WO2024039148A1 - Procédé de préparation de nanoparticules d'oxyde de fer superparamagnétiques pour immunothérapie - Google Patents

Procédé de préparation de nanoparticules d'oxyde de fer superparamagnétiques pour immunothérapie Download PDF

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WO2024039148A1
WO2024039148A1 PCT/KR2023/011971 KR2023011971W WO2024039148A1 WO 2024039148 A1 WO2024039148 A1 WO 2024039148A1 KR 2023011971 W KR2023011971 W KR 2023011971W WO 2024039148 A1 WO2024039148 A1 WO 2024039148A1
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superparamagnetic nanoparticles
nanoparticles
heating
cancer
minutes
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Korean (ko)
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백선하
임평원
박순범
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서울대학교산학협력단
주식회사 브레인앤비욘즈
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/32—Manganese; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a method for producing superparamagnetic nanoparticles for immunotherapy.
  • cancer unlike other disease treatments, requires very difficult and complex treatment, and the complex treatments are also not completely effective.
  • the methods currently used to treat cancer include surgery, radiation therapy, and chemotherapy. If you have cancer, surgery is performed to remove the cancer. If the cancer is localized and has not spread far, it can be completely cured through surgery. However, since cancer metastasis tends to occur in more than 70% of patients, adjuvant treatments are used concurrently.
  • Radiation therapy one of the adjuvant treatments, is a treatment that kills cancer cells using high-energy radiation. When radiation is applied to cancer, it does not immediately kill cancer cells, but it destroys the ability of cancer cells to proliferate, preventing new cancer cells from being created and dividing further.
  • Chemotherapy is an auxiliary treatment that uses drugs to kill cancer cells after surgery and is performed to kill invisible cancer cells.
  • chemotherapy can also cause side effects such as vomiting, diarrhea, and hair loss.
  • Immunotherapy is a method of treating disease using the patient's body's immune response.
  • most treatments for autoimmune diseases used to date tend to prescribe immunosuppressants that suppress excessive inflammatory responses rather than treatments that suppress the underlying cause of the disease, and biological agents developed through recent research are also used to provide a complete cure. It is not a fundamental treatment.
  • magnetic nanoparticles have self-induced heating characteristics when exposed to an alternating magnetic field, and the hyperthermic effect specifically exposed to a desired area can be applied to various treatments.
  • a new type of treatment method that combines hyperthermia therapy, chemotherapy, and radiation therapy has been in the spotlight.
  • the present inventors have made extensive research efforts to find a medium that can overcome side effects caused by cancer, immune disease, or anticancer therapy by enhancing immune function.
  • superparamagnetic nanomaterials with stable thermal properties to enhance immune function have been developed.
  • the present invention was completed by manufacturing particles Mn 0.5 Zn 0.5 Fe 2 O 4 .
  • the present invention aims to solve the above-described problems and other problems associated therewith.
  • An exemplary object of the present invention is to provide a method for producing superparamagnetic nanoparticles represented by the following general formula 1, including the following steps.
  • K or L is lithium (Li) or sodium (Na).
  • Monovalent to trivalent cationic metals including magnesium (Mg), calcium (Ca), manganese (Mn), zinc (Zn), aluminum (Al), and gallium (Ga).
  • Another exemplary object of the present invention is to provide a method for producing superparamagnetic nanoparticles represented by the following general formula 2, comprising the following steps.
  • K, L or M are lithium (Li) or sodium (Na).
  • Monovalent to trivalent cationic metals including magnesium (Mg), calcium (Ca), manganese (Mn), zinc (Zn), aluminum (Al), or gallium (Ga).
  • Another exemplary object of the present invention is to provide superparamagnetic nanoparticles prepared by the above production method.
  • the present invention provides a method for producing superparamagnetic nanoparticles represented by the following general formula 1, including the following steps.
  • K or L is lithium (Li) or sodium (Na).
  • Monovalent to trivalent cationic metals including magnesium (Mg), calcium (Ca), manganese (Mn), zinc (Zn), aluminum (Al), and gallium (Ga).
  • the heating in step (b) may be performed at a rate of 12 to 13°C/min for 10 to 30 minutes, and specifically, may be performed at a rate of 12 to 13°C/min for 20 minutes.
  • the cooling in step (b) may be performed for 30 to 120 minutes, specifically 30 to 90 minutes, and more specifically 30 to 60 minutes.
  • the heating in step (c) may be performed at a rate of 2 to 3°C/min for 5 to 20 minutes, specifically for 5 to 10 minutes.
  • step (c) may be performed for 10 to 60 minutes, specifically 20 to 50 minutes, more specifically 30 to 50 minutes, and more specifically 40 to 50 minutes. You can.
  • x and y in General Formula 1 are numbers between 0 and 3, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. It can be 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.
  • the superparamagnetic nanoparticle may be Mn x Zn 1-x Fe 2 O 4 , and more specifically, the superparamagnetic nanoparticle may be Mn 0.5 Zn 0.5 Fe 2 O 4 .
  • the present invention provides a method for producing superparamagnetic nanoparticles represented by the following general formula 2, comprising the following steps.
  • K, L or M are lithium (Li) or sodium (Na).
  • Monovalent to trivalent cationic metals including magnesium (Mg), calcium (Ca), manganese (Mn), zinc (Zn), aluminum (Al), or gallium (Ga).
  • x, y and z are numbers between 0 and 3, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. It can be 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0.
  • the heating in step (b) may be performed at a rate of 12 to 13°C/min for 10 to 30 minutes, and specifically, may be performed at a rate of 12 to 13°C/min for 20 minutes.
  • the cooling in step (b) may be performed for 30 to 120 minutes, specifically 30 to 90 minutes, and more specifically 30 to 60 minutes.
  • the heating in step (c) may be performed at a rate of 2 to 3°C/min for 5 to 20 minutes, specifically for 5 to 10 minutes.
  • step (c) may be performed for 10 to 60 minutes, specifically 20 to 50 minutes, more specifically 30 to 50 minutes, and more specifically 40 to 50 minutes. You can.
  • the superparamagnetic nanoparticles may be manufactured using a heating mantle.
  • the present invention provides superparamagnetic nanoparticles prepared by the above production method.
  • the present invention provides a composition for cancer immunotherapy comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • the superparamagnetic nanoparticle may be Mn x Zn 1-x Fe 2 O 4 , and more specifically, the superparamagnetic nanoparticle may be Mn 0.5 Zn 0.5 Fe 2 O 4 .
  • the superparamagnetic nanoparticles may be coated with a biocompatible polymer.
  • Biocompatible polymer materials useful to the human body that can be used in the present invention include polymers that can be easily dissolved in various solvents, such as Poly Ethyleneglycol (PEG), poly(lactide-co-glycolide) (PLGA), Poly( It may be one or more selected from the group of DL-lactide-co-glycolide (PDLGA), poly(hydroxybutyrate), and Polycaprolactone (PCL), and may specifically be Poly Ethyleneglycol.
  • PEG Poly Ethyleneglycol
  • PLGA poly(lactide-co-glycolide)
  • PCL Polycaprolactone
  • cancer immunotherapy refers to a method of treating cancer using the immune response within the patient's body. After activating cancer-specific immune cells, the activated immune cells specifically attack the cancer in the body. This is how to treat it.
  • the cancer immunotherapy may be achieved by injecting superparamagnetic nanoparticles into the subject's body, and specifically, it may be achieved by increasing immune cells by superparamagnetic nanoparticles, and the immune cells are macrophages. It may be one or more selected from the group consisting of macrophages, natural killer cells, and T cells, but is not limited thereto.
  • composition for cancer immunotherapy containing superparamagnetic nanoparticles according to the present invention as an active ingredient can achieve therapeutic efficacy by direct injection into the body.
  • composition for cancer immunotherapy containing superparamagnetic nanoparticles according to the present invention can selectively and uniformly generate high temperatures because it can continuously react with an external magnetic field when applying the magnetic nanoparticles dispersed in target organs.
  • This treatment method can be performed as a stand-alone treatment method or in combination with or auxiliary to conventional treatment methods.
  • superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 were injected into a fibrosarcoma mouse model and a glioblastoma mouse model, respectively, and an alternating magnetic field was applied, resulting in the formation of macrophages and natural cells around the cancer cells. It was confirmed that immune cells such as killer cells and T cells increased and the size of the tumor decreased.
  • composition for cancer immunotherapy of the present invention is typically provided as a pharmaceutical composition. Therefore, the composition for cancer immunotherapy of the present invention includes a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are those commonly used in preparation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, Includes, but is not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences, 19th ed., 1995.
  • the composition for cancer immunotherapy of the present invention is preferably administered parenterally.
  • parenterally When administered parenterally, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, or intralesional injection.
  • the appropriate dosage of the composition of the present invention can be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity. there is.
  • the composition for cancer immunotherapy of the present invention includes a therapeutically effective amount of superparamagnetic nanoparticles that exhibit a self-induced heating effect.
  • therapeutically effective amount refers to an amount sufficient to treat the disease for which treatment is intended, and is generally 0.0001-100 mg/kg.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by formulating it using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by a person skilled in the art. Alternatively, it can be manufactured by placing it in a multi-capacity container. At this time, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet, or capsule, and may additionally contain a dispersant or stabilizer.
  • the cancer may be fibrosarcoma, brain cancer, lung cancer, colon cancer, liver cancer, breast cancer, stomach cancer, ovarian cancer, skin cancer, pancreatic cancer, prostate cancer, kidney cancer, or thyroid cancer, but is not limited thereto.
  • the present invention provides a composition for treating immune diseases comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • the superparamagnetic nanoparticles are as described above.
  • the treatment of the immune disease may be achieved by injecting superparamagnetic nanoparticles into the body of the subject, and specifically, it may be achieved by increasing immune cells by superparamagnetic nanoparticles, and the immune cells are macrophages. It may be one or more selected from the group consisting of macrophages, natural killer cells, and T cells, but is not limited thereto.
  • composition for treating immune diseases containing superparamagnetic nanoparticles according to the present invention as an active ingredient can achieve therapeutic efficacy by direct injection into the body.
  • composition for treating immune diseases containing superparamagnetic nanoparticles according to the present invention can selectively and uniformly generate high temperatures because it can continuously react with an external magnetic field when applying the magnetic nanoparticles dispersed in target organs.
  • This treatment method can be performed as a stand-alone treatment method or in combination with or auxiliary to conventional treatment methods.
  • composition for treating immune diseases of the present invention is usually provided as a pharmaceutical composition.
  • Acceptable carriers, administration and preparation of the pharmaceutical composition are as described above.
  • the immune disease may include a disease in which the body's immunity is reduced or a disease in which the body's immunity is enhanced, and may specifically include an immunodeficiency disease, an infectious disease, or an autoimmune disease.
  • Representative diseases in which the body's immunity is reduced include congenital immune deficiency disease, acquired immune deficiency disease, bacterial and viral infectious diseases (e.g., various bacterial infectious diseases, incurable viruses including COVID-19, SARS, MERS, etc.) infection), but is not limited thereto.
  • the temperature can be appropriately adjusted using supermagnetic nanoparticles applied with an alternating magnetic field to prevent excessive heat generation and activate dysfunctional immune cells.
  • the disease in which the body's immunity is enhanced may include, but is not limited to, an autoimmune disease.
  • the disease can be treated by generating heat using supermagnetic nanoparticles applied with an alternating magnetic field to destroy the hyperfunctioning immune cells.
  • the autoimmune diseases include lupus (systemic lupus erythematosus), rheumatoid arthritis, progressive systemic sclerosis (Scleroderma), atopic dermatitis, alopecia areata, psoriasis, pemphigus, Asthma, aphthous stomatitis, chronic thyroiditis, inflammatory enteritis, Behcet's disease, Crohn's disease, dermatomyositis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune hemolytic anemia A group consisting of immune encephalomyelitis, myasthenia gravis, Grave's disease, polyarteritis nodosa, ankylosing spondylitis, fibromyalgia syndrome, and temporal arteritis. It may be selected from .
  • the present invention provides a composition for enhancing immunity containing superparamagnetic nanoparticles represented by the above general formula 1 or general formula 2 as an active ingredient.
  • the superparamagnetic nanoparticles are as described above.
  • immune enhancement refers to the function of promoting an immune response to an antigen non-specifically during the initial activation of immune cells or the function of strengthening immunity by increasing the activity of immune system cells, increasing the activity of immune cells.
  • An immune-enhancing effect can be achieved by stimulating the immune response.
  • macrophages play a major role in the immune response. Phagocytosis, a major role of macrophages, absorbs microorganisms and other pyrogenic particles, and also induces tumor necrosis factor- ⁇ (TNF- ⁇ ).
  • TNF- ⁇ tumor necrosis factor- ⁇
  • cytokines such as interleukin-1 ⁇ (IL-1 ⁇ ), interleukin-12 (IL-12), and cytotoxic and inflammatory substances such as nitric oxide (NO) thereby stimulating the immune response
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-12 interleukin-12
  • NO nitric oxide
  • the immune enhancement may be achieved by injecting superparamagnetic nanoparticles into the body of the subject, and specifically may be achieved by increasing immune cells by superparamagnetic nanoparticles, and the immune cells are macrophages ( It may be one or more selected from the group consisting of Macrophage, Natural killer cell, and T cell, but is not limited thereto.
  • composition for immune enhancement containing superparamagnetic nanoparticles according to the present invention as an active ingredient can achieve therapeutic efficacy by direct injection into the body.
  • composition for immune enhancement containing superparamagnetic nanoparticles according to the present invention can selectively and uniformly generate high temperatures because it can continuously react with an external magnetic field when applying the magnetic nanoparticles dispersed in target organs.
  • This treatment method can be performed as a stand-alone treatment method or in combination with or auxiliary to conventional treatment methods.
  • composition for enhancing immunity of the present invention is usually provided as a pharmaceutical composition.
  • Acceptable carriers, administration and preparation of the pharmaceutical composition are as described above.
  • the present invention provides a method for suppressing immune function decline or suppressing immune function administered in combination with a chemotherapy anticancer agent, comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • a composition for augmentation is provided.
  • the superparamagnetic nanoparticles are as described above.
  • the term “combined administration” can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually.
  • the combination treatment effect is obtained by administering two or more drugs or compositions simultaneously or sequentially, or alternately at regular or undetermined intervals.
  • the combination treatment method is not limited to this, but includes, for example, degree of response, Efficacy measured through response rate, time to disease progression, or survival period is therapeutically superior to the efficacy that can be obtained by administering one or the remaining components of the combination therapy at a typical dose and can provide a synergistic effect. can be defined.
  • the superparamagnetic nanoparticles of the present invention are administered in combination with an anticancer agent, the number of immune cells increases, thereby effectively killing cancer cells, resulting in synergistic anticancer treatment.
  • the anticancer agents include eribulin, carboplatin, cisplatin, Halaven, 5-fluorouracil (5-FU), Gleevec, vincristine, vinblastine, vinorelbine, paclitaxel, and docetaxel. , etoposide, topotecan, irinotecan, dactinomycin, doxorubicin, daunorubicin, valrubicin, flotamide, gemcitabine, mitomycin, or bleomycin, but is not limited thereto.
  • the suppression of immune function decline or the enhancement of immune function may be achieved by injecting superparamagnetic nanoparticles into the body of the subject, and specifically, may be achieved by increasing immune cells by superparamagnetic nanoparticles,
  • the immune cells may be one or more selected from the group consisting of macrophages, natural killer cells, and T cells, but are not limited thereto.
  • composition for suppressing decline in immune function or enhancing immune function which contains superparamagnetic nanoparticles according to the present invention as an active ingredient and is administered in combination with a chemotherapy anticancer agent, can achieve therapeutic efficacy by direct injection into the body.
  • composition for suppressing decline in immune function or enhancing immune function administered in combination with a chemotherapy anticancer agent containing superparamagnetic nanoparticles according to the present invention may continuously react with an external magnetic field when applying magnetic nanoparticles dispersed in target organs. Therefore, high temperatures can be selectively and uniformly generated.
  • This treatment method can be performed as a stand-alone treatment method or in combination with or auxiliary to conventional treatment methods.
  • a composition for suppressing decline in immune function or enhancing immune function which contains the superparamagnetic nanoparticle according to the present invention as an active ingredient and is administered in combination with a chemotherapy anticancer agent, is usually provided as a pharmaceutical composition.
  • Acceptable carriers, administration and preparation of the pharmaceutical composition are as described above.
  • the present invention provides a pharmaceutical composition for suppressing decline in immune function caused by anticancer treatment or enhancing immune function, comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • a composition is provided.
  • the superparamagnetic nanoparticles are as described above.
  • the anti-cancer treatment may be, for example, chemotherapy or radiotherapy administering an anti-cancer agent, but is not limited thereto.
  • the suppression of immune function decline or the enhancement of immune function may be achieved by injecting superparamagnetic nanoparticles into the body of the subject, and specifically, may be achieved by increasing immune cells by superparamagnetic nanoparticles,
  • the immune cells may be one or more selected from the group consisting of macrophages, natural killer cells, and T cells, but are not limited thereto.
  • compositions for suppressing decline in immune function due to anticancer treatment or enhancing immune function containing the superparamagnetic nanoparticles according to the present invention as an active ingredient, are typically provided as pharmaceutical compositions.
  • Acceptable carriers, administration and preparation of the pharmaceutical composition are as described above.
  • the present invention provides a method for alleviating, treating or preventing a decrease in immune response in an individual with cancer, comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • a composition for alleviating, treating or preventing a decrease in immune response in an individual with cancer comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
  • the superparamagnetic nanoparticles are as described above.
  • Cancer cells for example, are known to suppress the body's immune function and weaken the activity of immune cells by stimulating immune checkpoint-related proteins. Therefore, when the superparamagnetic nanoparticles of the present invention are administered to an individual with cancer, the number of immune cells increases, thereby suppressing the decline in immune function caused by cancer cells or effectively enhancing immune function.
  • the suppression of immune function decline or the enhancement of immune function may be achieved by injecting superparamagnetic nanoparticles into the body of the subject, and specifically, may be achieved by increasing immune cells by superparamagnetic nanoparticles,
  • the immune cells may be one or more selected from the group consisting of macrophages, natural killer cells, and T cells, but are not limited thereto.
  • a composition for alleviating, treating or preventing a decrease in immune response in an individual with cancer, comprising the superparamagnetic nanoparticle according to the present invention as an active ingredient, is typically provided as a pharmaceutical composition.
  • Acceptable carriers, administration and preparation of the pharmaceutical composition are as described above.
  • the cancer may be fibrosarcoma, brain cancer, lung cancer, colon cancer, liver cancer, breast cancer, stomach cancer, ovarian cancer, skin cancer, pancreatic cancer, prostate cancer, kidney cancer, or thyroid cancer, but is not limited thereto.
  • the present invention provides a composition containing the superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient to subjects (including humans, animals, and mammals such as mice).
  • subjects including humans, animals, and mammals such as mice.
  • a cancer immunotherapy method comprising the step of administering.
  • the present invention provides the use of superparamagnetic nanoparticles represented by Formula 1 or Formula 2 for cancer immunotherapy.
  • the superparamagnetic nanoparticles produced by the manufacturing method of the present invention exhibit self-induced heating characteristics and high biocompatibility due to stable thermal properties, and can be applied through in vivo injection, and induce an increase in immune cells to prevent cancer and immunity. It can be useful in treating diseases.
  • Figure 1 shows the thermal characteristic curves of superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 produced by the manufacturing method of the present invention and the conventional method, respectively.
  • Figure 2 shows the yield based on the self-induced heating characteristics of superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 produced by the manufacturing method of the present invention and the conventional method, respectively.
  • Figure 3 is an AC magnetic field generation system for magnetically inducing heat generation in the superparamagnetic nanoparticles of the present invention.
  • Figure 4 is a graph showing alternating current magnetic induction self-heating characteristics of superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 synthesized in an example of the present invention.
  • Figure 5 shows the results of visual observation of changes in tumor size over time in the control FSaLL mouse tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field.
  • Figure 6 shows the tumor size of the control FSaLL mouse tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applied an alternating magnetic field through tissue staining.
  • Figure 7 shows the results of confirming the expression levels of Ki67, Active-caspase3, and TUNEL in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 8 shows the results of confirming the expression levels of CD31 (PECAM-1) and CD3 (T cells) in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 9 shows the results of confirming the expression levels of CD4 and CD8 in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 10 shows the results of confirming the expression levels of CD161a and Iba1 in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 11 shows the results of confirming the expression levels of CD45RA, CD138, and Ly6c in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 12 shows the results of confirming the expression levels of HSP60 and HSP70 in the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field compared to the control FSaLL mouse tumor model.
  • Figure 13 shows the change in tumor temperature over time after superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 were administered to the U87MG mouse tumor model and a magnetic field was applied.
  • Figure 14 shows the experimental group in which superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 were administered and an alternating magnetic field was applied (experimental group 1: 3 alternating magnetic fields applied, experimental group 2: 6 alternating magnetic fields applied) compared to the control FSaLL mouse tumor model. This shows the change in tumor size.
  • Figure 15 shows the U87MG tumor model (control), a group administered Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles to the U87MG tumor model (MNP group), and Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles to the U87MG tumor model.
  • This shows the brain MR image of the group (MNP + AMF group) that was administered and the magnetic field was applied three times.
  • Figure 16 shows the change in tumor size in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applied an alternating magnetic field.
  • Figure 17 shows the results of confirming the expression levels of Ki67, Active-caspase3, and TUNEL in the U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applied an alternating magnetic field.
  • Figure 18 shows the results of confirming the expression levels of CD45RA and CD138 in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field.
  • Figure 19 shows the results of confirming the expression levels of CD3 and Ly6C in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field.
  • Figure 20 shows the results of confirming the expression levels of CD4 and CD8 in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field.
  • Figure 21 shows the results of confirming the expression levels of CD161 and Iba1 in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applying an alternating magnetic field.
  • Figure 22 shows the results of confirming the expression levels of HSP60 and HSP70 in the control U87MG tumor model and the experimental group administered superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and applied an alternating magnetic field.
  • Figures 23 to 25 show the results of observing the distribution of nanoparticles and immune cells on the surface of cancer tissue before and after administration of superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and application of an alternating magnetic field to the U87MG tumor model using a fluorescence microscope (red) : nanoparticles, green: fluorescent marker, blue: blood vessels, white: immune cells).
  • Figures 26 to 31 show the results of observing the distribution of nanoparticles and immune cells inside cancer tissue before and after administration of superparamagnetic nanoparticles Mn 0.5 Zn 0.5 Fe 2 O 4 and application of an alternating magnetic field to the U87MG tumor model using a fluorescence microscope (red) : nanoparticles, green: fluorescent marker, blue: blood vessels, white: immune cells).
  • Fe (III) acetylacetonate Fe(acac) 3 , Aldrich Chemical Co.
  • Mn (II) acetate tetrahydrate Aldrich Chemical Co.
  • Zn (II) acetate dihydrate Zn acetate dihydrate, Aldrich Chemical Co.
  • Oleic acid Aldrich Chemical Co.
  • Oleylamine Aldrich Chemical Co.
  • Benzylether Aldrich Chemical Co.
  • 1,2-hexadecanediol 1,2-hexadecanediol
  • Step 4 After adding 20 mL of benzyl ether, the flask was fixed inside a heating mantle for a round bottom flask, heated to 280°C for 20 minutes at a rate of 12 to 13°C/min, and then cooled to 270°C for 1 hour. (Step 2). Afterwards, it was heated to 296.5°C for 10 minutes at a rate of 2 to 3°C/min and the temperature was maintained for 46.5 minutes (step 3). After lowering the temperature to 80°C, 40 mL of ethanol was added to prepare Mn 0.5 Zn 0.5 Fe 2 O 4 (step 4).
  • the synthesized nanoparticles were coated with Methoxy-PEG-Silane, a biocompatible polymer of 500 Da (Dalton).
  • Methoxy-PEG-Silane a biocompatible polymer of 500 Da (Dalton).
  • the surface of the synthesized nanoparticles was first modified with oleic acid. Oleic acid (3 mL) and NH 4 Cl (0.7 mL) were added together with the nanoparticles in the ethanol solution. The mixture was stirred vigorously for 2 hours, and then the nanoparticles were precipitated by a permanent magnet and washed with acetone to obtain oleic acid-coated nanoparticles.
  • Nanoparticles coated with oleic acid were dispersed in toluene (7.5 mL), and then triethylamine (3.75 mL) and methoxy-PEG-silane 500 Da (0.75 mL) were added. The mixed solution was stirred well for 24 hours. The PEG-coated nanoparticles in the solution were washed with pentane and dispersed in water to create a nanofluid solution.
  • the thermal properties of Mn 0.5 Zn 0.5 Fe 2 O 4 prepared by the method of Example 1-1 and Mn 0.5 Zn 0.5 Fe 2 O 4 prepared by the conventional method were compared.
  • the conventional method uses a hot plate instead of a heating mantle in the manufacturing method of Example 1-1, and in the second step, it is heated to 200°C for 20 minutes at a rate of 8 to 9°C/min for 1 hour. There is a difference in maintaining it and heating it to 296.5°C for 10 minutes at a rate of 9 to 10°C/min in the third stage.
  • thermal properties were measured using a specially designed AC magnetic field generation system consisting of an AC coil, capacitor, DC power source, wave generator, and PC system.
  • AC magnetic field generation systems operate in a wide frequency range from 0 to 380 KHz with magnetic field strengths of up to 350 Oe without any harmful effects on the human body.
  • nanoparticles have different AC heating capabilities depending on the material, particle size, and size distribution, it is necessary to be able to evaluate the AC heating capacity of various nanoparticles over a wide range of frequencies and magnetic fields.
  • the total amount of solid nanoparticles measured for AC heating properties was fixed at 60 mg in an Eppendorf-tube.
  • each sample was placed on insulating Styrofoam in the center of the sample bed.
  • the tip of the optical fiber was placed inside an Eppendorf tube containing solid Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles prepared by the manufacturing method using the heating mantle of Example 1-1 and the manufacturing method using a conventional hot plate, respectively, were subjected to 8 different frequencies ( 31.9, 47.0, 98.9, 140.0, 168.1, 195.5, 239.9, 360.2 kHz) and five different magnetic field strengths (80,100,120,140,160 Oe).
  • the total magnetic field generation time is 600 seconds for each measurement.
  • the AC heating temperature was measured with an optical thermometer and cooled when the magnetic field was turned off.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 manufactured by the manufacturing method using the heating mantle of Example 1-1 and the manufacturing method using a conventional hot plate were replaced with Mn prepared by the conventional method. It shows stable thermal properties compared to 0.5 Zn 0.5 Fe 2 O 4 ( Figure 1, a: conventional method, b: method of Example 1-1), and all samples showed heat generation above 50°C, resulting in excellent superparamagnetic nano with 100% yield. It was confirmed that the particles were produced, and when produced by the conventional method, it was confirmed that superparamagnetic nanoparticles exhibiting heat generation above 50°C were produced with a yield of 49% ( Figure 2, a: conventional method, b: Example 1-1 method).
  • the heating characteristics induced by an alternating current (AC) magnetic field of the Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles manufactured by the manufacturing method using the heating mantle of Example 1-1 are suitable for use in AC coils, capacitors, DC power sources, Measurements were made using a specially designed AC magnetic field generation system consisting of a wave generator and a PC system ( Figure 3).
  • AC alternating current
  • mice used in this experiment were anesthetized and FSaLL cells (radiation-induced fibrosarcoma of C3H mice created in the Dr. Herman Suit laboratory at Massachusetts General Hospital, early generation cells donated by Dr. Suit) were used. used) (5 x 10 6 cells/50 ⁇ L) was administered by subcutaneous injection into the proximal femur of Balb/c nude mice (FSaLL mouse tumor model).
  • glioblastoma model 5 x 10 5 cells/5 ⁇ L of glioblastoma cells (U87MG) were injected into the brain of a nude mouse (U87MG mouse tumor model).
  • the FSaLL mouse tumor model was anesthetized and 100 ⁇ L (30 mg/mL) of PEG-coated Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were injected into the center of the induced tumor.
  • the mouse was placed in the center of the AC coil system for magnetic hyperthermia, and a magnetic field was applied at an intensity of 140 Oe and a frequency of 100 kHz.
  • a magnetic field was applied six times, for 20 minutes each time.
  • tissue staining using H&E staining and Prussian Blue confirmed that the size of the tumor was significantly reduced ( Figure 6).
  • H&E and Prussian Blue staining methods are widely used in medical diagnosis, and the composition of the tissue can be confirmed by biopsying tissue suspected of cancer through pathology and staining tissue sections with H&E and Prussian Blue staining methods.
  • CD161a a natural killer cell (NK cell), and Iba1, a macrophage, significantly increased in the experimental group compared to the control group ( Figure 10), CD45RA (naive T cell, B cell), and CD138 (plasma cell). ), Ly6c, a macrophage, significantly increased ( Figure 11), confirming that immune cells increased in the experimental group administered superparamagnetic nanoparticles.
  • HSP60 and HSP70 are representative heat shock proteins (HSP) that are responsible for the activation of immune cells such as macrophages and lymphocytes, and dendrite cells. It is well known to activate antigen presentation through activation and maturation of cells.
  • the U87MG mouse tumor model was anesthetized and 5 ⁇ L (30 mg/mL) of Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles was injected into the mouse brain.
  • the mouse was placed in the center of the AC coil system for magnetic hyperthermia, and a magnetic field was applied at an intensity of 140 Oe and a frequency of 100 kHz.
  • a magnetic field was applied 6 times for 20 minutes each time, and while the magnetic field was applied, the temperature of the tumor increased from 36.63°C to a maximum of 38.65°C and then decreased, as shown in Figure 13.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were administered to the control U87MG tumor model (control) and U87MG tumor model, and 5 ⁇ L of Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were treated and then an alternating magnetic field was applied 3 or 6 times.
  • IVIS images stained with GFP and luciferase in experimental groups 1 and 2 that underwent heat treatment MHT
  • the size of the tumor significantly increased in the control group, while the size of the tumor decreased in experimental groups 1 and 2. This was confirmed ( Figure 14).
  • the U87MG tumor model (control), a group administered Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles to the U87MG tumor model (MNP group), and the group administered Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles to the U87MG tumor model.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles had immunotherapy efficacy by inducing an increase in immune cells such as macrophages, natural killer cells, and T cells.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles were administered to the U87MG tumor model, and then the distribution of nanoparticles and immune cells in the cancer tissue before and after applying an alternating magnetic field was observed using a fluorescence microscope.
  • Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles 10 mg/kg were intraarterially injected into the carotid artery of the mouse model ( It was administered by intra-arterial injection and imaged with IVM-CM (Fontocal & Two-photon convertible microscopy) at 1-day intervals for a total of 4 days starting the day after administration. The same location was tracked and imaged at each time point, and the excitation laser source (Ex) and emission spectra (Em) for each fluorescent marker are as follows.
  • Blood vessels (fluorescent marker: CD31-mFluor405) Ex. 405, Em. 425-465; Tumor (fluorescent marker: U87MG-GFP) Ex. 488, Em. 500-550l; Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticle Ex. 640, Em. 663-733.

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Abstract

La présente invention concerne un procédé de préparation de nanoparticules superparamagnétiques pour l'immunothérapie. Les nanoparticules superparamagnétiques préparées par le procédé de préparation de la présente invention présentent des caractéristiques de chauffage induites par magnétique stables et une biocompatibilité élevée, peuvent ainsi être appliquées par injection in vivo et induire une augmentation des immunocytes de façon à être efficacement utilisées dans le traitement du cancer et de maladies immunitaires.
PCT/KR2023/011971 2022-08-17 2023-08-11 Procédé de préparation de nanoparticules d'oxyde de fer superparamagnétiques pour immunothérapie WO2024039148A1 (fr)

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