JP2014516153A - 二機能の腫瘍診断試薬及び方法 - Google Patents
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Abstract
【選択図】図3
Description
本発明はナノ技術、バイオニクス、免疫学と生物医薬のインターディシプリナリ分野に属している。特に、本発明は癌の病巣に対する特異的な識別と発色性の二機能を集合した腫瘍診断試薬、及び前記腫瘍診断試薬を癌組織及び癌細胞に応用する診断方法を提供する。
悪性腫瘍は、既に人間の生命及び生活質量に悪い影響をもたらす主な病気のひとつである。生検という検査は一番正確で、確実な方法であり、国内外で認可された腫瘍診断の「ゴールド標準」であった(非特許文献1、非特許文献2、非特許文献3)。今、生検に対する主な染色方法は、ヘマトキシリン−エオシン染色(HE)、免疫組織化学、免疫蛍光がある。HE染色においては、主にヘマトキシリンは細胞核内の染色質を紫青色に染色して、エオシンは細胞質と細胞外基質中の成分を赤色に染色していることで、細胞形態学の情報を提供する。病理科の医者は、これらの細胞形態学の変化に基づいて、組織細胞の腫瘍化を概ねに同定する。この染色方法は、操作が便利で、快速であるが、組織形態学の変化を提供できるしかなくて、情報量が少ないので、ちょっと複雑で、ポリタイプの腫瘍に対して、正確に診断できない。免疫組織化学または免疫蛍光においては、一次抗体と被検組織抗原が結合し、蛍光シグナル分子または酵素標識された二次抗体、三次抗体が一次抗体と結合し、後に蛍光シグナルによりまたは酵素サブストレートと反応するにより発色して、検出したい抗原の位置決め及び半定量の情報を提供して、さらに組織細胞の腫瘍化、壊死、炎症細胞の浸潤等の病理変化を同定する。免疫組織化学または免疫蛍光は、ある特定な抗原の分布、含有量及び細胞形態学の詳細な情報を提供できるので、病理学のもっと深い研究に対して非常に意味がある。しかしながら、免疫染色は、一次抗体、二次抗体乃至三次抗体の多段階インキュベート、PBSで繰り返し洗浄、及び酵素または蛍光分子での標識が必要で、その過程が複雑で、その操作時間が長い。したがって、臨床病理診断の効率を向上して、十分な患者治療時間を獲得するために、豊かな情報を簡単で、快速に提供できる癌組織、癌細胞の検出試薬及び方法を研究する必要がある。
本発明は、ナノ材料のペルオキシダーゼ活性を利用して、腫瘍識別蛋白質を結合して、そして新規な腫瘍診断試薬及び方法を提供した。
下の図面を参考して本発明の好ましい実施形態を説明する。
以下の実施例を挙げることは目的を説明するためですが、本発明の範囲を限定しない。
遺伝子組み換えでフルヘビーチェーンヒトフェリチン殻を獲得して、ヒトバイオミネラル化のメカニズムを利用して、鉄イオンをトランスロードし蛋白質殻に入らせ、酸化鉄ナノ粒子に酸化し、磁性酸化鉄ナノコアを内包しているフルヘビーチェーンヒトフェリチンをビオニックスで合成して、それをビオニックスフェリチンと呼び、腫瘍の検出に用いる。具体的な操作が以下の通りである。まず、ヒトフルヘビーチェーンサブユニットフェリチン遺伝子配列の組み換えプラスミドpET12b−HFn(Santambrogio P. et al.,(2000), Protein Expr. Purif., 19:212−218)を構築した。ヒト骨格筋の総cDNAライブラリーはInvitrogen会社から購入されたものであり(D8090−01, Carlsbad, CA, USA)、PCR技術を利用してcDNAからフルヘビーチェーンヒトフェリチン遺伝子を分離して増幅し、デザインされた二つのプライマーが以下のとおりである:フォワードPCRプライマー:5’−A GTC GCC CAT ATG ACG ACC GCG TCC−3’で、酵素切断サイトはNdeI(下線を施した部分)であり、7つの酵素切断サイトの保護ベースを加えている;リバースPCRプライマー:5’−GCC GGA TCC TTA GCT TTC ATT ATC AC−3’で、酵素切断サイトはBamHI(下線を施した部分)であり、3つの酵素切断サイトの保護ベースを加えている。552bpの遺伝子産物はフルヘビーチェーンヒトフェリチンのターゲット遺伝子産物であり、その配列は以下の通りである:
われわれの研究チームの報告に基づいて、磁性酸化鉄ナノ粒子は、ペルオキシダーゼと類似する触媒活性を有して(Gao L, et al. (2007) Nature Nanotech., 2: 577−583.)、ビオニックスフェリチン中に酸化鉄のコアを内包しているので、ペルオキシダーゼ様活性を有するはずである。ホースラディッシュペルオキシダーゼのサブストレートを利用してビオニックスフェリチンの酵素活性を検出して、具体的な方法は以下のようである:ビオニックスフェリチンに30% H2O2と、TMBまたはDABを加入して、色の変化を観測する。図1Bに示したように、TMB中にビオニックスフェリチンとH2O2を加入した後、暗青色になり、DAB中にビオニックスフェリチンとH2O2を加入した後、暗褐色になり、ホースラディッシュペルオキシダーゼと同じ色反応が発生して、ビオニックスフェリチンは、ペルオキシダーゼ様活性を有すると分かった。
ビオニックスフェリチンとヒト腫瘍細胞の結合を研究するために、常用のヒト腫瘍細胞と蛍光分子標識のビオニックスフェリチンを選択してインキュベートして、フローサイトメトリーを利用してビオニックスフェリチンと各腫瘍細胞の結合を検出した。
ビオニックスフェリチンと腫瘍細胞表面受容体の結合状況を研究するために、濃度が異なるCy5.5標識のビオニックスフェリチンと結腸直腸癌細胞HT29をインキュベートし、ビオニックスフェリチンの結合飽和曲線を得、且つ、過剰の抗TfR1の抗体で受容体サイトを遮断し、TfR1がビオニックスフェリチンと癌細胞との相互作用を媒介すること立証した。
ビオニックスフェリチンが腫瘍組織に対する識別及び染色能力を検出するために、それをヌードマウスの移植腫瘍組織とインキュベートし、且つ、伝統の抗体免疫組織化学結果と比較した。具体的な実験方法が以下のようである:
肝組織サンプルが北京安貞病院と北京腫瘍病院から来た。すべての肝組織サンプルは、手術で切除された腫瘍及び隣接組織のバルクサンプルである。すべての組織をパラフィンで埋め込んだ。
ビオニックスフェリチンが腫瘍化組織とヒト正常組織に対する特異的識別能力を系統的に研究するために、ヒト腫瘍組織と48ケースのヒトの正常組織または炎症組織のパラフィン切片サンプルを選び、ビオニックスフェリチンで染色した。患者の組織サンプルは北京安貞病院、北京腫瘍病院と西安オメイ生物バイオテック株式会社から来た。すべての組織サンプルは、手術で切除された腫瘍及び隣接組織のバルクサンプルである。すべての組織をパラフィンで埋め込んだ。
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Claims (10)
- 癌組織及び/または癌細胞を特異的に識別する蛋白質殻、及びペルオキシダーゼ触媒活性を有する無機ナノコアからなることを特徴とする二機能の腫瘍診断試薬。
- 前記蛋白質殻は、アポフェリチン、熱ショックプロテイン、DNA結合蛋白質、プテリジンシンターゼ、及びナノキャビティー構造を有するウィルス蛋白質殻を含み、
前記ナノキャビティー構造のウィルス蛋白質殻が、ササゲクロロティックモットルウィルスとササゲモザイクウィルス蛋白質を含むことを特徴とする請求項1に記載の二機能の腫瘍診断試薬。 - 前記アポフェリチンは、12個または24個のヘビーチェーンサブユニットとライトチェーンサブユニットとが任意の比例で自己組織化してなることを特徴とする請求項2に記載の二機能の腫瘍診断試薬。
- 前記アポフェリチンは、天然アポフェリチンまたは遺伝子組み換えのアポフェリチンであり、
前記天然アポフェリチンが真核生物または原核生物から由来しており、好ましくは哺乳動物から由来していることを特徴とする請求項3に記載の二機能の腫瘍診断試薬。 - 前記蛋白質殻は、ターゲット分子及び/またはシグナル分子が化学カップリングまたは遺伝子融合された蛋白質殻を含み、
前記ターゲット分子は、ポリペプチドまたは核酸アプタマーを含み、
前記ポリペプチドは、抗体を含み、
前記シグナル分子は、蛍光分子、放射性核種と酵素を含むことを特徴とする請求項1〜4のいずれかに記載の二機能の腫瘍診断試薬。 - 前記無機ナノコアは、磁性酸化鉄ナノ粒子、硫化鉄ナノ粒子、貴金属ドープ酸化鉄ナノ粒子、二金属合金ナノ粒子と酸化セリウムナノ粒子を含むことを特徴とする請求項1〜4のいずれかに記載の二機能の腫瘍診断試薬。
- 前記蛋白質殻は、遺伝子組み換えのフルヘビーチェーンサブユニットフェリチンであり、前記の無機コアは磁性酸化鉄ナノ粒子であることを特徴とする請求項1〜4のいずれかに記載の二機能の腫瘍診断試薬。
- 請求項1〜7のいずれかに記載の二機能の腫瘍診断試薬とペルオキシダーゼサブストレートを含む腫瘍診断キット。
- 蛋白質殻及び無機ナノコアからなるビオニックスフェリチンであって、前記蛋白質殻は遺伝子組み換えのフルヘビーチェーンサブユニットフェリチンであり、前記無機コアは磁性酸化鉄ナノ粒子であるビオニックスフェリチン及びその腫瘍検出試薬の製造における用途。
- 前記個体から生体組織または細胞サンプルを獲得し、該サンプルを請求項1〜7のいずれかに記載の二機能の腫瘍診断試薬に接触させ、サブストレートを加入し直接に発色することで、前記個体における腫瘍の存在を検出することを含み、
好ましくは、前記組織が臨床患者または動物モデルの穿剌活組織検体、術後の病理学的切片または死体解剖組織であり、前記細胞は循環系における剥離細胞、組織溶解細胞またはin vitroでの培養細胞である個体における腫瘍の検出方法。
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CN109148067B (zh) * | 2018-07-16 | 2020-09-11 | 中国计量科学研究院 | 表面共价有机框架材料修饰的磁性纳米材料及制备、应用 |
CN110179997B (zh) * | 2018-08-08 | 2020-02-14 | 昆山新蕴达生物科技有限公司 | 一种用于糖尿病治疗的纳米药物载体及其组合药物 |
CN109852666B (zh) * | 2019-01-17 | 2021-01-01 | 中国科学院生物物理研究所 | 一种用于肝癌诊断的特异性靶点及诊断试剂 |
CN111840250B (zh) * | 2019-04-29 | 2023-07-04 | 中国科学院生物物理研究所 | 一种用于恶性脑疟治疗的新型试剂及方法 |
CN112708415B (zh) * | 2020-12-23 | 2023-02-07 | 国家纳米科学中心 | 含铁纳米探针、制备方法及同步辐射用途 |
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US20150037817A1 (en) | 2015-02-05 |
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EP2733490A1 (en) | 2014-05-21 |
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