JP2010189373A - 癌標的性に優れたタンパク質複合体及びその製造方法 - Google Patents
癌標的性に優れたタンパク質複合体及びその製造方法 Download PDFInfo
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- JP2010189373A JP2010189373A JP2009102647A JP2009102647A JP2010189373A JP 2010189373 A JP2010189373 A JP 2010189373A JP 2009102647 A JP2009102647 A JP 2009102647A JP 2009102647 A JP2009102647 A JP 2009102647A JP 2010189373 A JP2010189373 A JP 2010189373A
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Abstract
癌標的性に優れたタンパク質複合体及びその製造方法を提供する。
【解決手段】
本発明は、水系で自己集合体を形成して、30〜400nmの大きさのナノ粒子を形成するアルブミン−胆汁酸複合体及びその製造方法に関するものである。本発明のアルブミン−胆汁酸複合体は、癌標的性が優秀で、疎水性抗癌剤封入が可能であり、近赤外線蛍光体が結合された形態で製造することができるので、癌診断または治療のための新規ナノ粒子造影剤及びナノ粒子薬物伝達システムに有用である。
【選択図】図1
Description
1)親水性アルブミンを水溶性溶媒に溶解してアルブミン溶液を製造する工程、
2)疎水性胆汁酸を有機溶媒に溶解して胆汁酸溶液を製造する工程、
3)前記工程1)のアルブミン溶液に、工程2)の胆汁酸溶液を加えた後、撹拌して反応液を製造する工程、及び
4)前記工程3)の反応液を透析して未反応胆汁酸を除去した後、凍結乾燥する工程
を含む、前記アルブミン−胆汁酸複合体の製造方法を提供する。
1)前記アルブミン−胆汁酸複合体に抗癌剤を封入させる工程、及び
2)前記抗癌剤が封入されたアルブミン−胆汁酸複合体を個体に投与する工程
を含む癌治療方法を提供する。
1)前記造影剤を個体に投与する工程、及び
2)近赤外線を照射して癌組織を映像化する工程
を含む癌診断方法を提供する。
Bはアルブミンのリジン基に結合された胆汁酸を表わし、Cは胆汁酸に結合された近赤外線蛍光体を表わし、
Dは追加的な結合物質であり、例えば、造影剤に使用される場合、放射線同位元素またはガドリニウム金属イオンなどを表示するものである。また、aはアルブミンタンパク質内のリジン基の数を示して1〜59の値を有し、bは胆汁酸が結合した数を示して1〜59の値を有し、cは近赤外線蛍光体が結合した数を示して1〜10の値を有し、dは追加的な結合物質が結合した数を示して0〜10の値を有する。
1)親水性アルブミンを水溶性溶媒に溶解してアルブミン溶液を製造する工程、
2)疎水性胆汁酸を有機溶媒に溶解して胆汁酸溶液を製造する工程、
3)前記工程1)のアルブミン溶液に工程2)の胆汁酸溶液を加えた後、撹拌して反応液を製造する工程、及び
4)前記工程3)の反応液を透析して未反応胆汁酸を除去した後、凍結乾燥する工程
を含む前記アルブミン−胆汁酸複合体の製造方法を提供する。
1)前記アルブミン−胆汁酸複合体に抗癌剤を封入させる工程、及び
2)前記抗癌剤が封入されたアルブミン−胆汁酸複合体を個体に投与する工程
を含む癌治療方法を提供する。
1)前記造影剤を個体に投与する工程、及び
2)近赤外線を照射して癌組織を映像化する工程
を含む癌診断方法を提供する。
但し、下記の実施例は、本発明を例示するだけであって、本発明の範囲がこれによって限定されるものではない。
本発明者等は、500mgのアルブミンを60mlの水に溶解して、90mlのメタノールを加えてアルブミン溶液を製造し、胆汁酸として前記[化学式1]で表わされる5β−コラン酸をアルブミンに対する質量比10〜100%(6mg〜60mg)で、10%単位で各々100mlのメタノールに添加した。化学反応の触媒として、1−エチル−3−(3−ジメチル−アミノプロピル)カルボジイミド(EDC)とN−ヒドロスクシンイミド(NHS)を胆汁酸のモル濃度の1.5倍を50mlのメタノールに溶解して反応液に加えた後、常温で24時間撹拌した。以後、前記反応液を2日間透析して、未反応5β−コラン酸を除去した後、凍結乾燥して、本発明のアルブミン−胆汁酸複合体を製造した(図1)。
本発明者等は、前記<実施例1>で製造したアルブミン−胆汁酸−Cy5.5複合体の光学的特性を観察するために、それぞれのアルブミン−胆汁酸−Cy5.5複合体1mgを1mLのPBSに溶解した後、近赤外線蛍光分光光度計(fluorescence spectrophotometer,F-7000 model, HITACHI high technologies corporation)を使用して測定した。
本発明者等は、前記<実施例1>で製造したアルブミン−胆汁酸−Cy5.5複合体の疎水性抗癌剤の封入率を測定するために、下記のように実験した。各々のアルブミン−胆汁酸−Cy5.5複合体5mgをPBS5mlに溶解して、タキソール0.5mg(10%)をメタノール0.5ml(総体積10%以内のメタノールを使用する)に溶解する。二つの溶液を撹拌後、充分に撹拌した後、超音波分解(sonication)5分、3時間撹拌、透析(MWCO 12000〜14000)した後、2000rpmで15分間遠心分離した後、上澄み液を凍結乾燥した。封入物1mgを計ってメタノール1mlに溶解し、超音波分解を10分行なった後、12時間撹拌した。前記溶液を10000rpmで15分間遠心分離して、上澄み液を0.45ミクロメーターフィルターでろ過して、HPLC(高性能液体クロマトグラフィー)で定量した。
本発明者等は、前記<実施例1>で製造したアルブミン−胆汁酸−Cy5.5複合体の癌組織内蓄積効果を測定するために、下記のように実験を行なった。対照群としてアルブミンを、実験群としてアルブミン−胆汁酸−Cy5.5複合体(胆汁酸のアルブミンに対する質量比がそれぞれ10wt%及び20wt%)のナノ粒子溶液(5mg/kg)100μlをそれぞれ皮膚癌細胞が注入されたネズミ(SCC-7 cell, balb-c nude mouse,中央実験動物)に静脈注射した後、一定時間(1時間、6時間、12時間、24時間、及び48時間)が経過後、近赤外線蛍光分光光度計(fluorescence spectrophotometer, F-7000 model, HITACHI high technologies corporation)を使用して、近赤外線の照射を実施して1cm以下の小さな癌組織映像を獲得した。
本発明者等は、前記<実施例3>で製造したタキソールを含むアルブミン−胆汁酸−Cy5.5複合体の抗癌効果を測定するために、下記のように実験を行なった。マウス黒色腫皮膚癌細胞(B16F10)を移植した黒色腫マウス(C57BL/6)に、本発明のタキソールを含むアルブミン−胆汁酸−Cy5.5複合体をそれぞれ20mg/kgまたは50mg/kgを21日間投与した後、実験動物の体重を測定した。その後、摘出した腫瘍の大きさを測定した。ここで、比較群としてタキソールを含むクレモポアEL(polyethoxylated castor oil derivatives, BASF社)を使用し、陰性対照群として食塩水を使用した。
Claims (24)
- 親水性アルブミンと疎水性胆汁酸で構成され、水溶液で自己集合体を形成する、薬物伝達用アルブミン−胆汁酸複合体。
- アルブミンのリジン基のアミノ基(−NH2)と胆汁酸のカルボキシル基(−COOH)とがペプチド結合することを特徴とする、請求項1に記載のアルブミン−胆汁酸複合体。
- アルブミンが、ヒトアルブミン、その断片またはその変異体であることを特徴とする、請求項1に記載の薬物伝達用アルブミン−胆汁酸複合体。
- 胆汁酸が、5β−コラン酸であることを特徴とする、請求項1に記載のアルブミン−胆汁酸複合体。
- アルブミン−胆汁酸複合体が、胆汁酸の重量部に比例して粒子サイズが増加し、直径が30〜400nmの範囲の粒子サイズを有することを特徴とする、請求項1に記載のアルブミン−胆汁酸複合体。
- 薬物が、疎水性抗癌剤であることを特徴とする、請求項1に記載のアルブミン−胆汁酸複合体。
- 疎水性抗癌剤が、ドセタキセル、シスプラチン、カンプトテシン、パクリタキセル、タモキシフェン、アナストロゾール、グリベック、5−フルオロウラシル(5−FU)、フロクスウリジン、リュープロリド、フルタミド、ゾレドロネート、ドキソルビシン、ビンクリスチン、ゲムシタビン、ストレプトゾシン、カルボプラチン、トポテカン、ベロテカン、イリノテカン、ビノレルビン、ヒドロキシウレア、バルルビシン、レチノイン酸系列、メソトレキセート、メクロレタミン、クロラムブシル、ブスルファン、ドキシフルリジン、ヴィンブラスチン、マイトマイシン、プレドニソン、テストステロン、ミトキサントロン、アスピリン、サリチル酸、イブプロフェン、ナプロキセン、フェノプロフェン、インドメタシン、フェニルタゾン、シクロホスファミド、デキサメタゾン、プレドニゾロン、セレコキシブ、バルデコキシブ、ニメスリド、コルチゾン及びコルチコステロイドからなる群から選択される1または2以上であることを特徴とする、請求項6に記載のアルブミン−胆汁酸複合体。
- アルブミン−胆汁酸複合体にさらに近赤外線蛍光体が結合された、請求項1に記載のアルブミン−胆汁酸複合体。
- 近赤外線蛍光体が、シアニン(Cy)、フルオレセイン、テトラメチルローダミン、ボデピー及びアレクサからなる群から選択される1または2以上であることを特徴とする、請求項8に記載の薬物伝達用アルブミン−胆汁酸複合体。
- 近赤外線蛍光体が、Cy5.5であることを特徴とする、請求項8に記載のアルブミン−胆汁酸複合体。
- アルブミン−胆汁酸複合体の内部にさらに疎水性抗癌剤が封入されることを特徴とする、請求項1に記載のアルブミン−胆汁酸複合体。
- 1)親水性アルブミンを水溶性溶媒に溶解した後、有機溶媒を加えてアルブミン溶液を製造する工程、
2)疎水性胆汁酸を有機溶媒に溶解して胆汁酸溶液を製造する工程、
3)前記工程1)のアルブミン溶液に工程2)の胆汁酸溶液を加えた後、撹拌して反応液を製造する工程、及び
4)前記工程3)の反応液を透析して未反応胆汁酸を除去した後、凍結乾燥する工程
を含む、請求項1に記載のアルブミン−胆汁酸複合体の製造方法。 - 工程1)のアルブミンが、ヒトアルブミン、その断片またはその変異体であることを特徴とする、請求項12に記載の製造方法。
- 工程1)の水溶性溶媒が、水であることを特徴とする、請求項12に記載の製造方法。
- 工程2)の胆汁酸が、5β−コラン酸であることを特徴とする、請求項12に記載の製造方法。
- 工程1)及び工程2)の有機溶媒が、メタノールであることを特徴とする、請求項12に記載の製造方法。
- 請求項1に記載のアルブミン−胆汁酸複合体の薬物伝達体の製造における使用。
- 請求項1に記載のアルブミン−胆汁酸複合体に抗癌剤を封入させてなる、癌治療のための薬物伝達システム。
- 請求項1に記載のアルブミン−胆汁酸複合体に近赤外線蛍光体が結合されたアルブミン−胆汁酸−近赤外線蛍光体複合体を含む癌診断用造影剤。
- 近赤外線蛍光体が、シアニン(Cy)、フルオレセイン、テトラメチルローダミン、ボデピー及びアレクサからなる群から選択される1または2以上であることを特徴とする、請求項19に記載の造影剤。
- 近赤外線蛍光体が、Cy5.5であることを特徴とする、請求項19に記載の造影剤。
- 放射線同位元素、量子ドットまたはMRI造影剤をさらに含むことを特徴とする、請求項19に記載の造影剤。
- 請求項19に記載の造影剤を投与した個体に照射した近赤外線により癌組織を映像化する工程を含む癌検出方法。
- 請求項8に記載のアルブミン−胆汁酸複合体の癌診断用造影剤の製造における使用。
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JP2016500098A (ja) * | 2012-11-27 | 2016-01-07 | ユタ−イナ ディーディーエス アンド アドバンスト セラピューティクス リサーチ センター | 陰イオン性高分子を含む抗癌剤吸着能力の向上された生分解性マイクロビーズ及びその製造方法 |
JP2022503696A (ja) * | 2018-10-17 | 2022-01-12 | サンステイト バイオサイエンシーズ, エルエルシー | 治療効果を高めるために単一タンパク質でカプセル化された医薬品 |
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KR101329646B1 (ko) | 2013-05-02 | 2013-11-14 | 주식회사 지니스 | 표적지향증폭형 항암나노입자 및 이의 제조방법 |
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