JP6522340B2 - 治療薬を脳腫瘍に送達するための細菌由来のインタクトなミニセル - Google Patents
治療薬を脳腫瘍に送達するための細菌由来のインタクトなミニセル Download PDFInfo
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- JP6522340B2 JP6522340B2 JP2014546670A JP2014546670A JP6522340B2 JP 6522340 B2 JP6522340 B2 JP 6522340B2 JP 2014546670 A JP2014546670 A JP 2014546670A JP 2014546670 A JP2014546670 A JP 2014546670A JP 6522340 B2 JP6522340 B2 JP 6522340B2
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Description
・BBBを横切る輸送体を有する化合物に治療薬を連結する企て(Bickelら、2001;ZhangおよびPardridge、2007)
・脳腫瘍中におよび周辺への薬物の直接投与(Hassenbuschら、2002;Hauら、2002;Reardonら、2002;Weberら、2002)。この手法は腫瘍切除床を囲む薬物充填ウエハーの設置、腫瘍切除腔の中もしくは周りへの薬剤の注入、または腫瘍本体中への薬物の直接注入を必要とする。
本開示は脳腫瘍を治療する組成物および方法を提供する。この点について、本発明者らは、1種以上の抗新生物剤を充填したインタクトな、細菌由来のミニセルを全身投与すると、治療上有効な濃度で脳腫瘍のミクロ環境に速やかに蓄積することを発見した。この発見は驚くべきことであった、何故なら、直径およそ400nmのミニセルは、通常の解釈が血液脳関門(BBB)を通過できる粒子の上限とする12nmより遥かに大きいからである(Sarinら(2008)およびLaquintanaら(2009)を参照されたい)。
特に断らない限り、本明細書で用いる全ての技術的および化学的用語は、関連業者が通常解釈しているのと同じ意味を有する。
本発明の開示は、本発明者らの発見を踏まえて、直径約400nmである細菌由来のインタクトなミニセルが静脈内(i.v.)投与時に治療上有意な濃度で脳腫瘍ミクロ環境に速やかに蓄積するという実験的確証に反映されかつ実証される。本発明者らはまた、この脳腫瘍貫入は、ナノ粒子が脳腫瘍ミクロ環境中へ進入する機構として提案されているBBB内皮エンドサイトーシス/経細胞輸送または他のいずれの機構にも頼らないことを発見した。それ故に、これらの発見は通常知識の視点から全く予期しないことであった。
ナノ粒子はBBBを通って薬物を運ぶための可能な担体であると考えられている(Juillerat-Jeanneret、2008)。これに関する実例はナノ粒子送達戦略であり、この戦略はナノ粒子の、BBBを含む内皮細胞の内腔中の受容体との結合、続いてエンドサイトーシスおよび内皮細胞を横切る脳腫瘍ミクロ環境中への経細胞輸送によるナノ粒子薬物送達による克服を目指す。他の手法は、以下に考察した「浸透と保持効果の増強」を利用して、BBBの内皮細胞間の細かいギャップを通って粒子の経路を達成することである。
ポリソルベート80(Tween(登録商標)80)でコートしたポリブチルシアノアクリレート(PBCA)ナノ粒子は、遊離型ではBBBを横切らないいくつもの薬物の脳送達を可能にすることが示された(Kreuterら、1995、1997、2001、2002、2003、および2008;Steinigerら、2004)。
最近の確証は、悪性神経膠腫微小血管系のBBB孔径の生理学的上限はわずか約12nmであることを示している(Sarinら、2008)。さらに、分子がBBBに見出される孔を横切るには<400ダルトンまで小さい必要があることが示されている(Bickel、2005;Pardridge、2007)。
脳取込みは、BBBに加えてさらに、脳毛細管内皮細胞内の窓およびピノサイトーシス小胞の相対的な不足により、ならびに周囲の細胞外マトリックス、周皮細胞、および星状膠細胞足突起の存在により制限を受ける(HawkinsおよびDavis、2005)。さらに、BBBは通常、薬物を脳外へ動かす多数の薬物輸送タンパク質の所為で薬物および高分子に不浸透性であるとみなされる。
記載したように、本開示のミニセル組成物は抗新生物剤を脳腫瘍に送達するのに有用である。この文脈において、表現「抗新生物剤」は、新生物細胞の増殖、発生、成熟、または伝播を阻止または阻害する化学的または生物学的薬物を意味する。
・ヒストンデアセチラーゼ(HDAC)インヒビター、例えば、ボリノスタット、エンチノスタット(SNDX-275)、モセチノスタット(MGCD0103)、パノビノスタット(LBH589)、ロミデプシン、バルプロ酸。
本開示に使用可能な活性剤は上に掲げた薬物クラスまたは特定の薬剤に限定されるものでない。色々な発見の場が、癌細胞のユニークな分子的特徴を指向する新しい薬剤を生じている;実に、数千のかかる化学的および生物学的薬物が発見されており、そのいくつかだけをここに掲げたに過ぎない。さらに、親水性または疎水性の様々な活性剤の充填に適応するインタクトな、細菌由来のミニセルの驚くべき能力は、本質的にいずれのかかる薬物も、ミニセルに充填されると、本開示の発見により脳癌を治療する可能性を有することを意味する。
「放射性核種」は不安定な核を持つ原子である、すなわち、核内で新しく作られた照射粒子へまたは原子性電子へ与えられる利用可能な過剰エネルギーを特徴とする前記原子である。それ故に、放射性核種は放射性崩壊を起こしてガンマ線および/または素粒子を放射する。多数の放射性核種が当技術分野で公知であり、そのいくつか、例えば、イットリウム-90、テクネチウム-99m、ヨウ素-123、ヨウ素-131、ルビジウム-82、タリウム-201、ガリウム-67、フッ素-18、キセノン-133、およびインジウム-111は医療用に好適であることが知られる。
本開示で用いた抗新生物剤はまた、化学療法薬であってもよい。本明細書においては「化学療法薬」、「化学療法剤」および「化学療法」を互換的に用いて、新生物細胞を殺滅または破壊する能力を有する薬物を意味する。化学療法薬は、以下でさらに詳述する小分子薬物または生物学的薬物であってもよい。
「機能性核酸」は、宿主細胞中に導入するとタンパク質の発現に特異的に干渉する核酸分子を意味する。本開示に従う脳腫瘍の治療に関しては、インタクトな、細菌由来のミニセルを介して腫瘍細胞に送達される機能性核酸の積荷は、腫瘍細胞増殖、血管新生または化学療法耐性を増強するおよび/またはアポトーシスまたは細胞サイクル停止を阻害する遺伝子を阻害する遺伝子(すなわち、「腫瘍促進遺伝子」)を阻害することが好ましい。
以上詳述した血管の完全性の喪失が脳腫瘍の全ての型および段階の特徴であるという事実は、本明細書による技法をいずれの脳腫瘍の治療における使用にも適応しうることを意味する。この点について「脳腫瘍」は頭蓋内または中心脊柱管に存在する固体新生物を含む。
グレードI:組織は良性である。細胞がほとんど正常な脳細胞の様に見え、かつ細胞増殖が遅い。
「ミニセル」はDNA分離を伴う細胞分裂の二分裂中に、染色体を欠く(「染色体を含まない」)かつ協調の障害により生じる細菌細胞誘導体を意味する。ミニセルはいわゆる「膜ブレブ」(〜0.2μm以下のサイズ)などの他の小胞(特定の状況で自発的に作製されかつ放出されるが、特異的な遺伝子再配列またはエピソームの遺伝子発現によらないもの)と異なる。同様に、インタクトなミニセルは細菌ゴースト(bacterial ghost)(特定の遺伝子再配列またはエピソームの遺伝子発現に因らない)と異なる。本開示で使われる細菌由来のミニセルは完全にインタクトであって、従って、破壊もしくは分解、または除去すらされた外膜または定義膜を特徴とする他の染色体を含まない型の細菌細胞誘導体とは区別される。米国特許7,183,105のカラム111、ライン54以下を参照されたい。本開示のミニセルを特徴づけるインタクトな膜は、治療用積荷が腫瘍細胞内で取込まれた後に放出されるまで、その積荷のミニセル内の保持を可能にする。
核酸がコードし得る抗新生物剤、例えば、タンパク質および機能性核酸は、抗新生物剤をコードするプラスミドなどのベクターを親細菌細胞中に形質転換することによりミニセル中に導入することができる。ミニセルが親細菌細胞から形成される場合、ミニセルはプラスミドおよび/または発現産物、抗新生物剤のある特定のコピーを保持する。発現産物のミニセル中への充填のさらなる詳細はWO 03/033519に記載されており、その内容は参照によりその全てが本開示に組み込まれる。
本開示のさらなる態様によれば、先に記したように、組成物のミニセルをリガンドを介して哺乳動物の腫瘍細胞に指向させる。いくつかの実施形態において、リガンドは「二特異的」である。すなわち、リガンドはミニセルと哺乳動物(腫瘍)細胞成分の両方に対して特異性を示し、その結果、所与のミニセルは標的細胞と結合するようになり、後者が前者を呑み込む。ミニセルを腫瘍細胞に標的化するための二特異性リガンドの使用はさらにWO05/056749およびWO05/079854に記載され、これらのそれぞれの内容は本明細書にその全てが参照により組み込まれる。かかるリガンドがミニセルに付着すると、リガンドの非占有特異性(「一特異性」)はリガンドが標的(腫瘍)哺乳動物細胞と相互作用するまで付随する。
本開示の組成物の製剤は単位投与剤形、例えば、アンプルまたはバイアルで、または複数回用量容器に入れて、防腐剤を加えもしくは加えないで提供しうる。製剤は、油性もしくは水性ビヒクルの溶液、懸濁液、または乳濁液であり、かつ懸濁化剤、安定化剤、および/または分散化剤などの製剤用薬剤を含有しうる。好適な溶液は、受給者の血液と等張であり、生理食塩水、リンゲル液、およびデキストロース溶液により例示される。あるいは、製剤は、好適なビヒクル、例えば、滅菌しパイロジェンを含まない水または生理食塩水によって再調製するための凍結乾燥粉末であってよい。製剤はまた、デポー製剤の剤形であってよい。かかる長時間作用製剤は、移植(例えば、皮下にまたは筋肉内)または筋肉内注射によって投与しうる。
ミニセルを、先にMacDiarmidら(2007)が記載した通り、サルモネラ菌enterica serovar Typhimurium、S. typhimuriumのminCDE-染色体欠失突然変異体から誘導し、精製し、ドキソルビシン(dox)を充填し、そして、抗ミニセル表面O-多糖および抗イヌEGFR特異性を含む二特異的モノクローナル抗体(MAb)の付着を介して標的化した(EGFRミニセルDoxと名付けた)。
ヒト(Smithら、2001)とイヌ(Higginsら、2010)両方のGBM症例のほぼ60%におけるEGFRのアップレギュレーションおよび過剰発現は公知である。特定のイヌEGFR MAbを利用できなかったので、市販の抗ヒトEGFR MAbをイヌおよびヒト脳腫瘍細胞株で試験し、MAbのイヌ脳腫瘍細胞上のEGFRに対する交差反応性を確認した。
dox充填、EGFR標的化ミニセルを用いて後期脳癌のイヌを治療する前に、イヌ脳腫瘍細胞が化学療法薬ドキソルビシンに対して感受性か不応性であるかを確認することが重要である。
イヌおよびヒト腫瘍細胞を2時間、特異的-および非-特異的に標的化したミニセル、EGFRミニセルDoxおよびgpl20ミニセルDOxでそれぞれトランスフェクトし、そして非接着ミニセルを洗浄除去した後に、それらの細胞をAlexa-Fluor488蛍光染料(AF-488)でタグ付けした抗マウスIgG2a MAbで処理した。gpl20 MAbはヒト免疫不全ウイルス1エンベロープ糖タンパク質を指向し、本研究で試験した脳腫瘍細胞株の表面上には見出されない。次いで細胞をFACSを用いて分析した。その結果(図3)は、EGFRミニセルDoxで処理すると細胞の>95%が強く蛍光を発し、対照のspl20ミニセルDOxで処理すると細胞は蛍光を発しないことを示した。
この研究のイヌは、動物専門医センター(Veterinary Specialist Centre (VSC))または小動物専門医病院(the Small Specialist Hospital(SASH))(Sydney、Australia)に患者として滞在するペットのイヌであった。研究参加はイヌの所有者が標準療法を辞退していたか、または意味のある標準療法が存在しない進行性疾患の事例において提案した。イヌは、国家保健および医療研究委員会、実験動物のケアおよび使用のオーストラリア指針、ならびにEnGeneIC動物倫理委員会の承認を遵守して治療した。説明と同意の署名を全ての所有者から得た。全患者はその時点でまたはいずれかの原因による死亡時に剖検を受けた。
毒性を胃腸器官の機能障害の徴候(摂食障害、下痢、嘔吐、および腸炎)および本質的な徴候(嗜眠/疲労)についての顧客への質問により評価した。血液学的および生化学的毒性を各治療に先だって毎週ベースで確認した。毒性をイヌおよびネコの化学的または生物学的抗新生物療法後の副作用に対する「獣医学共同腫瘍学グループ−有害事象共通用語規準(Veterinary Co-operative Oncology Group-common terminology criteria for adverse events (VCOG-CTCAE))v1.0」に従って格付けした。
R&D Systems(USA)より補給されたELISA DuoSetキットを用いて、製造業者の取扱説明書による各ELISAの検証後に、イヌ血清をイヌ炎症性サイトカインTNFα、IL-6および抗炎症性のサイトカインIL-10について分析した。高結合マイクロウエルプレート(Greiner)をTMB基質(Sigma)を用いて現像し、Biotek uQuant プレートリーダーで450nmにて読み取った。
興味深いことに、イヌBCD-1〜BCD-7はそれぞれ822、709、471、288、408、140および101日生存し、それぞれ97、43、44、39、32、20および13用量のEGFRミニセルDoxを受けた(図10)。BCD-2、-3および-5は生存中であり、BCD-2は300日にわたり用量を受けず、腫瘍の再発がない。BCD-4は288日生存し、安定な疾患で留まったが、腎臓感染で死んだ。死後分析は死亡が脳腫瘍とは無関係であることを明らかにした。驚いたことに、全身投与したEGFRミニセルDoxが非常に多数の用量であったにも関わらず、有害事象の臨床徴候は存在しなかった。
ナノ粒子のin vivo体内分布は、特に大きい動物種において、粒子のサイズが非常に小さいので、1粒子当たり可視化を可能にする十分な蛍光分子を運ぶ能力ならびにいずれかの特定の器官でin vivoで達成される濃度により妨げられてきた。さらに、現行の解釈では12nmより大きいナノ粒子はBBBの存在によって脳腫瘍に進入しないだろうとされている。しかし、全ての7匹のイヌで観察された著しい抗腫瘍効力は、EGFRミニセルDoxが禁じられた大サイズの〜400nmにも関わらず、脳腫瘍中への進入を何とか果たしたのかを急いで確認するよう本発明者らを促した。
本実施例は多様な小分子薬物のミニセル中への充填の実施可能性、および得られる小分子薬物充填ミニセルを含有する組成物の顕著な抗腫瘍効力の両方を説明する。
A. ドキソルビシン、
B. パクリタキセル、
C. フルオロ-パクリタキセル、
D. シスプラチン、
E. ビンブラスチン、
F. モナストロール、
G. チミジル酸シンターゼ(TS)インヒビターOSI-7904
H. イリノテカン、
I. 5-フルオロウラシル、
J. ゲムシタビン、および
K. カルボプラチン。
ドキソルビシン、蛍光ビンブラスチンおよびフルオロ-パクリタキセルのインタクトなミニセル中への充填の有効性は本発明者らの出版物である"MacDiarmid et al., Cancer Cell 11: 431-45 (2007)"に示されている。MacDiarmidら、Cancer Cell(2007)の図1Eは色々な蛍光色で、ミニセルがそれぞれ大量の(DOX)、ビンブラスチン(VIN)およびパクリタキセル(PAC)によって充填されているのを示す。
MacDiarmidら、Cancer Cell(2007)はさらに、動力学を用いて、(ドキソルビシン、フルオロ-パクリタキセルおよびシスプラチン)はただインタクトなミニセル中に十分充填されるだけでなく、これらの薬物は一旦充填されると洩れ出さないことを示した(この文献の図2Aを参照されたい)。
さらにMacDiarmidら、Cancer Cell(2007)の図4Aに示したデータは、ヒト乳癌異種移植片がドキソルビシン-またはパクリタキセル充填ミニセルを用いて効果的に治療されることを示した。
本発明者ら、MacDiarmid ら、Cell Cycle 17: 1-7 (2007)が出版した他の文献は、ヒト乳癌異種移植片を含有するマウスの腫瘍増殖を阻害するのにモナストロール充填ミニセルの有効性を実証するデータを提示している(この文献の図1Aを参照されたい)。
ヒト大腸癌異種移植片は、同様に、薬物積載ミニセルを用いて効果的に治療された。MacDiarmidら(2007)の図1Bは、OSI-7904積載ミニセルはOSI-7904Lのリポソーム製剤より〜385倍少ない用量で、リポソーム製剤OSI-7904Lより効果的であったことを示す。従って、ミニセル送達ベクターはOSI-7904の治療指数を劇的に増加した。
イリノテカンもインタクトなミニセル中に充填した。さらに、shRNA-MDR1充填ミニセルに続くイリノテカン標的化ミニセルによる二重連続治療後の、イリノテカン耐性ヒト大腸癌異種移植片の効果的な治療が図5Aおよび本発明者らの他の文献である"MacDiarmid et al., Nature Biotechnology 27: 643-51 (2009)"の5Aに示されている。
イリノテカンの様に、5-フルオロウラシルもインタクトなミニセル中も充填し、そしてshRNA-MDR1充填ミニセルに続く5-フルオロウラシル標的化ミニセルによる二重連続治療後に、5-フルオロウラシル-耐性ヒト大腸癌異種移植の効果的治療を達成した。
図12は、ヒト膵臓癌異種移植片がゲムシタビン(Gemzar(登録商標))充填ミニセルを用いて効果的に治療されたことを示す。
カルボプラチン充填ミニセルのヒト乳癌異種移植片を治療する効果を図13に示す。
Claims (44)
- 治療上有効量の複数のインタクトな、細菌由来のミニセルを含む、被験体の脳腫瘍を治療するための医薬組成物であって、
(A) 前記複数の各ミニセルが、(i)腫瘍細胞抗原を特異的に認識する抗体を含む、および(ii)抗新生物剤を包含する、ならびに
(B) 脳腫瘍はその壁に窓を有する血管を有し、ミニセルは該窓を通って受動的に遊出することができる、前記医薬組成物。 - 前記抗新生物剤が放射性核種である、請求項1に記載の医薬組成物。
- 放射性核種がイットリウム-90、テクネチウム-99m、ヨウ素-123、ヨウ素-131、ルビジウム-82、タリウム-201、ガリウム-67、フッ素-18、キセノン-133、およびインジウム-111から選択される、請求項2に記載の医薬組成物。
- 放射性核種が前記ミニセルの表面上のタンパク質または糖質と結合している、請求項2に記載の医薬組成物。
- 放射性核種がミニセルの表面と会合した二特異的抗体と結合している、請求項4に記載の医薬組成物。
- 30Gy〜100Gy放射能を含有する、請求項2〜5のいずれか1項に記載の医薬組成物。
- 前記抗新生物剤が化学療法薬である、請求項1に記載の医薬組成物。
- 前記化学療法薬が400ダルトン超の分子量を有する、請求項7に記載の医薬組成物。
- 前記化学療法薬が高毒性の化学療法薬である、請求項7または8に記載の医薬組成物。
- 多くても1mgの前記化学療法薬を含有する、請求項7〜9のいずれか1項に記載の医薬組成物。
- 前記抗新生物剤が機能性核酸または機能性核酸をコードするポリヌクレオチドである、請求項1に記載の医薬組成物。
- 前記機能性核酸が腫瘍細胞増殖、血管新生もしくは化学療法に対する耐性を促進する遺伝子および/またはアポトーシスもしくは細胞周期停止を阻害する遺伝子を阻害する、請求項11に記載の医薬組成物。
- 前記機能性核酸がsiRNA、miRNA、shRNA、lincRNA、アンチセンスRNA、またはリボザイムから選択される、請求項11に記載の医薬組成物。
- 前記抗新生物剤がアポトーシスを促進する遺伝子をコードするポリヌクレオチドである、請求項1に記載の医薬組成物。
- 前記複数の各ミニセルが非ファゴサイトーシス哺乳動物細胞表面受容体に対して特異性を有するリガンドを含むものである、請求項1〜14のいずれか1項に記載の医薬組成物。
- 前記受容体が腫瘍細胞抗原である、請求項15に記載の医薬組成物。
- 少なくとも108ミニセルを含む、請求項1〜16のいずれか1項に記載の医薬組成物。
- 少なくとも1010ミニセルを含む、請求項17に記載の医薬組成物。
- 10 EU未満の遊離内毒素を含有する、請求項1〜18のいずれか1項に記載の医薬組成物。
- 108 ミニセル当たり多くても1つの親細菌細胞を含有する、請求項1〜19のいずれか1項に記載の医薬組成物。
- 前記脳腫瘍が膠芽細胞腫、星状膠細胞腫、希突起膠細胞腫、上衣細胞腫、頭蓋咽頭腫、下垂体腫、脳の原発性リンパ腫、松果体腺腫、脳の原発性胚細胞腫、およびそれらの組み合わせからなる群より選択される、請求項1〜20のいずれか1項に記載の医薬組成物。
- 前記脳腫瘍が転移性脳腫瘍である、請求項21に記載の医薬組成物。
- 脳腫瘍の治療用医薬品を製造するための組成物の使用であって、組成物が複数のインタクトな、細菌由来のミニセルを含み、
(A)前記複数の各ミニセルが、(i)腫瘍細胞抗原を特異的に認識する抗体を含む、および(ii)抗新生物剤を包含する、ならびに
(B) 脳腫瘍はその壁に窓を有する血管を有し、ミニセルは該窓を通って受動的に遊出することができる、前記使用。 - 前記組成物が多くとも1mgの化学療法薬を前記抗新生物剤として含有する、請求項23に記載の使用。
- 前記抗新生物剤が機能性核酸または機能性核酸をコードするポリヌクレオチドである、請求項23に記載の使用。
- 前記機能性核酸が腫瘍細胞増殖、血管新生もしくは化学療法に対する耐性を促進する遺伝子および/またはアポトーシスもしくは細胞周期停止を阻害する遺伝子を阻害する、請求項25に記載の使用。
- 前記抗新生物剤がアポトーシスを促進する遺伝子をコードするポリヌクレオチドである、請求項23に記載の使用。
- 前記抗新生物剤が放射性核種である、請求項23に記載の使用。
- 前記組成物が少なくとも1010ミニセルを含む、請求項23に記載の使用。
- 前記組成物が10 EU未満の遊離内毒素を含有する、請求項23に記載の使用。
- 前記複数の各ミニセルが非ファゴサイトーシス哺乳動物細胞の表面受容体に対して特異性を有するリガンドを含むものである、請求項23に記載の使用。
- 前記脳腫瘍が膠芽細胞腫、星状膠細胞腫、希突起膠細胞腫、上衣細胞腫、頭蓋咽頭腫、下垂体腫、脳の原発性リンパ腫、松果体腺腫、脳の原発性胚細胞腫、およびそれらの組み合わせからなる群より選択される、請求項23に記載の使用。
- 前記脳腫瘍が転移性脳腫瘍である、請求項32に記載の使用。
- 前記抗新生物剤が400ダルトン超の分子量を有する化学療法薬である、請求項23に記載の使用。
- 前記化学療法薬が高毒性の化学療法薬である、請求項34に記載の使用。
- 前記脳腫瘍が膠芽細胞腫である、請求項1に記載の医薬組成物。
- 前記腫瘍がステージII、III又はIVの腫瘍である、請求項36に記載の医薬組成物。
- 前記腫瘍がステージIII又はIVの腫瘍である、請求項36に記載の医薬組成物。
- 腫瘍にて血管新生が引き起こされている、請求項36に記載の医薬組成物。
- 腫瘍にて血管形成が引き起こされている、請求項36に記載の医薬組成物。
- 前記腫瘍がステージII、III又はIVの腫瘍である、請求項1に記載の医薬組成物。
- 前記腫瘍がステージIII又はIVの腫瘍である、請求項1に記載の医薬組成物。
- 腫瘍にて血管新生が引き起こされている、請求項1に記載の医薬組成物。
- 腫瘍にて血管形成が引き起こされている、請求項1に記載の医薬組成物。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2018024678A (ja) * | 2011-12-13 | 2018-02-15 | エンジーンアイシー モレキュラー デリバリー ピーティーワイ リミテッド | 治療薬を脳腫瘍に送達するための細菌由来のインタクトなミニセル |
US10994014B2 (en) | 2011-12-13 | 2021-05-04 | Engeneic Molecular Delivery Pty Ltd | Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors |
US11964021B2 (en) | 2011-12-13 | 2024-04-23 | Engenelc Molecular Delivery Pty Ltd | Bacterially derived, intact minicells for delivery of therapeutic agents to brain tumors |
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