JP7394493B2 - 抗癌剤および多孔性シリカ粒子の製造方法 - Google Patents
抗癌剤および多孔性シリカ粒子の製造方法 Download PDFInfo
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- JP7394493B2 JP7394493B2 JP2022505382A JP2022505382A JP7394493B2 JP 7394493 B2 JP7394493 B2 JP 7394493B2 JP 2022505382 A JP2022505382 A JP 2022505382A JP 2022505382 A JP2022505382 A JP 2022505382A JP 7394493 B2 JP7394493 B2 JP 7394493B2
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Description
実施例1.多孔性シリカ粒子
1.多孔性シリカ粒子の製造
(1)多孔性シリカ粒子の製造
1)小気孔粒子の製造
2L丸底フラスコに蒸留水(DW)の960mlとMeOHの810mlを入れた。前記フラスコにCTABを7.88g入れた後、攪拌しながら1M NaOHの4.52mlを素早く入れた。10分間攪拌して均一な混合液を得た後、TMOSの2.6mlを入れた。6時間攪拌して均一に混合した後、24時間熟成し、反応液を得た。
1.5gの小気孔多孔性シリカ粒子の粉末をエタノール10mlに添加して超音波分散し、水10ml、TMB(trimethyl benzene)10mlを添加して超音波分散し、分散液を得た。
気孔拡張時の反応条件を140℃、72時間に変更した以外は、前記1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
5倍大きな容器を使用し、各物質をいずれも5倍の容量で使用した以外は、実施例1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
小気孔粒子の製造時に蒸留水920ml、メタノール850mlを使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
小気孔粒子の製造時に蒸留水800ml、メタノール1,010ml、CTAB 10.6gを使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
小気孔粒子の製造時に蒸留水620ml、メタノール1,380ml、CTAB 7.88gを使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
気孔拡張時にTMBを2.5ml使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
気孔拡張時にTMBを4.5ml使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
気孔拡張時にTMBを11ml使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
気孔拡張時にTMBを12.5ml使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
小気孔粒子の製造時に蒸留水900ml、メタノール850ml、CTAB 8gを使用した以外は、1-1-(1)の方法と同様にして多孔性シリカ粒子を製造した。
実施例1-1-(1)~(3)の粒子の小気孔粒子、製造された多孔性シリカ粒子を顕微鏡で観察し、小気孔粒子が均一に生成されているか、気孔が十分に拡張されて多孔性シリカ粒子が均一に形成されているかを確認した(図2~5)。
実施例1-1-(1)の小気孔粒子、実施例1-1-(1)、(7)、(8)、(10)、(11)の多孔性シリカ粒子の表面積を計算した。表面積は、ブルナウアー-エメット-テラー(Brunauer-Emmett-Teller)(BET)方法により計算し、気孔直径の分布は、バーレット-ジョイナー-ハレンダ(Barrett-Joyner-Halenda)(BJH)方法により計算した。
前記各粒子の顕微鏡写真を図6に、計算の結果を下記表1に示す。
実施例1-1-(1)の100mgのナノ粒子(BALL)を10mLのトルエンに分散し、110℃に加熱した。温度が110℃に達した時点で、2mlの3-アミノプロピルトリエトキシシラン(APTES)を添加し、16時間還流した。15分間8500rpmで遠心分離して粒子(aBALL、BALLに窒素含有基を結合)を得、エタノール及び蒸留水で交互に2回洗浄した。
得られたFabBALLをTEMで観察し、粒径を測定した。そして、各BALLのゼータ電位を測定した(図7)。
図13に示すように、葉酸の処理量を変えた以外は実施例1-4の方法と同様にして表面改質を行い、粒子の沈殿が生じるかどうかを確認した。
実施例1-2で得られた粒子10mgを水1mlに浮遊し、N-ヒドロキシスクシンイミドエステル(N-hydroxysuccinimyl ester)-活性(activated)Cyanine3(Cy3-NHS)20μgを混合した。混合液は攪拌下で16時間反応させた。非反応の蛍光染料は、エタノールおよび水で10回洗浄して除去した。乾燥して染料標識された粒子を得、水に再分散した。
MCF-7細胞(autophagy deficient breast cancer cell overexpressing folate receptor)を、50units/mLペニシリン/ストレプトマイシン溶液および10% ウシ胎児血清(Fetal Bovine Serum、FBS)を混合したRPMI1640培地で培養した。
FabBALLおよびabBALLのMCF-7細胞へのエンドサイトーシス(endocytosis)効率の差を評価した。染料標識されたFabBALLおよびabBALLをMCF-7細胞に処理し、蛍光強度を評価した。平均蛍光強度はFabBALLの方がabBALLよりも2倍高かった(図8c)。
1.ペプチドの合成
Bec1ペプチド(CGGTNVFNATFHIWHSGQFGT、配列番号1)をリンクアミドレジン(Rink amide resin)を用いて、固相(solid-phase)合成法により合成した。蛍光標識のために、3eqのフルオレセイン(fluorescein)、3eqのNHSおよび3eqのEDCをペプチドに添加した。得られたペプチドはHPLCで精製し、MALDI-ToF質量分析(Mass spectrometry)で確認した。
過剰量の4,4-ジピリジルジスルフィド(4,4-dipyridyldisufide)を実施例1-2-5の粒子に添加し、エタノールで3回洗浄した。その後、互いに異なる量の粒子を20%DMSO溶液下の固定量のBec1ペプチドに添加し、1時間反応させた。15分間8500rpmで遠心分離して上澄液を得、324nmにおける吸光度を測定した。残りのペプチドの濃度は、4-チオピリドン(4-thiopyridone)の標準曲線(standard curve)と比較して計算した。ペプチドは、FabBALLに約10%w/wだけロードされた(図8a)。
実施例1-2-4の粒子100μgと蛍光標識されたBecペプチド10μgを、異なる濃度のGSHを有する160μlの1×PBS中で混合した。DMSOの40μlを添加してBec1ペプチドを溶解し、蛍光強度を測定した。放出されるペプチドの量は、Bec1ペプチドの最初の蛍光に基づいて計算した。
MCF-7細胞を96ウェル細胞培養プレートに10,000細胞/ウェルで播種(seeding)した。1日後、異なる濃度の各粒子(4~500μg/mL)を各ウェルで血清含有培地で1日間処理した。その後、培地をMTTアッセイキット(assay kit)10μlを含有する無血清培地に交換して4時間培養し、上澄液をアスピレーションした。各ウェルにDMSOを加えてホルマザンを溶解し、1時間反応させた。吸光度は570nm波長で測定し、細胞生存率は非処理群との相対値として計算した。
MCF-7細胞をガラス底の12ウェル細胞培養プレートに100,000細胞/ウェルで播種した。1日後、染料標識された粒子5μgと蛍光標識されたbec1ペプチド0.5μgを混合し、細胞は無血清培地下で複合体で互いに異なる期間(1、2、3、6、12、24時間)処理された。粒子で処理された細胞を4%PFA溶液で15分間固定し、1xPBS溶液で2回洗浄した。細胞の核はDAPI溶液で染色した。画像はデルタビジョン顕微鏡(Delta-vision microscope)から得た。
リポフェクタミン(lipofectamine)2000を用いて、LC3-GFPプラスミドをMCF-7細胞にトランスフェクトした。トランスフェクトされたMCF-7は、3ヶ月間G418の800μg/mLで選択された。GFPの発現は、1ヶ月以上観察し、プラスミドが適切に挿入されたことを確認した。LC3-GFPを発現するMCF-7細胞を100,000個播種した。
前記MCF-7における細胞毒性の評価と同様の方法で、PC-3、LNCaP、HeLa細胞における細胞毒性を評価した。
Claims (20)
- 抗癌活性ペプチドが組み込まれた多数の多孔性シリカ粒子を含み、各前記多孔性シリカ粒子の外部表面に多数の窒素含有基が位置し、前記窒素含有基の少なくとも一部に葉酸が結合し、
前記多孔性シリカ粒子は、粒径が50~500nmであり、気孔の直径が7~25nmであり、
前記抗癌活性ペプチドの長さは、5aa~50aaであることを特徴とする抗癌剤。 - 前記窒素含有基中の0.9%以下に前記葉酸が結合している、請求項1に記載の抗癌剤。
- 前記窒素含有基中の11%以上に前記葉酸が結合している、請求項1に記載の抗癌剤。
- 前記窒素含有基中の0.001%~0.3%に前記葉酸が結合している、請求項1に記載の抗癌剤。
- 前記抗癌活性ペプチドは、二硫化結合によって前記多孔性シリカ粒子に結合している、請求項1に記載の抗癌剤。
- 前記多孔性シリカ粒子は、不規則に配置された多数の気孔を含む、請求項1に記載の抗癌剤。
- 前記抗癌活性ペプチドは、その末端にC(GG)n(nは1~3)のアミノ酸配列を有するリンカーを含む、請求項1に記載の抗癌剤。
- 前記抗癌活性ペプチドは、配列番号1のアミノ酸配列を有する、請求項1に記載の抗癌剤。
- 前記多孔性シリカ粒子は、BET表面積が280m2/g~680m2/gである、請求項1に記載の抗癌剤。
- 前記抗癌活性ペプチドは、前記多孔性シリカ粒子に1:1~20の重量比で組み込まれる、請求項1に記載の抗癌剤。
- 注射剤である、請求項1に記載の抗癌剤。
- 前記癌は、乳癌、卵巣癌、子宮頸癌、前立腺癌、精巣癌、陰茎癌、尿道癌、尿管癌、腎盂癌、食道癌、喉頭癌、胃癌、胃腸管癌、皮膚癌、角化棘細胞腫、卵胞癌腫、黒色腫、肺癌、小細胞肺癌腫、非小細胞肺癌腫(NSCLC)、肺腺癌、肺扁平細胞癌、結腸癌、膵臓癌、甲状腺癌、乳頭癌、膀胱癌、肝癌、胆管癌、骨癌、ヘアリー細胞癌、口腔癌、口唇癌、舌癌、唾液腺癌、咽頭癌、小腸癌、結腸癌、直腸癌、腎癌、前立腺癌、陰門癌、甲状腺癌、大腸癌、子宮内膜癌、子宮癌、脳癌、中枢神経系の癌、腹膜癌、肝細胞癌、ホジキン又は白血病である、請求項1に記載の抗癌剤。
- 前記多孔性シリカ粒子は、前記外部表面の前記窒素原子の量が0.1mmol/g以上である、請求項1に記載の抗癌剤。
- 多孔性シリカ粒子の内部気孔が界面活性剤で満たされた状態で前記多孔性シリカ粒子の外部表面に窒素含有基を導入する第1ステップと、前記窒素含有基の少なくとも一部に葉酸を結合させる第2ステップと、前記多孔性シリカ粒子の前記内部気孔を満たしていた前記界面活性剤を除去する第3ステップと、前記多孔性シリカ粒子に活性ペプチドを組み込む第4ステップとを含み、
前記多孔性シリカ粒子は、粒径が50~500nmであり、気孔の直径が7~25nmであり、
前記活性ペプチドの長さは、5aa~50aaであることを特徴とする、活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。 - 前記界面活性剤は、CTAB(cetyltrimethylammonium bromide)、TMABr(hexadecyltrimethylammonium bromide)、TMPrCl(hexadecyltrimethylpyridinium chloride)およびTMACl(tetramethylammonium chloride)からなる群より選択される、請求項14に記載の活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。
- 前記活性ペプチドは、前記多孔性シリカ粒子に1:1~20の重量比で結合する、請求項14に記載の活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。
- 前記葉酸は、前記多孔性シリカ粒子100重量部に対して0.01~10重量部処理される、請求項14に記載の活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。
- 第1ステップの前に、前記界面活性剤およびシリカ前駆物質を溶媒に入れて撹拌し、気孔が前記界面活性剤で満たされた小気孔シリカ粒子を製造するステップをさらに含む、請求項14に記載の活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。
- 第1ステップの前に、前記小気孔シリカ粒子を膨張剤と反応させて前記小気孔を膨張させるステップをさらに含む、請求項18に記載の活性ペプチドが組み込まれた多孔性シリカ粒子の製造方法。
- 請求項14~19のいずれか一項に記載の多孔性シリカ粒子の製造方法を含む、請求項1~13のいずれか一項に記載の抗癌剤の製造方法。
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WO2018202818A1 (en) | 2017-05-04 | 2018-11-08 | Nanologica Ab | A process for manufacturing porous silica particles loaded with at least one bioactive compound adapted for lung, nasal, sublingual and/or pharyngeal delivery |
JP2018533543A (ja) | 2014-08-07 | 2018-11-15 | ナショナル タイワン ユニバーシティ | シリカ系生体分子担体、それを含む医薬組成物、その作製方法、及びその使用 |
JP6426288B2 (ja) | 2014-07-22 | 2018-11-21 | レモネックス インコーポレイテッドLemonex Inc. | 生理活性物質又はタンパク質伝達用組成物及びその用途 |
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US20050226935A1 (en) | 2004-03-30 | 2005-10-13 | Kalpana Kamath | Embolization |
JP6426288B2 (ja) | 2014-07-22 | 2018-11-21 | レモネックス インコーポレイテッドLemonex Inc. | 生理活性物質又はタンパク質伝達用組成物及びその用途 |
JP2018533543A (ja) | 2014-08-07 | 2018-11-15 | ナショナル タイワン ユニバーシティ | シリカ系生体分子担体、それを含む医薬組成物、その作製方法、及びその使用 |
WO2018202818A1 (en) | 2017-05-04 | 2018-11-08 | Nanologica Ab | A process for manufacturing porous silica particles loaded with at least one bioactive compound adapted for lung, nasal, sublingual and/or pharyngeal delivery |
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