CN105408257B - 用于治疗氧化应激的螯合纳米铈氧化物 - Google Patents
用于治疗氧化应激的螯合纳米铈氧化物 Download PDFInfo
- Publication number
- CN105408257B CN105408257B CN201480030435.9A CN201480030435A CN105408257B CN 105408257 B CN105408257 B CN 105408257B CN 201480030435 A CN201480030435 A CN 201480030435A CN 105408257 B CN105408257 B CN 105408257B
- Authority
- CN
- China
- Prior art keywords
- nano particle
- cerium
- method described
- stabilizer
- dispersion
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000036542 oxidative stress Effects 0.000 title claims abstract description 22
- 229910000420 cerium oxide Inorganic materials 0.000 title description 51
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 title description 51
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 127
- 239000002105 nanoparticle Substances 0.000 claims abstract description 97
- 229910052684 Cerium Inorganic materials 0.000 claims abstract description 60
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 29
- 239000003381 stabilizer Substances 0.000 claims abstract description 28
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 claims abstract description 16
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical group OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000007800 oxidant agent Substances 0.000 claims abstract description 11
- 230000001590 oxidative effect Effects 0.000 claims abstract description 11
- 229960003330 pentetic acid Drugs 0.000 claims abstract description 11
- 208000032382 Ischaemic stroke Diseases 0.000 claims abstract description 7
- 239000006185 dispersion Substances 0.000 claims description 47
- 239000000203 mixture Substances 0.000 claims description 41
- 239000002245 particle Substances 0.000 claims description 36
- 239000000376 reactant Substances 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- -1 cerium ion Chemical class 0.000 claims description 20
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 230000002776 aggregation Effects 0.000 claims description 5
- 238000004220 aggregation Methods 0.000 claims description 5
- WUKWITHWXAAZEY-UHFFFAOYSA-L calcium difluoride Chemical compound [F-].[F-].[Ca+2] WUKWITHWXAAZEY-UHFFFAOYSA-L 0.000 claims description 5
- 230000008859 change Effects 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 206010063837 Reperfusion injury Diseases 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 239000010436 fluorite Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000004062 sedimentation Methods 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- 239000012530 fluid Substances 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 abstract description 3
- 239000002738 chelating agent Substances 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 20
- 210000004556 brain Anatomy 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 235000013339 cereals Nutrition 0.000 description 9
- CETPSERCERDGAM-UHFFFAOYSA-N ceric oxide Chemical compound O=[Ce]=O CETPSERCERDGAM-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000002296 dynamic light scattering Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 235000005979 Citrus limon Nutrition 0.000 description 7
- 244000131522 Citrus pyriformis Species 0.000 description 7
- 239000000908 ammonium hydroxide Substances 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 238000013019 agitation Methods 0.000 description 6
- 229910000422 cerium(IV) oxide Inorganic materials 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012467 final product Substances 0.000 description 6
- 210000001320 hippocampus Anatomy 0.000 description 6
- 230000000302 ischemic effect Effects 0.000 description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 230000008499 blood brain barrier function Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960001484 edetic acid Drugs 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 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 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000000971 hippocampal effect Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 208000028867 ischemia Diseases 0.000 description 4
- 201000006417 multiple sclerosis Diseases 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 238000005169 Debye-Scherrer Methods 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 238000011026 diafiltration Methods 0.000 description 3
- 229910001882 dioxygen Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- AHKZTVQIVOEVFO-UHFFFAOYSA-N oxide(2-) Chemical compound [O-2] AHKZTVQIVOEVFO-UHFFFAOYSA-N 0.000 description 3
- 208000021090 palsy Diseases 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010010947 Coordination abnormal Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000019926 Keshan disease Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000005098 blood-cerebrospinal fluid barrier Anatomy 0.000 description 2
- 210000004958 brain cell Anatomy 0.000 description 2
- 244000144987 brood Species 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 230000003532 cataractogenesis Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 229910000421 cerium(III) oxide Inorganic materials 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 238000000799 fluorescence microscopy Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 208000016290 incoordination Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 210000004400 mucous membrane Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000004792 oxidative damage Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000002110 toxicologic effect Effects 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 230000009529 traumatic brain injury Effects 0.000 description 2
- 239000012498 ultrapure water Substances 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- GDDNTTHUKVNJRA-UHFFFAOYSA-N 3-bromo-3,3-difluoroprop-1-ene Chemical compound FC(F)(Br)C=C GDDNTTHUKVNJRA-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- RXSVKUSMDPFWFZ-UHFFFAOYSA-N CCCCCC([Na])CC.OC(=O)CC(C(O)=O)S(O)(=O)=O Chemical compound CCCCCC([Na])CC.OC(=O)CC(C(O)=O)S(O)(=O)=O RXSVKUSMDPFWFZ-UHFFFAOYSA-N 0.000 description 1
- 229910003389 CeO2-δ Inorganic materials 0.000 description 1
- 229910003385 CeO2–δ Inorganic materials 0.000 description 1
- 229910003411 CeO2−δ Inorganic materials 0.000 description 1
- 235000019743 Choline chloride Nutrition 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010048554 Endothelial dysfunction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 208000025499 G6PD deficiency Diseases 0.000 description 1
- 206010018444 Glucose-6-phosphate dehydrogenase deficiency Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 241001484259 Lacuna Species 0.000 description 1
- 241000270322 Lepidosauria Species 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 206010029897 Obsessive thoughts Diseases 0.000 description 1
- 241001282736 Oriens Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 235000014676 Phragmites communis Nutrition 0.000 description 1
- 201000001068 Prinzmetal angina Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 230000002292 Radical scavenging effect Effects 0.000 description 1
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229930006000 Sucrose Natural products 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
- 206010042496 Sunburn Diseases 0.000 description 1
- OUUQCZGPVNCOIJ-UHFFFAOYSA-M Superoxide Chemical compound [O-][O] OUUQCZGPVNCOIJ-UHFFFAOYSA-M 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 238000003917 TEM image Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 235000012545 Vaccinium macrocarpon Nutrition 0.000 description 1
- 244000291414 Vaccinium oxycoccus Species 0.000 description 1
- 235000002118 Vaccinium oxycoccus Nutrition 0.000 description 1
- 208000009325 Variant Angina Pectoris Diseases 0.000 description 1
- 240000006677 Vicia faba Species 0.000 description 1
- 235000010749 Vicia faba Nutrition 0.000 description 1
- 235000002098 Vicia faba var. major Nutrition 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- DGUFGVRBHSFJGU-UHFFFAOYSA-N acetic acid ethane-1,2-diol Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.OCCO DGUFGVRBHSFJGU-UHFFFAOYSA-N 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 210000001691 amnion Anatomy 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000000576 arachnoid Anatomy 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000005784 autoimmunity Effects 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- DRVWBEJJZZTIGJ-UHFFFAOYSA-N cerium(3+);oxygen(2-) Chemical class [O-2].[O-2].[O-2].[Ce+3].[Ce+3] DRVWBEJJZZTIGJ-UHFFFAOYSA-N 0.000 description 1
- LARZRSCHQOPNHD-UHFFFAOYSA-N cerium(4+);hydrate Chemical compound O.[Ce+4] LARZRSCHQOPNHD-UHFFFAOYSA-N 0.000 description 1
- UNJPQTDTZAKTFK-UHFFFAOYSA-K cerium(iii) hydroxide Chemical compound [OH-].[OH-].[OH-].[Ce+3] UNJPQTDTZAKTFK-UHFFFAOYSA-K 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000013626 chemical specie Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 235000004634 cranberry Nutrition 0.000 description 1
- 210000000806 cranial fontanelle Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000000959 ear middle Anatomy 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000008694 endothelial dysfunction Effects 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 208000008605 glucosephosphate dehydrogenase deficiency Diseases 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 238000002173 high-resolution transmission electron microscopy Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000000640 hydroxylating effect Effects 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008798 inflammatory stress Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000009940 knitting Methods 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 210000003712 lysosome Anatomy 0.000 description 1
- 230000001868 lysosomic effect Effects 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002052 molecular layer Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 210000004224 pleura Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000007845 reactive nitrogen species Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000009938 salting Methods 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 210000003454 tympanic membrane Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000003026 viability measurement method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 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
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5192—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01F—COMPOUNDS OF THE METALS BERYLLIUM, MAGNESIUM, ALUMINIUM, CALCIUM, STRONTIUM, BARIUM, RADIUM, THORIUM, OR OF THE RARE-EARTH METALS
- C01F17/00—Compounds of rare earth metals
- C01F17/20—Compounds containing only rare earth metals as the metal element
- C01F17/206—Compounds containing only rare earth metals as the metal element oxide or hydroxide being the only anion
- C01F17/224—Oxides or hydroxides of lanthanides
- C01F17/235—Cerium oxides or hydroxides
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/30—Three-dimensional structures
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/60—Compounds characterised by their crystallite size
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2002/00—Crystal-structural characteristics
- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
- C01P2002/76—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data by a space-group or by other symmetry indications
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/51—Particles with a specific particle size distribution
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2004/00—Particle morphology
- C01P2004/60—Particles characterised by their size
- C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
-
- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
- C01P2006/00—Physical properties of inorganic compounds
- C01P2006/40—Electric properties
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nanotechnology (AREA)
- Inorganic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biomedical Technology (AREA)
- Optics & Photonics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Composite Materials (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- General Physics & Mathematics (AREA)
- Condensed Matter Physics & Semiconductors (AREA)
- Geology (AREA)
- Neurology (AREA)
- Dispersion Chemistry (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
描述了用于制备具有生物相容性稳定剂的含铈纳米颗粒的方法,其中提供了包含三价铈离子、柠檬酸、稳定剂(螯合剂)和氧化剂的水性反应混合物,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸;随后进行加热步骤以有效地形成纳米颗粒。这些生物相容性纳米颗粒可用于治疗氧化应激相关疾病和事件,例如缺血性卒中。
Description
相关申请的交叉引用
本专利申请要求于2013年4月25日提交的临时申请序列号61/854,507,“STABILIZED NANOCERIA FOR THE TREATMENT OF OXIDATIVE STRESS”的优先权,其公开内容通过引用整体并入本文。
技术领域
本发明一般地涉及纳米医学领域的改进。特别地,本发明涉及用生物相容性材料制备的含铈纳米颗粒;制备所述纳米颗粒的方法;以及所述纳米颗粒用于治疗疾病(例如神经退行性疾病)或者治疗因氧化应激(由例如缺血性卒中引起)而产生的并发症的用途。
背景技术
氧化应激在许多人类疾病(特别是神经退行性疾病)的发病机制中发挥主要作用。因此,使用可降低特定自由基物质的抗氧化剂进行治疗在理论上可防止组织损伤并改善存活和神经结果二者。生理环境中的自由基通常可分类为活性氧簇(reactive oxygenspecies,ROS)或活性氮簇(reactive nitrogen species,RNS)。自由基是具有高度反应性的化学物类并且易于在亚细胞水平上与蛋白质、脂类和核酸反应,从而导致产生氧化应激的多种疾病和事件(例如缺血性卒中)的进展。
在纳米医学中使用纳米铈氧化物(nanoceria)的起源可追溯至Bailey和Rzigalinski的开创性工作,其中观察到将超细铈氧化物颗粒施用于培养的脑细胞大大增强了细胞存活能力,如Rzigalinski在Nanoparticles and Cell Longevity,Technologyin Cancer Research&Treatment 4(6),651-659(2005)中所描述的。更特别地,当使用通过反胶束微乳化技术合成的2至10纳米(nm)大小的铈氧化物纳米颗粒处理体外大鼠脑细胞培养物时,其显示出存活约3至4倍长,如Rzigalinski等人于2003年9月4日提交的美国专利7,534,453中所公开的。铈氧化物纳米颗粒为暴露于由过氧化氢或紫外线暴露所产生的致死剂量自由基的培养的脑细胞提供了相当大的保护。此外,有报道称铈氧化物纳米颗粒在鼠体内是相对惰性的,具有较低毒性(例如,尾静脉注射不产生毒性作用)。虽然没有报道在体内的医学益处,但是假设了用这些铈氧化物(ceria)纳米颗粒进行治疗的益处,包括降低与伤口、植入物、关节炎、关节病、血管病、组织老化、卒中和创伤性脑损伤相关的炎症。
然而,Rzigalinski等随后在WO 2007/002662中公开了这些特定纳米铈氧化物颗粒的许多问题。通过这种反胶束微乳化技术产生的纳米铈氧化物具有若干问题:(1)粒径没有良好地控制在所报道的2至10纳米(nm)范围中,使得批次之间的可变性较高;(2)用于最终产物加工的表面活性剂尾料如二(乙基己基)磺基琥珀酸钠(也称为多库酯钠或(AOT))导致了毒性反应;(3)当将这些纳米颗粒放置在生物介质中时,表面活性剂尾料量的无法控制产生了聚集的问题,导致效力和可递送性降低;以及(4)铈的价态(+3/+4)随时间不稳定。因此,通过反胶束微乳化技术产生的铈氧化物纳米颗粒在批次之间是高度可变的,并且对哺乳动物细胞显示出比期望毒性更高的毒性。
作为替代方案,Rzigalinski等在WO 2007/002662中描述了由至少三个商业来源获得的通过高温技术合成的纳米铈氧化物的生物学效力。报道称,铈氧化物纳米颗粒的这些新来源提供了批次之间活性的优异可再现性。还报道了在不考虑来源的情况下,具有小尺寸、窄尺寸分布和低聚集速率的铈氧化物颗粒是最有利的。就尺寸而言,该公开内容具体地教导了在颗粒进入细胞内部的实施方案中,进入细胞内的颗粒的优选尺寸范围为约11nm至约50nm,如约20nm。在颗粒从细胞外对细胞发挥其作用的一些实施方案中,这些细胞外颗粒的优选尺寸范围为约11nm至约500nm。
这些发明人(Rzigalinski等)还报道了对于递送,纳米颗粒的非聚集形式是有利的。为了实现该目标,他们报道可在超高纯水中或在用超高纯水制备的生理盐水中超声处理按重量计约10%的原液。然而,如其他人已注意到的,我们观察到,通过高温技术合成的纳米铈氧化物(例如,从商业来源获得)的超声处理水性分散体是高度不稳定的并且迅速沉降(即,在几分钟内),造成施用来自这些来源的纳米铈氧化物的水性分散体时具有显著的可变性。
Hardas等,Toxicological Sciences 116(2),562-576(2010)报道了纳米铈氧化物的水性分散体的生物分布和毒理效应,所述纳米铈氧化物的水性分散体通过Masui等,J.Mater.Sci.Lett.21,489-491(2002)的直接两步热液制备法来制备,其中包括柠檬酸钠作为生物相容性稳定剂。高分辨率TEM表明,这种形式的纳米铈氧化物具有边缘尖锐的结晶多面体颗粒形态以及4nm至6nm的窄尺寸分布。报道称,在7.35的生理pH下,这些经柠檬酸盐稳定的铈氧化物纳米颗粒分散体稳定超过2个月。因此,在施用前不需要进行超声处理。
然而,相当出乎意料地,他们报道,与先前研究的商业来源的纳米铈氧化物(Aldrich Chemical Co.(Cat.#639648))相比,这种形式的经柠檬酸盐稳定的纳米铈氧化物更具毒性,在脑中没有见到,并且对海马和小脑产生很小的氧化应激作用。
DiFrancesco等在共同转让的于2007年9月4日提交的PCT/US2007/077545,“METHOD OF PREPARING CERIUM DIOXIDE NANOPARTICLES”中描述了在生物相容性稳定剂(如柠檬酸(citric acid,CA)、乳酸、酒石酸、葡萄糖酸、乙二胺四乙酸(EDTA)及其组合)的存在下,在低pH(<4.5)下三价铈离子被过氧化氢氧化。具体地,稳定剂乳酸和乳酸与EDTA的组合显示出直接产生了平均粒径为3至8nm的纳米铈氧化物的稳定分散体。
Reed等在共同转让的于2013年3月15日提交的US2013/0337083,“NANOCERIA FORTHE TREATMENT OF OXIDATIVE STRESS”中描述了对于经用柠檬酸(CA)和EDTA制备的纳米铈氧化物处理的小鼠,海马细胞节制(sparing)的协同提高,其中CA/EDTA的摩尔比为3.0至0.1。在慢性进行性多发性硬化、复发缓解型多发性硬化(relapse-remitting multiplesclerosis多发性硬化症)、肌萎缩性侧索硬化(amyotrophic lateral sclerosis)和缺血再灌注损伤的鼠模型中,产生了疾病进展的改善和运动行为测试的改进。
如先前所述,已报道了用于制备含铈纳米颗粒的生物相容性分散体,并且特别是经柠檬酸和柠檬酸盐离子稳定化的那些分散体的多种方法。然而,仍需要进一步改善经柠檬酸稳定化的含铈纳米颗粒分散体用于例如治疗氧化应激效应相关疾病和事件(如缺血性卒中)的自由基清除能力。
发明概述
根据本发明的一个方面,提供了制备纳米颗粒的分散体的方法,其包括:形成包含三价铈离子、柠檬酸、稳定剂、氧化剂和水的反应混合物,所述稳定剂选自次氨基三乙酸(nitrilotriacetic acid)、乙二醇四乙酸(ethylene glycol tetracetic acid)和二亚乙基三胺五乙酸(diethylenetriaminepentaacetic acid);任选地加热或冷却所述反应混合物,从而在所述反应混合物中形成含铈纳米颗粒的分散体。
在本发明的第二方面中,提供了治疗氧化应激相关疾病或事件(如缺血性卒中)的方法,其包括:在疾病或事件发生之前、期间或之后施用含铈纳米颗粒,所述含铈纳米颗粒在柠檬酸和稳定剂的混合物存在下制备,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸。
在本发明的第三方面中,提供了包含铈、柠檬酸和稳定剂的纳米颗粒,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸。
发明详述
应理解,没有具体示出或描述的元件可采用本领域技术人员公知的多种形式。本发明由权利要求限定。
在本申请中,术语纳米颗粒包括平均直径小于100nm的颗粒。为了本公开内容的目的,除非另有说明,否则纳米颗粒的直径是指其流体动力学直径,其是通过动态光散射技术测定的直径并且包括分子吸附物和颗粒附随的溶剂化壳。或者,可通过分析透射电子显微镜照片(transmission electron micrograph,TEM)来评估几何粒径。
在本申请中,多种含铈材料名义上描述为“铈氧化物”或“铈二氧化物”。化学领域的技术人员应理解,这些材料中存在的实际氧化阴离子可包括氧化物阴离子或氢氧根阴离子或其混合物,如水合氧化物相(例如,羟基氧化物)。此外,已知物质的组合物可由多价阳离子的固体溶液构成,并且被称为非化学计量的固体。因此,对于由多种氧化态的金属阳离子构成的氧化相,应理解主体相(bulk phase)中存在的氧化物阴离子总量将通过存在的多种氧化态的金属阳离子(例如Ce3+和Ce4+)的具体量来确定,使得电荷中性得以保持。对于名义上描述为金属二氧化物的非化学剂量相来说,其具体为化学式MO2-δ,其中δ(delta)的值可变化。对于铈氧化物CeO2-δ,δ(delta)的值范围通常为约0.0至约0.5,前者表示铈(IV)氧化物CeO2,后者表示铈(III)氧化物CeO1.5(或者表示为Ce2O3)。或者,δ(delta)的值表示相对于铈(IV)氧化物(CeO2)存在的氧空位的量。对于存在的每个氧二价阴离子空位,存在两个三价铈离子(Ce3+),以保持电荷中性。
在本发明的一个方面中,提供了制备纳米颗粒分散体的方法,其包括:形成包含三价铈离子、柠檬酸、稳定剂(螯合剂)、氧化剂的反应混合物,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸;任选地加热或冷却所述反应混合物,从而在反应混合物中形成含铈纳米颗粒的分散体。
根据至少一个实施方案,柠檬酸与稳定剂的摩尔比可以是约0.1∶0.9至约0.9∶0.1,例如,约0.25∶0.75至约0.75∶0.25或约0.4∶0.6至约0.6∶0.4。在至少一个实施方案中,柠檬酸和稳定剂以约0.5∶0.5的摩尔比存在。
在本发明的一个实施方案中,提供了制备纳米颗粒分散体的方法,其包括:形成包含三价铈离子、柠檬酸、稳定剂、氧化剂和水的反应混合物,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸;任选地加热或冷却所述反应混合物;以及直接在反应混合物中形成含铈纳米颗粒的分散体而不需要分离所述纳米颗粒。
在多个实施方案中,氧化剂包括比分子氧(或空气的环境气氛)更具氧化性的化合物。在另一些实施方案中,氧化剂的水性半电池还原电位比标准氢电极大-0.13伏。在至少一个实施方案中,氧化剂是碱金属或高氯酸铵、氯酸盐、次氯酸盐或过硫酸盐;臭氧、过氧化物或其组合。在至少一个实施方案中,使用双电子氧化剂,例如过氧化氢。根据至少一个实施方案,过氧化氢以比三价铈离子摩尔量大二分之一的量存在。在又一些实施方案中,存在的氧化剂的量相对于存在的铈离子或另一些金属离子的量变化很大。
在至少一个实施方案中,使分子氧通过反应混合物。
在多个实施方案中,反应混合物的温度高于或低于环境温度。在至少一个实施方案中,将反应混合物加热或冷却至高于、低于或等于20℃的温度。在多个实施方案中,将反应混合物加热或冷却至高于约30℃、约40℃、约50℃、约60℃、约70℃、约80℃或约90℃的温度。在另一个实施方案中,将反应混合物加热或冷却至低于或等于水沸腾温度的温度。
在多个实施方案中,所形成的纳米颗粒是无定形的、半结晶的或结晶的。除非另外特别说明,否则本文中使用的术语“结晶的”用来描述具有至少某种晶体结构的纳米颗粒,即,半结晶的或结晶的。在至少一个实施方案中,所形成的纳米颗粒的特征在于立方萤石晶体结构。根据至少一个实施方案,所形成的纳米颗粒的特征在于铈氧化物晶体结构。
在至少一个实施方案中,通过加热反应混合物使所形成的纳米颗粒的结晶性增强。
根据至少一个实施方案,通过加热反应混合物对所形成的纳米颗粒进行脱水或脱羟基化。
在多个实施方案中,含铈纳米颗粒的分散体包含基本上非聚集的纳米颗粒、多于90%的非聚集纳米颗粒、多于95%的非聚集纳米颗粒、多于98%的非聚集纳米颗粒和完全非聚集的纳米颗粒。
在至少一个实施方案中,非聚集纳米颗粒是结晶的,或者被称为单颗粒微晶或单个微晶。
在多个实施方案中,所形成的纳米颗粒的流体动力学直径小于100nm、小于20nm、小于10nm、小于5.0nm、小于3.0nm或小于约2.0nm,并且流体动力学直径大于约1.0nm。
在至少一个实施方案中,提供了包含铈的纳米颗粒。在另一些实施方案中,提供了包含铈氧化物、铈氢氧化物或铈羟基氧化物的纳米颗粒。
根据至少一个实施方案,提供了包含铈、柠檬酸和稳定剂的纳米颗粒,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸。
在多个实施方案中,所形成的纳米颗粒分散体的特征在于ζ电位为约-30mV至约+30mV。在至少一个实施方案中,纳米颗粒分散体的ζ电位为-15mV至约-30mV。
在另一些实施方案中,通过调节纳米颗粒分散体的pH、通过将稳定剂(例如柠檬酸、次氨基三乙酸、乙二醇四乙酸或二亚乙基三胺五乙酸)成分的类型和量调节至小于饱和覆盖,或者通过这二者来改变纳米颗粒的ζ电位。
在至少一个实施方案中,洗涤所形成的纳米颗粒分散体以除去过量的离子或副产物盐。在多个实施方案中,洗涤纳米颗粒分散体使得离子电导率降低至小于约15毫西门子/厘米(mS/cm)、小于约10mS/cm、小于约5mS/cm或小于约3mS/cm。在多个实施方案中,通过透析或渗滤来洗涤所形成的纳米颗粒分散体。
根据至少一个实施方案,浓缩所形成的纳米颗粒分散体以除去过量的溶剂或过量的水。在多个实施方案中,通过渗滤或离心来浓缩纳米颗粒分散体。
在多个实施方案中,分散体中纳米颗粒的浓度大于约0.05重量摩尔浓度(molal)、大于约0.5重量摩尔浓度或大于约2.0重量摩尔浓度(在给定分散体中约35%的固体)。
在多个实施方案中,纳米颗粒的尺寸分布基本上是单峰的。在另一些实施方案中,纳米颗粒尺寸的变异系数(coefficient of variation,COV)小于约30%、小于约25%、小于约20%、小于约15%、小于约10%或小于约5%,其中COV定义为标准偏差除以平均值。
在多个实施方案中,含铈纳米颗粒的分散体针对颗粒聚集和沉降是稳定的,如例如通过维持清澈的液体外观多于3个月、多于6个月、多于9个月、多于12个月和多于16个月所证明的。
在多个实施方案中,反应混合物在分批反应器、连续反应器或胶体磨中形成。在至少一个实施方案中,连续反应器是连续搅拌罐反应器或活塞流反应器。
在至少一个实施方案中,混合器可用于搅动和混合反应物。在多个实施方案中,使用包括搅拌棒、船用叶片螺旋桨(marine blade propeller)、倾斜叶片涡轮或平叶片涡轮在内的混合器。在至少一个实施方案中,使用迫使反应混合物通过筛网的高剪切混合器,其中孔的尺寸从毫米级至数毫米级变化。
生理pH通常在约7.2至约7.4的范围内。
不受限于任何理论,提出的使用铈氧化物来治疗炎症和氧化应激相关疾病(例如,ROS介导的疾病)部分基于铈氧化物可起自由基的催化性清除剂的作用的认知。Ce3+和Ce4+价态的混合物中铈的存在和易于相互转换可使得铈氧化物能够以催化或自动再生方式将自由基还原和/或氧化为危害较小的物质。氧化还原反应可发生在中和损伤组织之自由基的铈氧化纳米颗粒(CeNP)的表面。例如,认为期望将超氧化物阴离子(O2 -)氧化为分子氧,以将过氧亚硝酸根阴离子(ONOO-)氧化为生理学上良性物质,并且将羟基自由基(·OH)还原为氢氧根阴离子。与例如目前可用的用于治疗氧化应激相关疾病和事件的牺牲性抗氧化剂相比,这可继而能够大大降低剂量方案。
在至少一个实施方案中,所施用的本发明纳米铈氧化物颗粒通过细胞膜进入细胞中并且存在于细胞的细胞质或多种细胞器(如细胞核和线粒体)中。在另一些实施方案中,本发明的纳米铈氧化物颗粒存在于血管内空间或间质空间中,其中其可通过除去自由基或降低自身免疫应答来降低氧化应激和炎症。在至少一个实施方案中,由血脑屏障(blood-brain barrier,BBB)或血-脑脊液屏障(blood cerebrospinal fluid barrier,BCFB)或血-眼屏障(blood-ocular barrier,BOB)故障造成的中枢神经***的免疫***入侵通过本发明的纳米铈氧化物颗粒来调节。
在另一个实施方案中,本发明的纳米铈氧化物颗粒是能够穿过哺乳类动物血脑屏障的颗粒。在多个实施方案中,本发明的纳米铈氧化物颗粒穿过哺乳类动物的血脑屏障并且作为尺寸小于约100nm、小于约50nm、小于约20nm、小于约10nm、小于约5nm的聚集体或团聚体存在于脑实质组织中。在至少一个实施方案中,本发明的纳米铈氧化物颗粒穿过哺乳类动物的血脑屏障,并且作为尺寸小于约3.5nm的独立的非聚集纳米颗粒存在于脑实质组织中。
在至少一个实施方案中,特别地考虑了包含本发明纳米铈氧化物颗粒的药物组合物用于预防和/或治疗氧化应激相关疾病和事件,例如但不限于阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩性侧索硬化(amyotrophic lateral sclerosis,ALS)、共济失调、弗里德赖希共济失调(Friedreich’s ataxia)、孤独症、强迫症、注意缺陷多动障碍(attentiondeficit hyperactivity disorder)、偏头痛、卒中、创伤性脑损伤、癌症、炎症、自身免疫病、狼疮、多发性硬化症(multiple sclerosis,MS)、炎性肠病、克罗恩病、溃疡性结肠炎、狭窄、再狭窄、动脉粥样硬化、代谢综合征、内皮功能障碍、血管痉挛、糖尿病、衰老、慢性疲劳、冠心病、心脏纤维化、心肌梗死、高血压、心绞痛、变异型心绞痛(Prizmetal’s angina)、局部缺血、血管成形术、缺氧、克山病(Keshan disease)、葡萄糖-6-磷酸脱氢酶缺乏症、蚕豆病、缺血再灌注损伤、类风湿性关节炎和骨关节炎、哮喘、慢性阻塞性肺病(例如,肺气肿和支气管炎)、***反应、急性呼吸窘迫综合征、慢性肾病、肾移植、肾炎、电离辐射损伤、晒伤、皮炎、黑素瘤、银屑病、黄斑变性、视网膜变性、白内障形成(cataractogenesis)等。
根据多个实施方案,特别地考虑了包含本发明纳米铈氧化物颗粒的药物组合物用于预防和/或治疗氧化应激相关疾病和事件,例如但不限于线粒体功能障碍、溶酶体和蛋白酶体功能障碍、核酸(例如,RNA和DNA)氧化、酪氨酸硝化、磷酸化介导的信号级联的损失、细胞凋亡的启动、脂质过氧化和膜脂环境的破坏。
在多个实施方案中,将包含本发明纳米铈氧化物颗粒的药物组合物施用于人或非人对象,例如其他哺乳动物,包括但不限于犬、猫、牛、马、绵羊、猪或啮齿动物。或者,施用对象可以是动物,如鸟、昆虫、爬行动物、两栖动物或者任意的伴侣动物或农业动物。
在多个实施方案中,本发明的纳米铈氧化物颗粒通过局部、经肠或肠胃外方法体内施用至对象,包括注射、输注或植入。更特别地,特别地考虑了通过任意以下途径施用本发明的纳米铈氧化物颗粒:经耳(耳部)、经口腔、经结膜、经皮肤、经牙齿、电渗、宫颈内、窦内(endosinusial)、气管内、经肠、硬膜外、羊膜腔外(extra-amniotic)、体外(extracorporeal)、血液透析、渗透、间质、腹膜内、羊膜内、动脉内、胆内、支气管内、囊内、心脏内、软骨内、尾脊内(intracaudal)、海绵体内(intracavernous)、腔内、脑内、脑池内(intracisternal)、角膜内、冠状牙齿内(intracornal-dental)、冠状动脉内、海绵体内(intracorporus cavernosum)、皮内、椎间盘内、管内、十二指肠内、硬膜内、表皮内、食管内、胃内、齿龈内、回肠内、病灶内、管腔内、***内、髓内、脑膜内、肌肉内、眼内、卵巢内、心包内、腹膜内、胸膜内、***内、肺内、窦内(intrasinal)、脊柱内、滑膜内、腱内(intratendinous)、睾丸内、鞘内、胸内、小管内、肿瘤内、鼓室内、子宫内、血管内、静脉内、静脉内推注、静脉内滴注、心室内、膀胱内、玻璃体内、离子电渗、冲洗、经喉、经鼻、鼻饲、封闭敷裹技术(occlusive dressing technique)、眼用、经口、经口咽、肠胃外、经皮、关节周围、硬膜外、神经周围、牙周、经直肠、经呼吸(吸入)、眼球后、经软组织、蛛网膜下、结膜下、皮下、舌下、黏膜下、局部、经皮、经乳腺、经黏膜、经胎盘(transplacenta)、经气管、经鼓膜、经输尿管、经尿道、经***、以及任意其他或未指定的途径。
在另一些实施方案中,使本发明的纳米铈氧化物颗粒保留在医疗装置或假体(例如,套管、导管或支架)中或其表面上,从而在短时间或长时间内局部或全身地减轻炎症。
在多个实施方案中,本发明的纳米铈氧化物颗粒以本领域已知的任意合适的形式递送,所述形式包括但不限于,混悬剂、凝胶剂、片剂、肠衣片剂、负载脂质体、散剂、栓剂、难熔剂(infusible)、锭剂、乳膏剂、洗剂、油膏(salve)或吸入剂。
在多个实施方案中,本发明的纳米铈氧化物颗粒与其他可药用物质组合,所述物质例如但不限于:水、盐、缓冲剂、磷酸盐缓冲盐水(PBS)、糖、人或牛血清白蛋白、脂质、药物、着色剂、矫味剂、黏合剂、胶、表面活性剂、填充剂或本领域已知的任意赋形剂。
在至少一个实施方案中,包含本发明纳米铈氧化物颗粒的载剂在施用之前进行灭菌。
在另一些实施方案中,使细胞或细胞培养物与本发明纳米铈氧化物颗粒接触。接触可通过体内或体外方法通过暴露细胞或细胞培养物来实施,其中后一种方法包括将经处理细胞重新引入对象中,例如最初从其获得所述细胞的对象。在多个实施方案中,所述细胞本质上是原核的或真核的。在至少一个实施方案中,将经处理细胞用于生产用于制药工业中的蛋白质(一般称为生物制品),例如但不限于抗原、抗体和疫苗。在另一个实施方案中,将经处理的细胞用于发酵工艺。
通过以下实施例进一步举例说明了本发明,所述实施例并不旨在以任何方式限制本发明。
实验部分
纳米颗粒散射和尺寸评估
通过评估当红激光笔灯照射时相对于来自纯溶剂样品的散射量由分散体表现出的Tyndell散射度进行了颗粒分散体的简单定性表征。使用配备有石英杯(quartzcuvette)的Brookhaven 90Plus颗粒尺寸分析仪(Brookhaven Instruments Corp.,Holtzville,New York,U.S.A.)通过动态光散射(dynamic light scattering,DLS)进行了纳米颗粒分散体颗粒尺寸的定量评估。所报道的DLS尺寸是对数加权参数。
纳米颗粒电荷评估
通过使用来自Malvern Instruments的Zetasizer Nano ZS测量ζ电位进行了纳米颗粒电荷的定量评估。
实施例1:使用铈和柠檬酸制备纳米颗粒
向带有磁力搅拌棒的800ml玻璃烧杯中引入500ml高纯(high purity,HP)水。然后将水加热至70℃,并将4.83克柠檬酸(CA)溶解在其中。添加氢氧化铵(28%至30%)以将溶液的pH调节至约8.5。将反应容器的温度升高至约80℃。将10.0克量的Ce(NO3)3·6(H2O)溶解于30ml HP水中,并在几分钟内将该溶液缓缓添加至搅拌的反应混合物中。以这种方式将等摩尔量的CA和Ce添加到反应混合物中。然后在几分钟内将包含4.8ml 50%H2O2(H2O2与铈的摩尔比为3.0)的50ml溶液缓慢添加到三价铈离子和柠檬酸的等摩尔量反应混合物中。覆盖反应产物,然后再加热1小时,得到透明的黄色悬液。在搅拌下冷却之后,通过渗滤将直接形成的纳米颗粒分散体洗涤至离子电导率小于约10mS/cm,以除去过量的盐。
最终产物分散体是透明的黄色液体,当用低强度激光束照射时其表现出高度的Tyndall散射,表明其包含良好分散的胶体颗粒。通过动态光散射进行的颗粒尺寸分析表明平均流体动力学直径为7.8nm。X射线衍射(X-ray diffraction,XRD)谱分析表明存在与以立方萤石结构为特征的CeO2(PDF#34-394,方铈矿)结构不同的主晶相。通过使用Scherrer法分析(220)峰宽确定了平均微晶尺寸为2.0nm。
实施例2:用铈、柠檬酸和DCTA制备纳米颗粒
向带有磁力搅拌棒的600ml玻璃烧杯中引入500ml高纯(HP)水。将2.41克量的柠檬酸(CA)添加到反应混合物中。将4.264克量的1,2-二氨基环己烷四乙酸单水合物(DCTA)连同约6ml的氢氧化铵一起溶解于水中以帮助溶解,并添加到反应混合物中。添加氢氧化铵(28%至30%)以将溶液的pH调节至约8.5。添加10.0克量的Ce(NO3)3·6(H2O)。CA/DCTA/Ce的摩尔比例为0.5/0.5/1.0。然后将10ml包含4.8克50%H2O2的溶液(H2O2与铈离子的摩尔比为3.0)缓慢添加到铈、柠檬酸和DCTA溶液混合物中。然后在80℃下将反应产物加热1小时。在搅拌下冷却之后,通过渗滤将直接形成的纳米颗粒分散体洗涤至离子电导率小于约10mS/cm,以除去过量的盐。
冷却之后,最终产物分散体是透明的浅橙色液体,在用低强度激光束照射时,其表现出高度的Tyndall散射,表明其包含分散良好的胶体颗粒。通过动态光散射进行的颗粒尺寸分析表明其流体动力学直径为2.6nm,多分散度为0.227。X射线衍射(XRD)谱分析表明存在与以立方萤石结构为特征的CeO2(PDF#34-394,方铈矿)结构不同的主晶相。通过使用Scherrer法分析(220)峰宽确定了平均微晶尺寸为1.9nm。
实施例3:使用铈、柠檬酸和NTA制备纳米颗粒
向带有磁力搅拌棒的600ml玻璃烧杯中引入500ml高纯(HP)水。将2.41克量的柠檬酸(CA)添加到反应混合物中。将3.129克量的2,2’,2”-次氨基三乙酸(NTA,CAS No.139-13-9)连同氢氧化铵一起溶解于水中以帮助溶解,并添加到反应混合物中。添加氢氧化铵(28%至30%)以将溶液的pH调节至约8.5。添加10.0克量的Ce(NO3)3·6(H2O)。CA/NTA/Ce的摩尔比例为0.5/0.5/1.0。然后将10ml包含4.8克50%H2O2的溶液(H2O2与铈离子的摩尔比为3.0)缓慢添加到铈、柠檬酸和NTA溶液混合物中。然后在80℃下将反应产物加热1小时。在搅拌下冷却之后,通过渗滤将直接形成的纳米颗粒分散体洗涤至离子电导率小于约10mS/cm,从而除去过量的盐。
最终产物分散体是透明的黄色液体,在用低强度激光束照射时,其表现出高度的Tyndall散射,表明其包含分散良好的胶体颗粒。通过动态光散射进行的颗粒尺寸分析表明其流体动力学直径为2.8nm,多分散度为0.264。
实施例4:使用铈、柠檬酸和EGTA制备纳米颗粒
向带有磁力搅拌棒的600ml玻璃烧杯中引入500ml高纯(HP)水。将2.41克量的柠檬酸(CA)添加到反应混合物中。将4.497克量的乙二醇四乙酸(EGTA,CAS No.67-42-5)连同氢氧化铵一起溶解于水中以帮助溶解,并添加到反应混合物中。添加氢氧化铵(28%至30%)以将溶液的pH调节至约8.5。添加10.0克量的Ce(NO3)3·6(H2O)。CA/EGTA/Ce的摩尔比例为0.5/0.5/1.0。然后将10ml包含4.8克50%H2O2的溶液(H2O2与铈离子的摩尔比为3.0)缓慢添加到铈、柠檬酸和EGTA溶液混合物中。然后在70℃下将反应产物加热1小时。在搅拌下冷却之后,通过渗滤将直接形成的纳米颗粒分散体洗涤至离子电导率小于约10mS/cm,以除去过量的盐。
最终产物分散体是透明的橙色液体,在用低强度激光束照射时,其表现出高度的Tyndall散射,表明其包含分散良好的胶体颗粒。通过动态光散射进行的颗粒尺寸分析表明其流体动力学直径为8.5nm,多分散度为0.393。
实施例5:使用铈、柠檬酸和DTPA制备纳米颗粒
向带有磁力搅拌棒的600ml玻璃烧杯中引入500ml高纯(HP)水。将2.89克量的柠檬酸(CA)添加到反应混合物中。将3.606克量的二亚乙基三胺五乙酸(DTPA,CAS No.67-43-6)添加到反应混合物中。添加氢氧化铵(28%至30%)以将溶液的pH调节至约8.5。添加10.0克量的Ce(NO3)3·6(H2O)。CA/DTPA/Ce的摩尔比例为0.6/0.4/1.0。然后将10ml包含4.8克50%H2O2的溶液(H2O2与铈离子的摩尔比为3.0))缓慢添加到铈、柠檬酸和DTPA溶液混合物中。然后在80℃下将反应产物加热1小时。在搅拌下冷却之后,通过渗滤将直接形成的纳米颗粒分散体洗涤至离子电导率小于约10mS/cm,以除去过量的盐。
最终产物分散体是透明的红色液体,在用低强度激光束照射时,其表现出高度的Tyndall散射,表明其包含分散良好的胶体颗粒。通过动态光散射进行的颗粒尺寸分析表明其流体动力学直径为2.4nm,多分散度为0.212。X射线衍射(XRD)光谱分析表明存在与以立方萤石结构为特征的CeO2(PDF#34-394,方铈矿)结构不同的主晶相。通过使用Scherrer法分析(220)峰宽确定了平均微晶尺寸为2.1nm。
将最终产物分散体的样品在环境温度和压力下在暗处存储多于16个月的时间,液体的透明度没有改变并且颗粒的流体动力学直径和多分散度也没有改变。
在缺血性卒中的鼠模型中评估经稳定化的纳米铈氧化物
对由Estevez,AY等,Neuroprotective mechanisms of cerium oxidenanoparticles in a mouse hippocampal brain slice model of ischemia,FreeRadic.Biol.Med.(2011)51(6):1155-63(doi:10.1016/j.radbiomed.2011.06.006)所述的局部缺血体外小鼠海马脑切片模型进行修改,评估了含铈纳米颗粒(例如,纳米铈氧化物)降低氧化应激的能力。
通过快速断头处死成年(2至5月龄)CD1小鼠,快速摘除其脑并放置在经冷冻的基于胆碱的切片溶液(315mOsm)中,所述溶液包含24mM胆碱碳酸氢盐、135mM氯化胆碱、1mM犬尿酸、0.5mM CaCl2、1.4mM Na2PO4、10mM葡萄糖、1mM KCl和20mM MgCl2。使用Leica VT1200振动切片机(Leica Microsystems,Wetzlar,Germany)将横向海马切片(400μm厚)沿喙-尾(rostral-to-caudal)轴(-1.2mm至-2.8mm前囱)切割,并使其在对照人工脑脊髓液(aCSF)(pH 7.4,300mOsm)中恢复1小时,所述人工脑脊髓液包含124mM NaCl、3mM KCl、2.4mMCaCl2、1.3mM MgSO4、1.24mM K3PO4、26mM NaHCO3、10mM葡萄糖并用5%CO2、95%O2气体进行鼓泡。将海马切片放置于培养皿中,并在37℃下在具有5%CO2的NuAire湿润孵育箱(NuAire,Plymouth,MN,USA)中存储长达48小时。
通过在37℃下将脑切片放置在低血糖、酸性和缺氧的aCSF(葡萄糖和pH分别降至2mM和6.8,并且溶液用84%N2、15%CO2和1%O2进行鼓泡)中放置30分钟来诱导局部缺血的氧化应激。添加蔗糖以将溶液的渗量保持在约295mOsm。
在缺血事件发生时,在1μg/1ml aCSF或培养基的递送体积(相当于5.8μM)中以匹配剂量施用如以上实施例1至5所述制备的含铈纳米颗粒的水性分散体,并且在整个实验的剩余时间中保留在培养基中。对照切片接受相等体积的载剂对照。对于如本文中所述制备的铈氧化物纳米颗粒,使用多种递送载剂都取得了相似的成功,所述载剂包括单独的蒸馏水、盐溶液、柠檬酸钠溶液、PBS及其组合。
在暴露于氧化应激(缺血情况)30分钟之后,活的脑切片(测试和对照)通过将其放置于包含培养基和Millipore***物(Millipore,Billerica,MA,USA)的35mm培养皿中而在器官型培养物中孵育24小时。培养基包含50%极限必需培养基(Hyclone Scientific,Logan UT,USA)、25%马血清、25%Hank平衡盐溶液(补充有28mM葡萄糖、20mM HEPES和4mMNaHCO3)、50U/ml青霉素和50μl/ml链霉素,pH 7.2。
在氧化损伤24小时之后使用荧光成像技术测定了细胞死亡的程度。除了单独施用载剂之外,在测试条件(即,施用含铈纳米颗粒)下所研究的每组脑切片与在各方面都进行相同处理的相似组对照脑切片相匹配。因此,在每个研究日,使取自年龄匹配且性别匹配的同窝仔畜的解剖学上匹配的两组脑切片经历测试条件(施用含铈纳米颗粒)或对照(单独施用载剂)。在荧光成像测量期间,光强度、图像捕获持续时间和图像收集时间对于测试条件和载剂对照脑切片是相同的。结果表示为在实验程序中同一时间点成像的测试条件下荧光与匹配对照切片中荧光的比值。
在氧化损伤24小时之后,将成对的(对照和测试)脑切片在包含0.81μM活体***染料Green(Invitrogen,Carlbad,CA,USA)的培养基中孵育20分钟,并且随后在培养基中清洗15至20分钟以除去未掺入的染料。Green是结合于DNA和RNA的荧光染料。然而,其在完整的活细胞中通过细胞膜从细胞核中被排除。因此,其充当活体染料只对死亡细胞或垂死细胞(其中细胞膜变得可渗透使得染料可进入细胞内部)染色。在染色和清洗之后,将脑切片转移至配备有荧光显微镜附件和150-W氙光源(Optiquip,HighlandMills,NY,USA)的Nikon TE 2000-U(Nikon Instruments,Melville,NY,USA)显微镜的台上。将对照aCSF溶液负载到60-ml注射器中,经95%O2/5%CO2平衡并使用伺服控制的(servo-controlled)注射器加热部件、回热加热器(stage heater)和同轴灌注加热器(in-line perfusion heater)(Warner Instruments,Hamden,CT,USA)加热至37℃。以1ml/分钟的速率向脑切片连续地灌注经加热的经95%O2/5%CO2平衡的aCSF。5分钟之后,使用4×Plan Flour物镜(Nikon Instruments)在相同条件下(即,光强度、曝光时间、相机采集参数)收集每个对照和测试脑切片的海马形成图像。通过在480±40nm短暂地(620ms)激发组织;使用505nm的长通二色镜(Chroma technology,Bennington,VT,USA)过滤来自探针的发射荧光(535±50nm);强化并用冷却的CCD增益EM照相机(Hamamatsu CCD EM C9100;Bridgewater,NJ,USA)测量Green荧光。获得了数字图像并使用CompixSimplePCI 6.5软件(C成像***,Cranberry Township,PA,USA)进行处理。
由Green装载得到的光强度反映出所计算面积中死亡或垂死细胞的数目。使用Compix SimplePCI 6.5软件自动地进行光强度测量,从而消除了选择目标区域时的实验者偏差。
死亡细胞的降低报道为:对于取自年龄匹配且性别匹配的同窝仔畜脑并在同一天切片并暴露于缺血性氧化应激并且在缺血性损伤后24小时进行荧光成像的解剖学上匹配的海马部分,测试条件(即经纳米铈氧化物处理)与对照(未处理)的阿蒙角区域(起始层(oriens layer)、放射层和腔隙分子层(stratum radiatum and lacunosum moleculare)的Green荧光的光强度之比。
使用5.8μM的处理浓度在缺血性卒中的小鼠海马脑切片模型中评估含铈纳米颗粒,所述纳米颗粒如实施例1至5所述用单独的柠檬酸稳定剂,以及用包含DCTA、NTA、EGTA或DTPA之一和柠檬酸的生物相容性稳定剂的混合物来制备。下表1中给出了作为纳米颗粒稳定剂的函数的细胞死亡降低(相对于对照降低的百分比)(通常称为节制(sparing))的结果。
表1
纳米颗粒来源 | 稳定剂 | DLS(nm) | 节制 | 注释 |
实施例1 | CA | 7.8 | 15.5% | 对比 |
实施例2 | CA/DCTA | 2.6 | 14.2% | 对比 |
实施例3 | CA/NTA | 2.8 | 17.0% | 本发明 |
实施例4 | CA/EGTA | 8.5 | 23.3% | 本发明 |
实施例5 | CA/DTPA | 2.4 | 34.0% | 本发明 |
上表1中示出的结果表明,当用柠檬酸(CA)与NTA、EGTA或DTPA的组合制备含铈纳米颗粒时,节制(即,细胞死亡的大大降低)发生改善。
虽然已参照多个具体实施方案对本发明进行了描述,但是应理解,在所述的发明构思的精神和范围内可做出很多改变。因此,意味着本发明不限于所述的实施方案,而是具有由权利要求限定的全部范围。
Claims (14)
1.制备纳米颗粒的分散体的方法,其包括:
a.形成包含三价铈离子、柠檬酸、稳定剂、氧化剂和水的反应混合物,其中所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸;以及
b.在所述反应混合物中形成含铈纳米颗粒的分散体,
其中所述反应混合物的温度低于或等于水的沸腾温度。
2.权利要求1所述的方法,其还包括加热或冷却所述反应混合物。
3.权利要求1所述的方法,其中所述含铈纳米颗粒包含铈的氧化物。
4.权利要求1所述的方法,其中所述含铈纳米颗粒是结晶的。
5.权利要求4所述的方法,其中所述纳米颗粒的特征在于立方萤石晶体结构。
6.权利要求1所述的方法,其中所述氧化剂包含过氧化氢。
7.权利要求1所述的方法,其中所述含铈纳米颗粒是基本上非聚集的。
8.权利要求1所述的方法,其中所述含铈纳米颗粒的分散体在大于12个月中针对颗粒聚集和沉降是稳定的。
9.权利要求1所述的方法,其中所述含铈纳米颗粒的分散体的ζ电位为-15mV至-30mV。
10.权利要求1所述的方法,其中所述含铈纳米颗粒的特征在于小于10纳米的流体动力学直径。
11.权利要求1所述的方法,其中所述含铈纳米颗粒的分散体用作药物组合物以预防或治疗疾病或氧化应激相关事件。
12.权利要求11所述的方法,所述疾病或氧化应激相关事件为缺血性卒中、多发性硬化、肌萎缩性侧索硬化或缺血再灌注损伤。
13.通过权利要求1所述的方法制备的纳米颗粒。
14.纳米颗粒,其包含铈、柠檬酸和稳定剂,所述稳定剂选自次氨基三乙酸、乙二醇四乙酸和二亚乙基三胺五乙酸。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361854507P | 2013-04-25 | 2013-04-25 | |
US61/854,507 | 2013-04-25 | ||
PCT/US2014/035434 WO2014176487A2 (en) | 2013-04-25 | 2014-04-25 | Chelated nanoceria for the treatment of oxidative stress |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105408257A CN105408257A (zh) | 2016-03-16 |
CN105408257B true CN105408257B (zh) | 2017-11-21 |
Family
ID=50819979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201480030435.9A Expired - Fee Related CN105408257B (zh) | 2013-04-25 | 2014-04-25 | 用于治疗氧化应激的螯合纳米铈氧化物 |
Country Status (8)
Country | Link |
---|---|
US (2) | US9549950B2 (zh) |
EP (1) | EP2989054A2 (zh) |
JP (1) | JP6382952B2 (zh) |
KR (1) | KR20160003117A (zh) |
CN (1) | CN105408257B (zh) |
AU (1) | AU2014256983B2 (zh) |
CA (1) | CA2910212A1 (zh) |
WO (1) | WO2014176487A2 (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6382952B2 (ja) * | 2013-04-25 | 2018-08-29 | セリオン エンタープライジズ リミテッド ライアビリティ カンパニー | 酸化ストレスを治療するためのキレート化ナノセリア |
EP3042981A1 (en) * | 2015-01-09 | 2016-07-13 | Vito NV | An electrochemical process for preparing a compound comprising a metal or metalloid and a peroxide, ionic or radical species |
US10722474B2 (en) * | 2015-01-20 | 2020-07-28 | Cerion, Llc | EDDS chelated nanoceria with catalase-like activity |
EP3081942A1 (en) * | 2015-04-17 | 2016-10-19 | Roche Diagniostics GmbH | Pressure transmission liquid for cellular analyzer, cellular analyzer and method for analyzing a liquid cellular sample |
FR3049465B1 (fr) * | 2016-03-29 | 2018-04-27 | Oxymo Technologies Inc. | Composition pharmaceutique preventive et curative a base de peroxometallate |
KR102102535B1 (ko) * | 2018-07-26 | 2020-04-21 | 서울대학교산학협력단 | 방사선 보호 나노입자 |
JP7328480B2 (ja) * | 2018-09-14 | 2023-08-17 | 株式会社applause Pharma | チロシン-チロシナーゼ反応阻害剤 |
JPWO2021251436A1 (zh) * | 2020-06-10 | 2021-12-16 | ||
CN112569253A (zh) * | 2020-11-24 | 2021-03-30 | 深圳大学 | 一种用于急性肾损伤的纳米酶药物及其制备方法与应用 |
WO2023168056A2 (en) * | 2022-03-04 | 2023-09-07 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods for using cerium oxide nanoparticles for macrophage-mediated efficacy in respiratory syncytial viral infection |
CN115737678A (zh) * | 2022-11-30 | 2023-03-07 | 浙江大学金华研究院 | 载三苯基膦修饰的氧化铈和全反式维甲酸的脂质体凝胶 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5545386A (en) * | 1994-10-21 | 1996-08-13 | Shin-Etsu Chemical Co., Ltd. | Method for the preparation of globular particles of a rare earth oxide |
KR20030092605A (ko) * | 2002-05-30 | 2003-12-06 | 동우 화인켐 주식회사 | 금속 cmp용 연마 슬러리 조성물 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US954950A (en) * | 1909-01-04 | 1910-04-12 | Robert Henry Fowler | Disk plow for steam cultivation. |
JPS6034566A (ja) | 1983-08-04 | 1985-02-22 | Nippon Cable Syst Inc | 内索の自動伸び吸収装置 |
US4778671A (en) * | 1986-07-14 | 1988-10-18 | Corning Glass Works | Preparation of unagglomerated metal oxide particles with uniform particle size |
EP2243827B2 (en) * | 1996-08-30 | 2017-11-22 | Life Technologies Corporation | Serum-free mammalian cell culture medium, and uses thereof |
FR2803224B1 (fr) * | 1999-12-30 | 2002-09-27 | Rhodia Chimie Sa | Dispersion colloidale aqueuse a base d'au moins un compose d'un metal et d'un complexant, procede de preparation et utilisation |
JP4186529B2 (ja) * | 2002-07-09 | 2008-11-26 | 昭栄化学工業株式会社 | 高結晶性複酸化物粉末の製造方法 |
US7534453B1 (en) | 2002-09-05 | 2009-05-19 | University Of Central Florida Research Foundation, Inc. | Cerium oxide nanoparticles and use in enhancing cell survivability |
EP1858989B1 (fr) * | 2005-01-07 | 2015-12-09 | Rhodia Chimie | Compositions de peintures aqueuses comprenant une dispersion colloïdale de cerium |
EP1726688A1 (en) * | 2005-05-23 | 2006-11-29 | Shin-Etsu Chemical Co., Ltd. | Cerium ion-containing solution and corrosion inhibitor |
EP1904072A4 (en) | 2005-06-27 | 2009-06-17 | Edward Via Virginia College Of | ANTI-INFLAMMATORY, RADIOPROTECTIVE CERTIFICATE OXIDE NANOPARTICLE CAPACITIES AND ENHANCING LONGEVITY |
CA2662769A1 (en) * | 2006-09-05 | 2008-03-13 | Cerion Technology, Inc. | Method of conditioning an internal combustion engine |
US20100172994A1 (en) * | 2006-11-22 | 2010-07-08 | University Of Florida Research Foundation, Inc. | Nanoparticles for Protection of Cells from Oxidative Stress |
ES2384060B1 (es) * | 2010-03-24 | 2013-09-23 | Lipotec S.A. | Cápsulas de nanopartículas lipídicas. |
US20130089602A1 (en) * | 2011-10-10 | 2013-04-11 | International Business Machines Corporation | Encapsulated chelator |
US9446070B2 (en) * | 2012-06-13 | 2016-09-20 | Cerion, Llc | Nanoceria with citric acid additive |
JP6174692B2 (ja) | 2012-06-13 | 2017-08-02 | セリオン エンタープライジズ リミテッド ライアビリティ カンパニー | 酸化ストレスの処置のためのナノセリア |
JP6382952B2 (ja) * | 2013-04-25 | 2018-08-29 | セリオン エンタープライジズ リミテッド ライアビリティ カンパニー | 酸化ストレスを治療するためのキレート化ナノセリア |
-
2014
- 2014-04-25 JP JP2016510794A patent/JP6382952B2/ja not_active Expired - Fee Related
- 2014-04-25 KR KR1020157033653A patent/KR20160003117A/ko active IP Right Grant
- 2014-04-25 CA CA2910212A patent/CA2910212A1/en not_active Abandoned
- 2014-04-25 CN CN201480030435.9A patent/CN105408257B/zh not_active Expired - Fee Related
- 2014-04-25 AU AU2014256983A patent/AU2014256983B2/en not_active Ceased
- 2014-04-25 US US14/261,756 patent/US9549950B2/en active Active
- 2014-04-25 EP EP14726490.7A patent/EP2989054A2/en not_active Withdrawn
- 2014-04-25 WO PCT/US2014/035434 patent/WO2014176487A2/en active Application Filing
-
2017
- 2017-01-23 US US15/412,694 patent/US10751366B2/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5545386A (en) * | 1994-10-21 | 1996-08-13 | Shin-Etsu Chemical Co., Ltd. | Method for the preparation of globular particles of a rare earth oxide |
KR20030092605A (ko) * | 2002-05-30 | 2003-12-06 | 동우 화인켐 주식회사 | 금속 cmp용 연마 슬러리 조성물 |
Also Published As
Publication number | Publication date |
---|---|
WO2014176487A3 (en) | 2014-12-18 |
JP2016525994A (ja) | 2016-09-01 |
EP2989054A2 (en) | 2016-03-02 |
AU2014256983B2 (en) | 2018-10-04 |
KR20160003117A (ko) | 2016-01-08 |
US9549950B2 (en) | 2017-01-24 |
CA2910212A1 (en) | 2014-10-30 |
JP6382952B2 (ja) | 2018-08-29 |
AU2014256983A1 (en) | 2015-11-12 |
US20170128488A1 (en) | 2017-05-11 |
US10751366B2 (en) | 2020-08-25 |
CN105408257A (zh) | 2016-03-16 |
US20140322333A1 (en) | 2014-10-30 |
WO2014176487A2 (en) | 2014-10-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105408257B (zh) | 用于治疗氧化应激的螯合纳米铈氧化物 | |
CN104812375B (zh) | 用于治疗氧化应激的纳米二氧化铈 | |
US11771658B2 (en) | Edds chelated nanoceria with catalase-like activity | |
Shirokikh et al. | Bioavailability of nanoemulsions modified with curcumin and cerium dioxide nanoparticles | |
US9446070B2 (en) | Nanoceria with citric acid additive | |
US10143661B2 (en) | Malic acid stabilized nanoceria particles |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171121 Termination date: 20210425 |
|
CF01 | Termination of patent right due to non-payment of annual fee |