JP5923177B2 - 新規な遺伝子伝達用組成物 - Google Patents
新規な遺伝子伝達用組成物 Download PDFInfo
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- JP5923177B2 JP5923177B2 JP2014540950A JP2014540950A JP5923177B2 JP 5923177 B2 JP5923177 B2 JP 5923177B2 JP 2014540950 A JP2014540950 A JP 2014540950A JP 2014540950 A JP2014540950 A JP 2014540950A JP 5923177 B2 JP5923177 B2 JP 5923177B2
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Description
本発明は、(i)遺伝子、(ii)水溶性キトサン、(iii)チアミンピロリン酸、(iv)プロタミン、および(v)中性または陰イオン性リン脂質を含有する遺伝子伝達用薬学的組成物、およびその製造方法を提供する。
本発明は、(i)遺伝子、(ii)水溶性キトサン、(iii)チアミンピロリン酸、(iv)プロタミン、および(v)中性または陰イオン性リン脂質を含有する遺伝子伝達用薬学的組成物を提供する。また、本発明は、前述した遺伝子伝達用薬学的組成物の製造方法を提供する。
また、本発明の遺伝子伝達用組成物は、保管および流通過程上のナノ粒子の変質または変形を防止する目的で糖類をさらに含有することができる。糖類として、マンノース、グルコース、フルクトース、アラビノース、マンニトール、ソルビトール、スクロース、トレハロース、マルトース、ラクトース、セロビオース、イソマルトース、デキストラン、デキストリン、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン、ヒドロキシプロピル−β−シクロデキストリン、ヒドロキシエチル−β−シクロデキストリン、ジメチル−β−シクロデキストリン、トリメチル−β−シクロデキストリン、およびスルホブチルエーテル−β−シクロデキストリンの中から選ばれた1種以上の糖類が選択できる。
分子量150〜400kDaのキトサンHCl4mg(FMC CL214、FMC社製)、チアミンピロリン酸2mg(Thiamine pyrophosphate、Sigma−Aldrich社製)、プロタミン0.5mg(Protamine sulfate、Alps pharmaceutical社製)をそれぞれ滅菌蒸留水1mlに溶かした溶液を製造し、これらの溶液を0.22μmのフィルターで濾過した。Survivin siRNA遺伝子(バイオニア社製)は滅菌蒸留水を用いて1mg/mlの濃度で製造した。リン脂質としてのLipoid S−100(Lipoid S−100、Lipoid社製)および distearoyl-glycero-phosphoethanolamine-methyl polyethyleneglycol-2000(DSPE−mPEG2000)(Lipoid PE 18:0/18:0−PEG 2000、Lipoid社製)はリン脂質の全量が30mgとなるようにして、エタノール1mlに溶かして、表1に指定された割合に応じて溶解した後、0.22μmのフィルターで濾過した。下記表1の重量比となるようにSurvivin siRNA遺伝子水溶液とプロタミン溶液を混合して前複合体を形成させた後、水溶性キトサン、チアミンピロリン酸およびリン脂質溶液を混合し、ナノ粒子を含有する組成物を製造した。ここで、Survivin siRNAのシークエンスは、センス:5’−AAG GAG AUC AAC AUU UUC A(dTdT)−3’、アンチセンス:5’−UGA AAA UGU UGA UCU CCU U(dTdT)−3’を使用した。
分子量150〜400kDaのキトサンHCl 4mg、チアミンピロリン酸2mg、プロタミン硫酸(Alps Pharmaceutical社製)0.5mgをそれぞれ滅菌蒸留水1mLに溶かした溶液を製造した。これらの溶液を0.22μmのフィルターで濾過した。Gataparsen(survivin antisense)遺伝子(バイオニア社製)は滅菌蒸留水を用いて1mg/mLの濃度で製造した。Lipoid S−100およびDSPE−mPEG2000はリン脂質の全量が30mgとなるようにして、エタノール1mlに溶かして、表3に指定された割合に応じて溶解した後、0.22μmのフィルターで濾過した。下記表3の重量比となるように、Gataparsen(survivin antisense)遺伝子水溶液とプロタミン溶液を混合して前複合体を形成させた後、水溶性キトサン、チアミンピロリン酸およびリン脂質溶液を混合し、ナノ粒子を含有する組成物を製造した。ここで、Gataparsenのシークエンスは、3’−d(P−thio)([2’−O−(2−methoxyethyl)]m5rU−[2’−O−(2−methoxyethyl)]rG−[2’−O−(2−methoxyethyl)]m5rU−[2’−O−(2−methoxyethyl)]rG−m5C−T−A−T−T−m5C−T−G−T−G−[2’−O−(2−methoxyethyl)]rA−[2’−O−(2−methoxyethyl)]rA−[2’−O−(2−methoxyethyl)]m5rU−[2’−O−(2−methoxyethyl)m5rU]−5’を使用した。
分子量150〜400kDaのキトサンHCl 4mg、チアミンピロリン酸2mg、プロタミン硫酸(Alps Pharmaceutical 社製)0.5mgをそれぞれ滅菌蒸留水1mLに溶かした溶液を製造した。これらの溶液を0.22μmのフィルターで濾過した。Survivin siRNA遺伝子は滅菌蒸留水を用いて1mg/mlの濃度で製造した。30mgのLipoid S−100をエタノール1mLに溶かした溶液を製造し、0.22μmのフィルターで濾過した。下記表4の重量比となるように、Survivin siRNA遺伝子水溶液とプロタミン溶液を混合して前複合体を形成させた後、水溶性キトサン、チアミンピロリン酸およびリン脂質溶液を混合することにより、ナノ粒子を含有する組成物を製造した。ここで、survivin siRNAのシークエンスは、実施例1〜4と同様のものを使用した。滅菌蒸留水で、30%の溶液として製造した糖類の賦形剤(トレハロース(Trehalose SG、林原社製)、グルコース)を下記表4の重量比のように混合した。これを−70℃に冷凍させ、凍結乾燥させて固体状の凍結乾燥物を得た。
<比較例1>遺伝子、プロタミン、チアミンピロリン酸およびリン脂質で構成される組成物の製造
組成成分のうちキトサンHClを除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表5のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
組成成分のうちチアミンピロリン酸を除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表6のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
組成成分のうちプロタミンを除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表7のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
組成成分のうちリン脂質を除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表8のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
腫瘍増殖抑制活性を確認するために、組成成分のうちSurvivin siRNA遺伝子の代わりにFL dsRNA(Fluorescein-labeled dsRNA oligomer、Invitrogen社製)遺伝子を使用した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表9のとおりである(単位:μg)。ここで、FL dsRNAのシークエンスは、5’−UUG UUU UGG AGC ACG GAA A(dTdT)−3’を使用した。
組成成分のうちプロタミンとリン脂質を除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成成分の含量は下記表10のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
組成成分のうちチアミンピロリン酸とプロタミンを除外した以外は実施例1と同様の方法で、ナノ粒子を含有する組成物を製造した。その組成は下記表11のとおりである(単位:μg)。これを本発明の遺伝子伝達用組成物(実施例1)との効果対比のための対照群として使用した。
<実験例1>遺伝子伝達用組成物中のナノ粒子形成の確認
前記実施例1で製造された組成物に対してクライオ電子顕微鏡(Tecnai12 electron microscope、Philips社製、オランダ)を用いてナノ粒子形成を観察した。実施例1で製造された組成物を薄い水膜形態でグリッド上に載置した後、−170℃で急速凍結させた。次いで、製造社の説明書に従ってグリッド(grid)上の急速凍結した組成物を電子顕微鏡によって観察した(図1)。
前記実施例1〜4および11で製造された組成物中に形成されたナノ粒子について、粒度分析器および電荷分析器ELS-Z(ectrophoretic Light Scattering Spectrophotometer)(大塚、日本)を用いて直径を測定した。実施例1〜4および11で製造された組成物の粒子径は、製造会社の説明書に従ってparticle size cellを用いて測定された。(図2)。
前記実施例1、3および11で製造された組成物に対して、ELS(Electrophoretic Light Scattering Spectrophotometer)粒度分析器および電荷分析器(ELS−Z、大塚、日本)を用いて表面電荷を測定した。実施例1、3および11で製造した組成物の表面電荷は、製造会社の説明書に従ってzeta potential cellを用いて測定された(図3)。
実験は、survivin ELISA kit(R&D systems、catalog No.SVE00)を用いて標的タンパク質発現について前記実施例1および11と比較例1、2および7の組成物処理群と遺伝子単独処理群の抑制活性について行われた。
前記実施例1、3および11の組成物と比較例2、3、4および6の組成物を同じ体積の血清(Invitrogen社製)と混合した。3時間後にELS(Electrophoretic Light Scattering Spectrophotometer)粒度分析器および電荷分析器(ELS−Z、大塚、日本)を用いて粒子径の変化を測定した。これに関連して、particel size cellはELS製造会社の説明書に従って使用した(図5)。
前記実施例15、16および17で製造された遺伝子伝達用組成物の凍結乾燥物を遺伝子として100μg/mLとなるように精製水で再分散させた後、ELS(Electrophoretic Light Scattering Spectrophotometer)粒度分析器および電荷分析器(ELS−Z、大塚、日本)を用いて粒子径を観察した。これに関連して、particle size cellは、製造会社の説明書に従って使用した(図6)。
前記実施例1の組成物および比較例5および7の組成物の生体内における遺伝子薬物伝達能を評価するために、前立腺癌が移植された免疫不全マウスモデルを使用した。これに関連して、RPMI培養液50μLに再分散した前立腺癌細胞株2×106個をマトリゲル(Matrigel、BD biosciences)50μLと混合し、これを5週齢の免疫不全雄マウスの皮下に注射した。腫瘍サイズを100mm3まで増大させた後、3グループのマウスに対して(グループ当たり8匹)、それぞれ遺伝子量が100μg/mLとなるように実施例1の組成物、比較例5および7の組成物をマウスの尾静脈に注射した。対照群には組成物を投与しなかった(無処理群)。1回に投与される各遺伝子薬物は40μgであり、2週間で合計6回投与した。腫瘍サイズはカリパースを用いて腫瘍中部の幅(短い方)と長さ(長い方)を測定した後、下記の公式で算出した(Biomaterials, 2011; 32: 9786-9795)。
Claims (12)
- (i)遺伝子、(ii)水溶性キトサン、(iii)チアミンピロリン酸またはその薬学的に許容される塩、(iv)プロタミンまたはその薬学的に許容される塩、および(v)中性または陰イオン性リン脂質を含有する、遺伝子伝達用薬学的組成物であって、
遺伝子100重量部に対して、水溶性キトサン43〜1,710重量部、チアミンピロリン酸7〜290重量部、プロタミン20〜500重量部、および中性または陰イオン性リン脂質600〜3,200重量部を含有し、ならびに
粒子径が10〜300nmであり、かつ陽イオン性の表面電荷を有するナノ粒子を含有する組成物。 - 遺伝子100重量部に対して、水溶性キトサン1,710重量部、チアミンピロリン酸290重量部、プロタミン60重量部、および中性または陰イオン性リン脂質3,200重量部を含有する、請求項1に記載の薬学的組成物。
- 遺伝子100重量部に対して、水溶性キトサン860重量部、チアミンピロリン酸290重量部、プロタミン500重量部、および中性または陰イオン性リン脂質3,200重量部を含有する、請求項1に記載の薬学的組成物。
- 遺伝子100重量部に対して、水溶性キトサン170重量部、チアミンピロリン酸30重量部、プロタミン20重量部、および中性または陰イオン性リン脂質1,200重量部を含有する、請求項1に記載の薬学的組成物。
- 遺伝子100重量部に対して、水溶性キトサン43重量部、チアミンピロリン酸7重量部、プロタミン20重量部、および中性または陰イオン性リン脂質600重量部を含有する、請求項1に記載の薬学的組成物。
- 水溶性キトサンが、キトサンHCl、キトサン酢酸塩、キトサングルタミン酸塩、またはキトサン乳酸塩の中から選ばれる、請求項1〜5のいずれか1項に記載の薬学的組成物。
- プロタミンの薬学的に許容される塩が、プロタミン塩酸塩またはプロタミン硫酸塩である、請求項1〜5のいずれか1項に記載の薬学的組成物。
- 中性または陰イオン性リン脂質が、非極性尾部として、炭素数4〜30の飽和または不飽和アルキルエステル基を有し、極性頭部として、ホスファチジルコリン(phosphatidylcholine)、ホスファチジルエタノールアミン(phosphatidylethanolamine)、ホスファチジルセリン(phosphatidylserine)、ホスファチジルグリセリン(phosphatidylglycerine)、ホスファチジルイノシトール(phosphatidylinositol)、ホスファチジン酸(phosphatidic acid)、スフィンゴミエリン(sphingomyelin)、ホスファチジルコリン−N−メトキシポリエチレングリコール、ホスファチジルエタノールアミン−N−メトキシポリエチレングリコール、ホスファチジルセリン−N−メトキシポリエチレングリコール、ホスファチジン酸メトキシポリエチレングリコール、およびこれらの混合物の中から選ばれる極性頭部を有する、請求項1〜5のいずれか1項に記載の薬学的組成物。
- 遺伝子が、一本鎖または二本鎖DNA、一本鎖または二本鎖RNA、プラスミド型DNA、一本鎖または二本鎖siRNA、アンチセンスオリゴヌクレオチド、リボザイム、触媒的RNAまたはヌクレオチドの中から選ばれる、請求項1〜5のいずれか1項に記載の薬学的組成物。
- マンノース、グルコース、フルクトース、アラビノース、マンニトール、ソルビトール、スクロース、トレハロース、マルトース、ラクトース、セロビオース、イソマルトース、デキストラン、デキストリン、α−シクロデキストリン、β−シクロデキストリン、γ−シクロデキストリン、ヒドロキシプロピル−β−シクロデキストリン、ヒドロキシエチル−β−シクロデキストリン、ジメチル−β−シクロデキストリン、トリメチル−β−シクロデキストリン、およびスルホブチルエーテル−β−シクロデキストリンの中から選ばれる1種以上の糖類をさらに含有する、請求項1〜9のいずれか1項に記載の薬学的組成物。
- 安定化剤、緩衝剤、保存剤、無痛化剤、または等張化剤の中から選ばれる1種以上をさらに含有する、請求項1〜9のいずれか1項に記載の薬学的組成物。
- 注射剤、点滴溶剤、吸入剤、または凍結乾燥形態に剤形化された、請求項1〜9のいずれか1項に記載の薬学的組成物。
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PCT/KR2012/009443 WO2013070010A1 (en) | 2011-11-10 | 2012-11-09 | Novel composition for gene delivery |
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US9493430B2 (en) | 2013-01-31 | 2016-11-15 | Chong Kun Dang Pharmaceutical Corp. | Biaryl- or heterocyclic biaryl-substituted cyclohexene derivative compounds as CETP inhibitors |
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CL2014003514A1 (es) * | 2014-12-23 | 2015-05-08 | Univ De Concepción | Nanopartículas a base de quitosano para el transporte de péptidos con actividad en el sistema nervioso central. |
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US11767520B2 (en) | 2017-04-20 | 2023-09-26 | Atyr Pharma, Inc. | Compositions and methods for treating lung inflammation |
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US9173853B2 (en) | 2015-11-03 |
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