TWI811297B - 生物可相容磁性材料 - Google Patents
生物可相容磁性材料 Download PDFInfo
- Publication number
- TWI811297B TWI811297B TW108104248A TW108104248A TWI811297B TW I811297 B TWI811297 B TW I811297B TW 108104248 A TW108104248 A TW 108104248A TW 108104248 A TW108104248 A TW 108104248A TW I811297 B TWI811297 B TW I811297B
- Authority
- TW
- Taiwan
- Prior art keywords
- iron oxide
- magnetic material
- biocompatible
- oxide nanoparticles
- solution
- Prior art date
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- 239000000696 magnetic material Substances 0.000 title claims abstract description 56
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 57
- -1 Fe(II) ions Chemical class 0.000 claims abstract description 48
- 229920000249 biocompatible polymer Polymers 0.000 claims abstract description 32
- 229910052742 iron Inorganic materials 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims description 60
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 44
- 229940031182 nanoparticles iron oxide Drugs 0.000 claims description 44
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical class [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 15
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 10
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 10
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 10
- 239000005642 Oleic acid Substances 0.000 claims description 10
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 10
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 10
- 230000008685 targeting Effects 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical class [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims description 5
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 125000005647 linker group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000005985 organic acids Nutrition 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 108090000288 Glycoproteins Proteins 0.000 claims description 3
- 102000003886 Glycoproteins Human genes 0.000 claims description 3
- 150000001720 carbohydrates Chemical class 0.000 claims description 3
- 235000014633 carbohydrates Nutrition 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- 239000002773 nucleotide Substances 0.000 claims description 3
- 125000003729 nucleotide group Chemical group 0.000 claims description 3
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 3
- 108090000623 proteins and genes Proteins 0.000 claims description 3
- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000002105 nanoparticle Substances 0.000 abstract description 21
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 abstract description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 235000019152 folic acid Nutrition 0.000 description 9
- 239000011724 folic acid Substances 0.000 description 9
- 229910001566 austenite Inorganic materials 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 239000002245 particle Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 229960000304 folic acid Drugs 0.000 description 5
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 5
- 229940014800 succinic anhydride Drugs 0.000 description 5
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229940014144 folate Drugs 0.000 description 4
- 229920001427 mPEG Polymers 0.000 description 4
- 239000002122 magnetic nanoparticle Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
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- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
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- 231100000053 low toxicity Toxicity 0.000 description 3
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- 229910052711 selenium Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002616 MRI contrast agent Substances 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 2
- PXXSHCAEZBHGII-UHFFFAOYSA-N [O-2].[Fe+2].C(CCCCCCCC=C/CCCCCCCC)(=O)O Chemical compound [O-2].[Fe+2].C(CCCCCCCC=C/CCCCCCCC)(=O)O PXXSHCAEZBHGII-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 2
- 229910052785 arsenic Inorganic materials 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
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- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
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- 125000002993 cycloalkylene group Chemical group 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
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- 239000003814 drug Substances 0.000 description 2
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- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
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- 125000005956 isoquinolyl group Chemical group 0.000 description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 2
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- 238000001226 reprecipitation Methods 0.000 description 2
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- 125000000335 thiazolyl group Chemical group 0.000 description 2
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- 229910052718 tin Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000000108 ultra-filtration Methods 0.000 description 2
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
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- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 1
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
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- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
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- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 239000012265 solid product Substances 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
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- 125000004149 thio group Chemical group *S* 0.000 description 1
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- 238000000844 transformation Methods 0.000 description 1
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Abstract
一種生物可相容磁性材料,含有氧化鐵奈米粒子及一或多種生物可相容聚合物,各具有下式(I),共價性鍵結至氧化鐵奈米粒子:
Description
本發明係關於一種生物可相容磁性材料及其製造方法。
氧化鐵奈米粒子因其化學安定性及合適的磁化作用而有用於作為磁共振造影(MRI)的對比劑。磁鐵礦(Fe3O4)及磁赤鐵礦(γ-Fe2O3)為氧化鐵奈米粒子的二個實例。
該等氧化鐵奈米粒子能與生物可相容聚合物接合以形成生物可相容磁性材料,例如,MRI對比劑。
傳統地,Fe3O4磁性奈米粒子係藉由使用Fe(II)及Fe(III)鹽類的混合物合成。理論上,相對於總鐵離子,Fe3O4磁性奈米粒子含有約33% Fe(II)鐵。不同地,γ-Fe2O3磁性奈米粒子含有0% Fe(II)離子。
Fe3O4提供較強的T 2縮短效果,亦即,相比於γ-Fe2O3為較高的遲緩率r2。參照,例如,Basti et al.,J Colloid Interface Sci.,2010,341:248-254;及Li et al.,Theranostics,2013,3(8):595-615。另一方面,Fe3O4奈米粒子相比於γ-Fe2O3奈米粒子,於製造羥基自由基為顯著地更有效,及其結果為於臨床應用上,相較於γ-Fe2O3,Fe3O4可誘發較高毒性。參照,例如,Park et al.,Arch Toxicol.,2014,88(8):1607-1618;及Wu et al.,Journal of Food and Drug Analysis,2014,22,86-94。
有需求於開發具有高遲緩率及低毒性的新的生物可相容磁性材料。
本發明相關於具有高遲緩率及低毒性的可使用作為MRI對比劑的某生物可相容磁性材料。
此式中,R為H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C1-C10雜環烷基、芳基、雜芳基、C1-C10羰基或C1-C10胺基;L為連結子;x為1至10;及y為5至1000。
明顯地,相對於總鐵離子,該生物可相容磁性材料各含有4-15% Fe(II)離子。
氧化鐵奈米粒子可具有Fe(II)含量相同於或不同於生物可相容磁性材料所含有者。例示的氧化鐵奈米粒子,相對於其之中的總鐵離子,含有4-15%(例如,4-10%及4-8%)Fe(II)離子。
述及上述式(I),連結子L可為O、S、Si、C1-C6伸烷基、含有二個羰基及2-20個碳原子的羰基部分、具有下述式的基團:
式中,各m、n、p、q、及t獨立地為1至6;W為O、S或NRb;各L1、L3、L5、L7及L9獨立地為鍵結、O、S或NRc;各L2、L4、L6、L8及L10獨立地為鍵結、O、S或NRd;及V為ORe、SRf或NRgRh,各Ra、Rb、Rc、Rd、Re、Rf、Rg及Rh,獨立地為H、OH、C1-C10烷基、C1-C10雜烷基、C3-C10環烷基、C1-C10雜環烷基、芳基或雜芳基。
本文中用語「烷基」意指飽和、鏈狀或分支狀烴部分,如甲基、乙基、丙基、丁基、戊基及己基。用語「烯基」意指含有至少一個雙鍵的鏈狀或分支狀烴部分,如-CH=CH-CH3及-CH=CH-CH2-。用語「炔基」意指含有至少一個參鍵的鏈狀或分支狀烴部分,如-C≡C-CH3及-C≡C-CH2-。用語「環烷基」意指飽和、環狀烴部分,如環己基及伸環己基。用語「雜環烷基」意指含有至少一個選自N、O、P、B、S、Si、Sb、Al、Sn、As、Se及Ge的雜原子的飽和、環狀烴部分,如哌嗪基及哌啶基。
本文中用語「雜烷基」意指含有至少一個選自N、O、P、B、S、Si、Sb、Al、Sn、As、Se及Ge的雜原子的脂族部分。雜烷基的實例包括甲氧基甲基及甲基胺基乙基。
本文中用語「芳基」意指C6單環、C10雙環、C14三環、C20四環或C24五環的芳香族環系統。芳基的實例包括苯基、伸苯基、萘基、伸萘基、蒽基、伸蒽基、芘基及伸芘基。本文中用語「雜芳基」意指具有一或多個
雜原子(如O、N、S或Se)的5-8員單環、8-12員雙環、11-14員三環、及15-20員四環的環系統。雜芳基的實例包括呋喃基、伸呋喃基、芴基、伸芴基、吡咯基、伸吡咯基、噻吩基、伸噻吩基、噁唑基、伸噁唑基、咪唑基、伸咪唑基、苯并咪唑基、伸苯并咪唑基、噻唑基、伸噻唑基、吡啶基、伸吡啶基、嘧啶基、伸嘧啶基、喹唑啉基、伸喹唑啉基、喹啉基、伸喹啉基、異喹啉基、伸異喹啉基、吲哚基、及伸吲哚基。
除非具體指明,本文述及的烷基、烯基、炔基、環烷基、雜環烷基、雜烷基、芳基及雜芳基包括經取代及未經取代二部分。環烷基、伸環烷基、環烯基、伸環烯基、環炔基、伸環炔基、雜環烷基、伸雜環烷基、雜環烯基、伸雜環烯基、芳基及雜芳基上的可能取代基包括,但不限於,C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20環烷基、C3-C20環烯基、C3-C20雜環烷基、C3-C20雜環烯基、C1-C10烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1-C10烷基胺基、C2-C20二烷基胺基、芳基胺基、二芳基胺基、C1-C10烷基碸基胺基、芳基碸基胺基、C1-C10烷基亞胺基、芳基亞胺基、C1-C10烷基碸基亞胺基、芳基碸基亞胺基、羥基、鹵基、硫基、C1-C10烷基硫基、芳基硫基、C1-C10烷基磺醯基、芳基磺醯基、醯基胺基、胺基醯基、胺基硫醯基、醯胺基、甲脒基、胍、脲基、硫脲基、氰基、硝基、亞硝基、疊氮基、醯基、硫醯基、醯養雞、羧基及羧基酯。另一方面,於脂族、雜脂族、氧脂族、烷基、伸烷基、烯基、伸烯基、炔基及伸炔基上可能的取代基包括所有上述取代基,除了C1-C10烷基。環烷基、伸環烷基、環烯基、伸環烯基、雜環烷基、伸雜環烷基、雜環烯基、伸雜環烯基、芳基及雜芳基以可彼此稠合。
本發明進一步涵蓋的為用於製備上述的生物可相容磁性材料的方法。
該方法包括四步驟:(i)提供於第一有機溶劑中含有氧化鐵奈米粒子的第一溶液,相對於總鐵離子,該氧化鐵奈米粒子含有4-15% Fe(II)離子;(ii)提供於第二有機溶劑中含有式(I)的生物可相容聚合物的第二溶液;(iii)混合該第一溶液與第二溶液以提供混合溶液;以及(iv)添加水至該混合溶液且攪拌所得溶液至少20小時以獲得生物可相容磁性材料。
較佳地,該氧化鐵奈米粒子係藉由於惰性氣體環境下混合氫氧化物溶液與含有Fe(II)的鐵溶液而形成。
下文揭露內容前述的一或多個具體例的詳細內容。具體例的其他特徵、目的及有利點由本發明說明及申請專利範圍而明顯可知。
圖1為IO-OA(批次4)的XRPD圖型。
圖2為IO-OA/mPEG-矽烷-2000(批次2)的XRPD圖型。
本文詳細揭露為含有氧化鐵奈米粒子及共價性鍵結至該氧化鐵奈米粒子的一或多種生物可相容聚合物的生物可相容磁性材料。
氧化鐵奈米粒子可為具有粒徑1至100nm(例如,2至50nm及5至25nm)的超順磁性芯(superparamagnetic core)。超順磁性芯的製備為所屬技術領域所習知。參照,Laurent et al.,Chem.Rev.,2008,108,2064-2110。
氧化鐵奈米粒子典型地由有機酸或其鹽形成。有機酸或鹽的實例包括,但不限於,油酸及其鹽。
應注意地,氧化鐵奈米粒子相對於其之中的總鐵離子較佳含有4-15% Fe(II)離子。例示性的氧鐵奈米粒子相對於總鐵離子含有4-10%或4-8% Fe(II)離子。氧化鐵奈米粒子中的Fe(II)離子含量對於生物可相容磁性材料顯現高遲緩率及低毒性為重要的。更具體地,低Fe(II)含量,例如,相對於總鐵離子為低於4% Fe(II)離子,典型地顯現低遲緩率。另一方面,高Fe(II)含量,例如相對於總鐵離子為大於15% Fe(II)離子,可引起高毒性。
一具體例中,氧化鐵奈米粒子係共價性鍵結至各具有下式的一或多種生物可相容聚合物:
式中,R1為H、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10環烷基、C1-C10雜環烷基、芳基、雜芳基、C1-C10羰基或C1-C10胺基;R2為H、C1-C6烷基、C2-
C6烯基、C2-C6炔基、C3-C10環烷基、C1-C10雜環烷基、芳基或雜芳基;x為1至10;以及y為5至1000。
較佳地,R1為C1-C6烷基、C1-C10羰基或C1-C10胺基,以及R2為H或C1-C6烷基。舉例而言,R1為甲基(-CH3)、羧基(-COOH)或胺基(-NH2),以及R2為H。
當R1為羧基(-COOH)或胺基(-NH2)時,羧基-終端或胺-終端的生物可相容聚合物可與生物分子偶合,例如,葉酸。舉例而言,葉酸藉由形成-CONH-連結與胺-終端生物可相容聚合物偶合。
本發明的生物可相容磁性材料可偶合至用於生物應用的特定靶定劑。特定靶定劑的實例包括,但不限於,抗體、蛋白質、肽、酵素、碳水化合物、糖蛋白、核苷酸及脂質。例示性生物可相容磁性材料中,R1偶合至抗體(例如,My10)。
仍為本發明範疇為用於製備上述生物可相容磁性材料的方法。
再次地,該方法包括下述步驟:提供於第一有機溶劑中含有氧化鐵奈米粒子的第一溶液,其中,該氧化鐵奈米粒子相對總鐵離子含有4-15% Fe(II)離子;提供於第二有機溶劑中含有式(I)的生物可相容聚合物的第二溶液;混合該第一溶液及第二溶液以提供混合溶液;以及添加水至該混合溶液且攪拌至少20小時以獲得生物可相容磁性材料。
使用本方法的氧化鐵奈米粒子典型地係藉由於惰性氣體環境下混合氫氧化物溶液與含有Fe(II)鹽的鐵溶液而形成。
例示性鐵溶液含有Fe(II)鹽(例如,FeCl2)及Fe(III)鹽(例如,FeCl3),其中Fe(III)/Fe(II)的莫耳比為1.70或更高(例如,1.75或更高,1.80或更高及1.90或更高)。
氫氧化物溶液可為具有濃度2N或更低(例如1.5N或更低及1N或更低)的氫氧化鈉溶液。
惰性氣體的實例包括,但不限於,氮及氬。
再次重申,氧化鐵奈米粒子可由有機酸或其鹽所形成。例示性有機酸或鹽為油酸或其鹽。當使用油酸時,其可存在的量對於每莫耳鐵為100mL或更少(例如,90mL或更少、70mL或更少、及50mL或更少)。
一實例中,氧化鐵奈米粒子係由油酸與含有FeCl2及FeCl3的鐵溶液形成,提供氧化鐵-油酸奈米粒子或IO-OA。此例示性氧化鐵奈米粒子可依下述方式製備:於溶劑(例如,水)中混合FeCl2及FeCl3,於氮環境下對上述混合物添加氫氧化鈉溶液(例如,1N),以及處理該溶液而藉此獲得與油酸形成IO-OA奈米粒子。
較佳地,以有機酸或其鹽處理後,藉由移除水,溶解於甲苯,以及離心由此獲得得液體以去除某些大的粒子,而收集氧化鐵奈米粒子。
轉移至使用於本方法的生物可相容聚合物,其等包括聚合物本身,以及較佳時為其鹽及溶劑合物。舉例而言,鹽可於聚合物形成於陰離子與正電荷基團(例如,胺基)之間。合適的陰離子包括氯化物、溴化物、碘化物、硫酸鹽、硝酸鹽、磷酸鹽、檸檬酸鹽、甲磺酸鹽、三氟乙酸鹽、乙酸鹽、蘋果酸鹽、甲苯磺酸鹽、酒石酸鹽、富馬酸鹽、麩胺酸鹽、葡萄醣醛酸鹽及馬來酸鹽。同樣地,鹽亦可於聚合物形成於陽離子與負電荷基團(例如,羧酸鹽)之
間。合適的陽離子包括,鈉離子、鉀離子、鎂離子、鈣離子及如四甲基銨離子的銨陽離子。聚合物亦包括含有四級氮原子者。溶劑合物意指聚合物與醫藥可接受溶劑之間的複合物。醫藥可接受溶劑的實例包括水、乙醇、異丙醇、乙酸乙酯、乙酸及乙醇胺。
下文流程(I)顯示製備例示性含矽烷的生物可相容聚合物的步驟。
如上述流程所示,烷氧基-聚乙二醇(分子量2000)與琥珀酸酐於鹼(例如,二甲基胺基吡啶)的存在下反應以形成mPEG-COOH,其後續使用亞硫醯氯轉化為mPEG-COCl。混合mPEG-COCl與(3-胺基丙基)-三乙氧基矽烷產生mPEG-矽烷。
所屬技術領域中具有通常知識者可修改示於流程(I)的步驟以使用習知方法製備生物可相容聚合物。參照,R.Larock,Comprehensive Organic Transformations(VCH Publishers 1989);T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis(3rd Ed.,John Wiley and Sons 1999);L.Fieser and M. Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley
and Sons 1994);以及L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(John Wiley and Sons 1995)及其後續編輯版本。可使用於合成生物可相容聚合物的具體途徑可見於:(a)Rist et al.,Molecules 2005,10,1169-1178,(b)Koheler et al.,JACS,2004,126,7206-7211;以及(c)Zhang et al.,Biom mircod 2004,6:1 33-40。
為了實施用於製備生物可相容磁性材料的方法,於第一有機溶劑中形成含有上述氧化鐵奈米粒子的第一溶液,以及提供於第二有機溶劑中含有生物可相容聚合物的第二溶液。
各第一有機溶劑及第二有機溶劑,獨立地可為甲苯、脂族烴、四氫呋喃、酮、醇、烷基酯或其組合。較佳地,二有機溶劑皆為甲苯。
在混合第一溶液與第二溶液以提供混合溶液時,實施添加水至該混合溶液作為催化劑且攪拌所得溶液至少20小時以提供生物可相容磁性材料為重要的。
如上所述,使用於此方法的氧化鐵奈米粒子相對於其之中的總鐵離子含有4-15% Fe(II)離子。實施此方法後,由此所得的生物可相容磁性材料相對於總鐵離子典型地含有4-15% Fe(II)離子。
上述流程(I)所合成的生物可相容聚合物有用於其可化學性修飾氧化鐵奈米粒子的表面以增加生物可相容性。此外,生物可相容聚合物有用於其可標示粒子(例如,奈米粒子、磁性粒子、磁性奈米粒子及超順磁性粒子),以賦予粒子進一步反應性朝向一或多種標靶、螢光、治療或診斷藥劑。
靶定劑較佳係經由共價鍵偶合至生物可相容聚合物。通常使用的靶定劑包括抗體、蛋白質、肽、酵素、碳水化合物、糖蛋白、核苷酸及脂
質。與靶定劑偶合後,生物可相容磁性材料可具有約3至500nm的直徑。所屬技術領域中具有通常知識者可附加任何合適的靶定劑於奈米粒子以對其賦予特異性。舉例而言,可使用葉酸以特異化具有葉酸受體的乳癌細胞。葉酸的結構允許與胺-終端或羧基-終端的生物可相容聚合物偶合。舉例而言,葉酸藉由形成-CONH-連結與-終端的生物可相容聚合物偶合。
無須進一步的闡述,咸信所屬技術領域中具有通常知識者,基於本發明說明可充分地利用本發明具體例至其最大可能範圍。下述特定實例僅為說明性解釋,且不易圖以任何方式侷限本揭露的其餘部分。本文所引用的所有文獻皆以引用方式將其全文併入本文。
實施例1:製備生物可相容磁性材料
根據下述步驟製備二種生物可相容磁性材料。
製備氧化鐵-油酸(IO-OA)奈米粒子
於25℃,FeCl2.4H2O(900g;4.53莫耳)、FeCl3(1327g;8.18莫耳)及水(23.6L)的混合物於100L玻璃反應器中以150-200rpm攪拌。於氮氣下,以速率0.2-0.3kg/min對反應器添加氫氧化鈉溶液(1N),得到pH值11-12。後續地,添加油酸(800mL;每莫耳鐵63mL)且所得混合物攪拌額外的60分鐘,藉此形成IO-OA肽米粒子於水溶液中呈暗色糊狀物。水溶液的pH以鹽酸(3N)調整為pH值1置2後移除水。然後對殘餘暗色糊狀物添加12L甲苯以懸浮粗製IO-OA奈米粒子於甲苯溶液中。甲苯中的粗製IO-OA奈米粒子以6000rpm離心15分鐘以獲得於甲苯中的IO-OA奈米粒子。
製備生物可相容聚合物mPEG-矽烷-750及mPEG-矽烷-2000
生物可相容聚合物mPEG-矽烷-750依下述方式製備。真空下(20托耳),300g(0.4莫耳)的甲氧基-PEG(mPEG,分子量750)、琥珀酸酐(48
g;0.48莫耳)及4-二甲基胺基-吡啶(DMAP;19.5g;0.159莫耳)的混合物使其於1000-mL圓底燒平靜置2小時。對該混合物添加600mL甲苯,然後將其於30℃攪拌一日以形成mPEG-COOH。後續地,以速率1mL/min添加36mL(0.48莫耳)亞硫醯氯且該混合物攪拌2至3小時。之後,以速率1mL/min添加333.8mL(2.4莫耳)三乙基胺以獲得pH約6-7。冷卻至室溫後,含有mPEG-COCl的混合物與94.5mL(0.4莫耳)3-胺基丙基三乙氧基矽烷於室溫反應至少8小時以產生粗製mPEG-矽烷-750。粗製mPEG-矽烷-750於對反應混合物添加9L異丙基醚後沉澱。藉由過濾收集固體產物,再溶解於500mL甲苯,以5000rpm離心5分鐘以收集上清液,對其添加9L異丙基醚。由異丙基醚分離棕色油狀液體且於真空乾燥以獲得生物可相容聚合物mPEG-矽烷-750。
生物可相容聚合物mPEG-矽烷-2000依下述方式製備。甲氧基-PEG(mPEG,分子量2000)(3kg)添加至配備有狄恩-史塔克捕捉器(Dean-Stark Trap)的20L反應槽。對反應槽添加15L甲苯且反應混合物利用機械攪拌器以150±20rpm攪拌。反應於120℃進行且回流60分鐘。然後對該反應槽添加琥珀酸酐(SA,180g)及4-二甲基胺基吡啶(DMAP,70g)且反應於65℃持續20小時以形成mPEG-COOH。後續地,對反應槽添加170g亞硫醯氯,利用N2氣體外罩反應且反應持續3小時。之後,對反應槽添加三乙基胺(TEA,436g)且以250rpm攪拌。冷卻至室溫後,含有mPEG-COCl的混合物與300g 3-胺基丙基三乙氧基矽烷於室溫反應至少8小時以產生粗製mPEG-矽烷-2000。由此獲得的粗製材料過濾以移除鹽類且製得澄清棕色溶液為mPEG-矽烷-2000。
製備生物可相容聚合物COOH-PEG-矽烷-750及COOH-PEG-矽烷-2000
300g(0.4莫耳)PEG(分子量:750)及600mL N-甲基-2-吡咯啶酮置入1000mL圓底燒瓶且真空下(20托耳)於60℃加熱超過2小時。添加88g(0.88莫耳)琥珀酸酐及19.5g(0.16莫耳)4-二甲基胺基-吡啶(DMAP)且於30℃反應二日,由此獲得二羧基-終端PEG(COOH-PEG)。
以速率1mL/min添加36ml(0.48莫耳)亞硫醯氯且攪拌2-3小時
。後續地,以速率1mL/min添加133.8mL(0.96莫耳)三乙基胺,然後對反應添加94.5mL(0.4莫耳)3-胺基丙基三乙氧基矽烷,持續至少12小時。反應混合物添加至9L的異丙基醚用以再沉澱,且收集所得沉澱,再溶解於100mL二氯甲烷。由此獲得的混合物再次添加至9L冷的異丙基醚用以再沉澱。收集灰白色沉澱後真空下乾燥二日,由此獲得商務可相容聚合物,亦即,COOH-PEG-矽烷-750。
生物可相容聚合物COOH-mPEG-矽烷-2000使用800g(0.4莫耳)PEG(PEG,分子量2000)、琥珀酸酐(88g;0.88莫耳)及4-二甲基胺基-吡啶(DMAP;19.5g;0.16莫耳)的混合物依上述相同步驟製備。
製備具有mPEG-矽烷-2000的生物可相容磁性材料
生物可相容磁性材料係如下述藉由於甲苯中接合mPEG-矽烷-2000與氧化鐵奈米粒子,亦即IO-OA奈米粒子而製備。
IO-OA奈米粒子(6mg Fe/mL,700mL)的甲苯溶液及mPEG-矽烷-2000(160mg/mL,500mL)的甲苯溶液係於2L圓底燒瓶中與經添加至所得溶液的水混合。24小時反應後,mPEG-矽烷-2000接合氧化鐵奈米粒子係藉由水萃取,且過濾移除大的粒子以製得澄清水溶液。所得水溶液以超過濾裝置醇化及濃縮以獲得生物可相容磁性材料標記為IO-OA/mPEG-矽烷-2000。
製備具有COOH-PEG-矽烷-2000的生物可相容磁性材料
250g的COOH-mPEG-矽烷-2000添加至含有10g Fe的IO-OA奈米粒子的1-1.2L甲苯溶液。添加1.5L去離子水後,所得混合物藉由超過濾裝置純化且濃縮至100mL以獲得生物可相容磁性材料標記為IO-OA/COOH-PEG-矽烷-2000。
實施例2:氧化鐵奈米粒子及生物可相容磁性材料的特徵化
進行研究以特徵化實施例1製備的生物可相容磁性材料,以及某氧化鐵奈米粒子,如下述。
Fe(II)離子測定
氧化鐵奈米粒子及生物可相容磁性材料的Fe(II)/Fe(III)離子比例係藉由Iron Test kit(Spectroquant 1.00796.0001,Merck)測定。於測試套組中的藥劑,亦即1,10-啡啉,係對於Fe(II)離子敏感而非Fe(III)離子。緩衝介質中,Fe(II)離子與1,10-啡啉反應以形成紅色錯合物而以光度性測定。測試的氧化鐵奈米粒子或生物可相容磁性材料首先藉由添加硫酸降解為鐵離子且所得溶液的pH藉由使用0.8M NaHCO3調整為2至8。於此過程中觀察到Fe(II)離子不轉換為Fe(III)離子。不添加抗壞血酸,僅測量Fe(II)離子的含量。藉由添加抗壞血酸以轉換所有鐵離子為Fe(II)離子而進一步測量總鐵離子。Fe(II)離子的含量相對於總鐵離子經測量為約4-15%。詳細的結果示於下表1。應注意此表亦包括對市售藥劑菲拉赫米(Feraheme)的1.26% Fe(II)含量。
該等結果顯示本發明的生物可相容磁性材料,相較於菲拉赫米(Feraheme),預期外地顯示大幅較高的Fe(II)含量。
X-射線粉末繞射(XRPD)
某氧化鐵奈米粒子及生物可相容磁性材料的結構係如下述藉由
XRPD調查。
測試樣品係經乾燥以提供粉末形式用於XRPD測量。圖1及2顯示IO-OA(批次4)及IO-OA/mPEG-矽烷-2000(批次2)的XRPD圖型。
由於γ-Fe2O3及Fe3O4於XRPD之間的差異為不可分辨,該等圖顯示IO-OA(批次4)及IO-OA/mPEG-矽烷-2000(批次2)的晶體結構可為Fe3O4、γ-Fe2O3或Fe3O4及γ-Fe2O3的混合物。
實施例3:遲緩率測量
如下述進行研究以測量實施例1所製備的生物可相容磁性材料,以及菲拉赫米的遲緩率。
以各種濃度(0.1、0.2、0.3、0.4及0.5mM)製備氧化鐵溶液。各溶液的T2遲緩時間係藉由得自Bruker Corporation的Minispec mq 20測量。以遲緩時間作為縱軸且以溶液的濃度作為橫軸的倒數之間建立線性關係。線性關係的斜率測定為r2遲緩率。結果示於下表2。
意外地,如上述表2所示,相對於總鐵離子含有6.29% Fe(II)離子的IO-OA/mPEG-矽烷-2000(批次2),展現173(mM.s)-1的r2遲緩率。明顯的對比,相對於總鐵離子含有1.26% Fe(II)離子的菲拉赫米展現69(mM.s)-1的r2遲緩率值。
該等結果顯示本發明的生物可相容磁性材料,相較於菲拉赫米意外地顯現大幅較高的r2遲緩率。
實施例4:與特定靶定劑偶合
下文所述為用於偶合本發明的生物可相容磁性材料與特定靶定
劑的方案。
與葉酸鹽偶合
226μl的葉酸鹽溶液(葉酸鹽/二甲亞碸:10mg/mL)置入50mL棕色圓底燒瓶。5mL二甲亞碸(DMSO)及176.5μL二環己基碳二亞胺溶液(二環己基碳二亞胺/DMSO:5mg/mL)添加至該溶液且攪拌一小時。之後,添加98.5μl的NHS溶液(N-羥基琥珀醯亞胺/DMSO:5mg/mL)且攪拌額外的一小時。然後添加289μL伸乙二胺以製得溶液A。
真空下,1mL IO-OA/COOH-PEG-矽烷-2000(4.48mg Fe/mL)及10ml DMSO置入50mL圓底燒瓶。對該溶液添加176.5μl二環己基碳二亞胺溶液(二環己基碳二亞胺/DMSO:5mg/mL)且攪拌一小時。之後添加98.5μl NHS溶液(N-羥基琥珀醯亞胺/DMSO:5mg/mL)且攪拌額外的一小時以製得溶液B。
289μL的溶液A係添加至溶液B且所得溶液攪拌8小時。所得溶液添加至透析膜(Mw:3000)且使用蒸餾水透析。然後藉由超過率裝置濃縮所得溶液至2mL以獲得與靶定劑偶合的生物可相容磁性材料,亦即葉酸鹽-偶合IO-OA/COOH-PEG-矽烷-2000。
與抗體偶合
IO-OA/COOH-PEG-矽烷-2000(4.48mg Fe/mL)與5mL冷的去離子水混合且保持於冰浴。對溶液添加1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(10-6莫耳)且攪拌30分鐘。然後對該混合物添加N-羥基琥珀醯亞胺(10-6莫耳)且攪拌30分鐘。對所得混合物添加抗體My10(1mL,2μg/mL)且反應2小時。由此所得溶液藉由通過磁性選別裝置以獲得與抗體偶合的生物可相容磁性材料,亦即My10-偶合IO-OA/COOH-PEG-矽烷-2000。
本說明書所揭露的所有特徵可以任何組合方式予以組合。本說明書所揭露各特徵可由提供相同、均等或類似目的的替代特徵置換。因此,除非另行指明,各揭露的特徵僅為均等特徵或類似特徵的上位系列的示例。
由上述說明,所屬技術領域中具有通常知識者可容易地探明所揭露的具體例的本質特徵,且可做成該具體例的各種變化與修改以適用其各種用途與條件而不悖離其精神與範疇。因此,其他具體亦涵蓋於本申請專利範圍中。明顯地,所屬技術領域中具有通常知識者可根據所揭露的具體例完成各種修改與改變。意欲說明所揭露的說明書及實例應僅認為為例示性,所揭露的真實範疇由後述的申請專利範圍及其均等物所界定。
(無)
Claims (19)
- 如請求項1的生物可相容磁性材料,其中,該氧化鐵奈米粒子相對於總鐵離子含有4-8% Fe(II)離子。
- 如請求項1的生物可相容磁性材料,其中,該氧化鐵奈米粒子係由有機酸或其鹽形成。
- 如請求項3的生物可相容磁性材料,其中,該有機酸或鹽係油酸或其鹽。
- 如請求項6的生物可相容磁性材料,其中,該R1為C1-C6烷基、C1-C10羰基或C1-C10胺基,以及R2為H或C1-C6烷基。
- 如請求項7的生物可相容磁性材料,其中,該R1為甲基、羧基或胺基,以及R2為H。
- 如請求項6的生物可相容磁性材料,其中,該R1係偶合至選自下屬所成群組的特定靶定劑:抗體、蛋白質、肽、酵素、碳水化合物、糖蛋白、核苷酸及脂質。
- 如請求項9的生物可相容磁性材料,其中,該特定靶定劑為抗體。
- 如請求項1的生物可相容磁性材料,其中,該氧化鐵奈米粒子係由油酸或其鹽形成。
- 一種製備請求項1的生物可相容磁性材料的方法,該方法包含:提供於第一有機溶劑中含有氧化鐵奈米粒子的第一溶液,該氧化鐵奈米粒子相對於總鐵離子含有4-10% Fe(II)離子;提供於第二有機溶劑中含有式(I)的生物可相容聚合物的第二溶液;混合該第一溶液與第二溶液以獲得混合溶液;以及對該混合溶液添加水且攪拌所得溶液至少20小時以獲得生物可相容磁性材料。
- 如請求項13的方法,其中,該氧化鐵奈米粒子係藉由於惰性氣體環境下混合氫氧化物溶液與含有Fe(II)鹽的鐵溶液而形成。
- 如請求項14的方法,其中,該鐵溶液含有Fe(II)鹽及Fe(III)鹽,其中,Fe(III)/Fe(II)的莫耳比為1.70或更高。
- 如請求項15的方法,其中,該氧化鐵奈米粒子係由油酸或其鹽所形成。
- 如請求項16的方法,其中,該氧化鐵奈米粒子係由存在的量對於每莫耳鐵為100mL或更少的油酸形成。
- 如請求項13的方法,其中,各該第一有機溶劑及該第二有機溶劑獨立地為甲苯、脂族烴、四氫呋喃、酮、醇、烷基酯、或其組合。
- 如請求項13的方法,其中,該惰性氣體為氮或氬。
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