JPWO2010101178A1 - アミノ酸抱合シアノアクリレートポリマー粒子 - Google Patents
アミノ酸抱合シアノアクリレートポリマー粒子 Download PDFInfo
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Abstract
Description
塩基性アミノ酸(Lys, His, Arg)、酸性アミノ酸(Asp)及び中性アミノ酸(Gly, Ala, Val, Leu, Try, Phe, Ser, Thr, Met)を用いて、各アミノ酸を抱合するシアノアクリレートポリマー粒子を製造した。重合開始・安定化剤としてデキストラン70Kを用いた。
上記で製造したアミノ酸抱合粒子で各種細胞株を処理し、MTT法による細胞増殖アッセイを行なうことにより、各種アミノ酸抱合粒子の細胞障害活性を評価した。アッセイにはMTTアッセイキット(ロシュ)を用いた。細胞株としては、RAW267.4(マウス単球性白血病由来細胞株)、HeLa(ヒト子宮頚癌由来細胞株)、HEK293.T(ヒト胎児腎癌由来細胞株)及びEL-4(マウスT細胞リンパ腫由来細胞株)を用いた。
アポトーシスでは、初期段階において細胞膜の内側にあるホスファチジルセリン(PS)が細胞膜の外側に表出し、次いで細胞膜の完全性が失われDNA断片化に至る。従って、PSに親和性の高いAnnexin Vと、死細胞を染色する核染色剤(ヨウ化プロピジウム等)とを用いて、アポトーシス初期段階、アポトーシス後期段階及び死細胞を識別することができる。本実験では、Annexin Vアッセイにより、アルギニン抱合ナノ粒子によるEL-4細胞のアポトーシス誘導を調べた。
(1) 冷PBS(pH7.4)でEL-4細胞を2回洗浄し、〜1×106細胞/mLの細胞濃度になるように1X Binding bufferに再浮遊した。
(2) 5 mLのFalconチューブに上記細胞浮遊液を100μL(〜1×105細胞)加えた。
(3) 下記表2に従い、各チューブにAnnexin V 試薬(5μL)又はヨウ化プロピジウム(PI)(2μL)を加えた。
(4) チューブを緩やかに混和し、室温、暗所で15分間インキュベートした。
(5) 各チューブに1X Binding bufferを400μL加えた。製造者のプロトコールに従い、下記表2のコントロールサンプル1〜5を用いて機器のコンペンセーション調整を行なった。
(6) テストサンプルのチューブには、1X Binding bufferと共に終濃度100μg/mLのアルギニン抱合粒子を加え、CO2インキュベーターで37℃にてインキュベートした。粒子添加後8時間まで2時間おきにテストサンプルの測定を行なった。測定条件を以下に示す。
Annexin V-FITC:
吸収極大492nm、発光極大520nm
ヨウ化プロピジウム:
吸収極大370nm及び550nm、発光域:560-680nm
5:アポトーシス非誘導のネガティブコントロールには、アミノ酸抱合ナノ粒子懸濁用の超純水を用いた。
上記2と同様にして、公知のヒトB細胞リンパ腫由来細胞株であるYCUB-2を使用し、アミノ酸抱合粒子のヒトB細胞リンパ腫に対する増殖抑制効果をMTTアッセイにより評価した。YCUB-2細胞株を37℃、5%CO2下で培養し、培養液中にアミノ酸抱合粒子(終濃度10μg/ml)を添加した。細胞と粒子を48時間接触させた後の細胞の生存率を図16に示す。また、抱合粒子の処理濃度を0〜10μg/mlとして48時間処理した後の細胞の生存率を図17に示す。
上記2と同様にして、公知のヒトT細胞リンパ腫由来細胞株であるH9を使用し、アミノ酸抱合粒子のヒトT細胞リンパ腫に対する増殖抑制効果をMTTアッセイにより評価した。H9細胞株を37℃、5%CO2下で培養し、培養液中にアミノ酸抱合粒子を所定の濃度で添加した。細胞と粒子を24〜72時間接触させ、細胞の生存率を調べた。
上記2と同様にして、公知のヒト膵臓癌由来細胞株を使用し、アミノ酸抱合粒子のヒトT細胞リンパ腫に対する増殖抑制効果をMTTアッセイにより評価した。膵臓癌由来細胞株として、Panc1、MIA-PaCa2、BxPC3、AsPC-1、NOZを用いた。これらの細胞株はいずれもヒト膵臓癌に由来するものであるが、発現プロファイルや化学物質に対する応答等において相違があることが知られている。各細胞株を37℃、5%CO2下で培養し、培養液中にアミノ酸抱合粒子を10μg/mlの濃度で添加して48時間処理し、MTTアッセイにより増殖抑制効果を調べた。
下記2通りにてアミノ酸抱合粒子のin vivo毒性を調べた。
(1) 健常マウス10匹にアミノ酸抱合ナノ粒子を各1g単回経口投与し、経過を観察した。投与後1ヶ月間の観察においても、マウスに異常は認められず正常に生存していた。
(2) 各種アミノ酸抱合粒子を生理食塩水にて1 mg/mlに調製し、健常マウス5匹に週1回1 ml(粒子として1 mg)を経口、静注又は腹腔内に投与し、これを4週間繰り返した。便や体重等を含め、マウスに何らの毒性も見られなかった。
Claims (16)
- 平均粒径が1000nm未満である、アミノ酸を抱合したシアノアクリレートポリマー粒子。
- シアノアクリレートモノマー、糖類及び/又はポリソルベート、並びにアミノ酸の共存下において、前記モノマーをアニオン重合させることにより製造される請求項1記載の粒子。
- 前記糖類が、水酸基を有する単糖類及び水酸基を有する多糖類から成る群より選ばれる少なくとも1種の糖類である請求項2記載の粒子。
- 前記糖類がデキストランである請求項2記載の粒子。
- 前記シアノアクリレートがn−ブチルシアノアクリレートである請求項1ないし4のいずれか1項に記載の粒子。
- 平均粒径が20nm〜600nmである請求項1ないし5のいずれか1項に記載の粒子。
- 請求項1ないし6のいずれか1項に記載の粒子を有効成分として含有するがんの治療及び/又は予防剤。
- 前記がんがリンパ腫である請求項7記載の治療及び/又は予防剤。
- 前記がんがT細胞リンパ腫である請求項8記載の治療及び/又は予防剤。
- 前記粒子に抱合されるアミノ酸がグリシン、アスパラギン酸及びアルギニンから選択される少なくとも1種である請求項9記載の治療及び/又は予防剤。
- 前記がんがB細胞リンパ腫である請求項8記載の治療及び/又は予防剤。
- 前記粒子に抱合されるアミノ酸がグリシン、メチオニン、グルタミン酸、アスパラギン酸、リジン、アラニン、バリン、セリン、システイン、フェニルアラニン、ヒスチジン、ロイシン、スレオニン、トリプトファン、プロリン、アスパラギン、及びグルタミンから選択される少なくとも1種である請求項11記載の治療及び/又は予防剤。
- 前記がんが膵臓癌である請求項7記載の治療及び/又は予防剤。
- 前記粒子に抱合されるアミノ酸がアスパラギン酸及びグリシンから選択される少なくとも1種である請求項13記載の治療及び/又は予防剤。
- がんの治療及び/又は予防用の粒子である請求項1ないし6のいずれか1項に記載の粒子。
- がんの治療及び/又は予防を必要とする動物に対して請求項1ないし6のいずれか1項に記載の粒子の有効量を投与することを含む、がんの治療及び/又は予防方法。
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FR2504408B1 (fr) * | 1981-04-24 | 1986-02-14 | Couvreur Patrick | Procede de preparation de particules submicroscopiques, particules ainsi obtenues et compositions pharmaceutiques les contenant |
JPS6059211B2 (ja) * | 1981-09-07 | 1985-12-24 | 株式会社サンギ | 抗腫瘍剤 |
EP1582207A4 (en) * | 2002-12-26 | 2008-03-05 | Ajinomoto Kk | HEMMER FOR OUTBREAKING AND PROGREDIENCE OF LIVER CANCER |
CA2654593A1 (en) * | 2006-06-08 | 2007-12-13 | Bayer Schering Pharma Aktiengesellschaft | Functionalized, solid polymer nanoparticles for diagnostic and therapeutic applications |
EP1876188A1 (en) * | 2006-07-04 | 2008-01-09 | NanoDel Technologies GmbH | Two step miniemulsion process |
JP4696256B2 (ja) * | 2007-04-09 | 2011-06-08 | 公立大学法人横浜市立大学 | バンコマイシン耐性グラム陽性細菌用抗菌剤 |
DE102007059752A1 (de) * | 2007-12-10 | 2009-06-18 | Bayer Schering Pharma Aktiengesellschaft | Funktionalisierte, feste Polymernanopartikel enthaltend Epothilone |
US20110034557A1 (en) * | 2009-02-20 | 2011-02-10 | Modular Genetics, Inc. | Antimicrobial compositions and uses thereof |
-
2010
- 2010-03-03 CN CN2010800101727A patent/CN102361636A/zh active Pending
- 2010-03-03 WO PCT/JP2010/053426 patent/WO2010101178A1/ja active Application Filing
- 2010-03-03 US US13/254,721 patent/US20120027821A1/en not_active Abandoned
- 2010-03-03 EP EP10748772.0A patent/EP2404598A4/en not_active Withdrawn
- 2010-03-03 JP JP2011502778A patent/JP5663741B2/ja active Active
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2014
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US20120027821A1 (en) | 2012-02-02 |
JP5663741B2 (ja) | 2015-02-04 |
CN102361636A (zh) | 2012-02-22 |
US20140227521A1 (en) | 2014-08-14 |
EP2404598A4 (en) | 2013-10-23 |
EP2404598A1 (en) | 2012-01-11 |
WO2010101178A1 (ja) | 2010-09-10 |
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