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JP-7856674-B2 - Distribution of microparticles

JP7856674B2JP 7856674 B2JP7856674 B2JP 7856674B2JP-7856674-B2

Inventors

  • ヴィンス、ジョナサン ジェームズ
  • ストライド、エレノア フィービー ジェーン

Assignees

  • バイオコンパティブルズ ユーケー リミテッド
  • オックスフォード ユニヴァーシティ イノヴェーション リミテッド

Dates

Publication Date
20260511
Application Date
20220504
Priority Date
20210505

Claims (20)

  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.

Description

This invention relates to the distribution of microparticles, and in some embodiments, to the treatment of solid tumors by distributing microparticles containing radioactive isotopes. 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 within 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 precisely where intended. A specific application of radioactive microparticles is tumor treatment. Brachytherapy, and its latest evolutionary form, selective internal radiation therapy (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 radiation therapy (EBRT) is unsuitable due to the liver's low radiation tolerance. 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 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. While 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. 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 and use more microspheres, or to better distribute the same number of spheres. 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 radiation penetration depth is increased, allowing treatment of a larger portion of the tumor, an improved patient prognosis can be expected. 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; and generating gas bubbles by cavitation at cavitation nuclei located at the insertion site, and applying ultrasonic waves 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. Surprisingly, it has been discovered 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 it 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) of bubbles of various sizes from cavitation nuclei and their subsequent vibration. These bubbles may or may not subsequently collapse during the application of ultrasound. The applied ultrasound performs two functions: 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 th