JP5635690B2 - 細菌由来マイクロベシクルを用いた癌治療及び癌診断方法 - Google Patents
細菌由来マイクロベシクルを用いた癌治療及び癌診断方法 Download PDFInfo
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Description
本発明では、特定の組織に誘導される細菌由来マイクロベシクルを使用し、或いは標的タンパク質を発現した形質転換細菌由来マイクロベシクルを使用することができる。これに加えて、前記細菌と形質転換細菌に標的細胞との細胞膜融合に必要な物質が発現するように形質転換された細菌由来マイクロベシクルを使用することができる。
細菌由来マイクロベシクルは、伝達しようとする多様な治療用又は診断用物質を容易に負荷させることができて1種又は多種の物質を伝達することができるので、単独治療、併合治療、診断だけでなく、診断と治療の2つの目的で使用する診断−治療(theragnosis, pharmacodiagnosis)に利用することができる。この際、伝達しようとする多様な物質は、マイクロベシクルに内包されてマイクロベシクルの二重膜の内側に存在してもよく、細胞膜タンパク質のように前記物質の全部又は一部がマイクロベシクルの二重膜に埋め込まれているか組み込まれていてもよく、マイクロベシクルの表面に結合していてもよい。
本発明では、細菌又は形質転換された細菌が発現している物質を使用し、或いは必要に応じて、前記細菌に由来せずかつ細菌の外部から準備された物質を使用することができるが、これに限定されない。
押出法を用いて人工的に細菌由来マイクロベシクルを製造した。
本実験では、グラム陰性菌に自然に分泌されるシェディングマイクロベシクルを分離して使用した。グラム陰性菌としては大腸菌、緑膿菌、サルモネラ菌を使用した。具体的に、細菌を、100mLのLB培地が入っている三角フラスコに接種し、37℃で6時間培養した後、その中の8mLを600mLのLB培地が入っている2Lの三角フラスコに移し、37℃で5時間培養して吸光度(600nm)値が1.5となるようにした。培養液を容量500mLの高速遠心分離チューブ(high speed centrifuge tube)に入れた後、4℃で10,000×gで20分間遠心分離した。細菌を除去した上澄み液を孔径0.45μmのメンブランフィルターに1回通した後、分子量100kDa以下のタンパク質を除去することが可能なメンブランを装着したQuixstandシステムを用いて25倍濃縮した。濃縮液を孔径0.22μmのメンブランフィルターに通した後、容量70mLの超遠心分離チューブ(ultracentrifuge tube)に入れて4℃で150,000×gで3時間超遠心分離した。沈殿物をPBSで懸濁した後、細菌由来シェディングマイクロベシクルを得た。
本実験では、グラム陽性菌から自然に分泌されるシェディングマイクロベシクルを分離して使用した。グラム陽性菌としてはブドウ球菌と乳酸菌のラクトバチルス菌を使用した。具体的に、細菌を100mLの栄養培地(nutrient broth)が入っている三角フラスコに接種し、37℃で6時間培養した後、その中の8mLを600mLの栄養培地が入っている2Lの三角フラスコに移し、37℃で5時間培養して吸光度(600nm)値が1.5となるようにした。培養液を容量500mLの高速遠心分離チューブに入れた後、4℃で10,000×gで20分間遠心分離した。細菌を除去した上澄み液を孔径0.45μmのメンブランフィルターに1回通した後、分子量100kDa以下のタンパク質を除去することが可能なメンブランを装着したQuixstandシステムを用いて25倍濃縮した。濃縮液を孔径0.22μmのメンブランフィルターに通した後、容量70mLの超遠心分離チューブに入れて4℃で150,000×gで3時間超遠心分離した。沈殿物をPBSで懸濁した後、細菌由来シェディングマイクロベシクルを得た。
リポ多糖類の毒性が弱化するように形質転換された(msbB mutant)大腸菌を用いて実施例2の方法によってシェディングマイクロベシクルを得た後、これを用いて下記実験を行った。
リポタイコ酸の毒性が弱化するように形質転換された(LTA mutant)ブドウ球菌を用いて実施例3の方法によってシェディングマイクロベシクルを得た後、これを用いて下記実験を行った。
リポ多糖類の毒性が弱化するように形質転換された大腸菌を用いて実施例2の方法によってシェディングマイクロベシクルを得た後、これを用いて下記実験を行った。
癌の発生における炎症の重要性が数世紀前から提起されてきた。最近、VEGF/IL−6、STAT3(signal transducer and activator of transcription 3)シグナル伝達、Th17免疫反応などから生ずる炎症反応が癌の発生及び進行に重要であるという研究結果が注目を浴びている。アスピリン投与によって大腸癌の発生が減少するという報告があった。最近、本発明者は、アスピリンがTh17免疫反応による炎症反応を抑制するという事実を解明した。本実験では、細菌由来マイクロベシクルによる抗癌効能にTh17免疫反応を抑制する薬物を併用投与したときに抗癌効能が増加するかを評価した。本実験には、リポ多糖類の毒性が弱化するように形質転換された大腸菌から実施例2の方法によってシェディングマイクロベシクルを得た後、これを使用した。Th17免疫反応を抑制する薬物としてアスピリンを併用投与した。
リポ多糖類の毒性が弱化するように形質転換された大腸菌を用いて実施例2の方法によってシェディングマイクロベシクルを得た後、これを用いて下記実験を行った。
抗癌薬物を負荷した細菌由来マイクロベシクルが癌細胞へ抗癌薬物を伝達して細菌由来マイクロベシクルによる抗癌効能の増大に影響を与えるかを評価した。本実験では、抗癌薬物の一例としてドキソルビシンを使用した。
細菌由来マイクロベシクルの副作用に関連して、マイクロベシクルの構成成分であるリポ多糖類が敗血症の発生に重要な役割を果たすものと知られている。よって、本発明者は、前記マイクロベシクルが含有しているリポ多糖類の活性を抑制させる薬物を処理してリポ多糖類による副作用に及ぼす影響を評価した。本実験では、リポ多糖類の活性を抑制する薬物の一例としてポリミキシン(polymyxin)Bを使用した。
細菌由来マイクロベシクルの副作用と関連して、マイクロベシクルの構成成分であるリポ多糖類の毒性が弱化するように形質転換された大腸菌に由来するマイクロベシクルを用いてリポ多糖類による副作用の発生に及ぼす影響を評価した。本実験では、リポ多糖類の毒性が弱化するように形質転換された大腸菌の一例としてmsbB mutantを使用した。
細菌由来マイクロベシクルを静脈注射する場合に発生する副作用に対する評価のために、本実験ではリポ多糖類の毒性が弱化するように形質転換された大腸菌由来シェディングマイクロベシクルを使用した。また、静脈注射する場合に発生しうる副作用に対する一例として、血小板数の変化、血液凝固、及び溶血反応に対して評価した。
細菌由来マイクロベシクルの副作用に関連して、グラム陽性菌由来マイクロベシクルの構成成分であるリポタイコ酸が免疫反応を介して炎症反応を誘導する重要な物質として知られている。よって、リポタイコン酸の合成関連遺伝子を除去した形質転換細菌由来マイクロベシクルを用いて、グラム陽性菌由来マイクロベシクルによる副作用の発生におけるリポタイコ酸の役割を評価した。本実験では、前記リポタイコ酸の毒性が弱化するように形質転換されたブドウ球菌の一例として、細胞壁からリポタイコ酸成分を無くしたLTA mutantブドウ球菌を使用した。
細菌由来マイクロベシクルを使用する場合に副作用の発生メカニズムに重要なことは、マイクロベシクルによる免疫反応で炎症性媒介体が分泌されて局所又は全身性炎症反応が発生し、これと同時にマイクロベシクルによる凝固(coagulation)作用により血管に血栓/塞栓(thromboembolism)又は播種性血管内凝固(disseminated intravascular coagulation)が発生することである。本実験では、細菌由来マイクロベシクルによる副作用を減少させる目的で抗炎及び抗凝固作用をする薬物の一例としてアスピリンを用いて細菌由来マイクロベシクルによる副作用を評価した。
本実験では、リポ多糖類の毒性が弱化するように形質転換された大腸菌由来シェディングマイクロベシクルを用いて、抗癌薬物だけでなく、多様なサイズの薬物伝達体及び細胞を癌組織に伝達することが可能な効率を増加させることができるかを評価した。
グラム陰性菌の細胞外膜に最も多く存在する外膜タンパク質の一つであるOmpAは、シェディングマイクロベシクルにも最も多く存在していることを、本研究陣のタンパク質体の分析結果に基づいて確認することができた。よって、細菌由来マイクロベシクルの抗癌活性を媒介する因子として、シェディングマイクロベシクル外膜タンパク質の主要構成成分の一つであるOmpAに対して抗癌活性を評価した。
本研究陣で行った細菌由来シェディングマイクロベシクルのタンパク質体分析結果に基づいて、OmpAだけでなく、OmpF外膜タンパク質もグラム陰性群由来シェディングマイクロベシクルの主要構成成分であることを確認した。これにより、OmpF外膜タンパク質による細菌由来シェディングマイクロベシクルの抗癌活性を評価した。
リポソームを作るために、MPEG−DSPE(N-(carbonyl-methoxypolyethylene glycol 2000)-1,2-distearoyl-sn-glycero-3 phosphoethanolamine sodium salt)、HSPC(fully hydrogenated soy phosphatidylcholine)、及びコレステロール(cholesterol)をそれぞれ3.19mg/mL、9.58mg/mL、3.19mg/mLの濃度でクロロホルム(chloroform)に溶かした後、3つの脂質を1:1:1の比率で混合した。その後、窒素ガスを用いてクロロホルムを除去し、薄いフィルム(thin film)を生成した。生成されたフィルムに尿素バッファ(urea buffer)(344mM 尿素、10mM KCl、10mM HEPES(pH7.0、3mM NaN3))を仕込み、水浴超音波発生器(water bath sonicator)を用いて56℃で1時間超音波分解を行った。前記溶液を孔径1μmのメンブランフィルターに5回通した後、孔径400nmのメンブランフィルターに5回通し、しかる後に、孔径100nmのメンブランフィルターに5回通してリポソームを生成した。
Claims (11)
- 形質転換された細菌由来マイクロベシクルを含む、癌治療用又は癌診断用薬学的組成物であって、前記の形質転換された細菌は、脂質多糖類の毒性が弱化されたグラム陰性菌またはリポタイコ酸の毒性が弱化されたグラム陽性菌である、組成物。
- 前記細菌は癌治療用又は癌診断用物質を発現したりまたは、前記物質を発現するように形質転換された細菌である、請求項1に記載の組成物。
- 前記組成物は前記マイクロベシクルによる毒性を抑制させる薬物をさらに含む、請求項1に記載の組成物。
- 前記薬物がポリミキシンBまたはアスピリンである、請求項3に記載の組成物。
- 前記組成物は抗癌効能を増加させる薬物をさらに含む、請求項1に記載の組成物。
- 前記薬物がアスピリン、Th17(Tヘルパー17細胞)免疫反応を抑制する薬物、インターロイキン−6の生成或いは活性を抑制する薬物、血管の生成を抑制する薬物、血管内皮細胞成長因子の生成或いは活性を抑制する薬物、血管内皮細胞成長因子受容体によるシグナル伝達を抑制する薬物、STAT3(Signal transducer and activator of transcription)シグナル伝達を抑制する薬物、抗癌剤からなる群から選ばれるいずれかの一つである、請求項5に記載の組成物。
- 癌治療用又は癌診断用マイクロベシクルを製造する方法であって、下記の段階を含む方法:
(a)形質転換された細菌を含む懸濁液に薬物を添加し、前記形質転換された細菌と前記薬物を含む混合懸濁液を収得する段階であって、前記の形質転換された細菌は、脂質多糖類の毒性が弱化されたグラム陰性細菌またはリポタイコ酸の毒性が弱化されたグラム陽性菌である、段階及び
(b)前記混合懸濁液から分泌される前記薬物が負荷されたシェディング(shedding)マイクロベシクルを分離する段階。 - 癌治療用又は癌診断用細菌由来マイクロベシクルを製造する方法であって、下記の段階を含む方法:
(a)形質転換された細菌の培養液から分泌されるシェディングマイクロベシクルを分離する段階であって、前記の形質転換された細菌は、脂質多糖類の毒性が弱化されたグラム陰性細菌またはリポタイコ酸の毒性が弱化されたグラム陽性菌である、段階、及び
(b)前記分離されたマイクロベシクルを含む懸濁液に薬物を添加して培養する段階。 - 前記マイクロベシクル又はシェディングマイクロベシクルが含まれた懸濁液から、前記薬物が負荷されたマイクロベシクル又はシェディングマイクロベシクルを分離する段階をさらに含む、請求項8に記載の方法。
- 前記分離段階は密度構造、超遠心分離、濾過、透析及び自由流動電気泳動法よりなる群から選ばれた方法を用いて行われる、請求項7または8に記載の方法。
- 癌細胞又は癌組織へターゲッティングされるように形質転換された細菌に由来し、癌治療用又は癌診断用薬物が負荷されたマイクロベシクルを含む、癌治療用又は癌診断用薬学的組成物であって、前記の形質転換された細菌は、脂質多糖類の毒性が弱化されたグラム陰性細菌またはリポタイコ酸の毒性が弱化されたグラム陽性菌である、組成物。
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