JP6902235B2 - 核酸の送達のためのリポソーム製剤 - Google Patents
核酸の送達のためのリポソーム製剤 Download PDFInfo
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- JP6902235B2 JP6902235B2 JP2020018811A JP2020018811A JP6902235B2 JP 6902235 B2 JP6902235 B2 JP 6902235B2 JP 2020018811 A JP2020018811 A JP 2020018811A JP 2020018811 A JP2020018811 A JP 2020018811A JP 6902235 B2 JP6902235 B2 JP 6902235B2
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Description
を含む、リポソームを提供する。
組成物を提供する。
a)有機溶媒中で、カチオン性脂質、膜安定化脂質、およびリン脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を形成するステップと、
b)ステップa)の脂質混合物に核酸を含む水溶液を導入するステップによりリポソームを作製するステップと、
c)上記混合物に活性化したグリコサミノグリカンを添加するステップと
を含む、方法を提供する。
a)脂質相を形成するステップであって、
i)有機溶媒中、カチオン性脂質、膜安定化脂質、および脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を形成するステップと、
ii)緩衝液に脂質混合物を懸濁して多層小胞を作製するステップと
を含む、ステップと、
b)
i)上記核酸とともに、ステップa)の脂質相をインキュベートすることと、
ii)上記混合物に活性化グリコサミノグリカンを添加するステップと
により、リポソームを作製するステップと
を含む、方法を提供する。
a)脂質相を形成するステップであって、
i)有機溶媒中に、カチオン性脂質、膜安定化物質、および脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を形成するステップと、
ii)緩衝液に上記脂質混合物を懸濁して多層小胞を作製するステップと
を含むステップと、
b)
i)上記核酸とステップa)の脂質相をインキュベートするステップと、
ii)上記混合物に活性化グリコサミノグリカンを添加するステップと
によりリポソームを作製するステップと
を含む、方法を提供する。
本発明の理解を容易にするために、多くの用語および文言を以下に定義する。これらの用語および文言は説明の目的のためのものであり、限定するものではなく、このため、当業者は、本明細書の用語法および表現を、当業者の知識と合わせて、本明細書に提示される教示及び指針に照らして解釈すべきであると理解される。
標的部位は、限定するものではないが、細胞、組織、臓器、微生物などのいずれかの標的部位を含み得る。標的部位は、in vivoまたはin vitroの標的部位であり得る。
a)有機溶媒中、カチオン性脂質、膜安定化物質、およびリン脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を形成するステップを含む脂質相を形成するステップと、
b)ステップa)の脂質混合物に核酸水溶液を導入するステップによりリポソームを作製するステップと、
c)上記混合物に活性化グリコサミノグリカンを添加するステップと
のうちの1つまたは複数を含む、方法を提供する。
a)脂質相を形成するステップであって、
i)有機溶媒中、カチオン性脂質、膜安定化脂質、および脂質に結合したPEG―アミンを望ましい比率で混合し、脂質混合物を形成するステップと、
ii)緩衝液に脂質混合物を懸濁して多層小胞を作製するステップと
を含むステップと、
b)
i)酸性緩衝液にグリコサミノグリカンを溶解し、架橋剤を添加して、活性化グリコサミノグリカンを形成することを含む、グリコサミノグリカンの活性化のステップと、
c)
i)核酸とともにステップa)の脂質相をインキュベート/混合/懸濁するステップと、
ii)上記混合物に、上記活性化グリコサミノグリカンを添加するステップと
によりリポソームを作製するステップと
のうちの1つまたは複数を含む、方法を提供する。
実施例1−siRNAを被包するカチオン性リポソームの調製
カチオン性脂質の調製
3種類のカチオン性脂質を合成した:脂質のpKaが6.7(KC2およびMC3)ならびに6.8(DLinDMA)であるDLinDMA、DLin−MC3−DMA、およびDLin−KC2−DMA。カチオン性脂質を、本質的に図1に要約した通りに合成した。
ジリノレイルケトンの合成:CH2Cl2 100ml中ジリノレイルメタノール(2.0g、3.8mmol)および無水炭酸ナトリウム(0.2g)の混合物に、ピリジニウムクロロクロマート(PCC、2.0g、9.5mmol)を添加した。得られた懸濁物を室温で60分間攪拌した。次に、エーテル(300ml)を混合物に添加し、得られた褐色の懸濁物を、シリカゲル(300ml)のパッドを介してろ過した。シリカゲルパッドをエーテル(3×200ml)でさらに洗浄した。エーテルろ過物および洗浄水を合わせた。溶媒を蒸発させて、粗製生成物として油状の残渣3.0gを得た。粗製生成物を、ヘキサン中0〜3%のエーテルで溶出したシリカゲル(230〜400メッシュ、250ml)でのカラムクロマトグラフィーにより精製した。これにより、ジリノレイルケトン1.8g(90%)を得た。
2,2−ジリノレイル−4−(2−ヒドロキシエチル)−[1,3]‐ジオキソランの合成:トルエン50ml中のジリノレイルケトン(527mg、1.0mmol);1,2,4−ブタントリオール(工業等級、約90%、236mg、2mmol);およびピリジニウム p−トルエンスルホナート(50mg、0.2mmol)の混合物を、ディーン・スターク管を用いて窒素下で一晩還流して水を除去した。結果として得られる混合物を室温に冷却した。有機相を水(2×30ml)、次に鹹水(50ml)で洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させて、帯黄色の油状残渣(0.6g)を得た。粗製生成物を、溶離液としてのジクロロメタンを含むシリカゲル(230〜400メッシュ、100ml)でのカラムクロマトグラフィーにより精製した。これにより、純粋な2,2−ジリノレイル−4−(2−ヒドロキシエチル)−[1,3]−ジオキソラン0.5gを得た。2,2−ジリノレイル−4−(2−メタンスルホニルエチル)−[1,3]‐ジオキソランの合成:無水CH2Cl 250ml中に1(500mg、0.81mmmol)の無水トリエチルアミン(218mg、2.8mmol)の溶液に、窒素下でメタンスルホニル無水物(290mg、1.6mmol)を添加した。得られた混合物を室温で一晩攪拌した。混合物をCH2C12 25mlで希釈した。有機相を水(2×30ml)、次に鹹水(50ml)で洗浄し、無水Na2SO4で乾燥させた。溶媒を蒸発させ、帯黄色の油510mgを得た。粗製生成物(2,2−ジリノレイル−4−(2−メタンスルホニルエチル)−[1,3]−ジオキソラン)を、さらなる精製を行うことなく以下のステップに使用した。上記の粗製生成物に、窒素下で、THF中のジメチルアミン20ml(2.0M)を添加した。得られた混合物を室温で6日間攪拌した。油状残渣を、溶媒を蒸発して得た。溶離液としてのジクロロメタン中0〜5%のメタノール勾配を用いたシリカゲル(230〜400メッシュ、100ml)でのカラムクロマトグラフィーから、薄色の油として生成物DLin−KC2−DMA380mgを得た。
以下の製剤(脂質相組成物)を、100%エタノール中で調製した:
1.DLinDMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol/mol 40:40:18:1.5:0.5)
2.DLinDMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol/mol 40:40:15:3:2)
3.DLin−MC3−DMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol/mol 40:40:18:1.5:0.5).
4.DLin−MC3−DMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol mol 40:40:15:3:2).
5.DLin−KC2−DMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol/mol 40:40:18:1.5:0.5).
6.DLinKC2−DMA/Chol/DSPC/DMG−PEG/PE−PEG−アミン(mol/mol 40:40:15:3:2)。
(Chol=コレステロール;DSPC=1,2−ジステアロイル−sn−グリセロ−3−ホスホコリン;DMG−PEG=1,2−ジミリストイル−sn−グリセロール、メトキシポリエチレングリコール;PE−PEG−アミン 1,2−ジステアロイル−sn−グリセロ−3−エタノールホスホエタノールアミン−N−[アミノ(ポリエチレングリコール)]
低分子量および高分子量の大きさのHA(LifeCore)を結合に使用した
低MW HA 5kDaまたは7Kda
高MW HA −800KDa
siRNA捕捉効率のアッセイ
siRNA被包の効率を、以前に報告された(Landeman−Milo et al. 2012 Cancer Letters and Peer D. et al. Science 2008)Quant−iT RiboGreen RNAアッセイ(Invitrogen)により決定した。簡潔に述べると、捕捉効率を、TritonX−100の存在下および非存在下で、異なる製剤試料においてRNA結合色素RiboGreenの蛍光を比較することにより決定した。界面活性剤の非存在下では、蛍光を、利用可能な(捕捉されていない)siRNAのみから測定することができる。対して、界面活性剤の存在下では、蛍光は総siRNAから測定され、よって、捕捉(%)は、式:siRNAの捕捉(%)=[1−(遊離siRNA濃度/総siRNA濃度)]×100により表される。
材料および方法:
細胞株:
CD44を発現するヒトの肺腺癌細胞(A549)およびCD44を欠いているヒトの前立腺癌(LnCap)細胞(フローサイトメトリーによる)を、American Type Culture Collection(ATCC)から購入した。ATCCにより推奨されるように、15%のFBSおよび1%の抗生剤を補充したRPMI−1640で細胞を増殖させた。
2つの平均値間の差異を、対応のない両側スチューデントt検定を使用して試験した。治療グループ間の差異を、SPSSソフトウェアの一元配置分散分析により評価した。カプランマイヤー生存解析を、GraphPad Prism version 5.0bを用いて行った。
A549細胞(ヒトの肺腺癌細胞(3×106個の細胞)を、HBSS(biological industries, Israel)で3回洗浄した後に、ヌードマウス(Nu/Nu)の大腿関節の上に移植して、A459腫瘍モデルを確立した。
材料および方法
細胞株:ヒトの神経膠芽腫細胞株、T98G、U251、およびU87MG(WHOグレードIV)を、GBMのモデル細胞として使用した。選択した細胞株は、異なる遺伝的病変のスペクトラムを表す。すべての細胞株を、単層で増殖させ、10%のウシ胎仔血清、1%のペニシリン/ストレプトマイシン、および2mMLのグルタミン(Biological Industries)を補充した高グルコース(4.5g/l)のダルベッコ改変イーグル培地(DMEM)に維持した。細胞を、5%CO2、37℃でインキュベートし、週に2回継代培養した。
神経膠芽腫細胞は、化学療法に耐性があることが知られている。化学療法に対するU87MG細胞の耐性を検証するために、2つの従来の化学療法剤(すなわちドキソルビシン(DOX)および1,3−ビス(2−クロロエチル)−l−ニトロソウレア(BCNU))を、細胞に及ぼす効果に関して試験した。
材料および方法
U87MG同所性GBMモデルの確立:細胞を、10%のウシ血清を補充したダルベッコ改変イーグル培地に維持し、5%の二酸化炭素/95%の空気を含む加湿した大気中、37℃でインキュベートした。移植の日に、単層の細胞培養物を、0.05%のトリプシン/エチレンジアミン(ethylene ediamine)テトラ酢酸溶液を使用して回収した。細胞を計測し、PBS3μlに再懸濁した。5×105個のU87MG細胞を、各動物に3μl容量で注射した。
それぞれが〜20gの4〜6週齢の雌性ヌードマウス(系統nu/nu)をこの試験に使用した。すべての手法を、Sheba Medical Centerの動物実験委員会(Animal Care and Use Committee)の規則に従って行った。マウスを、標準化された隔離施設内のケージに1群5匹で収容し、23℃の12時間の明/暗周期に維持した。動物には実験動物飼料および水を自由に与えた。すべての器具を、取り扱う前に滅菌し、小動物用の無菌的外科技術を使用した。外科手術の時間までマウスに餌を与えた。0.15mg/10g体重の用量でのケタミン/キシラジン溶液(生理食塩水17ml中200mgのケタミンおよび20mgのキシラジン)の腹腔内注射により、動物に麻酔をかけた。
材料および方法
脳組織からの単細胞浮遊液の調製:製造社のプロトコルに従ってGentleMACS Dissociatorおよび神経組織分離キット(Miltenyi Biotech)を使用した酵素分解により、神経組織を単細胞浮遊液に解離させた。簡潔に述べると、HBSSまたはPBSのいずれかを用いてマウスを灌流し、脳を摘出し、組織量に対する緩衝液および酵素ミクスを調節するために重量を測定した。あらかじめ温めた酵素混合物を組織に添加し、37℃で攪拌しながらインキュベートした。組織を機械的に解離させて、浮遊液を70μmのろ過器に適用した。フローサイトメトリー解析に干渉する可能性があるため、ミエリンを、ミエリン除去ビーズII(Miltenyi Biotech)を使用して除去した。直ちに細胞を処理し、抗ヒトCD44v6−FITC(マウスと非交差反応性、クローンMCA1730F, Bio−Rad)で染色して、U87MG細胞を同定した。細胞を氷中で30分間インキュベートし、次に2回洗浄し、FACSAria III(BD)を使用してFACSソーティングを行った。ソーティングした細胞を、EzRNA RNA精製キット(Biological industries, Beit Haemek, Israel)に直接移動させ、上述のQPCRを使用してPLK1 mRNAレベルに関して解析した。
Claims (13)
- a)カチオン性脂質、膜安定化脂質、およびリン脂質に結合したPEG−アミンを含む脂質膜と、
b)前記リポソーム内に被包された核酸と、
c)600〜1000KDの範囲の分子量を有するヒアルロン酸であって、前記PEG−アミンに結合しているヒアルロン酸と、
を含む、核酸を送達するためのリポソームであって、
前記ヒアルロン酸は、リポソームの外部表面をコーティングしている、
リポソーム。 - 前記カチオン性脂質が、DLinDMA、DLin−MC3−DMAおよびDLin−KC2−DMA;モノカチオン性脂質 N−[1−(2,3−ジオレオイルオキシ)]−N,N,N−トリメチルアンモニウムプロパン(DOTAP)、BCAT O−(2R−1,2−ジ−O−(1’Z,9’Z−オクタデカジエニル−グリセロール)−3−N−(ビス−2−アミノエチル)−カルバメート、BGSC(ビス−グアニジニウム−スペルミジン−コレステロール)、BGTC(ビス−グアニジニウム−トレン−コレステロール)、CDAN(N’−コレステリルオキシカルボニル−3,7−ジアザノナン−1,9−ジアミン)、CHDTAEA(コレステリルヘミジチオジグリコリルトリス(アミノ(エチル)アミン)、DCAT(O−(1,2−ジ−O−(9’Z−オクタデカニル)−グリセロール)−3−N−(ビス−2−アミノエチル)−カルバメート)、DC−Chol(3β[Ν−(Ν’,Ν’−ジメチルアミノエタン)−カルバモイル]コレステロール)、DLKD(Ο,Ο’−ジラウリル N−リジルアスパルテート)、DMKD(Ο,Ο’−ジミリスチル N−リジルアスパルテート)、DOG(ジオレイル(diolcyl)グリセロール、DOGS(ジオクタデシルアミドグリシルスペルミン)、DOGSDSO(1,2−ジオレオイル−sn−グリセロ−3−スクシニル−2−ヒドロキシエチルジスルフィドオルニチン)、DOPC(1,2−ジオレオイル−sn−グリセロ−3−ホスホコリン)、DOPE(1,2−ジオレオイル−sn−グリセロール−3−ホスホエタノールアミン、DOSN(ジオレイルスクシニルエチルチオネオマイシン)、DOSP(ジオレイルスクシニルパロモマイシン)、DOST(ジオレイルスクシニルトブラマイシン)、DOTAP(1,2−ウイオコイル(Uiolcoyl)−3−トリメチルアンモニオプロパン)、DOTMA(N’[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(trimethvlammonium chloride))、DPPES(ジ−パルミトイルホスファチジルエタノールアミドスペルミン(sperminc))、DDABおよびDODAPからなる群から選択される、または、
前記膜安定化脂質が、コレステロール、リン脂質、セファリン、スフィンゴ脂質、およびグリセロ糖脂質からなる群から選択される、または、
リポソームが、1,2−ジラウロイル−L−ホスファチジルエタノールアミン(DLPE)、1,2−ジオレオイル−sn−グリセロ−3−ホスホエタノールアミン(DOPE)1,2−ジフィタノイル−sn−グリセロ−3−ホスホエタノールアミン(DPhPE)1,3−ジパルミトイル−sn−グリセロ−2−ホスホエタノールアミン(1,3−DPPE)1−パルミトイル−3−オレオイル−sn−グリセロ−2−ホスホエタノールアミン(1,3−POPE)、ビオチン−ホスファチジルエタノールアミン、1,2−ジミリストイル−sn−グリセロ−3−ホスホエタノールアミン(DMPE)、1,2−ジステアロイル−sn−グリセロ−3−ホスホエタノールアミン(DSPE)、およびジパルミトイルホスファチジルエタノールアミン(DPPE)からなる群から選択されるホスファチジルアミンをさらに含む、または、
リポソームが、DMG−PEG、PEG−cDMA、3−N−(−メトキシポリ(エチレングリコール)2000)カルバモイル−1,2−ジミリスチルオキシ−プロピルアミン;PEG−cDSA、3−N−(−メトキシポリ(エチレングリコール)2000)カルバモイル−1,2−ジステアリルオキシ−プロピルアミン、およびそれらの組み合わせからなる群から選択される1つまたは複数の追加的なPEG誘導体をさらに含む、または、
前記核酸が、DNA、RNA、およびそれらの修飾形態からなる群から選択され、前記RNAが、siRNA、miRNA、shRNA、アンチセンスRNA、mRNA、修飾されたRNA、およびそれらの組み合わせからなる群から選択される、または、
リポソームが、50nm〜300nmの直径を有する、
請求項1に記載のリポソーム。 - 前記脂質膜が、
DLinDMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン;
DLinMC3−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン;
DLin−KC2−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン;または
DLinMC3−DMA、コレステロール、DSPC、DMG−PEG及びDCPE−PEG−アミン;
を含む、請求項1に記載のリポソーム。 - 前記脂質膜が、
DLinDMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:18:1.5:0.5);
DLinDMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:15:3:2);
DLinMC3−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:18:1.5:0.5);
DLinMC3−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:15:3:2);
DLin−KC2−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:18:1.5:0.5);または
DLin−KC2−DMA、コレステロール、DSPC、DMG−PEG及びPE−PEG−アミン(mol/mol 40:40:15:3:2);
を含む、請求項1に記載のリポソーム。 - 請求項1に記載のリポソームを複数含む組成物。
- 前記リポソームが、標的部位に核酸を送達でき、前記標的部位が、細胞、組織、臓器、および微生物からなる群から選択され、前記標的細胞が、CD44受容体を有する、請求項5に記載の組成物。
- 局所投与または経口、非経口、および局所からなる群から選択される経路を介した投与に適した剤形の、請求項5に記載の組成物を含む医薬組成物。
- 癌の治療用の請求項7に記載の医薬組成物。
- 前記癌が、腺癌および多形膠芽細胞腫(GBM)からなる群から選択される、請求項8に記載の医薬組成物。
- 核酸の送達のためのヒアルロン酸でコーティングされたリポソームの調製のための方法であって、前記方法が、
a)有機溶媒中で、カチオン性脂質、膜安定化脂質、およびリン脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を得るステップと、
b)ステップa)の脂質混合物に、核酸を含む水溶液を導入するステップにより、リポソームを作製するステップと、
c)前記混合物に600〜1000KDの範囲の分子量を有するヒアルロン酸を添加するステップと
を含む、方法。 - 前記脂質の粒子が、50nm〜300nmの直径を有する、または、
前記カチオン性脂質が、DLinDMA、DLin−MC3−DMAおよびDLin−KC2−DMA;モノカチオン性脂質 N−[1−(2,3−ジオレオイルオキシ)]−N,N,N−トリメチルアンモニウムプロパン(DOTAP)、BCAT O−(2R−1,2−ジ−O−(1’Z,9’Z−オクタデカジエニル−グリセロール)−3−N−(ビス−2−アミノエチル)−カルバメート、BGSC(ビス−グアニジニウム−スペルミジン−コレステロール)、BGTC(ビス−グアニジニウム−トレン−コレステロール)、CDAN(N’−コレステリルオキシカルボニル−3,7−ジアザノナン−1,9−ジアミン)、CHDTAEA(コレステリルヘミジチオジグリコリルトリス(アミノ(エチル)アミン)、DCAT(O−(1,2−ジ−O−(9’Z−オクタデカニル)−グリセロール)−3−N−(ビス−2−アミノエチル)−カルバメート)、DC−Chol(3β[Ν−(Ν’,Ν’−ジメチルアミノエタン)−カルバモイル]コレステロール)、DLKD(Ο,Ο’−ジラウリル N−リジルアスパルテート)、DMKD(Ο,Ο’−ジミリスチル N−リジルアスパルテート)、DOG(ジオレイル(diolcyl)グリセロール、DOGS(ジオクタデシルアミドグリシルスペルミン)、DOGSDSO(1,2−ジオレオイル−sn−グリセロ−3−スクシニル−2−ヒドロキシエチルジスルフィドオルニチン)、DOPC(1,2−ジオレオイル−sn−グリセロ−3−ホスホコリン)、DOPE(1,2−ジオレオイル−sn−グリセロール−3−ホスホエタノールアミン、DOSN(ジオレイルスクシニルエチルチオネオマイシン)、DOSP(ジオレイルスクシニルパロモマイシン)、DOST(ジオレイルスクシニルトブラマイシン)、DOTAP(1,2−ウイオコイル(Uiolcoyl)−3−トリメチルアンモニオプロパン)、DOTMA(N’[1−(2,3−ジオレイルオキシ)プロピル]−N,N,N−トリメチルアンモニウムクロリド(trimethvlammonium chloride))、DPPES(ジ−パルミトイルホスファチジルエタノールアミドスペルミン(sperminc))、DDABおよびDODAPからなる群から選択される、または、
前記膜安定化脂質が、コレステロール、リン脂質、セファリン、スフィンゴ脂質、およびグリセロ糖脂質からなる群から選択される、または、
前記方法が、ホスファチジルアミンを混合することをさらに含み、前記ホスファチジルアミンが、1,2−ジラウロイル−L−ホスファチジルエタノールアミン(DLPE)、1,2−ジオレオイル−sn−グリセロ−3−ホスホエタノールアミン(DOPE)1,2−ジフィタノイル−sn−グリセロ−3−ホスホエタノールアミン(DPhPE)1,3−ジパルミトイル−sn−グリセロ−2−ホスホエタノールアミン(1,3−DPPE)1−パルミトイル−3−オレオイル−sn−グリセロ−2−ホスホエタノールアミン(1,3−POPE)、ビオチン−ホスファチジルエタノールアミン、1,2−ジミリストイル−sn−グリセロ−3−ホスホエタノールアミン(DMPE)、1,2−ジステアロイル−sn−グリセロ−3−ホスホエタノールアミン(DSPE)、およびジパルミトイルホスファチジルエタノールアミン(DPPE)から選択される、または、
前記方法が、1つまたは複数の追加的なPEG誘導体を混合することをさらに含み、前記追加的なPEG誘導体が、DMG−PEG、PEG−cDMA、3−N−(−メトキシポリ(エチレングリコール)2000)カルバモイル1,2−ジミリスチルオキシ−プロピルアミン;PEG−cDSA、3−N−(−メトキシポリ(エチレングリコール)2000)カルバモイル−1,2−ジステアリルオキシ−プロピルアミン、およびそれらの組み合わせからなる群から選択される、請求項10に記載の方法。 - 酸性緩衝液にヒアルロン酸を溶解し、架橋剤を添加することにより、前記ヒアルロン酸を活性化して、活性化ヒアルロン酸を形成する、または、
前記核酸が、DNA、RNA、それらの修飾形態、およびそれらの組み合わせからなる群から選択され、前記RNAが、siRNA、miRNA、shRNA、アンチセンスRNA、mRNA、修飾されたRNA、およびそれらの組み合わせからなる群から選択される、または、
前記核酸が酸性緩衝液中にある、
請求項10に記載の方法。 - 核酸の送達のための、ヒアルロン酸でコーティングされたリポソームの調製のための方法であって、
a)脂質相を形成するステップであって、
i)有機溶媒中、カチオン性脂質、膜安定化脂質、および脂質に結合したPEG−アミンを望ましい比率で混合し、脂質混合物を形成するステップと、
ii)緩衝液に前記脂質混合物を懸濁して多層小胞を作製するステップと
を含む、ステップと、
b)
i)前記核酸とともに、ステップa)の脂質相をインキュベートするステップと、
ii)前記混合物に600〜1000KDの範囲の分子量を有するヒアルロン酸を添加するステップと
により、前記リポソームを作製するステップと
を含む、方法。
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IL249727A0 (en) | 2017-02-28 |
US10583084B2 (en) | 2020-03-10 |
JP2020079287A (ja) | 2020-05-28 |
EP3160448A4 (en) | 2018-11-14 |
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WO2015198326A1 (en) | 2015-12-30 |
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