to 1.5W / cm 2 increases to 99%.

[0560] ΔT for SPION50, SPION100, and SPION20 nanoparticles dispersed in water and exposed to different ultrasonic powers of 0.5, 1, or 1.5 W / cm 10minreal(S50) , ΔT 10minreal(S100) and ΔT 10minreal(S20) We also estimated the values ​​of ΔT 10min(S50) -ΔT 10min(W) , ΔT 10min(S100) -ΔT 10min(W) and ΔT 10min(S20) -ΔT 10min(W) , is equal to ΔT 10min(S50) , ΔT 10min(S100) , ΔT 10min(S20) and ΔT 10min(W) are the temperature increases observed after 10 min of ultrasonic irradiation for samples containing SPION50, SPION100, and SPION20 nanoparticles dispersed in water, respectively, and for water without nanoparticles. ΔT 10minreal(S50) , ΔT 10minreal(S100) and ΔT 10minreal(S20) is 0.5-1.5W / cm 2 It was observed that the temperature remained at 0-7°C for 10 ... (S50) =(ΔT 10min(S50) / ΔT 10min(W) -1) × 100, Temperature rise for SPION 100 (S100) =(ΔT 10min(S100) / ΔT 10min(W) -1) × 100, Temperature rise for SPION20 (S20) =(ΔT 10min(S20) / ΔT 10min(W) Temperature rise expressed using -1) x 100 (S) The power of different SPIONs was estimated to be 0.5-1.5W / cm 2 The specific absorption rate (SAR) values ​​for SPION50, SPION100, and SPION20 nanoparticles inserted into tissues were also significantly higher than those for SPION100, SPION20, and SPION50 nanoparticles inserted into tissues. real(S50) , SAR real(S100) , ,SAR real(S20)was estimated in watts per gram of iron for SPION50, SPION100, and SPION20 nanoparticles (W / g Fe For this purpose, the following formulas were used for SPION50, SPION100, and SPION20 nanoparticles, respectively: SAR real(S50) =Slope real(S50) ×C v / C nano , SAR real(S100) =Slope real(S100) ×C v / C nano , SAR real(S20) =Slope real(S20) ×C v / C nano Slope real(S50) , Slope real(S100)、 Slope real(S20) represents the initial slope of the temperature change with time estimated from the plots in Figure 2(c) for SPION50, Figure 2(d) for SPION100, and Figure 2(e) for SPION20, and C v =4.2JK -1 g -1 is the specific heat of water, and C nano is the nanoparticle concentration in grams of SPION50, SPION20, or SPION100 nanoparticles in iron per mL of water. real(S20) , SAR real(S50) and SAR real(S100) is 0.5-1W / cm 2 0-677W / g Fe to 1.5 W / cm 2 787-2795W / g Fe (Table 2). (S20) , Sloperise (S50) , Sloperise (S100) The ratios of SPION20 to Sloperise were also estimated. They are expressed using the following formula: (S20) =(Slope (S20) / Slope (W) -1) × 100, Sloperize against SPION50 (S50) =(Slope (S50) / Slope (W)-1) × 100, Sloperize against SPION 100 (S100) =(Slope (S100) / Slope (W) -1)×100. 0.5~1.5W / cm 2 It remains between 0 and 104%.

[0561] c) Continuous heating experiment in water :

[0562] An Eppendorf containing 500 μg of magnetosomes dispersed in 100 μl of water was continuously exposed to ultrasound at a power of 1.5 W / cm for time t1 (Figure 3(a)). 2 The figure shows 13 sequences (SQ1 to SQ13) in which ultrasound was applied at a frequency of 3 MHz and then removed at time t2. Time t1 corresponds to the time required to reach the target temperature of 43.5 ± 1.5°C during the heating step, and time t2 corresponds to the time required to cool the sample from 43.5 ± 1.5°C to 34.5 ± 0.5°C during the cooling step. The values ​​of t1 and t2 are shown in Table 3 for the different sequences. The average frequency of the sequence, 1 / (t 1av +t 2av) was estimated to be 33 mHz. Here, t1av and t2av represent the average values ​​of t1 and t2 over the 13 sequences. Figure 3(b) shows the change in ΔT, the difference in temperature between the tube containing water with magnetosomes and the tube containing water without magnetosomes, as a function of time. ΔT is positive, indicating that the temperature increase is greater in the tube containing water with magnetosomes than in the tube containing only water without magnetosomes in all 13 sequences. Furthermore, as shown in Figure 3(b), the heating and cooling steps due to the presence of magnetosomes can be repeated many times (13), indicating that ultrasound is not damaging the magnetosomes or strongly impairing their heating power. The heating steps are larger in magnitude during the first two sequences. This is due to less dispersion and aggregation of magnetosomes during the first two sequences than during the remaining sequences. We also confirm that the sequences can be repeated with heating and cooling times that do not vary by more than 53% between different sequences (Table 3).

[0563] conclusion

[0564] The following conclusions can be drawn from this example: (i) The ΔT (temperature difference between the temperature of nanoparticles in the tissue or water exposed to ultrasound and the temperature of the tissue or water alone) values ​​were always positive, indicating that various nanoparticles (magnetosomes, Sigma, SPION20, SPION50, SPION100) enhance the heating efficiency of ultrasound under the tested conditions (ultrasonic frequency = 3 MHz, ultrasonic power = 0.5-1.5 W / cm², nanoparticle concentration varied between 60 μg / mL and 8 mg / mL, nanoparticles inserted into the tissue or dispersed in water). (ii) The lower SAR values ​​observed for magnetosomes in the water suspension compared to other nanoparticles (Table 2) can be explained by the greater aggregation of magnetosomes after ultrasound application than other nanoparticles (as observed by eye). (iii) In some cases, the SAR may be underestimated due to the heat generated by the ultrasound transducer, which heats the tissue and counteracts the heat generated by the nanoparticles exposed to ultrasound. This may be the reason, for example, that some SAR values ​​are reported as 0 W / g. (iv) SAR real If is zero, ΔT 10minreal The value of is not zero (Table 2), and nanoparticles increase the amount of heat generated by sound waves, but the SAR real is likely underestimated due to interference with the heat generated by the transducer. (v) Nanoparticle SAR values ​​estimated by applying ultrasound to tissues containing various nanoparticles reach a maximum value with magnetosomes. (vi) Using magnetosomes, we were able to create a sequence consisting of a heating step (application of ultrasound to magnetosomes) followed by a cooling step (non-application of ultrasound to magnetosomes), which resulted in enhanced heating and cooling magnitudes compared to the heating and cooling steps obtained without magnetosomes (Figures 3(a) and 3(b)).

[0565] Example 2

[0566] Figure 4 shows that when a 100 μl suspension of BNF-Starch nanoparticles mixed in water is exposed to an AC magnetic field with an average strength of 30 mT and a frequency of 196 kHz for 30 minutes, the SAR increases from 4 watts per gram of iron in nanoparticles at a concentration of 500 grams of iron per mL to 114 watts per gram of iron in nanoparticles at a concentration of 5 milligrams of iron per mL. This corresponds to a 29-fold increase in SAR for a 10-fold increase in nanoparticle concentration. Above 5 mg / mL, the SAR saturates at 110 watts per gram of iron in nanoparticles.

[0567] Example 3: Cytotoxicity and temperature measurements of cells contacted with different concentrations of magnetosomes and exposed (or not) to sequential or successive applications of ultrasound.

[0568] Materials and Methods

[0569] The magnetosomes used in this example were M-CMDU87-MG glioblastoma cells purchased from ATCC (ATCC® HTB-14). They were cultured in high-glucose Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 1 mM pyruvate, 10% fetal bovine serum, 100 units / mL penicillin, and 100 μg / mL streptomycin. Cells were seeded into T175 flasks containing medium. Upon reaching 80-90% confluence, the supernatant was removed and replaced with PBS to wash the cells. The PBS solution was then removed and replaced with 5% volume of 0.25% trypsin-EDTA. The cells were incubated at 37°C with 5% carbon dioxide in a 90-95% humidity incubator for 5 minutes. The cells were then harvested. To inactivate the trypsin, 10 ml of medium was added and the cells were homogenized. Thirty microliters of cells were collected and mixed with 30 μL of 4% trypan blue. The cells were counted using a cell counter (Countess® IIFL Automated Cell Counter (ThermoFisher Scientific)) to measure the cell concentration. 2 mL of cells per 250 mL Petri dish were cultured at 37°C with 5% CO2 for 24 hours to allow the cells to adhere to the surface of the Petri dish. The cell culture medium was then removed and replaced with new medium without magnetosomes or with new medium containing magnetosomes at a concentration of 100 μg / mL or 500 μg / mL in iron. The cells were then exposed to ultrasound continuously or sequentially. The ultrasound power used was 0 mW / cm. 2 , 100mW / cm 2 , or 500 mW / cm 2 The ultrasonic frequency used was 1 MHz.

[0570] Ultrasound was applied as follows: The transducer was placed face up, and a gel pad coated with ultrasound gel was deposited on the transducer surface to reduce heat emitted by the transducer. A Petri dish was then placed on top of the gel pad. The Petri dish was left on top of the gel pad for 5 minutes to allow the ultrasound waves to traverse the different surfaces.

[0571] For continuous application of ultrasound, ultrasound was applied continuously for 5 min to Petri dishes containing cells with or without magnetosomes.

[0572] For the sequential application of ultrasound, ultrasound was applied sequentially to Petri dishes containing cells with or without magnetosomes in the following manner: first, 1 minute of ultrasound followed by 1 minute of no ultrasound; second, 1 minute 24 seconds of ultrasound followed by 1 minute 24 seconds of no ultrasound; third, 1 minute of ultrasound followed by 1 minute 30 seconds of no ultrasound; fourth, 1 minute of ultrasound followed by 1 minute 18 seconds of no ultrasound; fifth, 1 minute 12 seconds of ultrasound followed by 1 minute 18 seconds of no ultrasound.

[0573] During ultrasound application, the heating temperature was measured using an infrared camera EasyIR-2 from GuideInfrared, positioned 20 cm above the Petri dish.

[0574] After 24 hours of treatment, the media with and without magnetosomes were removed and replaced with PBS buffer. The cells were washed twice with PBS buffer and then treated with 2 ml of a 1 mg / ml solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide. Over a 4-hour period, the tetrazolium salt was removed from the cells and replaced with 2 ml of isopropanol. After gentle agitation, 100 μL of each Petri dish was transferred to a 96-well plate. Absorbance was measured at 620 nm. The percentage of viable cells was determined by measuring the ratio of the optical density measured for cells treated with ultrasound with or without magnetosomes to that measured for cells treated alone without magnetosomes, and multiplying this ratio by 100.

[0575] result

[0576] Figure 5(a) is a histogram showing the percentage of viable U87-Luc cells after the following treatment: U87-Luc cells were exposed to 0, 100, or 500 μg of magnetosomal iron per mL and exposed to a power of 100 mW / cm. 2 or 500mW / cm2 The specimens were exposed (or not) to continuous ultrasound of 100 W / cm 2 represents the ultrasonic power exhibited by the ultrasonic generating device.

[0577] On the other hand, it is observed that as the magnetosome concentration increases from 0 to 500 μg / mL, the percentage of viable cells decreases i) from 100% without ultrasound to 35% and ii) at 500 mW / cm 2 When using ultrasound with an output of 87% to 10%.

[0578] On the other hand, the ultrasonic output is 0mW / cm 2 to 500mW / cm 2 As the concentration of magnetosomes increases, a decrease in the percentage of live cells is observed: i) from 100% to 87% in the absence of magnetosomes and from 35% to 10% in the presence of 500 μg / mL of magnetosomes;

[0579] It has been observed that the percentage of viable cells decreases with increasing ultrasound power and magnetosome concentration.

[0580] Figure 5(b) shows the results of contacting magnetosomes with various concentrations of iron (0, 100, or 500 μg per mL) at a power of 100 mW / cm as measured by an IR camera. 2 Figure 5(b) shows the temperature change as a function of time in U87-Luc cells exposed to continuous ultrasound at 1 MHz and 100 mW / cm. 2 This shows that at a power of 1000 kJ / s, there is no increase in temperature for the various magnetosome concentrations tested.

[0581] Figure 5(c) shows the 500 mW / cm of U87-Luc cells in contact with magnetosomes at different concentrations (0, 100, or 500 μg per mL ) in iron, measured with an infrared camera. 2 Figure 5(c) shows the temperature change as a function of time when continuously exposed to ultrasound at a power of 500 mW / cm and a frequency of 1 MHz. 2After 5 minutes of sonication at an output of 0.05μg / mL, the temperature increased by 4°C for magnetosomes at 0 and 100μg / mL, and by 15°C for magnetosomes at 500μg / mL.

[0582] From these results, the following can be inferred:

[0583] i) To raise the temperature by continuous ultrasound exposure to magnetosomes, a sufficiently large magnetosome concentration (500 μg / mL) and 500 mW / cm 2 It is necessary to use a sufficiently large ultrasonic power (Figure 5(c)). The temperature rise is the difference between the temperature rise reached in the presence of magnetosomes and the temperature rise reached in the absence of magnetosomes.

[0584] ii) 100 mW / cm to magnetosomes 2 and 500 mW / cm 2 The percentage of viable cells resulting from treatment with ultrasound at 500 mW / cm was similar for magnetosome concentrations of 100 and 500 μg / mL. 2 of ultrasound and 100mW / cm 2 The results show that the magnetosome concentration has only a limited effect on the effectiveness of cell destruction at this concentration range (Figure 5(a)). This suggests that high effectiveness of cell destruction can be achieved at low magnetosome concentrations.

[0585] iii) Output power 500mW / cm 2 Applying ultrasound to magnetosomes at concentrations of 100 μg / mL and 500 μg / mL results in similar percentages of viable cells (Figure 5(a)). In the case of 100 μg / mL, there is no increase in temperature, but in the case of 500 μg / mL there is a temperature increase of 15 °C (Figure 5(c)), and the presence (or absence) of an increase in temperature does not appear to play a role in cell viability under these conditions.

[0586] Figure 6(a) is a histogram showing the percentage of viable U87-Luc cells after treatment with: power 100 mW / cm 2 or 500mW / cm2 Ultrasound of .cm 2 denotes the surface of the transducer that generates the ultrasound. Overall, the results are similar to those obtained in Figure 5(a) when ultrasound was applied continuously.

[0587] Figure 6(b) shows the results of U86-Luc cells in contact with various amounts of magnetosomes (e.g., 0, 100, or 500 μg of magnetosome iron per mL) measured with an IR camera at a power of 100 mW / cm 2 , the temperature change as a function of time when continuously exposed to ultrasound at a frequency of 1 MHz. 2 It shows that the temperature decreases slightly from 23°C to 21°C for magnetosomes 0 and 100 μg / mL sequentially exposed to ultrasound at 100 mW / cm 2 For 500 μg / mL magnetosomes continuously exposed to ultrasound, the temperature remains unchanged or unchanged globally at 23 °C.

[0588] Figure 6(c) shows the power of 500 mW / cm of U87-Luc cells exposed to various magnetosome concentrations, i.e., 0, 100, or 500 μg of magnetosomal iron per mL, measured using an IR camera. 2 Figure 6(c) shows the temperature change over time when sequentially exposed to ultrasound at 1 MHz and 1 μg / mL. Figure 6(c) shows a series or sequence of moderate temperature increases followed by moderate temperature decreases, ranging in magnitude from 1.2-2°C at 0 μg / mL (no magnetosomes), 2.2-6°C at 100 μg / mL, and 2.4-4°C at 500 μg / mL of magnetosomes. The temperature fluctuations are slightly greater in the presence than in the absence of magnetosomes, especially at 500 μg / mL, but are very mild.

[0589] This demonstrates the feasibility of efficiently destroying U87 tumor cells by applying ultrasound to these cells in the presence of magnetosomes at powers and frequencies that result in limited or no cytotoxicity when ultrasound is applied alone without magnetosomes.

[0590] 500mW / cm 2 Increasing the amount of magnetosomes continuously exposed to ultrasound from 100 μg / mL to 500 μg / mL resulted in a significant improvement over the 500 W / cm without magnetosomes. 2 There is no additional heating at 100 μg / mL compared to the ultra...

Claims

1. A method for using nanoparticles for sonic treatment of a body part of an individual, wherein the nanoparticles are administered to the body part of the individual and sonic waves are applied to the body part, wherein the sonic waves are applied sequentially to the body part, and / or the nanoparticles are magnetosomes.

2. 2. The use of nanoparticles according to claim 1, wherein the acoustic waves have at least one of the following characteristics: i1) a power or power density of 1000 W or less; i2) a power or power density of W / cm, W / cm 2 , or W / cm 3 i) the power or power density is less than or equal to 1000 W per cm of the body part or per cm of the body part; 2 Per unit or body part in cm 3 i4) 1000W or less per 1cm transducer 2 per 1cm or transducer 3 i5) the power or power density is less than 1000 W per gram of nanoparticles; ii1) the energy or energy density is less than 10 5 ii) Energy or energy density is 10 5 W sec / cm, W sec / cm 2 , or W sec / cm 3 ii) The energy or energy density of the body part is less than or equal to 10 5 W sec per cm, cm of body part 2 per W·sec or cm of body part 3 ii4) The energy or energy density is less than 10 5 W·sec per cm, cm of transducer 2 per W·sec, cm of transducer 3 ii5) The energy or energy density is 10 5 ii6) Energy or energy density is 10 5 J / cm, J / cm 2 , or J / cm 3 ii7) the energy or energy density is less than or equal to 10 ... 2 Per unit or body part cm 3 10 per 5 ii8) The energy or energy density is less than or equal to 1 J per transducer cm 2 per transducer cm 3 Per 10 5 ii9) 10 J or less per gram of nanoparticles; 5 iii) has an energy or energy density of 10 J or less; 5 MHz; iv) the penetration depth of the body part is less than 10 -5 cm; v) not focused; and / or vi) not focused ultrasound or high-intensity focused ultrasound.

3. 3. The use of nanoparticles according to claim 1 or 2, wherein the sound waves are ultrasound waves.

4. 4. A method of using the nanoparticles according to any one of claims 1 to 3, wherein the nanoparticles are magnetosomes synthesised, originating from, extracted or isolated from magnetotactic bacteria.

5. 5. A method of using the nanoparticles of any one of claims 1 to 4, wherein the nanoparticles are chemical analogues of magnetosomes.

6. The concentration of nanoparticles located in a body part or nanoparticle region, particularly exposed to sound waves or radiation, or to which sound waves or radiation are applied, is determined based on the concentration of nanoparticles in cm 3 in nanoparticles per cm of body part 3 6. A method for using the nanoparticles according to claim 1, wherein the nanoparticles contain 10 g or less of iron per nanoparticle.

7. 7. A method of using the nanoparticles according to any one of claims 1 to 6, which has or results in at least one of the following properties: i) The initial change in temperature over time, especially the increase, creates a gradient per gram of nanoparticles or cm of body part. 3 Per unit or body part in cm 3 10 per second, measured per gram of nanoparticles -9 or 10 -50 °C, ii) over 10 -9 watts per gram or cm of body part 3 and or iii) the specific absorption rate increases with increasing acoustic power applied to the nanoparticles at a rate that increases with decreasing nanoparticle concentration.

8. The use of the nanoparticles according to any one of claims 1 to 7, wherein the medical treatment is the treatment of a disease or disorder selected from the group consisting of: diseases associated with cell proliferation different from cell proliferation, diseases associated with the presence of diseased cells in a body part of a healthy individual, diseases associated with the presence of diseased sites in an individual or body part, diseases or disorders or malfunctions of a body part, diseases associated with the presence of radioresistant or acoustic resistant cells, infectious diseases, autoimmune diseases, neuropathologies, cancers, tumors, diseases involving or caused by at least one cancer or tumor cell, skin conditions, endocrine diseases, eye diseases or disorders, bowel diseases, communication disorders, genetic disorders, neurological disorders, voice disorders, vulvovaginal disorders, liver disorders, cardiac disorders, heating disorders, mood disorders, anemia, in particular iron anemia, and personality disorders.

9. The application of sound waves to nanoparticles or body parts has -10 From 10 10 9. A method of using the nanoparticles of any one of claims 1 to 8 to induce a temperature increase in a body part or nanoparticles that is between 100 and 200 °C.

10. 10. A method of using the nanoparticles of any one of claims 1 to 9, wherein a compound is attached to the nanoparticles and application of acoustic waves to the nanoparticles induces dissociation of the compound from the nanoparticles.

11. A method of using the nanoparticles of any one of claims 1 to 10, wherein the sequential application of acoustic waves to a body part or to the nanoparticles induces: i) a series of temperature increases in the body part followed by a temperature decrease in the body part, and / or ii) a series of dissociation of the compound from the nanoparticle followed by non-dissociation of the compound from the nanoparticle.

12. 12. A method of using the nanoparticles of any one of claims 1 to 11, wherein the sequential application of acoustic waves to the body part or nanoparticles prevents a decrease in the temperature of the body part or nanoparticles.

13. 13. A method of using the nanoparticles according to any one of claims 1 to 12, wherein the application of sound waves to the nanoparticles produces or generates radicals or reactive species.

14. A composition comprising the nanoparticles according to any one of claims 1 to 13 as a component.

15. A medical device, drug or cosmetic composition comprising as a component the nanoparticles according to any one of claims 1 to 14.

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