JP5794541B2 - 核内移行性を有する脂質膜構造体 - Google Patents
核内移行性を有する脂質膜構造体 Download PDFInfo
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- JP5794541B2 JP5794541B2 JP2012511688A JP2012511688A JP5794541B2 JP 5794541 B2 JP5794541 B2 JP 5794541B2 JP 2012511688 A JP2012511688 A JP 2012511688A JP 2012511688 A JP2012511688 A JP 2012511688A JP 5794541 B2 JP5794541 B2 JP 5794541B2
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- lipid membrane
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Description
(a)配列番号1に記載のアミノ酸配列からなるポリペプチド;
(b)配列番号1に記載のアミノ酸配列において1個又は数個のアミノ酸が欠失及び/又は置換及び/又は挿入されたアミノ酸配列からなるポリペプチドであって、細胞の核内への脂質膜構造体の移行を促進する活性を有するポリペプチド
で修飾された脂質膜構造体が提供される。
(a)配列番号1に記載のアミノ酸配列からなるポリペプチド;
(b)配列番号1に記載のアミノ酸配列において1個又は数個のアミノ酸が欠失及び/又は置換及び/又は挿入されたアミノ酸配列からなるポリペプチド
が提供される。
リン脂質及びリン脂質誘導体としては、例えば、ホスファチジルエタノールアミン、ホスファリジルコリン、ホスファチジルセリン、ホスファチジルイノシトール、ホスファチジルグリセロール、カルジオリピン、スフィンゴミエリン、セラミドホスホリルエタノールアミン、セラミドホスホリルグリセロール、セラミドホスホリルグリセロールホスファート、1,2-ジミリストイル-1,2-デオキシホスファチジルコリン、プラスマロゲン、ホスファチジン酸などを挙げることができ、これらは1種又は2種以上を組み合わせて用いることができる。これらリン脂質における脂肪酸残基は特に限定されないが、例えば、炭素数12〜20の飽和又は不飽和の脂肪酸残基を挙げることができ、具体的には、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、リノール酸などの脂肪酸由来のアシル基を挙げることができる。また、卵黄レシチン、大豆レシチンなどの天然物由来のリン脂質を用いることもできる。
飽和又は不飽和の脂肪酸としては、例えば、パルミチン酸、オレイン酸、ステアリン酸、アラキドン酸、ミリスチン酸などの炭素数12〜20の飽和又は不飽和の脂肪酸が挙げられる。
例1
(a)封入する核酸の調製(プロタミンによる凝縮体)
ルシフェラーゼをコードしているプラスミド(pDNA、BD Biosciences Clontech社製)を10 mM HEPES緩衝液に0.1 mg/mLとなる様に溶解した。0.1 mg/mL(10 mM HEPES緩衝液)の プロタミン(Protamine)溶液150μLにpDNA溶液を100μL少量ずつ攪拌しながら滴下して、プロタミンとpDNAのコンパクション体を調製した(N/P比は2.2)。
1 mM DOPE 112.5μL及び1 mM CHEMS 25μLをDOPE:CHEMS=9:2となるようにガラス試験管に加えた。さらに、Biochemistry, 43, pp.5618-5628, 2004に記載の方法に従って合成された1mg/mL Chol-GALA、及び特開2003-343857号公報に記載された方法に準じて合成した1mg/mLステアリル化KALA(STR-KALA)を総脂質濃度の1〜8%分の修飾量となるように加え、さらに全量が200μLとなるようにクロロホルムを加えた後、デシケーターで減圧乾燥して溶媒を留去させて脂質膜を得た。この脂質膜に、総脂質濃度が0.55 mMとなるように上記(a)のコンパクション体を添加し、室温で10分間静置して水和させた後、ソニケーターで1分間超音波処理した。特開2003-343857号公報に記載の方法で合成したステアリル化オクタアルギニン(STR-R8)(2 mg/mL水溶液を総脂質の 5 mol%分添加し、室温で10 分間静置した。
ルシフェラーゼをコードしているプラスミド(pDNA、BD Biosciences Clontech社製)を10 mM HEPES緩衝液に0.1 mg/mLとなる様に溶解した。J. Control. Release, 131, pp.137-144, 2008に記載の方法に従って合成されたポリロタキサン(平均ポリエチレングリコール鎖長4,000、シクロデキストリン貫通数29、1鎖内平均カチオン数46)を10 mM HEPES緩衝液により溶解し(1 mM アミン濃度換算)、得られた溶液150μLにpDNA溶液を100μL少量ずつ攪拌しながら滴下して、ポリロタキサンとpDNAのコンパクション体を調製した(N/P比は5.0)。
1 mM DOPE 107 μL及び1 mM ホスファチジン酸(PA) 30.5μLをDOPE:PA=7:2となるようにガラス試験管に加えた。特開2003-343857号公報に記載された方法に準じて合成した1mg/mLのSTR-KALAを総脂質濃度の1.5〜5%分の修飾量(8.25μL〜27.5μL)となるように加え、さらに全量が200μLとなるようにクロロホルムを加えた後、デシケーターで減圧乾燥して溶媒を留去させて脂質膜を得た。この脂質膜に、総脂質濃度が0.55 mMとなるように上記(c)のコンパクション体を添加し、室温で10 min静置し水和させた後、ソニケーターで1分間超音波処理した。特開2003-343857号公報に記載の方法で合成したステアリル化オクタアルギニン(STR-R8)2 mg/mL水溶液を総脂質の 10 mol%となるように添加し、室温で10 分間静置し水和させた。
JAWS II細胞を8×104cells/ウェルとなるように24 ウェルプレートに播種し、αMEM培地で24 時間培養した。培養後の細胞をPBS 500 μLで洗浄した後、上記(b)及び(d)で作製したリポソームとコントロールリポソーム(ステアリル化KALA及びChol-GALA未修飾)をpDNA量が0.4μg/wellとなる様にαMEM に添加した後、各ウェルに加えて37 ℃、5% CO2で3時間インキュベーションした。インキュベーション後に細胞をPBS 500 μLで洗浄した後、αMEM 1 mLを各ウェルに添加し、37℃、5% CO2の条件下でさらに21時間インキュベーションして形質転換細胞を作製した。
上記(e)の形質転換細胞をPBS 500μLで洗浄し、そのPBSを1.5 mLサンプルチューブに回収し、遠心(4℃、2,000 rpm, 2分間)して上清を除去した。各ウェルにReporter Lysis Buffer(Promega社)75μLを添加し、-80℃のリーザーに移して凍結した。凍結させたサンプルを解凍させた後、セルスクレーパーを用いて細胞をはがし、1.5 mLサンプルチューブに回収した。回収した細胞溶解液を遠心(4℃、15,000 rpm、5分間)して遠心分離し、その上清45μLを回収した。得られた上清を用いてルシフェラーゼ活性測定(RLU/mL)を測定した。さらにBCA法によるタンパク定量(mg/mL)を行い、単位ポリペプチド量当たりのルシフェラーゼ活性(RLU/ mg protein)を算出し、ルシフェラーゼ発現量を比較した。結果を図1に示す。
(a)正電荷コアT-MENDの調製
3.3 mM カルジオリピン(CL) 84 μL及び10 mM DOPE 27.5 μLをCL:DOPE=1:1となるようにガラス試験管に加えた。1 mg/mLのSTR-KALAを総脂質濃度の0.5%、1%、2%、及び5%の修飾量となるようにそれぞれ加え、さらに全量が200μLとなるようにクロロホルムを加えた後、デシケーターで減圧乾燥して溶媒を留去させて脂質膜を得た。この脂質膜に総脂質濃度が0.55 mMとなるように10 mM HEPES溶液を1mL加え、水和した脂質膜をバスタイプソニケーターを用いてガラス試験管から剥離させた後、プローブ型ソニケーターを用いて10分間超音波処理した。超音波処理後、遠心分離(15,000 rpm、20℃、5分間)して上清を回収する操作を3回行い、STR-KALA濃度の異なる4種類のリポソーム(SUV1−1〜5)を回収した。
ルシフェラーゼをコードしているプラスミド(pDNA、BD Biosciences Clontech社製)を10 mM HEPES緩衝液に0.1 mg/mLとなるように溶解した。0.1 mg/mL pDNA 60μLにアミン濃度換算で1 mMのポリロタキサン溶液(平均ポリエチレングリコール鎖長4,000、シクロデキストリン貫通数29、1鎖内平均カチオン数46) 90μLを少量ずつ攪拌しながら滴下して、ポリロタキサンとpDNAのコンパクション体を調製した(N/P比は0.5)。
例1(e)に記載の方法に従って、上記(a)及び(b)でそれぞれ調製した2種のT-MENDを用いて形質転換細胞を作製し、さらに例1(f)に記載の方法に従って、各細胞におけるルシフェラーゼの発現量を測定した。その結果、カチオン性T-MENDにおいて、KALAの修飾密度依存的に封入された遺伝子発現の上昇が認められた(図2)。また、アニオン性T-MENDに対しても、内膜と外膜をKALAで修飾することで遺伝子発現が10倍以上に上昇した。特にアニオン性T-MENDは市販の遺伝子導入試薬であるLipofectamine PLUSよりも高い遺伝子発現を示した。
(a)抗原提示量の評価
種々のベクターを用いて、抗原である卵白抗原(Ovalbumin)をコードするプラスミドDNAを樹状細胞に導入し、トランスフェクションから24時間後に樹状細胞を回収し、培地で洗浄後96 well plateに1×104 cells/100μLの樹状細胞と2×105 cells/100μLのB3Z(MHC-I)細胞を播種し、16時間共培養した。その後PBSで細胞を洗い、CPRG buffer(5 mM CPRG(Roche Diagnotics), 0.125% NP-40(Igepal CA-630, SIGMA), 9 mM MgCl2となるように二回蒸留水に溶解し、1 mLずつ分注して-20℃で遮光保存したもの)100μLを添加して37℃で4時間インキュベートした。その後、Benchmark Plus microplate spectrophotometer(Bio-Rad)を用いて595 nmの吸光度を測定した。未処理の樹状細胞のみの吸光度を1として規格化した。結果を図3に示す。
(a) R8-MEND及びR8/KALA-MENDの調製
ベクターのコアとして、pDNA溶液、Protamine溶液をそれぞれ、10 mM HEPES bufferで0.1 mg/mLに希釈した。0.1 mg/mL Protamine 150 μLに対し、0.1 mg/mL pDNA 100 μLを攪拌しながら少量ずつ滴下してProtamineとpDNAのコンパクション体を調製した(N/P比=2.2)。脂質膜は、DOPE:CHEMS=9:2となるように、1 mM DOPE 112.5 μL、1 mM CHEMS 25 μLをガラス試験管に加え、全量が200 μLとなるようにCHCl3を加えた後、デシケーターで減圧乾燥し、溶媒を留去して脂質膜を得た。脂質膜に総脂質濃度が0.55 mMとなるようにコンパクション体溶液を添加した後、R8-MENDにおいてはSTR-R8単独を総脂質量の5mol%、、R8/KALA-MENDにおいてはSTR-KALA、STR-R8を総脂質の5 mol%となるようにそれぞれ添加し、室温で10 min静置し水和させた後、ソニケーターで1 min超音波処理した。
トランスフェクション 2日前にJAWS-II細胞を4×105 cells/wellとなるように6 well plateに播種した。細胞をPBS(-)500 μLでwashした後、αMEM(血清なし、抗生物質なし)によって2 μg/mL(プラスミドDNA濃度相当)に希釈したMEND溶液を1 mL細胞に加え、37℃で5% CO2インキュベーター内に静置した。トランスフェクションしてから1、3、及び6時間後に細胞をPBS(-) 500 μLで洗浄し、サンプルごとに合計1 mLとなるようにTRIzol Reagent(invitrogen社)を加えた。Cell scraperで細胞をはがし、エッペンドルフチューブに回収した。1分間 ボルテックスにより混合して-80℃で保存した。mRNAの精製に際し、各サンプルを室温で解凍した後、クロロホルムを200 μL加え、15 秒間 ボルテックスにより混合した。室温で3分間インキュベーションした後、4℃環境下で12,000 rpmで15 min遠心した。上清を他のエッペンドルフチューブに移し、イソプロパノールを500 μL加えた後に室温で10 minインキュベーションした。4℃環境下で12,000 rpm、10 min遠心した後、上清を除き、pelletに75%エタノールを1 mLを加えてボルテックスにより混合し、遠心した(4℃、12,000 rpm、4分間)。上清を除去し、ジエチルピロカーボネート(DEPC)処理水を25 μL加え、10 min インキュベーションし、Nano Drop(Thermo Scientific社)を用い、260 nmにおける吸光度よりRNA量を定量した。
DNAマイクロアレイ実験用のラベル化RNAをQuick Amp Labeling Kit、one-color(Agilent)を用いて添付プロトコルに従い調製した。Total RNA 500 ngから逆転写反応によりcDNAを合成した。次に、cDNAからin vitro転写反応によってCyanine3(Cy3)-CTPでラベルしたcRNAを調製した。未反応のCy3を除去するために、ラベル化cRNAをRNeasy Mini Kitを用いて精製した。得られたCy3ラベル化cRNA溶液について、Nano Dropを用いて濃度とCy3取り込み量を算出し、品質を確認した。
(1)以下の式で、cRNA濃度(ng/μL)を算出した。
cRNA濃度(ng/μL)=OD260×10※×40(μg/mL)
※ NanoDropの光路長は1 mm
(2)以下の式で、Cy3の取り込み量(pmol/μL)を算出した。
Cy3取り込み量(pmol/μL)=(OD550×10※×1000)/(150 mM-1cm-1)
※ NanoDropの光路長は1 mm
(3)以下の式で、Cy3の取り込み効率(pmol/μg)を算出した。
Cy3取り込み効率(pmol/μg)= Cy3取り込み量(pmol/μL)/ cRNA濃度(ng/μL)
全Cy3ラベル化cRNAサンプルに関して、cRNAの収量が1.65 μg以上かつCy3の取り込み効率が9 pmol/μg以上であることを確認した。
マウスオリゴDNAマイクロアレイ(4x44K)へのラベル化cRNAのハイブリダイゼーションは、Gene Expression Hybridization Kitを用いて添付プロトコルに従い実験を行った。ラベル化cRNAをランダムに切断してフラグメント化し、1.65 μgのRNAを使用してハイブリダイゼーション溶液を調製した。マイクロアレイスライドにサンプルをアプライし、65℃、17時間ハイブリダイゼーションを行った後、10% Triton X-102を含むExpression Wash Bufferでスライドを洗浄した。
(1)コントロールスポットの除去
解析ソフトGeneSpring GX11にデータを取り込むと、アレイの四隅を認識させるスポットなどを含むコントロールスポットまで検出するため、これらのスポットの除去を行った。
(2)フラグの除去
スポットの検出時に、形が乱れている、蛍光が飽和している、などシグナルの状況に応じてPresent(P)、Marginal(M)、Absent(A)の3段階のフラグが評価される。(P、M、Aの順に信頼度が低下する)。全サンプル中少なくとも1サンプルでPresentの評価が下された遺伝子を抽出した。
(3)低発現遺伝子の除去
発現レベルの低い遺伝子は、同一サンプル同士の発現レベルもばらつくため、除去を行った。シグナル強度の絶対値であるRaw値が全サンプル中少なくとも1サンプルで、100以上の遺伝子を抽出した。以上のQuality controlを行った後、21995遺伝子を対象として解析を進めた。
(1)抗原封入R8修飾リポソーム、KALA修飾リポソームの調整
ガラス試験管にEPC/Chol/CHEMS(モル比70:20:10)からなる脂質薄膜を調製し、OVA(5 mg/mL, 10 mM HB)を脂質濃度が10 mMとなるように添加後、室温で15分間水和した。水和後、ボルテックスにより混合し15 mLコニカルチューブに移し、凍結融解を5回行った。400 nmのメンブレンフィルターでエクストリュージョンし、超遠心(43,000 rpm, 4℃, 30 min)して上清を除去後、ペレットをHBG 200 μLで静かにすすぎ、適量のHBGに再懸濁した。下記の項にある手順に従い、OVA濃度及び脂質濃度を定量した。実験に使用する前にSTR-R8(10 mg/mL)又はSTR-KALA(10 mg/mL)を脂質モル濃度の7.5%添加し、室温で30分間以上インキュベートすることで、R8-Lip及びKALA-Lipを調製した。R8-Lipの粒子径は189.5 nm、PDIは0.095、ζ電位は47.8 mVであり、KALA-Lipの粒子径は188.4 nm、PDIは0.317、ζ電位は33.7 mVであった。
C57BL/6マウス(雌、7-9週齢)に50 μgのOVAを内封したR8-LipもしくはKALA-Lipを皮下投与した(26G針)。免疫から1週間後に、以下の方法で調製した標的細胞を投与した。頚椎脱臼したnaiveマウスより脾臓を摘出し、RPMI1640培地3〜5 mLの入ったシャーレ中で細胞をほぐし2.5 mLシリンジを用いて回収後、ナイロンメッシュを通して50 mLコニカルチューブに移した。遠心(1600〜1700 rpm、4℃、5分)後、上清を除去し、ACK Lysing buffer(Lonza, Walkersville, MD) 1 mLに懸濁して室温で5 分間インキュベートし溶血した。RPMI1640培地9 mLを添加後遠心し、さらに培地 10 mLで洗浄後、20 mLに懸濁しナイロンメッシュを通して50 mLコニカルチューブ2本に移した。細胞を計数後遠心し、培地に再懸濁した(107 cells/mL)。2本のうち1本にOVA257-264ペプチド(1 mM、終濃度 5 μM)を添加し、この細胞懸濁液を37℃、5% CO2条件下で60分間インキュベートした。培地10 mL及びPBS 10 mLで洗浄後、OVA257-264ペプチドによってパルスした細胞群は5 μM CFSE(Molecular probe) (CFSEHigh) により、パルスしていない細胞群は0.5 μM CFSE (CFESLow)を含むPBSに3×107 cells/mLとなるよう懸濁し、37℃で10分間インキュベーションした。RPMI1640培地10 mLで2回、PBS 10 mLで2回洗浄後、最終的にPBSに懸濁した(5×107 cells/mL)。投与直前に異なる濃度で染色した2種の細胞を等量混合し、免疫したマウスに尾静脈より投与した(1×107 cells/200 μL/mouse、26G針)。
(a)各種プラスミドDNAの調製
以下の4種類のプラスミドDNA:(1)プラスミドDNAのバックボーンにCpG配列を含み、かつマーカー遺伝子であるルシフェラーゼ配列の開始コドンからストップコドンにもCpG配列を有するプラスミドDNA(pcDNA3.1-Luc(+);CpG配列合計425個)、(2)プラスミドDNAのバックボーン及びルシフェラーゼ配列の開始コドンからストップコドンまでの間のいずれにもCpG配列を含まないもの(pCpGfree-Luc(0); CpG配列合計0個)、(3)プラスミドDNAのバックボーンにCpG配列を含み、ルシフェラーゼ配列の開始コドンからストップコドンにはCpG配列を含まないもの(pcDNA3.1-Luc (0);CpG配列合計332個)、及び(4)プラスミドDNAのバックボーンにはCpG配列を含まず、ルシフェラーゼ配列の開始コドンからストップコドンにはCpG配列を含むもの(pCpGfree-Luc(+);CpG配列合計98個)を作成した。
頚椎脱臼したC57BL/6マウス(6〜8週齢)より大腿骨および頸骨を摘出し、70%エタノールで軽く消毒した後、PBSに浸した。骨の両端を切断し、培地入りの1 mLシリンジ(26G針)で骨髄細胞をRPMI1640培地中に押しだした。細胞懸濁液を40 μmのセルストレイナー(FALCON)を通して50 mLコニカルチューブに移した。遠心(450 g、4℃、5分間)後上清を除去し、タッピングして細胞を分散させた後、ACK Lysing Buffer1 mLを添加、混合し、室温で3〜5分間静置した。培地10 mLを添加後、遠心して上清を除去し、さらに培地10 mLで2回洗浄した。次に、細胞を培地10 mLに懸濁し、10 cm細胞培養ディッシュ(FALCON)に添加し、37℃、5% CO2条件下で4時間以上培養した。軽くピペッティングして浮遊細胞のみを50 mLコニカルチューブに回収し、遠心、上清除去後、培地10 mLに懸濁して計数した。1×106 cells/mLとなるよう培地に懸濁し、GM-CSF(終濃度10 ng/mL)を添加後、24 well plate(Corning, NY)に1 mLずつ播種し、37℃、5% CO2条件下で2日間培養した。2日後および4日後に細胞の凝集塊を残し浮遊細胞を除去した後、新しいGM-CSF含有RPMI1640培地1 mLを添加した。GM-CSF存在下で培養開始後6〜8日目の浮遊及び弱付着細胞を未成熟樹状細胞として実験に用いた。CD11c抗体(PE anti-mouse CD11c, Clone: N418, BioLegend)を用いた評価では純度は85〜90%であった。
上記(a)で得られた各種プラスミドDNAを10 mM HEPES緩衝液に0.1 mg/mLとなる様に溶解した。0.1 mg/mL(10 mM HEPES緩衝液)の プロタミン(Protamine)溶液150 μLにpDNA溶液を100μL少量ずつ攪拌しながら滴下し、プロタミンとpDNAのコンパクション体を調製した(N/P比は2.2)。
上記(b)に示す方法により誘導したBMDCを24wellプレートに4×105 cells/wellとなるように播種した。調製したMENDをpDNA量が0.4 μg/well含むようにRPMI 1640(血清なし、抗生物質なし)で希釈し、500 μLとなるように調製した。各wellにMEND溶液をアプライし、37℃、5% CO2環境下でインキュベーションした。3時間後にRPMI 1640(血清、抗生物質有り) 500μLを各wellに添加し、さらに21時間後にルシフェラーゼ活性を測定した。ルシフェラーゼ活性の測定に関して、浮遊している細胞群はメディウムごと回収し、遠心(4℃、500 g、5分間)し、上清を除去することで集めた。各wellに残っている細胞、及び先に回収した浮遊細胞群にReporter Lysis Buffer(1×)を添加して両者を混合した後、合計75 μLにした後、ピペッティングを行い、-80℃で凍結した。-80℃で凍結させたサンプルを解凍させた後、セルスクレーパーを用いて細胞をはがし、エッペンドルフチューブに回収した。回収した細胞溶解液を15,000 rpm、4℃、2分間遠心分離し、その上清50 μLを回収した。得られた上清を用いてルシフェラーゼ活性測定(RLU/mL)を測定した。さらにBCA法によるタンパク定量(mg/mL)行い、単位タンパク質量当たりのルシフェラーゼ活性(RLU/ mg protein)を算出した。
(a)CpGフリーOVA発現プラスミドDNAの調製
CpG配列をすべて除いた抗原(OVA)遺伝子配列を設計し(配列表の配列番号2に示す1161bpのDNA配列)、カスタム合成を行った(TAKARA)。本配列を、pCpGfree-NEWmcsのマルチクローニングサイトのうち、NcoI/NheIサイトにサブクローニングした(pCpGfree-OVA(0))。
例6(b)に記載した方法により単離・分化された樹状細胞を24wellプレートに4×105 cells/wellとなるように播種した。CpGフリーのOVA発現プラスミドDNA(pCpGfree-OVA(0))を用いて調製されたKALA-MENDを例6(c)に記載した方法に従って調製した。MENDをpDNA量が0.4 μg/well含むようにRPMI 1640(血清なし、抗生物質なし)で希釈し、500 μLとなるように調製した。各wellにMEND溶液をアプライし、37℃、5% CO2環境下でインキュベーションした。3時間後にRPMI 1640(血清、抗生物質有り) 500μLを各wellに添加し、さらに21 時間後に細胞を回収した。浮遊している細胞及びPBS中でピペッティングすることによってはがした付着細胞をまとめ、遠心(4℃、500 g、5分間)することで回収した。
抗原(OVA)発現腫瘍細胞(E.G7-OVA細胞)を移植する14日前、7日前に、C57BL/6マウス(雌、8週齢)に(1)DCのアジュバントであるCpGのみを作用させたBMDC、(2)KALA-MENDを用いて非抗原タンパクであるルシフェラーゼを発現させたBMDC、(3)KALA-MENDを用いて抗原タンパク(OVA)を発現させたBMDC、(4)KALA-MENDを用いて抗原タンパク(OVA)を発現させ、かつCpGアジュバントにより活性化したBMDCを4×105 cells/40μL PBSになるように調製し、全量をマウスの足の裏に投与した。2回目の免疫から1週間後に8×105個のE.G7-OVA細胞を左脇腹に移植し、経時的に腫瘍体積を測定した。腫瘍体積(tumor volume (mm3))は長径×短径×短径×0.52の式により算出した。
(a)BMDCへの抗原(OVA)発現プラスミドDNAの遺伝子導入
例6(b)に記載した方法により単離・分化された樹状細胞を24wellプレートに4×105 cells/wellとなるように播種した。CpGフリーのOVA発現プラスミドDNA(pCpGfree-OVA(0))を用いて調製されたKALA-MENDを例6(c)に記載した方法に従って調製した。MENDをpDNA量が0.8 μg/well含むようにRPMI 1640(血清なし、抗生物質なし)で希釈し、500 μLとなるように調製した。各wellにMEND溶液をアプライし、37℃、5% CO2環境下でインキュベーションした。3 時間後にRPMI 1640(血清、抗生物質有り) 500μLを各wellに添加し、さらに21時間後に細胞を回収した。浮遊している細胞及びPBS中でピペッティングすることによってはがした付着細胞をまとめ、遠心(4℃、500 g、5分間)することで回収した。
8×105個の抗原(OVA)発現腫瘍細胞(E.G7-OVA細胞)をC57BL/6マウス(雌、8週齢)の左脇腹に移植して15日目及び22日目に、(1)未処理のBMDC、(2)KALA-MENDを用いて非抗原タンパクであるルシフェラーゼを発現させたBMDC、(3)KALA-MENDを用いて抗原タンパク(OVA)を発現させたBMDCを40μL PBS中に4x 105個のBMDCが入るように懸濁し、足の裏に投与した。経時的に腫瘍体積を測定し、腫瘍体積(tumor volume (mm3))は長径×短径×短径×0.52の式により算出した。
Claims (14)
- 細胞の核内に物質を送達するための脂質膜構造体であって、脂質膜が配列番号1に記載のアミノ酸配列からなるポリペプチドで修飾された脂質膜構造体。
- 脂質膜構造体がリポソームである請求項1に記載の脂質膜構造体。
- 細胞が免疫細胞である請求項1又は2に記載の脂質膜構造体。
- 請求項1に記載のポリペプチドが疎水性基で修飾されており、前記疎水性基が脂質膜に挿入された請求項1ないし3のいずれか1項に記載の脂質膜構造体。
- 連続した複数個のアルギニン残基を含むポリペプチドを表面に有する請求項1ないし4のいずれか1項に記載の脂質膜構造体。
- ポリアルキレングリコールを表面に有する請求項1ないし5のいずれか1項に記載の脂質膜構造体。
- 免疫細胞表面に提示すべき抗原ポリペプチドをコードする核酸を該細胞の核内に導入するために用いる請求項1ないし6のいずれか1項に記載の脂質膜構造体。
- 送達すべき物質が内部に封入された請求項1ないし7のいずれか1項に記載の脂質膜構造体。
- 内部に核酸及びカチオン性ポリマーが封入された請求項8に記載の脂質膜構造体。
- 送達すべき物質が免疫細胞表面に提示すべき抗原ポリペプチドをコードする核酸である請求項8又は9に記載の脂質膜構造体。
- 上記抗原ポリペプチドに対する免疫療法に用いるための請求項10に記載の脂質膜構造体。
- 該核酸がDNAであり、該DNAがCpGを含まないDNAである請求項10又は11に記載の脂質膜構造体。
- 請求項8ないし12のいずれか1項に記載の脂質膜構造体を有効成分として含む医薬組成物。
- 悪性腫瘍の予防及び/又は治療のために用いる請求項13に記載の医薬組成物。
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EP2572706A1 (en) | 2013-03-27 |
US20130122054A1 (en) | 2013-05-16 |
JPWO2011132713A1 (ja) | 2013-07-18 |
US20150202154A1 (en) | 2015-07-23 |
US8981044B2 (en) | 2015-03-17 |
CN103037840A (zh) | 2013-04-10 |
EP2572706A4 (en) | 2014-02-26 |
WO2011132713A1 (ja) | 2011-10-27 |
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