JP2019137674A - 生体適合性磁性材料 - Google Patents
生体適合性磁性材料 Download PDFInfo
- Publication number
- JP2019137674A JP2019137674A JP2019011014A JP2019011014A JP2019137674A JP 2019137674 A JP2019137674 A JP 2019137674A JP 2019011014 A JP2019011014 A JP 2019011014A JP 2019011014 A JP2019011014 A JP 2019011014A JP 2019137674 A JP2019137674 A JP 2019137674A
- Authority
- JP
- Japan
- Prior art keywords
- magnetic material
- ions
- biocompatible
- iron oxide
- oxide nanoparticles
- 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.)
- Granted
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- 239000000696 magnetic material Substances 0.000 title claims abstract description 59
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 99
- 229910052742 iron Inorganic materials 0.000 claims abstract description 54
- -1 Fe(II) ions Chemical class 0.000 claims abstract description 43
- 229920000249 biocompatible polymer Polymers 0.000 claims abstract description 32
- 125000003118 aryl group Chemical group 0.000 claims abstract description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 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
- 150000002500 ions Chemical class 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000008685 targeting Effects 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
- 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
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 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 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 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
- 229910052757 nitrogen Inorganic materials 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
- 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
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- 150000001720 carbohydrates Chemical class 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
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- 102000004169 proteins and genes Human genes 0.000 claims description 3
- 238000003756 stirring Methods 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 19
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 abstract description 10
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 239000002872 contrast media Substances 0.000 abstract description 2
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- 239000000203 mixture Substances 0.000 description 16
- 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 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
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- 238000010168 coupling process Methods 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
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- 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 6
- 229960000304 folic acid Drugs 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 238000002360 preparation method Methods 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
- 229920000642 polymer Polymers 0.000 description 5
- 229940014800 succinic anhydride Drugs 0.000 description 5
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 5
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
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- 238000012360 testing method 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
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940014144 folate Drugs 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
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- 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
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 2
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- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
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- 125000001931 aliphatic group Chemical group 0.000 description 2
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004957 naphthylene group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005564 oxazolylene group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 238000005375 photometry Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 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
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000005548 pyrenylene group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005557 thiazolylene group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005556 thienylene group Chemical group 0.000 description 1
- 125000003441 thioacyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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Abstract
Description
2つの生体適合性磁性材料を以下に記載される手順に従って作製した。
FeCl2・4H2O(900g、4.53モル)と、FeCl3・4H2O(1327g、8.18モル)と、水(23.6L)との混合物を100L容のガラス反応器において25℃、150rpm〜200rpmで撹拌した。窒素下で水酸化ナトリウム溶液(1N)を0.2kg/分〜0.3kg/分の速度で反応器に添加し、pH値11〜12を生じた。その後、オレイン酸(800mL、鉄1モル当たり63mL)を添加し、得られた混合物を更に60分間撹拌することにより、水溶液中に黒っぽいペーストとしてIO−OAナノ粒子を形成させた。水溶液のpHを塩酸(3N)によって1〜2のpH値に調整した後、水を除去した。その後、トルエン12Lを残りの黒っぽいペーストに添加し、トルエン溶液中に粗製IO−OAナノ粒子を懸濁した。トルエン中の粗製IO−OAナノ粒子を6000rpmで15分間遠心分離して、トルエン中にIO−OAナノ粒子を得た。
生体適合性ポリマーのmPEG−シラン−750を、以下の手順に従って作製した。メトキシ−PEG(mPEG、分子量750)300g(0.4モル)と、無水コハク酸(48g、0.48モル)と、4−ジメチルアミノ−ピリジン(DMAP、19.5g、0.159モル)との混合物を、1000mL容の丸底フラスコ内にて真空(20Torr)下で2時間に亘って静置した。その混合物にトルエン600mLを添加し、次いでそれを30℃で1日間に亘って撹拌することで、mPEG−COOHを形成させた。引き続き、塩化チオニル36mL(0.48モル)を1mL/分の速度で添加し、その混合物を2時間〜3時間に亘って撹拌した。その後に、トリエチルアミン333.8mL(2.4モル)を1mL/分の速度で添加することで、約6〜7のpHが得られた。室温に冷やした後に、mPEG−COClを含有する混合物を、3−アミノプロピルトリエトキシシラン94.5mL(0.4モル)と室温で少なくとも8時間に亘って反応させることで、粗製mPEG−シラン−750が得られた。粗製mPEG−シラン−750は、上記反応混合物にイソプロピルエーテル9Lを添加した後に析出した。固体生成物を濾過により回収し、トルエン500mL中に再溶解させ、5000rpmで5分間に亘って遠心分離して上清を回収し、そこにイソプロピルエーテル9Lを添加した。イソプロピルエーテルから褐色の油状液体が分離し、それを真空下で乾燥させることで、生体適合性ポリマーのmPEG−シラン−750を得た。
PEG(分子量:750)300g(0.4モル)及びN−メチル−2−ピロリドン600mLを1000mL容の丸底フラスコに入れ、2時間超に亘って真空(20Torr)下で60℃まで加熱した。無水コハク酸88g(0.88モル)及び4−ジメチルアミノ−ピリジン(DMAP)19.5g(0.16モル)を添加して、30℃で2日間反応させることでジカルボキシ末端PEG(COOH−PEG)を得た。
以下の通り、トルエン中でmPEG−シラン−2000を酸化鉄ナノ粒子、すなわちIO−OAナノ粒子とコンジュゲートさせることによって生体適合性磁性材料を作製した。
250gのCOOH−mPEG−シラン−2000を10gのFeのIO−OAナノ粒子を含むトルエン溶液1L〜1.2Lに添加した。得られた混合物を2時間〜3時間、超音波処理した。1.5Lの脱イオン水を添加した後、その混合物を限外濾過装置によって精製し、100mLまで濃縮して、IO−OA/COOH−PEG−シラン−2000と称される生体適合性磁性材料を得た。
実施例1で作製された生体適合性磁性材料と並んで、特定の酸化鉄ナノ粒子を以下の通り特性評価するため研究を行った。
酸化鉄ナノ粒子及び生体適合性磁性材料のFe(II)/Fe(III)イオン比を、Iron Testキット(Spectroquant 1.00796.0001、Merck)によって測定した。検査キット中の試薬、すなわち、1,10−フェナントロリンはFe(III)イオンではなくFe(II)イオンに感受性であった。緩衝培質では、Fe(II)イオンは1,10−フェナントロリンと反応して、測光によって特定された赤色の複合体を形成した。試験酸化鉄ナノ粒子又は生体適合性磁性材料は、硫酸の添加によって最初に鉄イオンに分解され、得られた溶液のpHを0.8M NaHCO3を使用して2〜8に調整した。Fe(II)イオンは処理の間Fe(III)イオンに変換されなかったことが観察された。アスコルビン酸を添加せずに、Fe(II)イオンのみの含有量を測定した。アスコルビン酸を添加して、全ての鉄イオンをFe(II)イオンに変換することで、全鉄イオンを更に測定した。Fe(II)イオンの含有量は、全鉄イオンに対して約4%〜15%であることが特定された。詳細な結果を下記表1に示す。またこの表には、市販の薬剤であるFerahemeについて1.26%のFe(II)の含有量が含まれていることに留意する。
特定の酸化鉄ナノ粒子及び生体適合性磁性材料の構造をXRPDによって以下の通り調査した。
実施例1で作製された生体適合性磁性材料の緩和度と並んで、Ferahemeについての緩和度を以下の通り測定して研究を行った。
以下に本発明の生体適合性磁性材料を特異的標的剤とカップリングさせるプロトコルを記載する。
葉酸溶液(葉酸塩/ジメチルスルホキシド:10mg/mL)226μLを50mL容の褐色丸底フラスコに入れた。ジメチルスルホキシド(DMSO)5mL及びジシクロヘキシルカルボジイミド溶液(ジシクロヘキシルカルボジイミド/DMSO:5mg/mL)176.5μLを上記溶液に添加し、1時間撹拌した。その後、NHS溶液(N−ヒドロキシスクシンイミド/DMSO:5mg/mL)98.5μlを添加し、更に1時間撹拌した。その後、エチレンジアミン289μLを添加して、溶液Aを得た。
IO−OA/COOH−PEG−シラン−2000(4.48mg Fe/mL)を、冷脱イオン水5mLと混合して、氷浴で維持した。1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド(10−6モル)を上記溶液に添加し、30分間撹拌した。次いで、N−ヒドロキシスクシンイミド(10−6モル)をその混合物に添加し、更に30分間撹拌した。抗体My10(1mL、2μg/mL)を得られた混合物に添加し、2時間反応させた。そのようにして得られた溶液を、磁力選別装置を通過させることによって精製して、抗体とカップリングした生体適合性磁性材料、すなわちMy10コンジュゲートIO−OA/COOH−PEG−シラン−2000を得た。
本明細書で開示された特徴は全てあらゆる組合せで組み合わせることができる。本明細書で開示される各特徴は同じ、同等の、又は同様の目的を果たす代替特徴に置き換えることができる。そのため特に明記しない限り、開示される各特徴は一連の包括的な同等又は同様の特徴の例にすぎない。
Claims (21)
- 生体適合性磁性材料であって、
酸化鉄ナノ粒子と、
それぞれ下記式(I):
RはH、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C10シクロアルキル、C1〜C10ヘテロシクロアルキル、アリール、ヘテロアリール、C1〜C10カルボニル基、又はC1〜C10アミン基であり、
Lはリンカーであり、
xは1〜10であり、かつ、
yは5〜1000である)を有し、前記酸化鉄ナノ粒子に共有結合されている1以上の生体適合性ポリマーと、
を含み、ここで、前記生体適合性磁性材料が、全鉄イオンに対して4%〜15%のFe(II)イオンを含む、生体適合性磁性材料。 - 前記酸化鉄ナノ粒子が、全鉄イオンに対して4%〜15%のFe(II)イオンを含む、請求項1に記載の生体適合性磁性材料。
- 前記酸化鉄ナノ粒子が全鉄イオンに対して4%〜10%のFe(II)イオンを含む、請求項2に記載の生体適合性磁性材料。
- 前記生体適合性磁性材料が、全鉄イオンに対して4%〜10%のFe(II)イオンを含む、請求項1に記載の生体適合性磁性材料。
- 前記酸化鉄ナノ粒子が有機酸又はその塩で形成される、請求項1に記載の生体適合性磁性材料。
- 前記有機酸又は塩が、オレイン酸又はその塩である、請求項5に記載の生体適合性磁性材料。
- 前記リンカーが、O、S、Si、C1〜C6アルキレン、2個のカルボニル基と、2個〜20個の炭素原子とを含むカルボニル部分、又は下記式:
- 前記酸化鉄ナノ粒子が、それぞれ下記式:
R1はH、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C10シクロアルキル、C1〜C10ヘテロシクロアルキル、アリール、ヘテロアリール、C1〜C10カルボニル基、又はC1〜C10アミン基であり、
R2はH、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニル、C3〜C10シクロアルキル、C1〜C10ヘテロシクロアルキル、アリール又はヘテロアリールであり、
xは1〜10であり、かつ、
yは5〜1000である)を有する1以上の生体適合性ポリマーに共有結合されている、請求項1に記載の生体適合性磁性材料。 - R1がC1〜C6アルキル、C1〜C10カルボニル基、又はC1〜C10アミン基であり、R2がH又はC1〜C6アルキルである、請求項8に記載の生体適合性磁性材料。
- R1がメチル、カルボキシル又はアミノであり、R2がHである、請求項9に記載の生体適合性磁性材料。
- R1が、抗体、タンパク質、ペプチド、酵素、炭水化物、糖タンパク質、ヌクレオチド、及び脂質からなる群から選択される特異的標的剤にカップリングされている、請求項8に記載の生体適合性磁性材料。
- 前記特異的標的剤が抗体である、請求項11に記載の生体適合性磁性材料。
- 前記酸化鉄ナノ粒子が、全鉄イオンに対して4%〜15%のFe(II)イオンを含み、オレイン酸又はその塩で形成される、請求項1に記載の生体適合性磁性材料。
- 前記酸化鉄ナノ粒子が、全鉄イオンに対して4%〜15%のFe(II)イオンを含み、それぞれ下記式:
- 請求項1に記載の生体適合性磁性材料を作製する方法であって、
全鉄イオンに対して4%〜15%のFe(II)イオンを含む酸化鉄ナノ粒子を第1の有機溶媒中に含む第1の溶液を準備することと、
第2の有機溶媒に式(I)の生体適合性ポリマーを含む第2の溶液を準備することと、
前記第1の溶液と前記第2の溶液とを混合して混合溶液を得ることと、
前記混合溶液に水を添加し、得られた溶液を少なくとも20時間に亘って撹拌して生体適合性磁性材料を得ることと、
を含む、方法。 - 前記酸化鉄ナノ粒子が、不活性ガス雰囲気下で、水酸化物溶液をFe(II)塩を含む鉄溶液と混合することによって形成される、請求項15に記載の方法。
- 前記鉄溶液がFe(II)塩及びFe(III)塩を含み、Fe(III)/Fe(II)のモル比が1.70以上である、請求項16に記載の方法。
- 前記酸化鉄ナノ粒子が、オレイン酸又はその塩で形成される、請求項17に記載の方法。
- 前記酸化鉄ナノ粒子が、鉄1モル当たり100mL以下の量で存在するオレイン酸で形成される、請求項18に記載の方法。
- 前記第1の有機溶媒及び前記第2の有機溶媒が、それぞれ独立して、トルエン、脂肪族炭化水素、テトラヒドロフラン、ケトン、アルコール、アルキルエステル、又はそれらの組み合わせである、請求項15に記載の方法。
- 前記不活性ガスが窒素又はアルゴンである、請求項15に記載の方法。
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