WO2022092411A1 - Liposome pour l'imagerie tep de suivi de phagocytose, et nanosonde le comprenant - Google Patents

Liposome pour l'imagerie tep de suivi de phagocytose, et nanosonde le comprenant Download PDF

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Publication number
WO2022092411A1
WO2022092411A1 PCT/KR2020/017273 KR2020017273W WO2022092411A1 WO 2022092411 A1 WO2022092411 A1 WO 2022092411A1 KR 2020017273 W KR2020017273 W KR 2020017273W WO 2022092411 A1 WO2022092411 A1 WO 2022092411A1
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Prior art keywords
liposome
nanoprobe
pip
liposomes
pet
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PCT/KR2020/017273
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English (en)
Korean (ko)
Inventor
이상윤
오병철
이지혜
이선학
Original Assignee
가천대학교 산학협력단
(의료)길의료재단
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Publication of WO2022092411A1 publication Critical patent/WO2022092411A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A61K51/1234—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • It relates to a liposome for phagocytosis tracking PET imaging and a nanoprobe including the same.
  • Microglial cells of the central nervous system contribute to activation of the nervous system and maintenance of homeostasis, and secrete neurotrophin, nitric oxide, or cytokines that induce inflammation to maintain or kill nerve cells (apoptosis) It has the function of causing the back.
  • activation of microglia has been reported in various degenerative neurological diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, cerebral infarction or injury, and brain infection. It is also known that the deposition of beta-amyl, which is a factor in the onset and progression of Alzheimer's disease, induces activation of microglia.
  • One object of the present invention is to provide a radiopharmaceutical for diagnosing degenerative brain disease or tumor.
  • Another object of the present invention is to provide a liposome comprising PIP 3 capable of tracking phagocytosis.
  • Another object of the present invention is to provide a liposome for radioactive imaging, including PIP 3 .
  • Another object of the present invention is to provide a nanoprobe for diagnosing a degenerative brain disease or tumor comprising a liposome.
  • One aspect of the present invention provides a radiopharmaceutical for diagnosing degenerative brain disease or tumor, wherein the radiopharmaceutical is a nanoparticle-type PET radiopharmaceutical containing F-18 radioisotope in a size of 50 to 200 nm.
  • One aspect of the present invention provides a liposome comprising PIP 3 capable of tracking phagocytosis.
  • Another aspect of the present invention provides a liposome for radioactive imaging, including PIP 3 .
  • an anchoring compound such as [ 18 F]HFB containing an F-18 isotope is labeled on a liposome composed of POPC and PIP 3 .
  • the nano-compound may include cholesterol or PEGylate phospholipid.
  • the above radioisotope-labeled nanomaterials are used for PET images of tumor tissues or PET images of brain inflammation.
  • Another aspect of the present invention provides a nanoprobe for diagnosing a degenerative brain disease or tumor comprising a liposome.
  • the macrophage tracking radioliposome nanoparticles derived through the present invention will be very useful for diagnosing brain inflammation or tumors by quantifying activated macrophages (microglia) distributed in inflammatory sites in the body with PET.
  • the method using the terminal stage radioisotope label has the advantage of being easy to put into practical use in the medical industry because it minimizes the exposure of workers and enables mass production.
  • FIG. 1 shows a nanoprobe including a liposome for radioactive images according to an embodiment.
  • Figure 2 shows the manufacturing process of POPC:PIP 3 liposome.
  • Figure 6 is a schematic diagram showing the apoptosis process and "eat me” signal.
  • Figure 7 is a pictorial representation of the liposome in the basal state and apoptosis.
  • FIG. 8 is a schematic diagram showing "eat-me signal" of PIP 3 .
  • 11 is a pictorial representation of M1 and M2 of microglia.
  • FIG. 12 shows DMF images of FDG PET (top) and F-18-labeled liposome PET images (bottom) in a tumor model (a model in which the B16F1 melanoma cell line was transplanted into C57BL/6 mice).
  • FIG. 13 shows a photograph of the tissue of the same entity as that of FIG. 12 .
  • POPC Phosphatidylcholine
  • PIP 3 Phosphoinositol-3,4,5-trisphosphate
  • It provides a liposome having a lipid bilayer structure.
  • the liposome may be anchored with radioisotope-labeled [ 18 F]HFB ([ 18 F]hexadecyl-4-[ 18 F]fluorobenzoate) or an analog thereof.
  • the liposome may be characterized in that it specifically binds to macrophages in which phagocytosis is activated.
  • the ratio of POPC and PIP 3 may be 2:1 to 100:1.
  • the present invention has an OPC (Phosphatidylcholine) of claim 1 as a main component, and PIP 3 (Phosphoinositol-3,4,5-trisphosphate) as a secondary component;
  • OPC Phosphatidylcholine
  • PIP 3 Phosphoinositol-3,4,5-trisphosphate
  • nanoprobe for tracking PET (positron emission tomography, position emission tomography) images including liposomes having a lipid bilayer structure.
  • the nano-probe may be 60 nm to 150 nm.
  • the present invention provides a composition for diagnosing degenerative brain disease comprising the nanoprobe.
  • the present invention provides a composition for diagnosing tumors comprising the nanoprobe.
  • the diagnostic composition may further include at least one selected from the group consisting of DSPE-PEG (2000) amines, cholesterol, and pegylated phospholipids.
  • the POPC Phosphatidylcholine
  • PIP 3 Phosphoinositol-3,4,5-trisphosphate
  • It provides a method for preparing a liposome, having a lipid bilayer structure.
  • a PET radiopharmaceutical in the form of nanoparticles composed of liposomes that can be easily used in patients in the clinic for the purpose of diagnosing cranial nerve inflammatory diseases and TAM (tumor associate macrophage)-activated cancer.
  • Macrophages found in tumor tissues or central nervous system inflammation can find macrophages in higher concentrations than normal tissues, and cause active macrophage.
  • “eat me” mechanism plays a very important role in which cells in the apoptosis process are killed and progresses to phagocytosis by macrophages.
  • phosphatidylserine and phytate which are present in a large number in the exposed inner cell membrane of dead cells, it is known as an important chemical factor recognized by these macrophages as an “eat me signal”, and the gadolinium-phytate complex using this action can be used to treat colon cancer, etc. It has been reported as a diagnostic MRI contrast agent.
  • PET positron emission tomography
  • diagnostic radioisotope F-18 is applied to liposomes carrying “eat me signal”. If it can be labeled and used, it is considered to be a diagnostic PET radiopharmaceutical with high sensitivity.
  • radiopharmaceuticals that image macrophages in the body in relation to inflammation have not been available in the medical market, so they are expected to be used in clinical practice for various purposes.
  • Liposomes in the present invention are nanoparticles having a size of 50 to 200 nm having a lipid bilayer structure containing POPC as a main component and POPS or POP-inositol as a secondary component, freezing and thawing or ultrasound It can be manufactured by controlling the size and uniformity of particles through methods such as sonication or extrusion.
  • the radioisotope F-18 (half-life 109 minutes) must be introduced into the liposome.
  • [18F]HFB hexadecyl-4-[18F]fluorobenzoate
  • an analog that can be easily anchored to the liposome is used.
  • a small amount of a steroid-like compound such as cholesterol may be included, or a certain amount of a pegylated phospholipid such as DSPE-PEG(2000) amine may be included to inhibit metabolism.
  • phosphatidylserine PS
  • phosphoinositides Phosphorylated forms of phosphatidylinositol; one or more phosphorylated phosphatidylinositols
  • liposome nanoparticles are manufactured to consist of a certain proportion of liposomes.
  • Liposomes are the only drug delivery nanoparticles that have been approved and marketed with FDA approval, and when loaded with a therapeutic agent, they are valuable to be used as a tool that can perform treatment and diagnosis at the same time.
  • a liposomal PET probe with a labeling efficiency of 10 to 15% is prepared and ready for use.
  • macrophages are widely distributed in tumor tissues and brain inflammation, they can be used for tumor imaging PET and brain inflammation PET imaging.
  • TSPO PET imaging is a macrophage image in the research stage, but the limitation is that there are true-negative patients due to polymorphism.
  • M1 status of macrophages can be traced. In the case of brain disease, the M1 status provides a pathological cause. M2 is also an activated macrophage and is not related to disease.

Abstract

Les nanoparticules de liposomes radioactifs pour le suivi de macrophages, obtenues via la présente invention, sont considérées comme étant très utiles dans le diagnostic d'une tumeur ou d'une inflammation cérébrale par quantification, à l'aide de TEP, de macrophages activés (cellules microgliales) diffusés dans la zone d'inflammation dans le corps. De plus, un procédé utilisant un marquage radio-isotopique en phase tardive réduit au minimum l'exposition d'un travailleur à un rayonnement, permet une production en masse et peut ainsi être facilement mis en pratique dans l'industrie médicale.
PCT/KR2020/017273 2020-10-30 2020-11-30 Liposome pour l'imagerie tep de suivi de phagocytose, et nanosonde le comprenant WO2022092411A1 (fr)

Applications Claiming Priority (2)

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KR10-2020-0143456 2020-10-30
KR20200143456 2020-10-30

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WO2022092411A1 true WO2022092411A1 (fr) 2022-05-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003515550A (ja) * 1999-11-30 2003-05-07 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ザ・ユニバーシティ・オブ・アリゾナ 放射線感受性リポソーム
KR101469156B1 (ko) * 2013-05-31 2014-12-04 경북대학교 산학협력단 Pet／mr/광학 이미지 삼중 조영제
KR101732844B1 (ko) * 2016-02-04 2017-05-08 강원대학교산학협력단 국소 피부 전달용 항염증 지질 나노 전달체를 포함하는 피부염 치료 또는 예방용 조성물
KR20170076935A (ko) * 2015-12-24 2017-07-05 (의료)길의료재단 뇌신경염증 진단을 위한 pet용 추적자로서 불소-18 동위원소를 함유하는 방사성 화합물 및 이의 제조방법

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003515550A (ja) * 1999-11-30 2003-05-07 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ザ・ユニバーシティ・オブ・アリゾナ 放射線感受性リポソーム
KR101469156B1 (ko) * 2013-05-31 2014-12-04 경북대학교 산학협력단 Pet／mr/광학 이미지 삼중 조영제
KR20170076935A (ko) * 2015-12-24 2017-07-05 (의료)길의료재단 뇌신경염증 진단을 위한 pet용 추적자로서 불소-18 동위원소를 함유하는 방사성 화합물 및 이의 제조방법
KR101732844B1 (ko) * 2016-02-04 2017-05-08 강원대학교산학협력단 국소 피부 전달용 항염증 지질 나노 전달체를 포함하는 피부염 치료 또는 예방용 조성물

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAUMANN MARTINA K., AMSTAD ESTHER, MASHAGHI ALIREZA, TEXTOR MARCUS, REIMHULT ERIK: "Characterization of supported lipid bilayers incorporating the phosphoinositides phosphatidylinositol 4,5-biphosphate and phosphoinositol-3,4,5-triphosphate by complementary techniques", BIOINTERPHASES, vol. 5, no. 4, 1 December 2010 (2010-12-01), US , pages 114 - 119, XP055926586, ISSN: 1934-8630, DOI: 10.1116/1.3516485 *

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