Distribution of microparticles

Abstract

A method of distributing microparticles is provided, the method comprising providing a plurality of microparticles at an insertion site in a medium, and applying ultrasound to the insertion site to generate gas bubbles by cavitation at cavitation nuclei located at the insertion site, the gas bubbles driving movement of the gas bubbles such that the gas bubbles drive movement of the microparticles to a desired spatial distribution in the tumor. The method may be a method of treating a tumor, and the microparticles may include a radioisotope for treating the tumor. Microparticles for use in treating a tumor according to the method are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to the distribution of microparticles, and in some embodiments, to the treatment of solid tumors by distributing microparticles containing radioactive isotopes. [Background technology]

[0002] Microparticles, such as microspheres, are used in many applications. For example, they may be used as diagnostic tools in medical assays, or to alter the density of plastics to increase buoyancy. Radioactive microparticles, i.e., microparticles containing at least one radioactive isotope, can be used for imaging or manipulating materials in a medium. These are widely used in medical imaging and the diagnosis of various diseases. In many of these applications, it can be difficult to position the microparticles in the intended location.

[0003] A specific application of radioactive microparticles is tumor treatment. Brachytherapy, and its latest evolutionary form, selective internal radiotherapy (SIRT), requires the injection of radioactive nuclei, such as bulk solids (e.g., iodine crystals) or colloidal suspensions (e.g., yttrium citrate suspension), into a liquid medium. SIRT was developed to extend the lifespan and improve the quality of life of patients with unresectable hepatocellular carcinoma (HCC) for whom external beam radiotherapy (EBRT) is unsuitable due to the liver's low radiosensitivity.

[0004] The current approach to SIRT uses high-purity isotopes of known grades and localizes radiation using permanent, biocompatible microspheres with calculated emission energies and treatment durations for specific indications. Similar to brachytherapy, SIRT enables precisely controlled radiotherapy for radiosensitive organs and tissues that cannot tolerate high doses of otherwise unfocused, diffused radiation. Because the treatment is minimally invasive via femoral or radial access, it can be delivered on an outpatient basis, making it an attractive alternative to EBRT. Although the initial concept of the treatment was developed in the 1950s, the adoption and practice of SIRT as a palliative technique did not become widespread until the approval of current SIRT products in the 2000s. SIRT remains a non-curative treatment and is recommended by several health organizations worldwide.

[0005] The therapeutic effect of SIRT is hindered by the final distribution of radioactive microspheres. Because the penetration depth of radiation from commercially available radioembolic materials is limited, the therapeutic effect directly correlates with the distribution of microspheres within the tumor tissue. To treat larger areas, it is necessary to either reduce the radiation intensity to use more microspheres or to better distribute the same number of spheres.

[0006] The distribution of microspheres is ultimately limited by the placement of the catheter delivering the microspheres. In hypoxic solid tumors, the cancer's vascular system is primarily located around the solid lesion, hindering the delivery of radioactive microspheres to the center of the solid mass, potentially leaving large areas of the tumor untreated. Therefore, the irradiation energy and subsequent irradiation depth are crucial to the feasibility of the procedure. If the penetration depth of radiation is increased, allowing treatment of a larger portion of the tumor, an improved patient prognosis can be expected. [Overview of the project]

[0007] According to a first aspect of the present invention, a method for distributing microparticles is provided, comprising the steps of: providing a plurality of microparticles to an insertion site in a medium; generating gas bubbles by cavitation at cavitation nuclei located at the insertion site; and applying ultrasound to the insertion site to drive the movement of gas bubbles so that the gas bubbles drive the movement of microparticles to a desired spatial distribution in the medium.

[0008] Surprisingly, it has been found that microscale particles can be driven by bubbles, particularly microbubbles, generated by ultrasound-induced cavitation. While ultrasound-induced cavitation of microbubbles has been used to entrain nanoscale particles into liquid media, it was unexpected that ultrasound-induced cavitation of microbubbles could also drive the movement of larger (and heavier) microscale particles. Entrainment mechanisms used under nanoscale conditions are not feasible for microscale particles with vastly different sizes and masses. However, the inventors have found that gas microbubbles generated by ultrasound-induced cavitation can directly impart kinetic energy to microscale particles, driving their movement. As used herein, cavitation refers to the generation (i.e., growth) and subsequent vibration of bubbles of various sizes from cavitation nuclei. The bubbles may or may not subsequently collapse during the application of ultrasound.

[0009] The applied ultrasound performs two functions: namely, generating gas bubbles suitable for driving microparticles through cavitation originating from cavitation nuclei, and driving the movement of these bubbles. The cavitation bubbles then drive the movement of the microparticles, distributing them into a desired spatial distribution. In particular, microbubbles can disperse microparticles within a medium and / or move them within the medium.

[0010] In this way, microparticles can be non-invasively diffused from their initial location, avoiding the limited distribution of microparticles described above, such as when further diffusion is hindered by the limited size of the capillary. In particular, when this method is used to distribute microparticles within a tumor, microspheres can diffuse into the tumor even if the vascular structure is restricted toward the center of the tumor.

[0011] In some embodiments, the step of providing a plurality of microparticles to the insertion site may include providing a plurality of microparticles at the location where cavitation nuclei are located. For example, the cavitation nuclei may be endogenous to the insertion site. In other embodiments, both microparticles and cavitation nuclei may be provided to the insertion site together or separately as a composition. The cavitation nuclei that generate microbubbles may include both endogenous nuclei already present at the insertion site and exogenous nuclei provided to the insertion site.

[0012] Because high ultrasonic energy may be required to generate bubbles from endogenous cavitation nuclei, extrinsic cavitation nuclei may generally be preferred. This may be due to the limited number of endogenous cavitation nuclei or the inefficiency or high activation energy required to generate bubbles from them. The high ultrasonic energy required for cavitation from endogenous nuclei can damage the surrounding medium.

[0013] The cavitation nuclei may include at least one of the following: microbubbles, nanobubbles, nanodroplets, and gas-stabilized nanoparticles (such as nanocups or nanocones, i.e., nanoscale gas-stabilized shells having voids that act as cavitation nuclei).

[0014] In some embodiments, each microparticle may contain a radioactive isotope, such as a beta- or gamma-ray emitting radioactive isotope. The radioactive isotope may be one or more of yttrium-90, iodine-125, copper-64, scandium-44, lutetium-176, or holmium-166. Ultrasonic approaches for driving the microparticles have been shown to provide an efficient and effective method for distributing radioactive microparticles in or around a medium.

[0015] In some embodiments, the microparticles may contain a therapeutic agent. The therapeutic agent may contain one or more radioisotopes, as described above. In some embodiments, the medium may be tissue, such as human tissue. The tissue may be present in the patient or removed from the patient. The tissue may be a tumor or a part of a tumor.

[0016] In certain embodiments, the method may be a method of treating a tumor by distributing microparticles containing a radioactive isotope. The tumor may be a tumor of the liver, brain, pancreas, kidney, lung, throat, neck, or intestine, and may be a glioma, glioblastoma, or meningioma in particular.

[0017] A second aspect of the present invention provides a method for treating a solid tumor, comprising the steps of: providing a plurality of microparticles to an insertion site in the patient's tissue, wherein the microparticles comprise at least one radioisotope; and applying ultrasound to the injection site to drive the movement of gas bubbles, such that the gas bubbles drive the movement of the microparticles into a spatial distribution for providing radiation to treat the tumor, thereby generating gas bubbles from cavitation nuclei located at the insertion site. The insertion site may be within the tumor or outside the tumor (e.g., adjacent to the tumor). The spatial distribution may be a distribution throughout the entire tumor.

[0018] Any embodiment of the first aspect of the present invention may be combined with an embodiment of the second aspect, particularly an embodiment related to the properties of ultrasound, cavitation nuclei, and / or microparticles. According to a third aspect of the present invention, a plurality of microparticles are provided, the microparticles contain a radioisotope, and are used for treating tumors by a method according to any embodiment of the second aspect of the present invention or any embodiment of the first aspect of the present invention, which is a method for treating solid tumors.

[0019] According to a fourth aspect of the present invention, a plurality of cavitation nuclei are provided, and the cavitation nuclei are used for treating tumors by a method according to any embodiment of the second aspect of the present invention or any embodiment of the first aspect of the present invention, which is a method for treating solid tumors.

[0020] According to a fifth aspect of the present invention, there is provided a composition containing a plurality of cavitation nuclei and a plurality of microparticles for use in treating tumors by a method according to any embodiment of the second aspect of the present invention or any embodiment of the first aspect of the present invention, which is a method for treating solid tumors, and the microparticles contain a radioisotope.

[0021] According to a sixth aspect of the present invention, there is provided a product containing a plurality of cavitation nuclei and a plurality of microparticles as a combined preparation for use simultaneously, separately, or sequentially in treating tumors by a method according to any embodiment of the second aspect of the present invention or any embodiment of the first aspect of the present invention, which is a method for treating solid tumors, and the microparticles contain a radioisotope. Thus, the cavitation nuclei and the microparticles may be separately supplied and inserted into the body, but are used together by applying ultrasound to treat tumors.

[0022] According to a seventh aspect of the present invention, there is provided the use of a plurality of microparticles, which contain a radioisotope, in the manufacture of a medicament for treating tumors by a method according to any embodiment of the second aspect of the present invention or any embodiment of the first aspect of the present invention, which is a method for treating tumors.

[0023] According to an eighth aspect of the present invention, there is provided the use of a plurality of cavitation nuclei in the manufacture of a medicament for the treatment of a tumor by a method according to any embodiment of the second aspect or any embodiment of the first aspect of the present invention, which is a method for treating a tumor.

[0024] According to a ninth aspect of the present invention, there is provided the use of a composition comprising a plurality of cavitation nuclei and a plurality of microparticles in the manufacture of a medicament for the treatment of a tumor by a method according to any embodiment of the second aspect or any embodiment of the first aspect of the present invention, which is a method for treating a solid tumor, wherein the microparticles comprise a radioisotope.

[0025] For better understanding, embodiments of the present invention will be described by way of non-limiting examples with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] [Figure 1(a)] Shows a method for dispersing microparticles according to the present invention. [Figure 1(b)] Shows a specific example of the first step of the method of FIG. 1(a). [Figure 1(c)] Shows a further example of the first step of the method of FIG. 1(a). [Figure 2] Schematically represents the method of FIG. 1(a) applied to microparticles. [Figure 3] Shows the formation of bubbles using a nanocup. [Figure 4] Schematic diagram of an electronic setup for generating ultrasonic waves from a HIFU transducer. [Figure 5] Shows μCT images showing the effect of the focal pressure on the microparticle distribution. [Figure 6] Same as above. [Figure 7] Shows μCT images showing the effect of the well diameter on the microparticle distribution. [Figure 8]This image shows the effect of duty cycles on the distribution of microparticles. [Modes for carrying out the invention]

[0027] Figure 1(a) shows a method for distributing microparticles using ultrasound according to the present invention. As mentioned above, it can be difficult to move microparticles to the intended location in a medium. In particular, when introducing microparticles into a medium using a capillary, the microparticles may cluster at the insertion site rather than move to the desired distribution. The method in Figure 1(a) improves the distribution of microparticles by applying ultrasonic energy.

[0028] The method shown in Figure 1(a) is used to distribute particles within a medium. The medium may be a material such as plastic, and the microparticles are used to alter material properties such as density or buoyancy, or for diagnostic purposes, for example, to function as externally detectable radioactive tracers.

[0029] The medium may be tissue, such as human tissue. The tissue may be in vivo or ex vivo. Microparticles may be used in tissue for diagnostic purposes (e.g., radioactive tracers) or for non-diagnostic and non-therapeutic purposes (e.g., altering tissue properties).

[0030] Microparticles may be used in tissues as an alternative or additional means to treat disease. In particular, this method may be used to distribute particles in a spatial distribution for treating tumors. The tumors may be solid tumors. In some embodiments, this method may be a method of treating tumors by distributing microparticles, each microparticle containing a therapeutic agent such as a radioisotope. In other words, this method may be used to provide selective internal radiotherapy (SIRT).

[0031] SIRT is used to treat various tumor types, but is most commonly used to treat liver cancers such as hepatocellular carcinoma (HCC), cholangiocarcinoma, and metastatic colorectal cancer (mCRC) of the liver. Other examples of SIRT treatment include pancreatic neuroendocrine tumors (pNETs), lung tumors, and CNS tumors such as gliomas. It is desirable to enable the conversion of SIRT technology to other areas of the body where external beam radiation is currently used as part of first-line treatment, and to improve the treatment of tumors where SIRT is already available. For example, glioblastoma is the second most frequently reported brain tumor after meningioma and is the most common malignant tumor. In the United States, glioblastoma accounts for 15.4% of all primary brain tumors and 45.6% of primary malignant brain tumors. The average survival time for patients with glioblastoma multiforme (GBM) is one year, with only 5% surviving for more than five years, and no preventive strategies or standardized second-line treatments are available. These bleak figures reflect the limited treatment options available, with most treatments resulting in recurrence and disease progression within 10 to 30 weeks. By providing a non-invasive ultrasound process to treat tumors by distributing radioactive microparticles, the method shown in Figure 1(a) can be used to treat glioblastoma, as well as gliomas and meningiomas. In general, this method may be used to treat solid tumors of the liver, brain, pancreas, kidneys, lungs, throat, neck, or intestines.

[0032] While the following explanation most frequently refers to the use of microparticles for treating tumors, please understand that the methods described can also be applied to non-therapeutic uses such as non-biological materials.

[0033] Microparticle injection The method in Figure 1(a) begins in step 101, in which multiple microparticles are provided to the insertion site in the medium. The insertion site is also provided with or already contains cavitation nuclei, as will be described in more detail below in relation to Figures 1(b) and 1(c). The step of providing the microparticles may include injecting or inserting multiple microparticles into a common location. If the microparticles are introduced via a capillary or cavity (naturally occurring or fabricated), the insertion site may be located away from the point where the microparticles are first introduced into the capillary. For example, the insertion site may be at the end of the capillary. If this method is used to treat a tumor, the providing step may include providing multiple microparticles to the insertion site in the patient's tissue. The tissue may be the tumor itself, tumor remnants (after incomplete resection), or tissue adjacent to or surrounding the tumor or remnants.

[0034] Figures 2(a) and 2(b) show schematic examples of the method in Figure 1(a). Figure 2(a) shows a medium 201 into which microparticles are distributed. Multiple microparticles 203 are inserted into a cavity 202 and accumulate at the insertion site 204. The microparticles 203 are distributed in the medium 201 by the application of ultrasound from an ultrasonic transducer 205, as will be described in more detail below in relation to step 102 of the method in Figure 1(a).

[0035] In certain cases, microparticles may also be microspheres. Microspheres are particles on a micron scale, which can be either solid or hollow and are nearly spherical. Microparticles may contain or be composed of ceramics. Such ceramics may contain a radioactive isotope such as yttrium-90 and one or more additional elements such as silicon, aluminum, gallium, strontium, manganese, or titanium. Since the starting materials are typically in the form of oxides or salts such as carbonates, the ceramics typically also contain oxygen. In one approach, the ceramic may be yttrium aluminosilicate glass. Ceramic materials can be particularly useful in providing inert and relatively incompressible microparticles. A specific example used in SIRT is TheraSphere®, manufactured by Biocompatibles UK Ltd (part of Boston Scientific Corp.). TheraSphere® microspheres are a combination of three high-purity metal oxides—yttrium, aluminum, and silicon—which are mixed and melted at extreme temperatures to produce solid (YAS) glass. The glass is pulverized, powdered, and sphered over an open flame to form YAS microspheres (see, for example, US4789501, incorporated herein by reference). Further examples of ceramic SIRT microspheres are described in WO16082045 and WO05087274.

[0036] The methods disclosed herein can generally be applied to microparticles, which are particles having a size (or diameter) in the range of 1 μm to 1000 μm. Microparticles may have an average size of 200 μm or less, preferably 150 μm or less, and more preferably 120 μm or less. Microparticles may have a minimum size of 1 μm or more, preferably 5 μm or more, more preferably 10 μm or more, or 20 μm or more, or 50 μm or more, or 100 μm or more. For example, TheraSphere® microspheres have a size in the range of 15 to 35 μm, with an average size in the range of 20 to 30 μm, and are well suited to both the method and placement in human tissue. Microparticle size can be determined by scanning electron microscopy (SEM), optical microscopy, and / or laser diffraction particle size analysis.

[0037] As mentioned above, radioactive microparticles represent a particularly useful application of microparticles. For this purpose, microparticles may contain at least one radioactive isotope. The radioactive isotope may be a beta- or gamma-ray emitting radioactive isotope such as yttrium-90, iodine-125, copper-64, scandium-44, lutetium-176, or holmium-166. In particular, in the treatment of tumors, isotope selection is screened against energy emission (electron volts, eV), and efficacy is compared with the systemic toxicity of the radioactive isotope decay product. Iodine-125 and yttrium-90 are particularly useful because they have lower bioavailability than iodine-127 and zirconium-90, the inert decay product of yttrium-90. Atypical beta-emitting isotopes (e.g., Cu-64, Sc-44, Lu-176, Ho-166) are gaining traction in radiotherapy due to their matching imaging potential, enabling real-time monitoring of procedures using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI).

[0038] To produce radioactive microspheres from YAS glass, 89YAS microspheres containing yttrium-90 are subjected to neutron bombardment in a reactor, producing yttrium-90 as the sole radioactive component. Other isotopes formed as a result of silicon or aluminum neutron bombardment are considered stable or compositionally insignificant. Enriched Y 90 The isotope has a half-life of 64.1 hours and a decay energy of 0.93 MeV, which is Zr 90 ni β - It collapses. Unstable Y 90 The emission of electrons from an atom is slowed down by electrostatic repulsion from adjacent atoms. This slowing down and loss of kinetic energy is emitted into surrounding cells as "bremsstrahlung" gamma rays (bremsstrahlung radiation or Cherenkov radiation), which can be detected externally for imaging. The energy emitted into adjacent cells causes DNA double-strand breaks, and downstream signaling of this DNA damage leads to cell necrosis.

[0039] Microparticles may be selected to have a radioactivity level suitable for providing a clinically acceptable absorbed dose of radiation for the intended treatment. TheraSphere® has a radioactivity of 2500 Bq per microsphere at calibration. Generally, microparticles may have a radioactivity of at least 10 Bq, preferably at least 40 Bq. In some embodiments, the radioactivity is at least 500, preferably at least 100, and most preferably at least 2000 Bq per sphere. The maximum radioactivity per sphere is determined by factors such as the selected isotope and the number of spheres delivered. In some embodiments, the maximum may be 3000 Bq, preferably 5000 Bq, to ​​provide optimal treatment while minimizing damage to surrounding healthy tissue. The total radioactivity of one dose of microspheres may range from 3 GBq to 20 GBq.

[0040] The target tumor absorbed dose depends on the radiosensitivity of the tumor tissue and surrounding healthy tissue to radiation. An absorbed dose of at least 50 Gy to tumor tissue is desirable, but preferably at least 150 Gy. For example, doses used for liver tumors may range from 50 Gy to 500 Gy, typically at least 150 Gy, preferably at least 200 Gy. The LEGACY study recently suggested that high levels of response can be obtained in liver tumors such as HCC with a dose of at least 400 Gy (Ann Oncol. 2020;31(suppl4):S692-S693). Doses of 35 Gy to 115 Gy have been reported for the treatment of CNS tumors such as gliomas (Pasciak et al., EJNMMI Res. 2020;10:96.), and approximately 250 Gy has been used for lung tumors (US10,232,063). Dose as used herein refers to the dose absorbed by tumor tissue. The dose can be measured as the dose to perfusion tissue, which includes tumor tissue and some surrounding tissue. The dose to perfusion tissue is generally lower than the dose to tumor tissue.

[0041] Microparticles may have a density of 10 g / ml or less, preferably 5 g / ml or less, and more preferably 4 g / ml or less. Microparticles may have a density of 1 g / ml or more, preferably 2 g / ml or more, and more preferably 3 g / ml or more. For example, TheraSphere®, which is a microparticle, has a relative density of 3.6 g / ml. These relatively high densities are obtained by using substantially incompressible materials, which is desirable for SIRT and other applications of microspheres. Combining high density with micron-sized particles produces relatively heavy particles, at least compared to nanoparticle conditions. Here, density is the density of individual microparticles. The density can be determined from the raw material (e.g., glass) on which the microparticles are formed before spheroidization.

[0042] When microparticles are used to treat a tumor, the insertion site may be within the tumor. Alternatively, the insertion site may be adjacent to the tumor, at a distance close enough to the tumor that the ultrasonic energy, for example as described in step 102 below, can drive the movement of microparticles into the tumor. The insertion site may be on the surface of the tumor, or within 5 cm, 2 cm, or 1 cm from the tumor surface. In particular, the insertion site may be within a cavity or capillary formed by excising a portion of the tumor. The method in Figure 1(a) may include the step of excising a portion of the tumor to form a cavity. Alternatively, the insertion site may be at the tumor margin formed by excising a portion of the tumor. The method in Figure 1(a) may include the step of excising a portion of the tumor to form a tumor margin or tumor residue.

[0043] Microparticle delivery is performed using sterile 0.9% saline solution, with spheres flowing into the arterial vascular system via a microcatheter from a V-glass vial in a secondary acrylic holder. The tip placement and microcatheter diameter are determined by the operator, availability, and regional preference. Delivery may be performed by catheter to a point in the vascular system that serves the overall tissue volume, rather than the tumor itself. This process relies on the tumor utilizing its local blood supply, so in practice, the majority of microparticles ultimately reach the tumor, but some still reach the surrounding tissue. Alternatively, microparticles may be delivered directly to the blood vessels that nourish the tumor. This is sometimes called superselective delivery, as almost all microparticles reach the tumor and only a limited amount reaches the surrounding tissue.

[0044] The irradiation treatment is completed within two weeks, and the patient is followed up at six weeks later with further imaging of the parenchyma and necrotic tissue, potentially involving further histology to assess the outcome of the procedure.

[0045] Cavitation nuclei Returning to step 101 of the method, the microparticles 203 are provided at the insertion site 204 where the cavitation nuclei are located. The cavitation nuclei can be considered any material that generates expanding gas bubbles that undergo inertial (collapse) or non-inertial cavitation when exposed to ultrasound. The expanded bubbles can have diameters ranging from 1 μm to 500 μm at most. Thus, the generated bubbles may be called microbubbles. The size of the bubbles can oscillate according to the frequency of the applied ultrasound field. The density of the expanded bubbles is generally much lower than the density of microspheres. The density (or average density) of the expanded bubbles is from 0.5 kg / m 3 to 2 kg / m 3 and can range from 0.9 kg / m 3 to 1.1 kg / m 3 and can be in the range of.

[0046] In some embodiments, exogenous cavitation nuclei are provided at the insertion site 204. In some embodiments, step 101 includes the step of providing at the insertion site 204 a composition of both the microparticles 203 and the cavitation nuclei. FIGS. 1(b) and 1(c) show two alternative embodiments using a combined composition where the cavitation nuclei and the microparticles 203 are provided in separate steps.

[0047] In the first alternative shown in FIG. 1(b), step 101 includes a first step 1001 of providing the microparticles 203 at the insertion site 204, for example using the insertion method described above. After inserting the microparticles 204, the method proceeds to step 1002 where the cavitation nuclei are provided at the insertion site 204. The process of providing the cavitation nuclei can be substantially the same as the process of inserting the microparticles described above.

[0048] In the second alternative example shown in Figure 1(c), these steps are reversed. Thus, in Figure 1(c), step 101 of the method includes a first step 1101 in which cavitation nuclei are provided to the insertion site 204. Subsequently, in step 1102, microparticles 203 are provided to the insertion site 204.

[0049] Alternatively, the insertion site 204 where multiple microparticles are provided in step 101 may be a site where cavitation nuclei are already located. In particular, the cavitation nuclei may be endogenous to the insertion site. In such embodiments, the step of providing exogenous cavitation nuclei may be omitted. Alternatively, exogenous cavitation nuclei may be provided to a site that already has endogenous cavitation nuclei in order to enhance the cavitation effect. In general, exogenous cavitation nuclei are preferred because they tend to require less ultrasonic energy to generate gas bubbles. Thus, the risk of damage to surrounding tissue caused by ultrasound is reduced.

[0050] Suitable cavitation nuclei include microbubbles, nanobubbles, gas-stabilized nanoparticles (e.g., nanocups), and nanodroplets. Each of these is described in detail below. Such cavitation nuclei are used in combination with ultrasound in nanoscale applications such as drug delivery. These nanoscale particles are on a very different scale from the microparticles of the present invention, particularly the high-density incompressible microspheres used in SIRT. Surprisingly, the inventors have found that these cavitation nuclei and the bubbles they generate can be applied to much larger and heavier microparticles, and thus help overcome the limited distribution of microparticles in SIRT and other microparticle applications.

[0051] Microbubbles and nanobubbles Cavitation nuclei may be microbubbles (MBs) and / or nanobubbles, or may contain them. Microbubbles and nanobubbles are very small gas pockets, typically containing a gas core of perfluorocarbon coated with phospholipids. When exposed to ultrasound, these gas pockets expand, increasing the diameter of the bubbles. If cavitation nuclei contain microbubbles and / or nanobubbles, the bubble generation by cavitation in the cavitation nuclei involves growing / evolving the micro / nanobubbles into larger bubbles suitable for driving microparticles.

[0052] Microbubbles have been confirmed to occur spontaneously in vivo in pig kidneys and pig livers, and the observation of microbubbles is linearly proportional to the concentration of human red blood cells (RBCs) in vitro.

[0053] Generating enough microbubbles to create a cloud in vivo is possible by using high-density focused ultrasound to evaporate the liquid (by heat or mechanical stress) in the focal area of ​​the ultrasonic transducer.

[0054] When exposed to an external ultrasonic field, gas-filled microbubbles (MBs) expand and contract with amplitudes corresponding to the field's energy and frequency. At low amplitudes, the bubble's oscillations are nearly linear, but as the amplitude increases, the bubble's behavior becomes increasingly nonlinear, and radial expansion and contraction can vary significantly depending on the wave pressure and the MB's maximum volume. When the bubble's resonant frequency exceeds the ultrasonic frequency, the periodic oscillations, which manifest as inertial instability or transient cavitation, are lost, and the bubble collapses. This unstable cavitation phenomenon can generate new, smaller MBs (nuclei) with different critical excitation pressures and oscillation frequencies. When exposed to ultrasound, the free energy of the bubbles in the system increases, increasing not only the bubble's temperature and volume, but also any dissolved gases from the surrounding liquid coalescing with the bubbles, further increasing volumetric expansion. Theoretically, the bubble's expansion increases the relative concentration of the trapped gas in the solution at the bubble-liquid interface (defined as rectified diffusion), further promoting gas inflow and subsequent MB expansion.

[0055] Synthetic microbubbles primarily consist of gas cores (often perfluorocarbons) stabilized by a lipid or protein shell to prevent the dissolution of larger bubbles (>1 μm) into the surrounding solution; stable bubbles smaller than 1 μm are called "nanobubbles." Core-shell chemistry influences the stability and cavitation threshold of the microbubble population, often accompanied by a target substrate (cytotoxin, metal particles, proteins, viruses) bound to the surface.

[0056] Gas-stabilized nanoparticles (nanocups) In some embodiments, the cavitation nuclei may be or comprise gas-stabilized nanoparticles in the form of cups or cones. Nanocups are nanoscale gas-stabilized polymer-based cavitation nuclei.

[0057] Nanocups are considered an improvement over microbubbles alone. One of the biggest drawbacks of microbubbles is that while eukaryotic cells are typically in the 5-10 μm range, their relative size (over 1 μm) compared to endothelial pores (100-800 nm) prevents them from passing through the membrane. Due to rapid depletion under ultrasound, cavitation phenomena with synthetic microbubbles usually cannot last longer than 1-2 minutes. However, using nanocups can increase the duration of sustained cavitation by four times.

[0058] Nanometer-sized (<1 μm) hollow polymer spheres can be prepared by seed-thermal-initiated emulsion polymerization. When organic monomers react, a polymer shell or lens is formed on the surface of the suspension droplet. Due to the osmotic pressure of the unsupported polymer film, the surface shell collapses inward, creating a polymer disc or "nanocup." Changing the monomer composition alters the viscosity within the particles during polymerization, and subsequently alters the size of the cavities formed within the nanocups.

[0059] Figure 3 schematically illustrates the bubble formation process from the nanocup 301. In the first step, the small cavity of the concave polymer nanocup 301 has nanobubbles 302 trapped on its surface, which are nucleation sites for the cavitation phenomenon. In the second step, the gas nanobubbles 302 expand radially outward from the cavity in which they are located, under exposure to ultrasound. In the third step, the nanobubbles 302 reach a critical size, where the contact angle between the bubble and the nanocup 301 approaches its maximum value, and the nanobubbles 302 dissociate from the nanocup 301 (at this point, the free nanobubbles 302 are probably micron-sized and can be considered microbubbles). The nanobubbles / microbubbles 302 continue to expand. Eventually, a complete bubble 303 is formed. The maximum radius of the bubble 303 is independent of the cavity of the nanocup or sound pressure, but is directly related to the frequency of the focused ultrasound. The amplitude of the ultrasound controls the number of nucleating bubbles and, consequently, the frequency of aspherical collapse. Further details on bubble formation from nanocups are described in Kwan, JJ et al., “Ultrahigh-Speed ​​Dynamics of Micrometer-Scale Inertial Cavitation from Nanoparticles” Phys. Rev. Appl. 6, 1-8 (2016), which is incorporated herein by reference.

[0060] Nanodroplets Unlike microbubbles with a stable gas core, nanodroplets have a liquid core of perfluorocarbon (e.g., perfluoropentane, perfluorohexane) stabilized by similar lipid or phospholipid molecules on their surface. Nanodroplets offer advantages over microbubbles and nanocups, particularly in their greater stability, especially in in vivo circulation, compared to gaseous ones. When exposed to ultrasound, the highly volatile liquid evaporates into a gas, generating bubbles. However, the energy required for this phase transition is much higher compared to that of gas-core cavitating agents, though it remains a viable option for highly sensitive therapeutic delivery applications.

[0061] Apply ultrasound Returning to the method in Figure 1(a), this method proceeds to step 102. In step 102, ultrasound is applied to the insertion site 204, generating bubbles through cavitation at cavitation nuclei located at the insertion site. The applied ultrasonic field drives the movement of the generated gas bubbles and their cloud, which in turn drives the movement of microparticles to a desired spatial distribution in the medium. The applied ultrasound can induce cavitation of exogenous or innate cavitation nuclei within the insertion site.

[0062] The applied ultrasound performs two functions. First, as described above in relation to step 101, it generates bubbles by cavitation at the cavitation nuclei. Second, it drives the movement of these generated gas bubbles by the acoustic radiation force acting on them. The cavitation gas bubbles then impart kinetic energy to the microparticles, causing them to move to a desired spatial distribution. The microparticles may disperse and / or move away from their position at the insertion site. The direction and intensity of the ultrasound may be selected to produce a specific movement of the microparticles.

[0063] Examples of this process are shown in Figures 2(a) and 2(b). In Figure 2(a), the ultrasonic generator 205 generates an ultrasonic beam focused on the insertion site 204. This utilizes the cavitation nuclei at the insertion site 204 (for clarity, the bubbles and cavitation nuclei are not shown in the figure). As shown in Figure 2(b), the bubbles drive the movement of the microparticles 203, in this case causing the microparticles to move and diffuse into the medium 201, resulting in a desired spatial distribution of microparticles within the medium 201. The term "desired spatial distribution" is used herein to refer to the overall distribution pattern of the microparticles (e.g., spread out relative to the initial insertion site). The desired spatial distribution varies depending on the intended use of the microparticles.

[0064] We found that a combination of ultrasound applied to a specific site, cavitation nuclei, and microparticles allows for the distribution of microparticles much further and more effectively than conventional methods of microparticle insertion. The maximum displacement of microparticles from the insertion site using this method can range from 1 mm to 4 cm, allowing microparticles to reach further into the tumor than with conventional SIRT methods.

[0065] It should be noted that the process driving the movement of microparticles by bubbles differs from the mechanism used in nanoscale ultrasonic drug delivery. In the latter case, the movement of bubbles creates a fluid flow, which then entrains the nanoparticles. This process of entraining particles is not suitable for the much larger and heavier microparticles considered in this invention.

[0066] When this method is used to treat tumors with radioactive microparticles such as TheraSphere® described above, the microbubbles can drive the movement of the microparticles into a spatial distribution to deliver radiation for treating the tumor. This may include driving the microparticles into the tumor (if the insertion site is in the surrounding tissue) and / or through the tumor. The resulting spatial distribution can penetrate into the tumor more deeply than previously possible, disperse more deeply within the tumor than possible by other methods, and significantly increase the amount of tumor that can be reached and treated. As a result, more effective treatment becomes possible.

[0067] Ultrasound is broadly defined as any frequency above the human audible range (20 kHz). Conventional ultrasound is well-established for medical applications as an imaging technique (ultrasound examination), allowing visualization of most areas of the human body with varying tissue densities. Because medical ultrasound uses very low energy input and frequencies, it provides a safe and non-destructive method suitable for imaging sensitive tissues and organs.

[0068] In medical applications, ultrasound is most commonly generated using piezoelectric (PZT) ceramics, where the displacement of the element's shape produces sound waves as a series of compressions and depressurizations from the transducer surface. In a non-focused planar transducer, the wave expands as a series of concentric concave wavefronts (one wavelength apart), and the velocity of the wave undulates as it propagates through the material. This results in the generation of high and low pressure bands. The intensity of the sound is related to the acoustic impedance, viscosity, and elastic behavior (Young's modulus, elasticity, or viscoelasticity) of the material. During wave propagation, particles can move either in the direction of the wave (longitudinal or compressional) or perpendicular to the wave (transverse or shear).

[0069] As ultrasound passes through tissue or a medium, energy is lost through scattering or heat accumulation, and the effective range of the ultrasound is limited by the energy input. The amplitude of the wave dissipates slowly, inversely to the propagation distance.

[0070] High-intensity focused ultrasound (HIFU) In some embodiments, the applied ultrasound is focused ultrasound with a focus located at or near the insertion site. Preferably, the applied ultrasound is high-intensity focused ultrasound (HIFU).

[0071] HIFU is achieved by placing a low-speed confocal lens at the boundary of a PZT element that generates ultrasound, narrowing the wavefront to a controlled single focal point at a constant distance from the planar element, determined by the curvature of the lens. The lens works by increasing the impedance of the wave propagation speed toward the center of the element, allowing the wavefront (compression and decompression) at the ends of the transducer to reach the wavefront simultaneously in the middle. Thus, the amplitude of the signal generated at the focal point increases without increasing the voltage applied to the transducer. Beyond the focal point (far-field), the wavefront diverges, and the signal intensity is lost as the distance increases.

[0072] When ultrasound is focused to a small focal region, a large pressure gradient is generated compared to the area outside the focal region. This pressure gradient of the sound wave acts on obstacles within the focal point, known as the acoustic radiation force (ARF), which can be approximated as follows:

[0073]

number

[0074] Equation 1: Acoustic radiation force on an object F Force (kg / s) 2 cm 2 ) Absorption coefficient of material A (Np / cm) I. Average intensity of sound waves over time at the focus of ultrasound (W / cm²) 2 ) C Speed ​​of sound in the medium (cm / s) The absorption of energy from HIFU waves and its conversion to kinetic energy can cause a rapid increase in localized temperature within tissues, potentially leading to tissue destruction. Tissue coagulation, a combination of protein denaturation and permanent cell damage, is induced at 43°C in vivo. Thermal ablation correlates with a thermal dose above 43°C over a period of time, and the required thermal dose varies depending on the tissue and species. The brain as a whole has particularly low heat tolerance, with each region having its own distinct threshold for damage. Thermal stress is inhibited by convection to surrounding areas, and increased inter-tissue cell permeability and perfusion via blood circulation makes it a less selective treatment compared to mechanical stress. Prefocal tissues receive lower intensity ultrasound compared to the focal area, but still experience prefocal energy accumulation and heating. Prefocal heating is a significant concern for in vivo treatments using HIFU, as undesirable collateral damage can cause thermal ablation before the focal point, potentially leading to skin burns due to continuous exposure of prefocal tissue to the converging HIFU wavefront.

[0075] To provide a balance between effective bubble drive and limiting damage to surrounding tissue, the ultrasound applied in this method may exert a peak focal negative pressure in the range of 1 to 20 MPa at the insertion site.

[0076] Device Figure 4 shows an example of an ultrasonic setup 205 that may be used to perform step 102 of the method in Figure 1(a). Transducer 401 may be configured to generate ultrasound using parameters selected by waveform generator 404 to provide a desired distribution of microparticles. The parameters may be selected to facilitate cavitation of bubbles from cavitation nuclei and the desired movement of microbubbles in order to provide a desired distribution of microparticles. In a particular example, transducer 401 may generate ultrasound having a fundamental frequency in the range of 0.1 to 5 MHz. The generated ultrasound may have a pulse repetition frequency in the range of 0.1 to 10 Hz. The generated ultrasound may have a duty cycle (continuous wave) in the range of 1% to 100%. Such parameters have been found to be particularly effective in bringing about a desired movement of microparticles, especially in tumor-like media.

[0077] The ultrasonic generator 205 in Figure 4 includes a HIFU transducer 401 with an impedance matching network 402, which is driven by the voltage output of amplifier 403. In the illustrated example, the output voltage of amplifier 403 is monitored by an oscilloscope 406 using a 1 MΩ high impedance cable 405 to check that there are no abnormalities in the transducer drive signal. The input voltage and other ultrasonic parameters are controlled by an arbitrary waveform generator 404. Although shown separately in Figure 4, a linear array 407 is concentrically inserted within the HIFU transducer 401 (represented by a dashed line within transducer 408). The linear array 407 is used for real-time passive acoustic mapping and post-exposure imaging and is operated by an imaging controller box 408. The imaging controller box 408 is connected to the waveform generator 404 to ensure that the transmitted and received signals are synchronized.

[0078] When used to move microparticles within the body, ultrasound imaging may be used to identify the area to which HIFU pulses should be applied. Since the physically aligned HIFU transducer 401 and linear array 407 have matching foci, identifying the imaging focus allows for the identification of the HIFU target focus. Alternatively, the ultrasound probe may be inserted directly into the postoperative tissue cavity.

[0079] result An experiment was conducted to investigate the distribution of TheraSphere® microspheres in a hydrogel medium mimicking a tumor. Wells were formed in the medium to serve as cavities for delivering microparticles. Therefore, the insertion sites for delivering microparticles were located within the wells. Ultrasound was applied using the apparatus shown in Figure 4. Alignment of the linear array, which was coaxially aligned with the transducer, was first advanced by aligning the depth of focus of the transducer with a central 1 mm stainless steel tip rod inserted into the well under test. To prevent the soft hydrogel from being unnecessarily exposed to HIFU, short, low-energy pulses were initially transmitted to the transducer using a pulse receiver. The transducer was adjusted in 0.1 mm increments until the maximum amplitude of the received signal was observed on an oscilloscope. Subsequently, a B-mode image was captured (using a Verasonics® system as the image controller 408). Subsequent wells in the same medium were aligned and visually confirmed using the x,y coordinates of the b-mode image before proceeding with ultrasound irradiation. After the initial alignment, the pulse receiver was replaced with a waveform generator. In this example, the pulse repetition frequency or interval (PRF) was determined by a Verasonics® instrument, and the remaining parameters were determined by a waveform generator.

[0080] Hydrogels as tissue-mimicking bodies Whether in vivo, ex vivo, or in vitro, tissues are unique to each individual organism and inherently vary not only between organisms but also within the tissues of the same organism. Therefore, creating tissue phantoms that mimic tissue properties across several key characteristics is inherently difficult. Hydrogels have been used for decades as in vitro substitutes for mammalian tissues for ultrasound imaging, with sound velocity, acoustic attenuation, and acoustic impedance being similar to indicators of serval cancer. By making subtle modifications to the hydrogel composition, tissue stiffness, porosity, acoustic properties, and cellular structure and environment can be replicated. As a result, hydrogels can simulate a wide range of properties observed in vivo. Although hydrogels are modeled and tested as solids, they are largely composed of water, and therefore their solid content is similar to many animal tissues in terms of sound velocity (approximately 1540 m / s), attenuation (approximately 0.5 dB / cm MHz), and backscatter coefficient (10 between 2 and 7 MHz). -5 ~10 -2 It satisfies the requirements (within the scope of).

[0081] Cellular structures are recognized as a complex mixture of bilayers, microfilaments and tubules, aqueous and organic liquid phases, osmotic pressure, and enzymatic catalysis of endogenous substances, making them nearly impossible to replicate in vitro. Therefore, hydrogels are a compromise, allowing for the simulation of intended material properties similar to their cellular counterparts. However, hydrogels are not perfect designs, and replicating one property in vivo often comes at the expense of another due to the complexity of mimicking cellular structures. For example, replicating material stiffness to simulate tissue often compromises material permeability. As an attempt to improve the various discrepancies of hydrogels, several additives, including mixtures of various polymers (with or without modification) with inorganic additives or inks, have been evaluated.

[0082] Despite possessing similar acoustic properties to tissue, hydrogels have a microstructure that differs significantly from that of tissue, exhibiting isolated fluid pockets that redistribute over time under stress within the polymer network. While particularly useful for mimicking the material properties of tissue, the fabrication and subsequent consistency of the resulting gel models are inherently variable due to the heterogeneity of the material properties. Despite the shortcomings of current hydrogel phantoms, gel tissue mimics remain the most suitable substitutes for simulating tissue due to their ex vivo effectiveness. 75 .

[0083] In the measurements described herein, agar-based hydrogels were used as tissue mimics. Agar gels are clear, well-demonstrated, less variable, and considerably faster to produce compared to PVA freeze-thaw hydrogels. Agar (3 kDa Mw, Sigma Aldrich) was added to deionized water (10 μm, MiliQ®, Type 1) at 0.5 or 1% w / v, degassed under vacuum for at least 2 hours, then heated the suspension to >85°C under microwave irradiation, and subsequently poured into a phantom mold and cooled at 4°C for at least 12 hours. The parameter changes and experimental results described thereafter are based on 0.5% agar gels.

[0084] parameters In most experiments, nanocups (manufactured by Oxsonics®) and Sonovue (Bracco®) were selected as cavitating agents. SonoVue® was reconstituted and supplied according to the manufacturer's instructions, with 1–5 × 10⁶ units. 8 It was used at a concentration of particles / mL. Nanocups were used for a 1:9 dilution (1.0 x 10). 9The suspension was used at a concentration of particles / mL, and the provided suspension was diluted with deionized water after degassing and filtration to match the SonoVue® concentration. Equal amounts of both cavitating agents were used. 20 mg of YAS glass microspheres (Biocompatibility UK Ltd, three size ranges (<15, 15~35, 35+ μm)) were added to diluted nanocups with 250 μL injection each to reduce the possibility of cavitating agent sedimentation and phase separation due to cold radioembolism.

[0085] The pulse repetition frequency was set to 3.3 Hz. This was to allow for equivalent duty cycles across the various frequencies investigated, limited by the 50,000-cycle burst of the waveform generator. Each test well received a total of 3 million cycles, with the ultrasonic exposure time and the number of cycles per ultrasonic burst adjusted as needed.

[0086] The fundamental frequencies investigated were 0.5, 1.1, 1.5, and 3.3 MHz. Subsequently, each frequency was also tested over several focal pressures (0.5 MHz (1.4, 3.0, 3.8 MPa), 1.1 MHz (2.6 MPa), 3.3 MHz (7.7, 11.7, 10.9 MPa)). The duty cycle (DC), like the pressure, varied with each fundamental frequency (0.5 MHz (2.5%, 5%, 16.5% DC), 1.1 MHz (9.7% DC), 3.3 MHz (1%, 2.5%, 5% DC)).

[0087] TheraSphere® glass is colorless and transparent, making it difficult to visualize individual microspheres with a bright-field microscope. However, like human bone, its high relative density (3.4 g / cm³) is a significant factor. 3 This allows for the visualization of ceramics using X-ray tomography. Under X-ray exposure, objects with higher density appear brighter in the image, according to the grayscale and corresponding Hounsfield values.

[0088] After applying ultrasound to investigate the distribution of microspheres, X-ray microcomputed tomography (μCT) images were acquired. Using the X-ray acquisition settings stored in the metadata of the file image stack, μCT images of the wells were generated from 512 sequential image slices (DICOM, 512x512 pixels), and these were superimposed on the Z-plane to create a 512x512x512 voxel image. After reconstruction, the distribution of microspheres was manually measured using a DICOM file viewer, but this is currently limited by operator interpretation and bias.

[0089] Figure 5 shows μCT images illustrating the effect of increasing the focal pressure of the applied ultrasound. In Figure 5(a), the peak focal pressure was 1.4 MPa. In Figure 5(b), the focal pressure was 3.0 MPa. In Figure 5(c), the peak focal pressure was 3.8 MPa. In all cases, the fundamental frequency was 0.5 MHz and the PRF was 3.3 Hz. The DC was 5% in Figures (a) and (b), and 16.5% in Figure 5(c). The ultrasound was applied from left to right throughout all images.

[0090] Figure 6 shows the fundamental frequency at 3.3 MHz and peak focal pressures of 7.7 MPa (6(a)), 11.7 MPa (6(b)), and 10.9 MPa (6(c)). A 5% DC, 3.3 Hz PRF, and 4 mm channel were used. Agar cracking was observed at 11.7 MPa (5(b)) and planar splitting at 10.9 MPa (5(c)). Pre-focal overflow was observed at peak focal pressures of 11.7 MPa (5(b)) and 10.7 MPa (5(c)). Ultrasound was applied from left to right throughout all images.

[0091] These figures show that increasing the peak negative pressure in the HIFU focal region increases the penetration depth of microspheres. The observed decrease in peak negative pressure (6(c)) is due to the nonlinearity of the ultrasonic field. Lower frequencies (0.5 MHz) appear to have a more substantial effect on more deposited microspheres, which is mainly attributed to the size of the focal region to which the spheres are exposed. Higher fundamental frequencies generate more discrete and smaller channels of overflowing microspheres rather than being part of an omnidirectional burst as seen at lower frequencies, which correlates with the decreasing size of the transducer focal point with increasing frequency.

[0092] Figure 7 shows the effect of well diameter on the microsphere distribution. The well diameters were 4 mm (7(a)), 2 mm (7(b)), and 1 mm (7(c)). The ultrasound parameters were 0.5 MHz 3.3 Hz PRF, 5% DC. 35+ μm TheraSphere® microspheres were used. Ultrasound was applied from left to right across all three images.

[0093] Although not a primary parameter, the well diameter appears to influence the distribution of microsphere projections, particularly at low fundamental frequencies where the focal region occupies most of the well's volume.

[0094] Figure 8 shows an image similar to Figure 7, but uses 2.5% DC instead of 5% to demonstrate the effect of DC on the microsphere distribution. TheraSphere® microparticles ranging from 15 to 35 μm were used. Compared to a control sample not exposed to ultrasound, no microsphere overflow was observed at less than 1% DC.

[0095] In summary, these results demonstrate that applying ultrasound to a combination of microspheres and cavitation nuclei distributes microparticles within the tumor-like medium, and that the present invention can improve tumor treatment by distributing microparticles more effectively than is possible with conventional SIRT methods.

Claims

1. A step of providing a plurality of microparticles to an insertion site in a medium that is not human tissue, wherein the plurality of microparticles include microparticles having an average size of 10 μm or more that contain radioactive isotopes, The step of providing a plurality of cavitation nuclei at the insertion site, wherein the cavitation nuclei are exogenous to the non-human tissue medium, A method comprising the steps of: applying ultrasound to the insertion site to generate gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and driving the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the medium.

2. The method according to claim 1, wherein the microparticles are microspheres.

3. The method according to claim 1 or 2, wherein the microparticles of the plurality of microparticles have an average size of 120 μm or less.

4. The method according to claim 1 or 2, wherein the microparticles of the plurality of microparticles have an average size of 20 μm or more.

5. The method according to claim 1 or 2, wherein the microparticles of the plurality of microparticles have a density of 4 g / ml or less.

6. The method according to claim 1 or 2, wherein the microparticles of the plurality of microparticles have a density of 3 g / ml or more.

7. The method according to claim 1 or 2, wherein the microparticles include ceramic.

8. The method according to claim 1 or 2, wherein the radioactive isotope is a beta-ray or gamma-ray emitting radioactive isotope.

9. The method according to claim 8, wherein the radioactive isotope is yttrium-90, iodine-125, copper-64, scandium-44, lutetium-176, or holmium-166.

10. The method according to claim 9, wherein the microparticles include yttrium aluminosilicate glass.

11. The method according to claim 1 or 2, wherein the microparticles emit radiation with a radioactivity of 10 Bq or more.

12. The method according to claim 1 or 2, wherein the microparticles emit radiation with a radioactivity of 5000 Bq or less.

13. The method according to claim 1 or 2, wherein the composition comprising the plurality of microparticles and the plurality of cavitation nuclei is provided to the insertion site.

14. The method according to claim 1 or 2, wherein the plurality of microparticles and the plurality of cavitation nuclei are provided to the insertion site in separate steps.

15. The method according to claim 1 or 2, wherein the cavitation nucleus comprises at least one of microbubbles, nanobubbles, nanodroplets, and gas-stabilized nanoparticles.

16. The method according to claim 1 or 2, wherein the ultrasonic wave has a fundamental frequency in the range of 0.1 to 5 MHz.

17. The method according to claim 1 or 2, wherein the ultrasonic wave has a pulse repetition frequency in the range of 0.1 to 10 Hz.

18. The method according to claim 1 or 2, wherein the ultrasound has a duty cycle in the range of 1% to 100%.

19. The method according to claim 1 or 2, wherein the ultrasound exerts a peak pressure in the range of 1 to 20 MPa at the insertion site.

20. The method according to claim 1 or 2, wherein the method is a method for treating a tumor in a patient, and the spatial distribution is for providing radiation to treat the tumor.

21. The method according to claim 20, wherein the insertion site is located within the tumor.

22. The method according to claim 20, wherein the insertion site is adjacent to the tumor.

23. The method according to claim 20, wherein the spatial distribution is the distribution of the entire tumor.

24. The method according to claim 22, wherein the insertion site is located within a cavity formed by excising a portion of the tumor, or the insertion site is located at the edge of a tumor formed by excising a portion of the tumor.

25. The method according to claim 20, wherein the tumor is a solid tumor.

26. The method according to claim 25, wherein the solid tumor is a tumor of the liver, brain, pancreas, kidney, lung, throat, neck, or intestine.

27. The method according to claim 26, wherein the tumor is a glioma, glioblastoma, or meningioma.

28. A plurality of microparticles, including microparticles having an average size of 10 μm or more that contain radioactive isotopes, The steps include providing the plurality of microparticles to the insertion site in the patient's tissue, The step of providing cavitation nuclei to the insertion site, wherein the cavitation nuclei are a plurality of cavitation nuclei that are extrinsic to the insertion site. Multiple microparticles used for treating a tumor by a method comprising the steps of: generating gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and applying ultrasound to the insertion site to drive the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

29. A composition comprising a plurality of cavitation nuclei and a plurality of microparticles, wherein the plurality of microparticles include microparticles having an average size of 10 μm or more containing radioactive isotopes, and the composition is The steps include providing the composition comprising the plurality of cavitation nuclei and the plurality of microparticles at the insertion site in the patient's tissue, A composition used for treating a tumor by a method comprising the steps of: applying ultrasound to the insertion site to generate gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and driving the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

30. A product comprising multiple cavitation nuclei and multiple microparticles, wherein the multiple microparticles include microparticles having an average size of 10 μm or more that contain radioactive isotopes. The steps include providing the plurality of microparticles to the insertion site in the patient's tissue, The steps include providing the plurality of cavitation nuclei to the insertion site, A product as a combination formulation for simultaneous or sequential use in the treatment of a tumor by a method comprising the steps of: generating gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and applying ultrasound to the insertion site to drive the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

31. The microparticles according to claim 28, the composition according to claim 29, or the product according to claim 30, wherein the radioactive isotope is a beta-ray or gamma-ray emitting radioactive isotope.

32. The microparticles according to claim 28, or the composition according to claim 29, or the product according to claim 30, wherein the radioactive isotope is yttrium-90, iodine-125, copper-64, scandium-44, lutetium-176, or holmium-166.

33. The use of multiple microparticles, including microparticles having an average size of 10 μm or more that contain radioactive isotopes, The steps include providing the plurality of microparticles to the insertion site in the patient's tissue, The step of providing a plurality of cavitation nuclei at the insertion site, wherein the cavitation nuclei are extrinsic to the tissue. Use in the manufacture of a drug for treating a tumor by a method comprising the steps of: generating gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and applying ultrasound to the insertion site to drive the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

34. A step of providing a plurality of microparticles to an insertion site in the patient's tissue, wherein the plurality of microparticles include microparticles having an average size of 10 μm or more that contain radioactive isotopes, The steps include providing a plurality of cavitation nuclei at the insertion site, The use of multiple cavitation nuclei in the manufacture of a drug for the treatment of a tumor, comprising the steps of: applying ultrasound to the insertion site to generate gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and driving the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

35. The use of a composition comprising a plurality of cavitation nuclei and a plurality of microparticles, wherein the plurality of microparticles include microparticles having an average size of 10 μm or more that contain radioactive isotopes. The steps include providing the plurality of cavitation nuclei and the plurality of microparticles to the insertion site in the patient's tissue, Use in the manufacture of a drug for treating a tumor by a method comprising the steps of: generating gas bubbles by cavitation at the cavitation nuclei located at the insertion site, and applying ultrasound to the insertion site to drive the movement of the gas bubbles so that the gas bubbles drive the movement of the microparticles to a desired spatial distribution within the patient's tissue.

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