KR20240024457A - Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy - Google Patents
Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy Download PDFInfo
- Publication number
- KR20240024457A KR20240024457A KR1020220102440A KR20220102440A KR20240024457A KR 20240024457 A KR20240024457 A KR 20240024457A KR 1020220102440 A KR1020220102440 A KR 1020220102440A KR 20220102440 A KR20220102440 A KR 20220102440A KR 20240024457 A KR20240024457 A KR 20240024457A
- Authority
- KR
- South Korea
- Prior art keywords
- nanoparticles
- superparamagnetic nanoparticles
- cancer
- heating
- cells
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 36
- 238000009169 immunotherapy Methods 0.000 title abstract description 7
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 title 1
- 229940031182 nanoparticles iron oxide Drugs 0.000 title 1
- 239000002105 nanoparticle Substances 0.000 claims abstract description 139
- 238000010438 heat treatment Methods 0.000 claims abstract description 45
- 239000011572 manganese Substances 0.000 claims description 65
- 239000000203 mixture Substances 0.000 claims description 54
- 238000001816 cooling Methods 0.000 claims description 22
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 12
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 12
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 12
- 239000005642 Oleic acid Substances 0.000 claims description 12
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000011575 calcium Substances 0.000 claims description 12
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 12
- 239000011777 magnesium Substances 0.000 claims description 12
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- NLTSCOZQKALPGZ-UHFFFAOYSA-N acetic acid;dihydrate Chemical compound O.O.CC(O)=O NLTSCOZQKALPGZ-UHFFFAOYSA-N 0.000 claims description 9
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 8
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 claims description 8
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 8
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 claims description 8
- JXNCBISRWFPKJU-UHFFFAOYSA-N acetic acid;manganese Chemical compound [Mn].CC(O)=O JXNCBISRWFPKJU-UHFFFAOYSA-N 0.000 claims description 8
- -1 cationic metals Chemical class 0.000 claims description 8
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 8
- BTOOAFQCTJZDRC-UHFFFAOYSA-N 1,2-hexadecanediol Chemical compound CCCCCCCCCCCCCCC(O)CO BTOOAFQCTJZDRC-UHFFFAOYSA-N 0.000 claims description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 6
- GYHNNYVSQQEPJS-UHFFFAOYSA-N Gallium Chemical compound [Ga] GYHNNYVSQQEPJS-UHFFFAOYSA-N 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 6
- 229910052733 gallium Inorganic materials 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 229910052748 manganese Inorganic materials 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- JBQYATWDVHIOAR-UHFFFAOYSA-N tellanylidenegermanium Chemical compound [Te]=[Ge] JBQYATWDVHIOAR-UHFFFAOYSA-N 0.000 claims description 6
- 125000002091 cationic group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 93
- 201000011510 cancer Diseases 0.000 abstract description 42
- 210000002865 immune cell Anatomy 0.000 abstract description 39
- 238000002347 injection Methods 0.000 abstract description 10
- 239000007924 injection Substances 0.000 abstract description 10
- 208000026278 immune system disease Diseases 0.000 abstract description 8
- 238000001727 in vivo Methods 0.000 abstract description 5
- 230000001939 inductive effect Effects 0.000 abstract description 3
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 57
- 239000011701 zinc Substances 0.000 description 54
- 238000000034 method Methods 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 29
- 230000036737 immune function Effects 0.000 description 27
- 230000001965 increasing effect Effects 0.000 description 27
- 238000011282 treatment Methods 0.000 description 27
- 241000699666 Mus <mouse, genus> Species 0.000 description 20
- 210000002540 macrophage Anatomy 0.000 description 18
- 230000007423 decrease Effects 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 238000002619 cancer immunotherapy Methods 0.000 description 13
- 239000008194 pharmaceutical composition Substances 0.000 description 13
- 230000036039 immunity Effects 0.000 description 11
- 210000000822 natural killer cell Anatomy 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 10
- 238000002512 chemotherapy Methods 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 230000002708 enhancing effect Effects 0.000 description 9
- 230000028993 immune response Effects 0.000 description 8
- 238000011394 anticancer treatment Methods 0.000 description 7
- 239000002246 antineoplastic agent Substances 0.000 description 7
- 238000009826 distribution Methods 0.000 description 7
- 210000000581 natural killer T-cell Anatomy 0.000 description 7
- 201000008808 Fibrosarcoma Diseases 0.000 description 6
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 6
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 6
- 239000002202 Polyethylene glycol Substances 0.000 description 6
- 210000001744 T-lymphocyte Anatomy 0.000 description 6
- 210000004204 blood vessel Anatomy 0.000 description 6
- 239000003550 marker Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 208000023275 Autoimmune disease Diseases 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000002122 magnetic nanoparticle Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 101150053137 AIF1 gene Proteins 0.000 description 4
- 102000017420 CD3 protein, epsilon/gamma/delta subunit Human genes 0.000 description 4
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 4
- 102000006303 Chaperonin 60 Human genes 0.000 description 4
- 108010058432 Chaperonin 60 Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 4
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 4
- 206010020843 Hyperthermia Diseases 0.000 description 4
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 description 4
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- 208000005017 glioblastoma Diseases 0.000 description 4
- 230000020169 heat generation Effects 0.000 description 4
- 230000036031 hyperthermia Effects 0.000 description 4
- 238000010172 mouse model Methods 0.000 description 4
- 210000000056 organ Anatomy 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000001356 surgical procedure Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229920000249 biocompatible polymer Polymers 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- DCYOBGZUOMKFPA-UHFFFAOYSA-N iron(2+);iron(3+);octadecacyanide Chemical compound [Fe+2].[Fe+2].[Fe+2].[Fe+3].[Fe+3].[Fe+3].[Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] DCYOBGZUOMKFPA-UHFFFAOYSA-N 0.000 description 3
- 229960003351 prussian blue Drugs 0.000 description 3
- 239000013225 prussian blue Substances 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 230000004936 stimulating effect Effects 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 238000011729 BALB/c nude mouse Methods 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 2
- 102000013462 Interleukin-12 Human genes 0.000 description 2
- 108010065805 Interleukin-12 Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 239000005089 Luciferase Substances 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 101100182715 Mus musculus Ly6c2 gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 108010069381 Platelet Endothelial Cell Adhesion Molecule-1 Proteins 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 238000009098 adjuvant therapy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003990 capacitor Substances 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000011284 combination treatment Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- UFNVPOGXISZXJD-JBQZKEIOSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-JBQZKEIOSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 206010017758 gastric cancer Diseases 0.000 description 2
- 208000024963 hair loss Diseases 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229940117681 interleukin-12 Drugs 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000007447 staining method Methods 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000007669 thermal treatment Methods 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- LOGFVTREOLYCPF-KXNHARMFSA-N (2s,3r)-2-[[(2r)-1-[(2s)-2,6-diaminohexanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoic acid Chemical compound C[C@@H](O)[C@@H](C(O)=O)NC(=O)[C@H]1CCCN1C(=O)[C@@H](N)CCCCN LOGFVTREOLYCPF-KXNHARMFSA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 238000011735 C3H mouse Methods 0.000 description 1
- 208000025721 COVID-19 Diseases 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 201000003066 Diffuse Scleroderma Diseases 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000007465 Giant cell arteritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000025370 Middle East respiratory syndrome Diseases 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229920006328 Styrofoam Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 206010043781 Thyroiditis chronic Diseases 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000011319 anticancer therapy Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000030741 antigen processing and presentation Effects 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 208000002399 aphthous stomatitis Diseases 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 230000003416 augmentation Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 229960001714 calcium phosphate Drugs 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- 229960003340 calcium silicate Drugs 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 190000008236 carboplatin Chemical compound 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- INSRQEMEVAMETL-UHFFFAOYSA-N decane-1,1-diol Chemical compound CCCCCCCCCC(O)O INSRQEMEVAMETL-UHFFFAOYSA-N 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 229960003649 eribulin Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940118951 halaven Drugs 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000009217 hyperthermia therapy Methods 0.000 description 1
- 230000002977 hyperthermial effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 208000003669 immune deficiency disease Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- LZKLAOYSENRNKR-LNTINUHCSA-N iron;(z)-4-oxoniumylidenepent-2-en-2-olate Chemical compound [Fe].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O LZKLAOYSENRNKR-LNTINUHCSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000002025 microglial effect Effects 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000013307 optical fiber Substances 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000008261 styrofoam Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000007761 synergistic anti-cancer Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- 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
- 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
- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
-
- 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
Abstract
본 발명은 면역 치료용 초상자성 나노입자의 제조방법에 관한 것이다.
본 발명의 제조방법에 의해 제조된 초상자성 나노입자는 안정적인 자기 유도 발열 특성 및 높은 생체적합성을 나타내어, 생체 내 주입을 통한 적용이 가능하며, 면역세포의 증가를 유도하여 암 및 면역질환 치료에 유용하게 사용될 수 있다.The present invention relates to a method for producing superparamagnetic nanoparticles for immunotherapy.
The superparamagnetic nanoparticles produced by the manufacturing method of the present invention exhibit stable magnetically induced heating characteristics and high biocompatibility, allowing application through in vivo injection, and are useful for treating cancer and immune diseases by inducing an increase in immune cells. It can be used effectively.
Description
본 발명은 면역 치료용 초상자성 나노입자의 제조방법에 관한 것이다.The present invention relates to a method for producing superparamagnetic nanoparticles for immunotherapy.
현대에 들어서 많은 질병들이 치료가 쉽게 가능하게 되었고, 치료가 불가능한 병은 거의 없어졌지만, 암은 다른 질병치료와는 달리 매우 힘들고 복잡한 치료가 요구되고 있으며, 그 복잡한 치료들 또한 완벽하게 효과적이지 못하다. 현재 암 치료에 사용되고 있는 방법은 크게 수술, 방사선 치료와 화학치료가 있다. 암에 걸리면 암을 제거하기 위하여 수술을 하게 되는데, 암이 멀리 퍼지지 않고 국소적으로만 있을 경우에는 수술로도 완치가 가능하다. 하지만 환자의 70%이상이 암 전이가 일어나는 경향이 있어서 보조 치료요법들이 병행된다. 보조 치료요법 중 하나인 방사선 치료는 고 에너지 방사선을 이용하여 암세포를 죽이는 치료법으로서 방사선을 암에 쪼일 경우, 암세포를 즉각 죽이지는 못하나 암세포가 증식하는 기능을 파괴하여 새로운 암세포가 생성되지 못하고 더 이상 분열하지 못하게 한다. 하지만 이 방법은 암세포뿐만 아니라 정상세포에도 영향을 끼친다는 부작용이 존재한다. 화학치료는 수술 후에 약을 사용하여 암세포를 죽이는 보조 치료법으로서 눈에 보이지 않는 암세포를 죽이기 위해 시행한다. 하지만 화학요법 역시 화학요법을 시행하면 구토, 설사, 탈모 등의 부작용이 뒤따를 수 있다.In modern times, many diseases have become easily treatable, and incurable diseases have almost disappeared, but 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. Don't let it happen. However, this method has the side effect of affecting not only cancer cells but also normal cells. Chemotherapy is an auxiliary treatment that uses drugs to kill cancer cells after surgery and is performed to kill invisible cancer cells. However, chemotherapy can also cause side effects such as vomiting, diarrhea, and hair loss.
이러한 부작용들을 최소화하고자, 최근 면역치료 방법이 대두되고 있다. 또한 앞서 언급했듯이 암 전이율은 전체환자의 70%가 넘기 때문에 전이암을 치료하는 것이 암을 완치하는 데에 있어서 필수적이라 볼 수 있고, 면역치료는 이러한 면에서 매우 효과적인 치료 방법이다.To minimize these side effects, immunotherapy methods have recently emerged. Additionally, as mentioned earlier, the cancer metastasis rate exceeds 70% of all patients, so treating metastatic cancer is essential for curing cancer, and immunotherapy is a very effective treatment method in this regard.
면역치료는 환자 체내의 면역반응을 이용하여 질병을 치료하는 방법이다. 그러나 현재까지 사용되는 대부분의 자가면역질환 치료제로는 근본적인 질병의 원인을 억제하는 치료제가 아닌 과도한 염증 반응을 억제하는 면역 억제제를 처방하는 경향이 있으며, 최근 연구를 통해 개발된 생물학적 제제 또한 완치를 위한 근본적인 치료제가 되지 못하는 실정이다.Immunotherapy is a method of treating disease using the patient's body's immune response. However, 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.
한편, 자성 나노입자는 교류 자기장에 노출되었을 시에 자기 유도 발열 특성을 가지게 되며, 원하는 부위에 특이적으로 노출된 고열 효과는 다양한 치료에 응용될 수 있다. 최근에는 온열 치료(Hyperthermia therapy)와 화학적 요법, 방사선 요법을 조합한 새로운 형태의 치료 방법이 각광받고 있다.Meanwhile, 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. Recently, a new type of treatment method that combines hyperthermia therapy, chemotherapy, and radiation therapy has been in the spotlight.
이러한 배경 하에서, 본 발명자들은 면역 기능을 증강시켜 암, 면역질환 또는 항암요법에 의한 부작용을 극복할 수 있는 매체에 대해 예의 연구 노력한 결과, 면역기능을 증강할 수 있도록 안정적인 열특성을 지닌 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 제조하여 본 발명을 완성하였다.Under this background, 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. As a result, 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 .
본 발명은 전술한 문제 및 이와 연관된 다른 문제를 해결하는 것을 목적으로 한다.The present invention aims to solve the above-described problems and other problems associated therewith.
본 발명의 일 예시적 목적은 다음의 단계를 포함하는, 하기 일반식 1로 표시되는 초상자성 나노입자의 제조방법을 제공하는 것이다.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.
일반식 1 General formula 1
KxLyFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)K x L y Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)
여기서, K 또는 L은 리튬(Li), 나트륨(Na). 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄 (Al), 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.Here, 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).
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 용기에서 혼합하여 혼합물을 제조하는 단계;(a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine, and benzyl ether were mixed in a container to form a mixture. manufacturing step;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.(d) cooling the mixture to 70 to 90° C. after the holding.
본 발명의 다른 예시적 목적은 다음의 단계를 포함하는, 하기 일반식 2로 표시되는 초상자성 나노입자의 제조방법을 제공하는 것이다.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.
일반식 2General formula 2
KxLyMzFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)K x L y M z Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)
여기서, K, L 또는 M은 리튬(Li), 나트륨(Na). 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄 (Al) 또는 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.Here, 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).
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 혼합하여 혼합물을 제조하는 단계; (a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine and benzyl ether are mixed to prepare a mixture. step;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.(d) cooling the mixture to 70 to 90° C. after the holding.
본 발명의 또 다른 예시적 목적은 상기 제조방법으로 제조된 초상자성 나노입자를 제공하는 것이다.Another exemplary object of the present invention is to provide superparamagnetic nanoparticles prepared by the above production method.
본 명세서에 개시된 발명의 기술적 사상에 따라 이루고자 하는 기술적 과제는 이상에서 언급한 문제점을 해결하기 위한 과제로 제한되지 않으며, 언급되지 않은 또 다른 과제는 아래의 기재로부터 통상의 기술자에게 명확하게 이해될 수 있을 것이다.The technical problem to be achieved according to the technical idea of the invention disclosed in this specification is not limited to the problem to solve the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 출원에서 개시된 각각의 설명 및 실시형태는 각각의 다른 설명 및 실시 형태에도 적용될 수 있다. 즉, 본 출원에서 개시된 다양한 요소들의 모든 조합이 본 출원의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 출원의 범주가 제한된다고 볼 수 없다.This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Additionally, the scope of the present application cannot be considered limited by the specific description described below.
상기 목적을 달성하기 위한 일 양태로서, 본 발명은 다음의 단계를 포함하는, 하기 일반식 1로 표시되는 초상자성 나노입자의 제조방법을 제공한다.As an aspect for achieving the above object, the present invention provides a method for producing superparamagnetic nanoparticles represented by the following general formula 1, including the following steps.
일반식 1 General formula 1
KxLyFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)K x L y Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)
여기서, K 또는 L은 리튬(Li), 나트륨(Na). 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄 (Al), 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.Here, 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).
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 혼합하여 혼합물을 제조하는 단계;(a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine and benzyl ether are mixed to prepare a mixture. step;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.(d) cooling the mixture to 70 to 90° C. after the holding.
본 발명에 있어서, 상기 (b)단계의 가열은 12 내지 13℃/min 속도로 10 내지 30분간 이루어질 수 있고, 구체적으로 12 내지 13℃/min 속도로 20분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (b)단계의 냉각은 30분 내지 120분간 이루어질 수 있고, 구체적으로 30 내지 90분간 이루어질 수 있으며, 더욱 구체적으로 30분 내지 60분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (c)단계의 가열은 2 내지 3℃/min 속도로 5 내지 20분간 이루어질 수 있고, 구체적으로 5 내지 10분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (c)단계의 유지는 10 내지 60분간 이루어질 수 있고, 구체적으로 20 내지 50분간 이루어질 수 있으며, 더욱 구체적으로 30분 내지 50분간 이루어질 수 있고 더욱 구체적으로 40 내지 50분간 이루어질 수 있다.In the present invention, the maintenance of 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.
본 발명에 있어서, 상기 일반식 1의 x 및 y는 0과 3사이의 수로, 예컨대, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. 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 또는 3.0일 수 있다.In the present invention, 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.
본 발명에 있어서 상기 초상자성 나노입자는 MnxZn1-xFe2O4일 수 있으며, 더욱 구체적으로, 상기 초상자성 나노입자는 Mn0.5Zn0.5Fe2O4일 수 있다.In the present invention, 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 .
본 발명의 다른 양태로서, 본 발명은 다음의 단계를 포함하는, 하기 일반식 2로 표시되는 초상자성 나노입자의 제조방법을 제공한다.In another aspect of the present invention, the present invention provides a method for producing superparamagnetic nanoparticles represented by the following general formula 2, comprising the following steps.
일반식 2General formula 2
KxLyMzFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)K x L y M z Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)
여기서, K, L 또는 M은 리튬(Li), 나트륨(Na). 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄 (Al) 또는 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.Here, 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).
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 혼합하여 혼합물을 제조하는 단계; (a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine and benzyl ether are mixed to prepare a mixture. step;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.(d) cooling the mixture to 70 to 90° C. after the holding.
구체적으로, 상기 x, y 및 z는 0과 3사이의 수로, 예컨대, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9. 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 또는 3.0일 수 있다.Specifically, 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.
본 발명에 있어서, 상기 (b)단계의 가열은 12 내지 13℃/min 속도로 10 내지 30분간 이루어질 수 있고, 구체적으로 12 내지 13℃/min 속도로 20분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (b)단계의 냉각은 30분 내지 120분간 이루어질 수 있고, 구체적으로 30 내지 90분간 이루어질 수 있으며, 더욱 구체적으로 30분 내지 60분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (c)단계의 가열은 2 내지 3℃/min 속도로 5 내지 20분간 이루어질 수 있고, 구체적으로 5 내지 10분간 이루어질 수 있다.In the present invention, 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.
본 발명에 있어서, 상기 (c)단계의 유지는 10 내지 60분간 이루어질 수 있고, 구체적으로 20 내지 50분간 이루어질 수 있으며, 더욱 구체적으로 30분 내지 50분간 이루어질 수 있고 더욱 구체적으로 40 내지 50분간 이루어질 수 있다.In the present invention, the maintenance of 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.
본 발명의 일 구현예에서, 상기 초상자성 나노입자의 제조는 히팅 맨틀(heating mantle)을 이용하여 이루어지는 것일 수 있다.In one embodiment of the present invention, the superparamagnetic nanoparticles may be manufactured using a heating mantle.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 제조방법으로 제조된 초상자성 나노입자를 제공한다.As another aspect for achieving the above object, the present invention provides superparamagnetic nanoparticles prepared by the above production method.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는 암 면역 치료용 조성물을 제공한다.As another aspect for achieving the above object, the present invention provides a composition for cancer immunotherapy comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
구체적으로, 상기 초상자성 나노입자는 MnxZn1-xFe2O4일 수 있으며, 더욱 구체적으로, 상기 초상자성 나노입자는 Mn0.5Zn0.5Fe2O4일 수 있다.Specifically, 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 .
본 발명에 있어서, 상기 초상자성 나노입자는 생체적합성 고분자로 코팅될 수 있다.In the present invention, the superparamagnetic nanoparticles may be coated with a biocompatible polymer.
본 발명에 사용될 수 있는 인체에 유용한 생체적합성 고분자 물질로는, 다양한 용매에 쉽게 용해될 수 있는 고분자로서, 예를 들어 Poly Ethyleneglycol (PEG), poly(lactide-co-glycolide) (PLGA), Poly(DL-lactide-co-glycolide) (PDLGA), poly(hydroxybutyrate) 및 Polycaprolactone (PCL) 군으로부터 선택되는 하나 이상일 수 있고, 구체적으로 Poly Ethyleneglycol일 수 있다.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.
본 발명의 용어 "암 면역 치료"는 환자 체내의 면역 반응을 이용하여 암을 치료하는 방법으로, 암에 특이적인 면역 세포들을 활성화시킨 후, 활성화된 면역 세포들이 체내에서 암을 특이적으로 공격하게 하여 치료하는 방법이다.The term "cancer immunotherapy" of the present invention 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.
본 발명에 있어서, 상기 암 면역 치료는 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는 암 면역 치료용 조성물은 직접 체내 주입에 의한 방식으로 치료 효능을 달성할 수 있다.The 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.
본 발명에 따른 초상자성 나노입자를 포함하는 암 면역 치료용 조성물은, 표적 기관에 분산되어있는 자성 나노입자 적용시 외부 자기장과 지속적으로 반응할 수 있기 때문에 고온을 선택적으로 균일하게 발생시킬 수 있다. 이러한 치료 방법은 단독의 치료 방법으로서 또는 종래의 치료 방법과 병행하여, 또는 보조적으로 수행될 수 있다.The 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.
구체적으로, 본 발명의 실시예에서는, 섬유육종 마우스 모델 및 교모세포종 마우스 모델에 각각 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 주입하고 교류 자기장을 인가한 결과, 암세포 주변에 대식세포, 자연살상세포 및 T 세포 등의 면역세포의 증가가 발생하고 종양의 크기가 줄어드는 것을 확인하였다.Specifically, in an embodiment of the present invention, 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.
본 발명의 암 면역 치료용 조성물은 통상적으로 약제학적 조성물로 제공된다. 따라서, 본 발명의 암 면역 치료용 조성물은 약제학적으로 허용되는 담체를 포함한다. 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것 으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록 시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘, 또는 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences, 19th ed., 1995에 상세히 기재되어 있다.The 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.
본 발명의 암 면역 치료용 조성물은 비경구 방식으로 투여되는 것이 바람직하다. 비경구 투여를 하는 경우, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 또는 병변내(intralesional) 주입 등으로 투여할 수 있다. 본 발명의 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 암 면역 치료용 조성물은 치료학적 유효량의 자기 유도 발열 효과를 나타내는 초상자성 나노입자를 포함한다. 용어 "치료학적 유효량" 은 치료 목적의 질환을 치료할 수 있는 충분한 양을 의미하며, 일반적으로 0.0001-100 mg/kg이다. The composition for cancer immunotherapy of the present invention is preferably administered 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. The term “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.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나, 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일, 또는 수성 매질중의 용액, 현탁액, 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제, 또는 캅셀제 형태일 수도 있으며, 분산제, 또는 안정화제를 추가적으로 포함할 수 있다. 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.
본 발명에 있어서, 상기 암은 섬유육종, 뇌암, 폐암, 대장암, 간암, 유방암, 위암, 난소암, 피부암, 췌장암, 전립선, 신장암 또는 갑상선암일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는 면역질환 치료용 조성물을 제공한다.As another aspect for achieving the above object, the present invention provides a composition for treating immune diseases comprising superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient.
상기 초상자성 나노입자는 전술한 바와 같다.The superparamagnetic nanoparticles are as described above.
본 발명에 있어서, 상기 면역질환 치료는 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는 면역질환 치료용 조성물은 직접 체내 주입에 의한 방식으로 치료 효능을 달성할 수 있다.The 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.
본 발명에 따른 초상자성 나노입자를 포함하는 면역질환 치료용 조성물은, 표적 기관에 분산되어있는 자성 나노입자 적용시 외부 자기장과 지속적으로 반응할 수 있기 때문에 고온을 선택적으로 균일하게 발생시킬 수 있다. 이러한 치료 방법은 단독의 치료 방법으로서 또는 종래의 치료 방법과 병행하여, 또는 보조적으로 수행될 수 있다.The 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.
본 발명의 면역질환 치료용 조성물은 통상적으로 약제학적 조성물로 제공된다. 상기 약제학적 조성물의 허용되는 담체, 투여 및 제조는 전술한 바와 같다. The 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.
상기 면역질환은 인체의 면역이 저하된 질환 또는 인체의 면역이 항진된 질환을 포함할 수 있으며, 구체적으로 면역결핍질환, 감염질환 또는 자가면역질환을 포함할 수 있다.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.
상기 인체의 면역이 저하된 질환으로는 대표적으로 선천성 면역 결핍질환, 후천성 면역 결핍 질환, 세균성 및 바이러스성 감염질환 (예를 들어, 각종 세균성 감염질환, COVID-19, SARS, MERS 등을 포함한 난치성 바이러스 감염)을 포함할 수 있으나, 이에 제한되지 않는다. 이러한 인체의 면역이 제한된 질환의 경우 교류 자기장을 인가한 초자성 나노입자에 의해 온도를 적당히 조절하여 발열이 많이 나지 않게 하여 기능이 손상된 면역세포를 활성화 시킬 수 있다. 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. In the case of diseases where the body's immunity is limited, the temperature can be adjusted appropriately using supermagnetic nanoparticles applied with an alternating magnetic field to prevent excessive heat generation and activate dysfunctional immune cells.
상기 인체의 면역이 항진된 질환은 자가면역질환을 포함할 수 있으나 이에 제한되지 않는다. 이러한 인체의 면역이 항진된 질환의 경우 교류 자기장을 인가한 초자성 나노입자에 의해 열을 발생시켜 기능이 항진된 면역세포를 파괴하여 질환을 치료할 수 있다.The disease in which the body's immunity is enhanced may include, but is not limited to, an autoimmune disease. In the case of diseases in which the body's immunity is enhanced, the disease can be treated by generating heat using supermagnetic nanoparticles applied with an alternating magnetic field to destroy the hyperfunctioning immune cells.
본 발명에 있어서, 상기 자가면역질환은 루푸스(전신 홍반성 낭창), 류머티스성 관절염(rheumatoid arthritis), 전신성 경피증 (Progressive systemic sclerosis,Scleroderma), 아토피 피부염, 원형탈모증(alopecia areata), 건선, 천포창, 천식, 아프타구내염, 만성 갑상선염, 염증성 장염, 베체씨병(Behcet's disease), 크론씨병, 피부근염 (dermatomyositis), 다발성 근염(polymyositis), 다발성 경화증(multiple sclerosis), 자가면역성 용혈성 빈혈 (Autoimmune hemolytic anemia), 자가면역성 뇌척수염, 중증 근무력증(Myasthenia gravis), 그레이브씨 갑상선 항진증(Grave's disease), 결절성 다발성 동맥염(Polyarteritis nodosa), 강직성 척추염(Ankylosing spondylitis), 섬유조직염(Fibromyalgia syndrome) 및 측두동맥염(Temporal arteritis)으로 구성된 군으로부터 선택되는 것일 수 있다.In the present invention, 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 .
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는 면역증강용 조성물을 제공한다.As another aspect for achieving the above object, 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.
상기 초상자성 나노입자는 전술한 바와 같다.The superparamagnetic nanoparticles are as described above.
본 발명의 용어 "면역증강"은 면역세포의 초기활성화 과정에서 비특이적으로 항원에 대해 면역반응을 촉진하는 기능 또는 면역계 세포의 활성을 증대시킴으로써 면역을 강화하는 기능을 의미하며, 면역세포의 활성을 증가시켜 면역반응을 자극함으로써 면역증강 효과를 얻을 수 있다. 예컨데, 대식세포(Macrophage)는 면역반응에서 주요한 역할을 수행하는데 대식세포에서의 주요한 역할인 식세포 작용은 미생물 및 기타 발열성 입자들을 흡수하고, 또한 종양괴사인자-α(tumor necrosis factor; TNF-α), 인터루킨-1β(interleukin; IL-1β), 인터루킨-12(interleukin; IL-12)와 같은 다수의 시토킨(cytokin) 및 일산화질소 (nitric oxide; NO)와 같은 세포독성 및 염증성 물질을 분비함으로써 면역 반응을 자극시킨다 (Wolf et al., 1994; Lee and Hong, 2011; Murray and Wynn, 2011). 따라서 대식세포 활성을 증가시키는 것은 면역증강을 위한 하나의 수단이 될 수 있다.The term "immune enhancement" of the present invention 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. For example, 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-α (TNF-α). ), secrete a number of cytokines such as interleukin-1β (IL-1β), interleukin-12 (IL-12), and cytotoxic and inflammatory substances such as nitric oxide (NO) thereby stimulating the immune response (Wolf et al., 1994; Lee and Hong, 2011; Murray and Wynn, 2011). Therefore, increasing macrophage activity can be a means to enhance immunity.
본 발명에 있어서, 상기 면역증강은 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는 면역증강용 조성물은 직접 체내 주입에 의한 방식으로 치료 효능을 달성할 수 있다.The 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.
본 발명에 따른 초상자성 나노입자를 포함하는 면역증강용 조성물은, 표적 기관에 분산되어있는 자성 나노입자 적용시 외부 자기장과 지속적으로 반응할 수 있기 때문에 고온을 선택적으로 균일하게 발생시킬 수 있다. 이러한 치료 방법은 단독의 치료 방법으로서 또는 종래의 치료 방법과 병행하여, 또는 보조적으로 수행될 수 있다.The 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.
본 발명의 면역증강용 조성물은 통상적으로 약제학적 조성물로 제공된다. 상기 약제학적 조성물의 허용되는 담체, 투여 및 제조는 전술한 바와 같다.The 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.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는, 화학요법 항암제와 병용 투여되는 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물을 제공한다. As another aspect to achieve the above object, 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.
상기 초상자성 나노입자는 전술한 바와 같다.The superparamagnetic nanoparticles are as described above.
본 발명에서 용어 "병용 투여"는 치료요법의 개별성분들을 동시, 순차적으로, 또는 개별적으로 투여하는 방식으로 이룰 수 있다. 2 이상의 약물 또는 조성물을 동시에 또는 순차적으로 투여하거나, 또는 일정한 또는 정해지지 않은 간격으로 교대로 투여하는 등의 방법으로 병용 치료 효과를 얻는 것으로, 병용치료법은 이에 한정되지 아니하지만, 예를 들어 반응정도, 반응 속도, 질병 진행까지의 기간 또는 생존 기간을 통해 측정된 효능이 병용치료법의 성분 중 하나 또는 나머지를 통상적인 용량으로 투약하여 얻을 수 있는 효능보다 치료학적으로 우수하면서 상승 효과를 제공할 수 있는 것으로 정의될 수 있다.In the present invention, 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.
본 발명의 초상자성 나노입자를 항암제와 병용하여 투여할 경우, 면역세포 수가 증가함으로써 암세포를 효과적으로 사멸하여 상승적인 항암 치료를 나타낼 수 있다.When 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.
본 발명에 있어서, 예를 들어, 상기 항암제는 에리불린, 카보플라틴, 시스플라틴, 할라벤, 5-플루오로우라실(5-FU), 글리벡, 빈크리스틴, 빈블라스틴, 비노렐빈, 파클리탁셀, 도세탁셀, 에토포사이드, 토포테칸, 이리노테칸, 닥티노마이신, 독소루비신, 다우노루비신, 발루비신, 플로타미드, 젬시타빈, 미토마이신 또는 블레오마이신일 수 있으나 이에 제한되지 않는다.In the present invention, for example, 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.
본 발명에 있어서, 상기 면역기능 저하 억제 또는 면역기능 증강은 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는, 화학요법 항암제와 병용 투여되는 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물은 직접 체내 주입에 의한 방식으로 치료 효능을 달성할 수 있다.The 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.
본 발명에 따른 초상자성 나노입자를 포함하는, 화학요법 항암제와 병용 투여되는 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물은, 표적 기관에 분산되어있는 자성 나노입자 적용시 외부 자기장과 지속적으로 반응할 수 있기 때문에 고온을 선택적으로 균일하게 발생시킬 수 있다. 이러한 치료 방법은 단독의 치료 방법으로서 또는 종래의 치료 방법과 병행하여, 또는 보조적으로 수행될 수 있다.The 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는, 화학요법 항암제와 병용 투여되는 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물은 통상적으로 약제학적 조성물로 제공된다. 상기 약제학적 조성물의 허용되는 담체, 투여 및 제조는 전술한 바와 같다.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.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는, 항암치료에 의한 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물을 제공한다.In another aspect for achieving the above object, 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.
상기 초상자성 나노입자는 전술한 바와 같다.The superparamagnetic nanoparticles are as described above.
본 발명에 있어서 상기 항암치료는, 예를 들어 항암제를 투여하는 화학요법 또는 방사선요법일 수 있으나 이에 제한되지 않는다.In the present invention, the anti-cancer treatment may be, for example, chemotherapy or radiotherapy administering an anti-cancer agent, but is not limited thereto.
종래 항암치료는 암세포뿐만 아니라 정상세포에도 치명적인 손상을 주어 면역기능 저하는 물론 탈모, 설사, 위장장애, 간, 신장독성 등의 부작용을 초래하며, 상기 면역기능 저하는 면역세포의 수가 줄어들고 면역세포 활성도가 감소하는 것을 말한다. 따라서 본 발명의 초상자성 나노입자를, 항암치료를 받고 있는 개체에 투여할 경우, 항암치료에 의해 발생한 면역기능 저하를 억제하거나 면역기능을 효과적으로 증강시킬 수 있다.Conventional anti-cancer treatment causes fatal damage not only to cancer cells but also to normal cells, resulting in side effects such as hair loss, diarrhea, gastrointestinal disorders, liver and kidney toxicity, as well as a decrease in immune function. The decrease in immune function reduces the number of immune cells and reduces immune cell activity. It means that is decreasing. Therefore, when the superparamagnetic nanoparticles of the present invention are administered to an individual undergoing anticancer treatment, the decrease in immune function caused by anticancer treatment can be suppressed or the immune function can be effectively enhanced.
본 발명에 있어서, 상기 면역기능 저하 억제 또는 면역기능 증강은 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는, 항암치료에 의한 면역기능 저하 억제 또는 면역기능 증강을 위한 조성물은 통상적으로 약제학적 조성물로 제공된다. 상기 약제학적 조성물의 허용되는 담체, 투여 및 제조는 전술한 바와 같다.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.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는, 암을 갖는 개체의 면역 반응 저하의 완화, 치료 또는 예방용 조성물을 제공한다.In another aspect for achieving the above object, 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. Provides a composition for
상기 초상자성 나노입자는 전술한 바와 같다.The superparamagnetic nanoparticles are as described above.
암세포는, 예를 들어 면역관문 관련 단백질들을 자극하여 인체의 면역기능을 억제시키며, 면역세포의 활성을 약화시키는 것으로 알려져 있다. 따라서, 본 발명의 초상자성 나노입자를, 암을 갖는 개체에 투여할 경우, 면역세포가 증가하므로 암세포에 의해 발생한 면역기능 저하를 억제하거나 면역기능을 효과적으로 증강시킬 수 있다.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.
본 발명에 있어서, 상기 면역기능 저하 억제 또는 면역기능 증강은 초상자성 나노입자를 대상의 신체에 주입하여 이루어지는 것일 수 있고, 구체적으로 초상자성 나노입자에 의한 면역세포 증가에 의해 이루어지는 것일 수 있으며, 상기 면역세포는 대식세포(Macrophage), 자연살상세포(Natural killer cell) 및 T 세포로 이루어진 군에서 선택된 하나 이상일 수 있으나 이에 제한되지 않는다.In the present invention, 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.
본 발명에 따른 초상자성 나노입자를 유효성분으로 포함하는, 암을 갖는 개체의 면역 반응 저하의 완화, 치료 또는 예방용 조성물은 통상적으로 약제학적 조성물로 제공된다. 상기 약제학적 조성물의 허용되는 담체, 투여 및 제조는 전술한 바와 같다.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.
본 발명에 있어서, 예를 들어, 상기 암은 섬유육종, 뇌암, 폐암, 대장암, 간암, 유방암, 위암, 난소암, 피부암, 췌장암, 전립선, 신장암 또는 갑상선암일 수 있으나 이에 제한되지 않는다.In the present invention, for example, 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.
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자를 유효성분으로 포함하는 자가면역질환 치료용 조성물을 대상(인간, 동물, 마우스 등의 포유류을 포함)에 투여하는 단계를 포함하는 암 면역 치료 방법을 제공한다.In another aspect to achieve the above object, the present invention provides a composition for treating autoimmune diseases containing superparamagnetic nanoparticles represented by Formula 1 or Formula 2 as an active ingredient in subjects (humans, animals, mice, etc.) Provides a cancer immunotherapy method comprising administering to a mammal (including mammals).
상기 목적을 달성하기 위한 또 다른 양태로서, 본 발명은 상기 일반식 1 또는 일반식 2로 표시되는 초상자성 나노입자의 암 면역 치료 용도를 제공한다.As another aspect for achieving the above object, the present invention provides the use of superparamagnetic nanoparticles represented by Formula 1 or Formula 2 for cancer immunotherapy.
본 발명의 제조방법에 의해 제조된 초상자성 나노입자는 안정적인 열특성으로 인해 자기 유도 발열 특성 및 높은 생체적합성을 나타내어, 생체 내 주입을 통한 적용이 가능하며, 면역세포의 증가를 유도하여 암 및 면역질환 치료에 유용하게 사용될 수 있다.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.
도 1은 본 발명의 제조방법과 종래 방법으로 각각 제조된 초상자성 나노입자 Mn0.5Zn0.5Fe2O4의 열특성 커브를 나타낸 것이다. (a: 종래의 핫 플레이트 (hot plate)에서의 제조방법, b: 실시예 1-1의 히팅 맨틀 (heating mantle)에서의 제조방법)
도 2는 본 발명의 제조방법과 종래 방법으로 각각 제조된 초상자성 나노입자 Mn0.5Zn0.5Fe2O4의 자기 유도 발열 특성에 의한 수율을 나타낸 것이다. (a: 종래 방법, b: 실시예 1-1의 방법).
도 3은 본 발명의 초상자성 나노입자에 자기적으로 발열을 유도하기 위한 AC 자기장 생성 시스템이다.
도 4는 본 발명의 실시예에 의해 합성된 초상자성 나노입자 Mn0.5Zn0.5Fe2O4의 교류 자기 유도 자기 발열 특성을 나타낸 그래프이다.
도 5는 대조군인 FSaLL 마우스 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 시간에 따른 종양 크기 변화를 육안으로 관찰한 결과이다.
도 6은 대조군인 FSaLL 마우스 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 종양 크기를 조직염색을 통해 나타낸 것이다.
도 7은 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 Ki67, Active-caspase3 및 TUNEL 발현 정도를 확인한 결과이다.
도 8은 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD31(PECAM-1) 및 CD3(T 세포) 발현 정도를 확인한 결과이다.
도 9는 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD4 및 CD8 발현 정도를 확인한 결과이다.
도 10은 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD161a 및 Iba1의 발현 정도를 확인한 결과이다.
도 11은 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD45RA, CD138 및 Ly6c의 발현 정도를 확인한 결과이다.
도 12는 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 HSP60 및 HSP70 발현 정도를 확인한 결과이다.
도 13은 U87MG 마우스 종양 모델에 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 자기장을 인가한 후 시간에 따른 종양 온도 변화를 나타낸 거이다.
도 14는 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군(실험군 1 : 3번 교류 자기장 인가, 실험군 2 : 6번 교류 자기장 인가)의 종양 크기 변화를 나타낸 것이다.
도 15는 대조군인 U87MG 종양 모델(control), U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여한 그룹(MNP group) 및 U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여하고 3회 자기장을 인가한 그룹(MNP + AMF group)의 뇌 MR 이미지를 나타낸 것이다.
도 16은 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 종양 크기 변화를 나타낸 것이다.
도 17은 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 Ki67, Active-caspase3 및 TUNEL 발현 정도를 확인한 결과이다.
도 18은 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD45RA 및 CD138의 발현 정도를 확인한 결과이다.
도 19는 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD3 및 Ly6C의 발현 정도를 확인한 결과이다.
도 20은 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD4 및 CD8의 발현 정도를 확인한 결과이다.
도 21은 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 CD161 및 Iba1의 발현 정도를 확인한 결과이다.
도 22는 대조군인 U87MG 종양 모델 및 초상자성 나노입자 Mn0.5Zn0.5Fe2O4를 투여하고 교류 자기장을 가한 실험군의 HSP60 및 HSP70 발현 정도를 확인한 결과이다.
도 23 내지 25는 U87MG 종양 모델에 초상자성 나노입자 Mn0.5Zn0.5Fe2O4 투여 및 교류 자기장 인가 전후 암조직 표면부의 나노입자 및 면역세포 분포를 형광 현미경을 이용하여 관찰한 결과이다(붉은색: 나노입자, 녹색: 형광표지자, 청색: 혈관, 백색: 면역세포).
도 26 내지 31은 U87MG 종양 모델에 초상자성 나노입자 Mn0.5Zn0.5Fe2O4 투여 및 교류 자기장 인가 전후 암조직 내부의 나노입자 및 면역세포 분포를 형광 현미경을 이용하여 관찰한 결과이다(붉은색: 나노입자, 녹색: 형광표지자, 청색: 혈관, 백색: 면역세포).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. (a: manufacturing method in a conventional hot plate, b: manufacturing method in the heating mantle of Example 1-1)
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. (a: conventional method, b: method of Example 1-1).
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).
이하, 실시예를 통하여 본 발명의 구성 및 효과를 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이에 의해 한정되는 것은 아니다.Hereinafter, the configuration and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예 1: 나노입자의 합성 및 표면 개질Example 1: Synthesis and surface modification of nanoparticles
1-1. 초상자성 나노입자 제조1-1. Superparamagnetic nanoparticle manufacturing
Fe (III) 아세틸아세토네이트(Fe(acac)3, Aldrich Chemical Co.), Mn (II) 아세테이트 테트라하이드레이트(Mn acetate tetrahydrate, Aldrich Chemical Co.), Zn (II) 아세테이트 디하이드레이트(Zn acetate dihydrate, Aldrich Chemical Co.), 올레산(Oleic acid, Aldrich Chemical Co.), 올레일아민(Oleylamine, Aldrich Chemical Co.), 벤질 에테르(Benzylether, Aldrich Chemical Co.) 및 1,2-헥사데칸디올(1,2-hexadecanediol, Tokyo Chemical Industries Co.)을 혼합하여 고체 상태 MnxZn1-xFe2O4 나노입자를 합성하였다.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.), and 1,2-hexadecanediol (1, Solid-state Mn x Zn 1-x Fe 2 O 4 nanoparticles were synthesized by mixing 2-hexadecanediol, Tokyo Chemical Industries Co.).
구체적으로, 3구 둥근 바닥 플라스크에서 Fe (III) 아세틸아세토네이트(2 mmol), Mn (II) 아세테이트 테트라하이드레이트(0.5 mmol), Zn (II) 아세테이트 디하이드레이트(0.5 mmol) 및 1,2-헥사데칸디올(10 mmol)을 파우더 형태로 혼합한 후 올레산 2.4 mL 및 올레일아민 3.5 mL을 추가하였다(1단계). 이후 벤질 에테르를 20 mL 추가한 후 둥근 바닥 플라스크용 히팅 맨틀(Heating mantle) 내부에 플라스크를 고정시키고 12 내지 13℃/min 속도로 20분간 280℃로 가열한 후 1시간 동안 270℃가 되도록 식혀주었다(2단계). 이후 2 내지 3℃/min 속도로 10분간 296.5℃가 되도록 가열한 뒤 46.5분간 온도를 유지시켰다(3단계). 80℃까지 온도를 낮춘 뒤 에탄올 40 mL를 첨가하여 Mn0.5Zn0.5Fe2O4 를 제조하였다(4단계).Specifically, in a three-neck round bottom flask, Fe (III) acetylacetonate (2 mmol), Mn (II) acetate tetrahydrate (0.5 mmol), Zn (II) acetate dihydrate (0.5 mmol) and 1,2-hexahydrate. After mixing decanediol (10 mmol) in powder form, 2.4 mL of oleic acid and 3.5 mL of oleylamine were added (step 1). 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).
1-2. 합성된 초상자성 나노입자의 표면 개질1-2. Surface modification of synthesized superparamagnetic nanoparticles
합성된 나노입자는 생체 적합성 고분자인 500 Da(Dalton)의 메톡시-PEG-실레인(Methoxy-PEG-Silane)으로 코팅되었다. PEG 층을 코팅하기 위해, 합성된 나노입자의 표면을 올레산에 의해 먼저 변형시켰다. 올레산(3mL)과 NH4Cl(0.7mL)을 에탄올 용액에 나노입자들과 함께 첨가하였다. 혼합물을 2시간 동안 격렬하게 교반한 다음, 나노입자가 영구 자석에 의해 침전된 후 아세톤으로 세척하여 올레산으로 코팅된 나노입자를 얻었다. 올레산으로 코팅된 나노입자를 톨루엔(7.5mL)에 분산시킨 후 트리에틸아민(3.75mL)과 메톡시-PEG-실레인 500 Da(0.75mL)을 첨가하였다. 혼합 용액을 24 시간 동안 잘 교반하였다. 용액에 PEG 코팅된 나노입자를 펜테인으로 세척하고 물에 분산시켜 나노유체 용액을 생성시켰다.The synthesized nanoparticles were coated with Methoxy-PEG-Silane, a biocompatible polymer of 500 Da (Dalton). To coat the PEG layer, 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.
실시예 2: 합성된 초상자성 나노입자의 특성 분석Example 2: Characterization of synthesized superparamagnetic nanoparticles
2-1. 제조방법에 따른 열특성 및 수율 비교2-1. Comparison of thermal properties and yield according to manufacturing method
상기 실시예 1-1의 방법으로 제조된 Mn0.5Zn0.5Fe2O4 와 종래 방법으로 제조된 Mn0.5Zn0.5Fe2O4 의 열특성을 비교하였다. 종래 방법은 실시예 1-1의 제조방법에서 히팅 맨틀(heating mantle) 대신 핫 플레이트(hot plate)를 사용하며, 2단계에서 8 내지 9℃/min 속도로 20분간 200℃로 가열하여 1시간동안 유지시키고, 3단계에서 9 내지 10℃/min 속도로 10분간 296.5℃가 되도록 가열하는 차이가 있다.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.
실시예 1-1의 히팅 맨틀(heating mantle)을 이용한 제조방법과 종래의 핫 플레이트(hot plate)를 이용한 제조방법으로 각각 제조된 Mn0.5Zn0.5Fe2O4의 열특성 및 수율을 비교하였다.The thermal properties and yields of Mn 0.5 Zn 0.5 Fe 2 O 4 produced by the manufacturing method using the heating mantle of Example 1-1 and the manufacturing method using a conventional hot plate were compared.
구체적으로, AC 코일, 커패시터, DC 전원, 웨이브 생성기 및 PC 시스템으로 구성된 특수 설계된 AC 자기장 생성 시스템을 사용하여 열특성을 측정하였다. AC 자기장 생성 시스템은 최대 350 Oe의 자기장 강도로 인체에 유해한 영향을 미치지 않는 0 ~ 380 KHz의 넓은 주파수 범위에서 작동한다. 나노입자는 물질, 입자 크기 및 크기 분포에 따라 다른 AC 발열 능력을 갖기 때문에 광범위한 주파수 및 자기장에 걸쳐 다양한 나노입자의 AC 발열 용량을 평가할 수 있어야 한다. AC 발열 특성에 대해 측정된 고체 나노입자의 총량은 에펜도르프 튜브 (Eppendorf-tube)에서 60mg으로 고정되었다. 격리된 시스템으로 측정 환경을 설계하기 위해 (주변 대기로부터의 AC 가열 측정 간섭을 방지하기 위해) 각 각의 샘플은 샘플 베드 중앙의 절연 스티로폼에 위치되었다. 광섬유의 팁은 고체 상태의 Mn0.5Zn0.5Fe2O4 나노입자를 함유하는 에펜도르프 튜브의 내부에 위치되었다. 실시예 1-1의 히팅 맨틀(heating mantle)을 이용한 제조방법과 종래의 핫 플레이트(hot plate)를 이용한 제조방법으로 각각 제조된 Mn0.5Zn0.5Fe2O4 나노입자를 8개의 서로 다른 주파수 (31.9, 47.0, 98.9, 140.0, 168.1, 195.5, 239.9, 360.2 kHz)와 5개의 서로 다른 자기장 세기 (80,100,120,140,160 Oe)로 조사하였다. 총 자기장 발생 시간은 각 측정에서 600 초이다. 자기장이 켜지면, 광학 온도계로 AC 가열 온도를 측정하고 자기장이 꺼지면 냉각시켰다.Specifically, 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. Because 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. To design the measurement environment as an isolated system (to prevent AC heating measurement interference from the surrounding atmosphere), 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. When the magnetic field was turned on, the AC heating temperature was measured with an optical thermometer and cooled when the magnetic field was turned off.
그 결과, 실시예 1-1의 히팅 맨틀(heating mantle)을 이용한 제조방법과 종래의 핫 플레이트(hot plate)를 이용한 제조방법으로 제조된 Mn0.5Zn0.5Fe2O4 가 종래 방법으로 제조된 Mn0.5Zn0.5Fe2O4 대비 안정적인 열특성을 나타내며(도 1, a: 종래 방법, b: 실시예 1-1의 방법), 모든 샘플에서 50℃ 이상의 발열을 나타내어 100% 수율로 우수한 초상자성 나노입자가 제조됨을 확인하였고, 종래 방법으로 제조된 경우 49%의 수율로 50℃ 이상의 발열을 나타내는 초상자성 나노입자가 제조됨을 확인하였다(도 2, a: 종래 방법, b: 실시예 1-1의 방법).As a result, 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).
2-2. 자기적으로 유도된 발열 특성 측정2-2. Measurement of magnetically induced heating characteristics
실시예 1-1의 히팅 맨틀(heating mantle)을 이용한 제조방법으로 제조된 Mn0.5Zn0.5Fe2O4 나노입자의 교류(AC) 자기장에 의해 유도된 발열 특성은 AC 코일, 커패시터, DC 전원, 웨이브 생성기 및 PC 시스템으로 구성된 특수 설계된 AC 자기장 생성 시스템을 사용하여 측정되었다(도 3).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).
7nm 크기의 Mn0.5Zn0.5Fe2O4 60mg을 100 kHz 의 주파수 및 140 Oe 세기의 교류 자기장에서 10회 반복적으로 노출시킨 결과, 모든 노출 횟수마다 동일하게 최대 80 ℃의 열이 발생함을 확인하였다(도 4).As a result of repeatedly exposing 60 mg of 7nm-sized Mn 0.5 Zn 0.5 Fe 2 O 4 to an alternating magnetic field with a frequency of 100 kHz and an intensity of 140 Oe 10 times, it was confirmed that heat of up to 80 ℃ was generated equally for every number of exposures. (Figure 4).
실시예 3: 합성된 초상자성 나노입자의 암 면역 치료 효능 확인Example 3: Confirmation of cancer immunotherapy efficacy of synthesized superparamagnetic nanoparticles
3-1. 마우스 종양 모델3-1. mouse tumor model
동물 치료, 피하 섬유 육종 세포 주입, 교모세포종 주입 및 생체 내 고온 증체 실험은 서울대학교 병원 동물 실험위원회(IACUC) (IACUC No. SNU-161129-2)의 승인을 받은 지침에 따라 수행되었다. 모든 절차는 Balb/c 누드 마우스로 인한 통증의 양을 줄이기 위해 수행되었다. 섬유육종 마우스 종양 모델의 경우, 본 실험에서 사용된 마우스를 마취시키고 FSaLL 세포 (Massachusetts General Hospital의 Dr. Herman Suit laboratory에서 만든 C3H 마우스의 radiation-induced fibrosarcoma으로, Early generation cells 을 Dr. Suit로부터 기증받아 사용함) (5 x 106 cell/50 μL)를 Balb/c 누드 마우스 근위 대퇴 부위에 피하 주사하여 투여하였다(FSaLL 마우스 종양 모델).Animal treatment, subcutaneous fibrosarcoma cell injection, glioblastoma injection, and in vivo hyperthermia experiments were performed in accordance with guidelines approved by the Seoul National University Hospital Animal Care and Use Committee (IACUC) (IACUC No. SNU-161129-2). All procedures were performed to reduce the amount of pain caused by Balb/c nude mice. In the case of the fibrosarcoma mouse tumor model, the 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 μL) was administered by subcutaneous injection into the proximal femur of Balb/c nude mice (FSaLL mouse tumor model).
교모세포종 모델의 경우, 교모세포종 세포(U87MG) 5 x 105 cell/5 μL를 누드 마우스의 뇌에 주입하여 투여하였다(U87MG 마우스 종양 모델).For the glioblastoma model, 5 x 10 5 cells/5 μL of glioblastoma cells (U87MG) were injected into the brain of a nude mouse (U87MG mouse tumor model).
3-2. 면역세포 증가 분석3-2. Immune cell increase analysis
각 마우스 모델에서 합성된 초상자성 나노입자에 의한 암 면역 치료 효능을 확인하였다.The cancer immunotherapy efficacy of the synthesized superparamagnetic nanoparticles was confirmed in each mouse model.
먼저, FSaLL 마우스 종양 모델을 마취시키고 PEG-코팅된 Mn0.5Zn0.5Fe2O4 나노입자 100μL(30mg/mL)를 유도된 종양의 중심에 주사하였다. 마우스를 자기 고열을 위해 AC 코일 시스템의 중앙에 놓고 140 Oe 세기 및 100 kHz 주파수로 자기장을 인가하였다. 온열 치료를 위해 6회, 회당 20분씩 교류 자기장을 가하였다. First, the FSaLL mouse tumor model was anesthetized and 100 μL (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. For thermal treatment, an alternating magnetic field was applied six times, for 20 minutes each time.
그 결과, 대조군인 FSaLL 마우스 종양 모델 대비 초상자성 나노입자를 투여하고 교류 자기장을 가한 실험군에서 시간이 지날수록 종양의 크기가 감소함을 육안을 통해 확인하였다(도 5).As a result, it was confirmed with the naked eye that the size of the tumor decreased over time in the experimental group administered superparamagnetic nanoparticles and applying an alternating magnetic field compared to the control FSaLL mouse tumor model (FIG. 5).
또한 H&E staining 및 Prussian Blue를 이용한 조직염색에서도 종양의 크기가 현저히 감소함을 확인하였다(도 6). H&E 및 Prussian Blue 염색법은 의학 진단에서 널리 이용되며, 병리학을 통해 암으로 의심되는 조직을 생검하여 조직 절편을 H&E 및 Prussian Blue 염색법으로 염색함으로써 해당 조직의 구성을 확인할 수 있다.In addition, 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.
아울러, 면역조직화학적 검사(immunohistochemistry)를 통해 Ki67, Active-caspase3 및 TUNEL 발현의 변화를 확인하였다. Ki67을 통하여 종양 세포의 핵 단백질의 분포 정도를 확인함으로써, 종양 세포의 세포 분열이 얼마나 활발히 진행되고 있는지 확인할 수 있다. 그와 상반되는 Active-caspase3 및 TUNEL은, 세포 사멸을 의미하는 표지자로서, 세포 사멸(Apoptosis)로 불리는, 세포가 스스로 죽어가는 자살 기전의 진행을 나타낸다. 따라서, 이와 같은 표지자가 활성되어 표시될수록, 종양 세포가 감소하는 결과를 나타내는 것으로 해석할 수 있다.In addition, changes in Ki67, Active-caspase3, and TUNEL expression were confirmed through immunohistochemistry. By checking the distribution of nuclear proteins in tumor cells through Ki67, it is possible to determine how actively the cell division of tumor cells is progressing. In contrast, Active-caspase3 and TUNEL are markers of cell death and indicate the progression of a suicide mechanism in which cells die by themselves, called apoptosis. Therefore, it can be interpreted that the more these markers are activated, the more the tumor cells decrease.
실험 결과, 대조군 대비 실험군에서 Ki67의 발현은 감소하고, Active-caspase3 및 TUNEL의 발현은 증가함을 확인하였다(도 7).As a result of the experiment, it was confirmed that the expression of Ki67 decreased and the expression of Active-caspase3 and TUNEL increased in the experimental group compared to the control group (Figure 7).
또한, 대조군 대비 실험군에서 CD31(PECAM-1)의 발현은 감소하나, CD3(T 세포)이 현저히 증가함을 확인하였으며(도 8), CD4 및 CD8의 발현이 증가함을 확인하였다(도 9).In addition, it was confirmed that the expression of CD31 (PECAM-1) decreased in the experimental group compared to the control group, but that CD3 (T cells) significantly increased (Figure 8), and that the expression of CD4 and CD8 increased (Figure 9) .
또한, 대조군 대비 실험군에서 자연살상세포(Natural killer cell, NK cell)인 CD161a, 대식세포인 Iba1이 현저히 증가함을 확인하였으며(도 10), CD45RA(na
아울러 면역화학염색에 의해 대조군 대비 실험군에서 HSP60 및 HSP70의 발현이 증가하는 것을 확인하였다(도 12). HSP(heat shock protein)60, HSP(heat shock protein)70는 대표적인 열 충격 단백질(heat shock protein, HSP)로 대식세포 및 림프구(lymphocyte) 등과 같은 면역세포들의 활성화(activation), 수상돌기 세포(dendrite cell)의 활성화(activation) 및 성숙화(maturation)를 통하여 항원제시(antigen presentation)를 활성화시키는 것으로 잘 알려져 있다. In addition, immunochemical staining confirmed that the expression of HSP60 and HSP70 increased in the experimental group compared to the control group (FIG. 12). HSP (heat shock protein)60 and HSP (heat shock protein)70 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.
이후, U87MG 마우스 종양 모델을 마취시키고 Mn0.5Zn0.5Fe2O4 나노입자 5μL(30mg/mL)를 마우스의 뇌에 주사하였다. 마우스를 자기 고열을 위해 AC 코일 시스템의 중앙에 놓고 140 Oe 세기 및 100 kHz 주파수로 자기장을 인가하였다. 온열 치료를 위해 6회, 회당 20분씩 교류 자기장을 가하였으며, 자기장을 가하는 동안 종양의 온도 변화는 도 13에 나타낸 바와 같이 처음 36.63℃에서 최대 38.65℃까지 증가하였다가 감소하는 양상을 나타내었다. Afterwards, the U87MG mouse tumor model was anesthetized and 5 μL (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. For thermal treatment, an alternating 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.
대조군인 U87MG 종양 모델(control)과 U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여하고 Mn0.5Zn0.5Fe2O4 나노입자 5μL를 처리한 후 3번 또는 6번 교류 자기장을 인가하여 온열 치료(magnetic hyperthermia, MHT)를 수행한 실험군 1 및 2에 GFP 및 루시퍼레이즈로 염색하여 나타낸 IVIS 이미지 결과, 대조군에서는 종양의 크기가 현저히 증가하는 반면 실험군1 및 2에서는 종양의 크기가 감소하는 것을 확인하였다(도 14). 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 μL 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. As a result of IVIS images stained with GFP and luciferase in experimental groups 1 and 2 that underwent heat treatment (magnetic hyperthermia, 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).
또한 대조군인 U87MG 종양 모델(control), U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여한 그룹(MNP group), U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여하고 3번 자기장을 인가한 그룹(MNP + AMF group)을 GFP 및 루시퍼레이즈로 처리하고 촬영한 뇌 MR 이미지(촬영조건: TR:2000ms/TE:48ms, FA:90o , 1.0mm thickness, spin echo)는 도 15에 나타낸 바와 같다.In addition, 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. Brain MR images taken after treating the group to which the third magnetic field was applied (MNP + AMF group) with GFP and luciferase (imaging conditions: TR: 2000ms/TE: 48ms, FA: 90o, 1.0mm thickness, spin echo) As shown in Figure 15.
대조군인 U87MG 종양 모델 대비 초상자성 나노입자를 투여하고 교류 자기장을 가한 실험군에서 종양의 크기가 현저히 감소하였으며(도 16), 면역조직화학적 검사 결과 대조군 대비 실험군에서 Ki67의 발현량이 감소하고 Active-caspase3 및 TUNEL의 발현량이 증가함을 확인하였으며(도 17), 마찬가지로 대조군 대비 실험군에서 CD45RA(B 세포, na
아울러, 대조군 대비 실험군에서 HSP60 및 HSP70의 발현이 증가함을 확인하였다(도 22).In addition, it was confirmed that the expression of HSP60 and HSP70 increased in the experimental group compared to the control group (FIG. 22).
따라서, 상기 결과로부터, Mn0.5Zn0.5Fe2O4 나노입자가 대식세포, 자연살상세포 및 T 세포 등 면역세포의 증가를 유도하여 면역 치료 효능을 가짐을 확인하였다. Therefore, from the above results, it was confirmed that 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.
3-3. in vivo 동물모델의 암조직 내 초상자성 나노입자 분포 분석3-3. Distribution analysis of superparamagnetic nanoparticles in cancer tissue of in vivo animal model
U87MG 종양 모델에 Mn0.5Zn0.5Fe2O4 나노입자를 투여한 다음, 교류 자기장을 인가하기 전과 후의 암조직 내 나노입자 및 면역세포의 분포를 형광 형미경을 이용하여 관찰하였다.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.
구체적으로, U87MG 종양 모델의 종양 세포와 Mn0.5Zn0.5Fe2O4 나노입자, 혈관에 형광표지 후, Mn0.5Zn0.5Fe2O4 나노입자 10mg/kg을 마우스 모델의 경동맥에 동맥 내 주사(intra-arterial injection)로 투여하고 투여 다음날부터 총 4일간, 1일 간격으로 IVM-CM(Fontocal & Two-photon convertible microscopy)으로 영상화하였다. 동일 위치를 각 시점별로 추적 영상화하였으며, 형광 표지자 별 여기 레이저 소스(excitation laser source, Ex) 및 방출 스펙트라(emission spectra, Em)은 다음과 같다. 혈관(형광 표지자: CD31-mFluor405) Ex. 405, Em. 425-465; 종양(형광 표지자: U87MG-GFP) Ex. 488, Em. 500-550l; Mn0.5Zn0.5Fe2O4 나노입자 Ex. 640, Em. 663-733. Specifically, after fluorescently labeling the tumor cells of the U87MG tumor model, Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles, and blood vessels, 10 mg/kg of Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles 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.
그 결과, 암조직 표면부의 경우 도 23 내지 25에 나타낸 것처럼, 초기(1 내지 2일)에는 대부분의 나노입자가 암 세포 사이 빈 공간이나 혈관 주변부에 위치하고 있으며, 시간이 경과함에 따라 많은 양의 나노입자가 면역세포에 포획된 형태로 관찰되었다. 또한 1일 내지 2일에는 교류 자기장 인가 후 관찰되는 나노입자가 증가하였으며, 3일 내지 4일 시점에는 교류 자기장 인가 전후 시점간 나노입자 분포에 큰 차이가 없는 것으로 나타났다(붉은색: 나노입자, 녹색: 형광표지자, 청색: 혈관, 백색: 면역세포).As a result, in the case of the surface area of cancer tissue, as shown in Figures 23 to 25, in the early stages (1 to 2 days), most nanoparticles are located in empty spaces between cancer cells or around blood vessels, and as time passes, a large amount of nanoparticles Particles were observed captured in immune cells. In addition, on the 1st to 2nd day, the number of nanoparticles observed after the application of the alternating magnetic field increased, and on the 3rd to 4th day, there was no significant difference in the distribution of nanoparticles before and after the application of the alternating magnetic field (red: nanoparticles, green : Fluorescent marker, blue: blood vessels, white: immune cells).
암조직 내부의 경우 도 26 내지 31에 나타낸 것처럼, 대부분의 나노입자가 암세포 사이 빈 공간 또는 형관신호로 구분되는 면역세포에 포획된 형태로 관찰되었으며, 일부 위치에서는 시일이 경과함에 따라 나노입자의 관찰범위가 감소하다가 다시 증가하는 양상이 나타났다.In the case of inside cancer tissue, as shown in Figures 26 to 31, most nanoparticles were observed in the empty space between cancer cells or captured in immune cells distinguished by fluorescence signals, and in some locations, nanoparticles were observed over time. The range decreased and then increased again.
이러한 결과를 통해, 생체 내 암세포에 Mn0.5Zn0.5Fe2O4 나노입자를 투여하면 면역세포의 증가가 유도된다는 것을 확인하였다. Through these results, it was confirmed that administration of Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles to cancer cells in vivo induces an increase in immune cells.
이상의 설명으로부터, 본 발명이 속하는 기술분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.
Claims (14)
일반식 1
KxLyFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)
여기서, K 또는 L은 리튬(Li), 나트륨(Na), 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄(Al) 또는 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 혼합하여 혼합물을 제조하는 단계;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.
A method for producing superparamagnetic nanoparticles represented by the following general formula 1, comprising the following steps:
General formula 1
K x L y Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3)
Here, K or L is a monovalent compound containing lithium (Li), sodium (Na), magnesium (Mg), calcium (Ca), manganese (Mn), zinc (Zn), aluminum (Al), or gallium (Ga). to trivalent cationic metal.
(a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine and benzyl ether are mixed to prepare a mixture. step;
(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) cooling the mixture to 70 to 90° C. after the holding.
상기 (b)단계의 가열은 12 내지 13℃/min 속도로 10 내지 30분간 이루어지는 것인, 제조방법.
According to paragraph 1,
Heating in step (b) is performed at a rate of 12 to 13°C/min for 10 to 30 minutes.
상기 (b)단계의 냉각은 30분 내지 120분간 이루어지는 것인, 제조방법.
According to paragraph 1,
The cooling in step (b) is performed for 30 to 120 minutes.
상기 (c)단계의 가열은 2 내지 3℃/min 속도로 5 내지 20분간 이루어지는 것인, 제조방법.
According to paragraph 1,
The heating in step (c) is performed at a rate of 2 to 3°C/min for 5 to 20 minutes.
상기 (c)단계의 유지는 10 내지 60분간 이루어지는 것인, 제조방법.
According to paragraph 1,
A manufacturing method in which step (c) is maintained for 10 to 60 minutes.
상기 초상자성 나노입자의 제조는 히팅맨틀(heating mantle)을 이용하여 이루어지는 것인, 제조방법.
According to paragraph 1,
The manufacturing method of the superparamagnetic nanoparticles is carried out using a heating mantle.
Superparamagnetic nanoparticles manufactured by the production method of any one of claims 1 to 6.
일반식 2
KxLyMzFe2(3)O4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)
여기서, K, L 또는 M은 리튬(Li), 나트륨(Na). 마그네슘(Mg), 칼슘(Ca), 망간(Mn), 아연(Zn), 알루미늄 (Al) 또는 갈륨(Ga)을 포함하는 1가 내지 3가의 양이온 금속.
(a) Fe (III) 아세틸아세토네이트, Mn (II) 아세테이트 테트라하이드레이트, Zn (II) 아세테이트 디하이드레이트, 1,2-헥사데칸디올, 올레산, 올레일아민 및 벤젤 에테르를 혼합하여 혼합물을 제조하는 단계;
(b) 상기 혼합물을 270 내지 300℃로 가열한 후, 250 내지 280℃로 냉각시키는 단계;
(c) 상기 냉각 이후 혼합물을 290 내지 310℃로 가열하고 온도를 유지하는 단계; 및
(d) 상기 유지 이후 혼합물을 70 내지 90℃로 냉각하는 단계.
Method for producing superparamagnetic nanoparticles represented by the following general formula 2, comprising the following steps:
General formula 2
K x L y M z Fe 2(3) O 4 (0 ≤ x ≤ 3, 0 ≤ y ≤ 3, 0 ≤ z ≤ 3)
Here, 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).
(a) Fe (III) acetylacetonate, Mn (II) acetate tetrahydrate, Zn (II) acetate dihydrate, 1,2-hexadecanediol, oleic acid, oleylamine and benzyl ether are mixed to prepare a mixture. step;
(b) heating the mixture to 270 to 300°C and then cooling to 250 to 280°C;
(c) heating the mixture after cooling to 290 to 310° C. and maintaining the temperature; and
(d) cooling the mixture to 70 to 90° C. after the holding.
상기 (b)단계의 가열은 12 내지 13℃/min 속도로 10 내지 30분간 이루어지는 것인, 제조방법.
According to clause 8,
Heating in step (b) is performed at a rate of 12 to 13°C/min for 10 to 30 minutes.
상기 (b)단계의 냉각은 30분 내지 120분간 이루어지는 것인, 제조방법.
According to clause 8,
The cooling in step (b) is performed for 30 to 120 minutes.
상기 (c)단계의 가열은 2 내지 3℃/min 속도로 5 내지 20분간 이루어지는 것인, 제조방법.
According to clause 8,
The heating in step (c) is performed at a rate of 2 to 3°C/min for 5 to 20 minutes.
상기 (c)단계의 유지는 10 내지 60분간 이루어지는 것인, 제조방법.
According to clause 8,
A manufacturing method in which step (c) is maintained for 10 to 60 minutes.
상기 초상자성 나노입자의 제조는 히팅 맨틀(heating mantle)을 이용하여 이루어지는 것인, 제조방법.
According to clause 8,
A manufacturing method wherein the production of the superparamagnetic nanoparticles is performed using a heating mantle.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220102440A KR20240024457A (en) | 2022-08-17 | 2022-08-17 | Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy |
| PCT/KR2023/011971 WO2024039148A1 (en) | 2022-08-17 | 2023-08-11 | Method for preparing superparamagnetic iron oxide nanoparticles for immunotherapy |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220102440A KR20240024457A (en) | 2022-08-17 | 2022-08-17 | Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20240024457A true KR20240024457A (en) | 2024-02-26 |
Family
ID=89941770
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020220102440A KR20240024457A (en) | 2022-08-17 | 2022-08-17 | Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20240024457A (en) |
| WO (1) | WO2024039148A1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101686341B1 (en) | 2015-08-26 | 2016-12-13 | 건양대학교산학협력단 | Synthesis method of magnetic nanoparticle for targetable drug delivery system |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4528959B2 (en) * | 2003-12-12 | 2010-08-25 | 国立大学法人 名古屋工業大学 | Magnetic material and method for producing the same |
| US20100063346A1 (en) * | 2006-05-17 | 2010-03-11 | Murphy William J | Magnetorheological fluids and therapeutic uses thereof |
| KR101280808B1 (en) * | 2012-07-18 | 2013-07-02 | 천선주 | Ferrite-based superparamagnetic nanoparticle having ultra high ac magnetically-induced heat generation ability and high specific loss power, preparation method thereof, and thermoablation agent comprising same |
| KR102238816B1 (en) * | 2018-06-14 | 2021-04-09 | 서울대학교산학협력단 | Superparamagnetic Nanoparticles for Hyperthermia Therapy |
-
2022
- 2022-08-17 KR KR1020220102440A patent/KR20240024457A/en unknown
-
2023
- 2023-08-11 WO PCT/KR2023/011971 patent/WO2024039148A1/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101686341B1 (en) | 2015-08-26 | 2016-12-13 | 건양대학교산학협력단 | Synthesis method of magnetic nanoparticle for targetable drug delivery system |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2024039148A1 (en) | 2024-02-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Ma et al. | Fe 3 O 4–Pd Janus nanoparticles with amplified dual-mode hyperthermia and enhanced ROS generation for breast cancer treatment | |
| Pan et al. | Combined magnetic hyperthermia and immune therapy for primary and metastatic tumor treatments | |
| Guo et al. | Magnetic-responsive and targeted cancer nanotheranostics by PA/MR bimodal imaging-guided photothermally triggered immunotherapy | |
| Zhang et al. | Thermosensitive/superparamagnetic iron oxide nanoparticle-loaded nanocapsule hydrogels for multiple cancer hyperthermia | |
| Le Duc et al. | Toward an image-guided microbeam radiation therapy using gadolinium-based nanoparticles | |
| US10806694B2 (en) | Nanoparticles for photodynamic therapy, X-ray induced photodynamic therapy, radiotherapy, radiodynamic therapy, chemotherapy, immunotherapy, and any combination thereof | |
| Li et al. | Enhanced synergism of thermo-chemotherapy for liver cancer with magnetothermally responsive nanocarriers | |
| Zhong et al. | Laser-triggered aggregated cubic α-Fe2O3@ Au nanocomposites for magnetic resonance imaging and photothermal/enhanced radiation synergistic therapy | |
| Niiyama et al. | Hyperthermia nanofiber platform synergized by sustained release of paclitaxel to improve antitumor efficiency | |
| JP2017532340A (en) | Nanoparticles for photodynamic therapy, X-ray induced photodynamic therapy, radiation therapy, chemotherapy, immunotherapy, and any combination thereof | |
| Xiang et al. | MOF-derived novel porous Fe 3 O 4@ C nanocomposites as smart nanomedical platforms for combined cancer therapy: magnetic-triggered synergistic hyperthermia and chemotherapy | |
| Zhang et al. | A synergistic cancer immunotherapy nano-system for preventing tumor growth | |
| Chung et al. | Iron oxide nanoparticles for immune cell labeling and cancer immunotherapy | |
| KR102175448B1 (en) | Heavy atom-Halogen Compound Doped Iron oxide Magnetic Nanoparticles | |
| Longo et al. | Prevention of distant lung metastasis after photodynamic therapy application in a breast cancer tumor model | |
| KR102175449B1 (en) | Iron Oxide/Heavy atom-Halogen Compound Core/Shell Magnetic Nanoparticles | |
| KR102238816B1 (en) | Superparamagnetic Nanoparticles for Hyperthermia Therapy | |
| Sadri et al. | Evaluation of glioblastoma (U87) treatment with ZnO nanoparticle and X-ray in spheroid culture model using MTT assay | |
| JP2018516256A (en) | Nanoparticles for use as therapeutic vaccines | |
| JP6534660B2 (en) | System for generating restricted field and medical device implementing the same | |
| KR20240024457A (en) | Method for producing Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy | |
| KR20240024448A (en) | Superparamagnetic Iron Oxide Nanoparticles[SPIONs] for immunotherapy | |
| Tang et al. | Study of the therapeutic effect of 188Re labeled folate targeting albumin nanoparticle coupled with cis-diamminedichloroplatinum cisplatin on human ovarian cancer | |
| Grumezescu | Engineering of nanobiomaterials: applications of nanobiomaterials | |
| Song et al. | Self-assembling ferrimagnetic fluorescent micelles for bioimaging guided efficient magnetic hyperthermia therapy |