JP7097629B2 - 最小侵襲投与のための注射可能な予成形される肉眼的三次元スキャフォールド - Google Patents
最小侵襲投与のための注射可能な予成形される肉眼的三次元スキャフォールド Download PDFInfo
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Description
本発明は、米国国立衛生研究所の助成金番号R01 DE013349号の下で米国政府の支援を受けてなされた。米国政府は本発明において一定の権利を有する。
本発明は、薬物および細胞の送達システムのためのポリマースキャフォールドに関する。
組織工学は、所望の組織の特異的構造または機能に応じて材料を操作することによって、損傷を受けた組織を再生、置換、およびその機能を改善するためのアプローチである。多孔性で生物分解性のポリマースキャフォールドは、細胞に基づく組織工学のための構造支持マトリクスとしてまたは細胞接着基質として利用される。三次元スキャフォールドを外科的に植え込む際の主な副次的な結果は、患者の病気の処置中に医師によってもたらされる外傷である。たとえば、三次元スキャフォールドを外科的に植え込むための現行の技術は、患者の疼痛、出血、および挫傷につながる切開を伴う。そのため、より侵襲性の低い構造のポリマースキャフォールドを開発することが当技術分野において逼迫して必要である。
ハイドロゲルが圧縮または脱水による変形後における形状記憶を特徴とする、高密度の相互接続した開口孔を含む細胞適合性の高度架橋ハイドロゲルポリマー組成物。
[本発明1002]
少なくとも50%のポリマー修飾を含む、本発明1001の組成物。
[本発明1003]
少なくとも90%のポリマー修飾を含む、本発明1001の組成物。
[本発明1004]
少なくとも75%の孔を含む、本発明1001の組成物。
[本発明1005]
少なくとも90%の孔を含む、本発明1001の組成物。
[本発明1006]
水和状態で少なくとも90%の水を含む、本発明1001の組成物。
[本発明1007]
圧縮または脱水されたハイドロゲルにおいて25%未満の水を含む、本発明1001の組成物。
[本発明1008]
前記ポリマーに共有結合した細胞接着組成物を含む、本発明1001の組成物。
[本発明1009]
細胞接着組成物が、RGDアミノ酸配列を含むペプチドを含む、本発明1008の組成物。
[本発明1010]
1つまたは複数の前記相互接続した開口孔中に真核細胞を含む、本発明1001の組成物。
[本発明1011]
前記真核細胞が生きた弱毒化がん細胞を含む、本発明1010の組成物。
[本発明1012]
1つまたは複数の前記相互接続した開口孔中に生体分子を含む、本発明1001の組成物。
[本発明1013]
前記生体分子が、小分子、核酸、またはタンパク質を含む、本発明1012の組成物。
[本発明1014]
前記タンパク質がGM-CSFを含む、本発明1013の組成物。
[本発明1015]
前記核酸がCpG核酸オリゴヌクレオチドを含む、本発明1013の組成物。
[本発明1016]
中空の針を通して注射可能である、本発明1001の組成物。
[本発明1017]
圧縮時に、構造の完全性および形状記憶特性を維持する、本発明1001の組成物。
[本発明1018]
アルギネートに基づくハイドロゲルである、本発明1001の組成物。
[本発明1019]
ヒアルロン酸、ゼラチン、ヘパリン、デキストラン、カロブガム、PEG、PEG誘導体、コラーゲン、キトサン、カルボキシメチルセルロース、プルラン、PVA、PHEMA、PNIPAAm、またはPAAcを含む、本発明1001の組成物。
[本発明1020]
円板、円柱、四角形、長方形、または紐の形状を含む、本発明1001の組成物。
[本発明1021]
スキャフォールド組成物のサイズが100μm3~100 mm3である、本発明1001の組成物。
[本発明1022]
本発明1001の組成物を対象に投与する段階を含む、組織を修復、再生、または再構築するための方法。
[本発明1023]
前記組成物が皮膚充填剤として皮下投与されて、それによって前記組織を再構築する、本発明1022の方法。
[本発明1024]
前記組成物が幹細胞を含み、前記装置が、対象の損傷組織または疾患組織に投与されて、それによって該組織を修復または再生する、本発明1022の方法。
[本発明1025]
本発明1001の組成物を投与する段階を含む、組織に遺伝子材料を送達するための方法であって、該組成物が核酸をさらに含む、方法。
[本発明1026]
前記核酸がプラスミドDNAを含む、本発明1025の方法。
[本発明1027]
本発明1001の装置を対象に投与する段階を含む、免疫応答を誘発するための方法であって、該装置が、それに対して免疫応答が誘発される微生物病原体または腫瘍細胞をさらに含む、方法。
[本発明1028]
前記装置が予防的または治療的に投与される、本発明1027の方法。
本発明の他の特色および利点は、その好ましい態様に関する以下の説明から、および特許請求の範囲から明らかであろう。他に定義される場合を除き、本明細書において用いられる全ての科学技術用語は、本発明が属する分野の当業者によって一般的に理解される意味と同じ意味を有する。本明細書において記述される方法および材料と類似または同等の方法および材料を、本発明の実施または試験において用いることができるが、適した方法および材料を以下に記述する。本明細書において引用される全ての公開された外国の特許および特許出願は、参照により本明細書に組み入れられる。本明細書において引用されるアクセッション番号によって示されるGenbankおよびNCBI提出物は、参照により本明細書に組み入れられる。本明細書において引用される他の全ての公表された参考文献、文書、原稿、および科学論文は、参照により本明細書に組み入れられる。矛盾する場合は、定義を含めて本明細書が優先される。さらに、材料、方法、および実施例は例示であるに過ぎず、限定することを意図しない。
三次元スキャフォールドの現行の外科的植え込みの主な欠点は、スキャフォールド/装置の投与の際に医師によってもたらされる外傷である。本明細書において記述される組成物および方法は、組織工学アプローチの費用および侵襲性を低減させる。本明細書において記述される本発明以前は、組織工学では、外科的植え込みを必要とする装置およびポリマースキャフォールドが用いられた。手術部位におけるポリマースキャフォールドの植え込みは、麻酔および切開を必要とし、その処置法の各々が望ましくない副次的な結果を有する。本明細書において、組織工学研究者および外科医が、より低侵襲的な様式で組織工学的適用に従事することができ、それによって外科的植え込みの必要性をなくす組成物および方法が記述される。以下に詳細に記述されるように、注射可能なスキャフォールドは、組織工学システムの侵襲性を低減させて、それによって該材料を植え込むために必要な、いかなる切開の必要性もなくすか、または切開のサイズを低減させるために開発された。システムが注射可能であるためには、システムは中空の小さい口径の針の中を流れることが可能でなければならない。予成形スキャフォールドを植え込む、またはインサイチューで重合させるために液体を注射する方法には、短い反応時間、適当なゲル化条件、適切な力学的強度および持続時間、生体適合性、ならびにいくつかの有害な環境においてタンパク質薬物または細胞を保護する可能性を含む、多くの難題が提示されていた。これらの制限を克服するために、容易に調製され、加工され、かつシリンジの針を通して注射される、変形可能な十分に架橋されかつ予成形される多孔性スキャフォールドを開発した。
メタクリル化アルギネート(MA-アルギネート)を、高分子量アルギネートをメタクリル酸アミノエチル(AEMA)と反応させることによって調製した。ウロン酸のカルボキシレート基の理論上の100%メタクリル化によってメタクリル化アルギネートを合成するために、高分子量アルギン酸ナトリウム(1 g)を、0.5 M NaClを含む100 mM MESの緩衝溶液(0.6%w/v、pH ~6.5)に溶解した。N-ヒドロキシスクシンイミド(NHS、1.3 g)およびN-(3-ジメチルアミノプロピル)-N'-エチルカルボジイミド塩酸塩(EDC、2.8 g)を反応混合物に加えて、アルギネートのカルボン酸基を活性化した。5分後、AEMA(2.24 g、NHS:EDC:AEMAのモル比=1:1.3:1.1)を生成物に加えて、反応を室温で24時間維持した。過剰量のアセトンを添加して混合物を沈殿させて、濾過して、真空オーブン中で室温で終夜乾燥させた。1H NMRを用いて、アルギネートの化学修飾を確認して、MA-アルギネートの官能基化の程度の特徴を調べた(図10)。
クリオゲルマトリクスを、水中でのMA-アルギネートのレドックス誘導性フリーラジカル重合によって合成した。アルギネートクリオゲルは、脱イオン水中でMA-アルギネートマクロモノマー10 mg(1%wt/v)をTEMED(0.5%wt/v)およびAPS(0.25 wt/v)と混合することによって合成される。混合物を予め冷却したテフロン鋳型に直ちに注ぎ込み、-20℃で凍結した。低温架橋が終了した後、ゲルを室温まで加熱して氷の結晶を除去して、蒸留水によって洗浄する。細胞接着クリオゲルは、重合の際のコモノマー(0.8%wt/v)としてRGD含有ペプチド組成物、たとえばACRL-PEG-G4RGDASSKYを用いて合成した。(アクリロイルはACRLと省略される)。RGD含有ペプチド組成物(モノマー)をアルギネートと混合することによって、RGDはポリマー構造に化学的に結合する(共有結合する)ようになる。細胞-基質相互作用を促進するために、RGD-インテグリン結合モチーフを用いた。NMR分光法を用いて、低温重合後のMA-アルギネートマクロモノマーのビニル変換の特徴を調べた。図2に示されるように、開始剤系(APS/TEMED)の存在下での低温重合プロセス後に、MA-アルギネートマクロモノマー(1%wt/v)のメチレンプロトン(5.3~5.8 ppm)の完全な消失に至った。このことは、クリオゲルに関して、高いビニル変換を達成できることを示している(図11を参照されたい)。注射可能なクリオゲルは、ポリマー自身の分子量および化学修飾の程度に応じて種々の濃度で調製することができる(概念の証明として1%wt/vを選択した)。
クリオゲルは、凍結向性の(cryotropic)ゲル化(すなわち、凍結ゲル化)技術を用いて生成される高度多孔性の相互接続した構造を有する材料の種類である。凍結ゲル化は、重合-架橋反応が準凍結(quasi-frozen)反応溶液中で行われる技術である。マクロモノマー(MA-アルギネート)溶液の凍結時に、氷から押し出されたマクロモノマーおよび開始剤系(APS/TEMED)は、氷の結晶のあいだの流路内で濃縮して、それによって反応がこれらの凍結していない液体流路においてのみ起こる。重合後および氷の融解後、その微小構造が形成された氷のネガティブ・レプリカである、多孔性材料が生成されている。氷の結晶は孔形成物質として作用する。孔のサイズは、凍結ゲル化プロセスの温度を変化させることによって調整される。たとえば、凍結ゲル化プロセスは典型的に、-20℃で溶液を急速に凍結することによって行われる。温度をたとえば-80℃まで低下させると、より多くの氷の結晶が生じ、より小さい孔が得られるであろう。
治療タンパク質の注射可能な送達システム(たとえば、ハイドロゲルおよびミクロスフェア)は、広く注目を集めている。しかし、従来のハイドロゲルは典型的に、大きな初回バーストで非常に急速にその親水性内容物を放出し、投与後比較的短期間のうちに貪食細胞がミクロスフェアを一掃しうる。
シリンジおよび針は、典型的にクリオゲルを身体に導入するために用いられる。「シリンジ」という用語は技術的に、リザーバー(液体を保持する)およびプランジャー(液体をリザーバーから押し出す)を意味する。「針」は、身体、たとえば静脈内に、皮膚の下に、または筋肉もしくは他の組織の下に入る部分である。「シリンジ」という用語はまた、時に、リザーバー/プランジャー/針の組み合わせ全体を意味するためにも用いられる。それらは多様なサイズであり、たとえば一般的なリザーバーのサイズは1 cc(1立方センチメートル(cc)=1ミリリットル)であり、25ゲージの針サイズまたはそれ以下を有する。
可逆的な圧密可能な挙動により、エクスビボで特徴が調べられているように、所望の物理学的特性を有する予成形クリオゲルは、シリンジを通しての注射の際に適度の非破壊的剪断応力が適用されることによりインビボで送達されうる。流体の速度、動圧、および注射に起因する剪断応力が、細胞の生存率に影響を及ぼすか否かを評価する試験を行った。
本明細書において記述される組成物および方法は、インビボでの適用のための形状記憶スキャフォールドの最小侵襲性送達のためのハイドロゲルを提供する。この方法は、注射可能で形状を画定されたマクロ多孔性スキャフォールドを非常に効率的にかつ再現可能に製作できることを証明している。共有結合によって架橋されたアルギネートに基づくゲルシステムの1つのタイプのみを本明細書において評価したが、材料の性能は、その組成、配合、および分解プロファイルを変化させることによって容易に操作される。特定の形状の成形および構造の安定性は、形状を画定される材料の望ましい特徴であり、最小侵襲治療のためにこれらのタイプの材料の最も重要な必要条件は、刺激に応答してスキャフォールドの構造を崩壊させてかつ忠実に再成形できることである。機械的圧縮および脱水の組み合わせは、本研究において開発されたスキャフォールドを圧縮するために十分であり、従来のゲージ針を通した最小侵襲性送達を可能にする。
剪断力を伴う機械的圧縮下での、従来の(ナノ多孔性の)ゲルおよびマクロ多孔性1%MA-アルギネートゲルの変形を調べた。機械的圧縮に供されると、ゲルは大きい力を受けて、それによって形状の変化が起こる。スキャフォールドの剛性が、適用された剪断力の下での変形の程度を決めることから、ゲルの力学的特性に及ぼすマクロ孔の影響もまた評価した。従来のゲルは、圧縮試験において42±4 kPaのヤング率(すなわち、図2における応力対ひずみ曲線の最初の部分の勾配)を生じる。しかし、マクロ多孔性ゲルでは、ヤング率は4±2 kPaへと劇的に低減した。図2に示されるように、円柱形(直径4 mm×高さ8 mm)のナノ多孔性ゲルは、垂直方向の負荷に供した場合にその高さが~16%低減して機械的破断に至った。比較すると、円柱形のマクロ多孔性ゲルは、そのより低いヤング率により、より低い機械的応力下でかなり大きい変形を生じる。マクロ多孔性スキャフォールドは、機械的に破断することなく、90%またはそれ以上の圧縮ひずみに達し、圧縮、圧密、および最小侵襲性送達の後にその構造的完全性を維持できることを証明している。同様に、これらの結果により、前記スキャフォールドがインビトロで形状記憶能を示すことが確認された。
形状記憶特性を有する、共有結合により架橋したアルギネートスキャフォールドを、インビボで薬物送達システムとして用いることに成功した。既定のサイズおよび構造を有するゲルは、マウスの皮下に最小侵襲的に挿入した後にその構造的特色を並外れて維持することが可能であった。PBS中に懸濁させたゲルは、マウスの背下部上での1部位あたり1回注射の後に、自発的に水和して完全な幾何学的回復を示した。注射された動物は、実験の時間枠のあいだ、摂食、毛繕い、もしくは行動に異常を示さず、苦痛の徴候もまた示さなかった。
本明細書において記述される組成物および方法の1つの適用は、細胞-スキャフォールドの組み込みに基づく非侵襲的な細胞注射の方法である。細胞の移植は、細胞死により局部のまたは全体的な機能が損なわれた患者にとって1つの治療の選択肢である。しかし、細胞移植法の数が限られていることは、細胞治療の効能を制限する主な要因であると考えられている。細胞および生理活性分子の担体として、注射可能な予成形スキャフォールドは、スキャフォールド全体に細胞および分子シグナルを均一に分配する可能性を提供する。その上、該スキャフォールドは、組織または腔に、たとえば、筋肉、骨、皮膚、脂肪、臓器、不規則な形状およびサイズのものにさえ、最小侵襲的に直接注射される。本明細書において記述される組成物および方法は、生体力学的負荷に耐えるのに十分な力学的強度を可能にして、細胞に対する一時的な支持を提供しながら、重合後の注射可能性および効率的な細胞封入などの重要な利点を提供する。
宿主病原体を含む最小侵襲スキャフォールドに基づく活性ワクチンを、がんの治療的処置のために開発した。がんの場合、免疫系は、がんと闘うのにより有効になることができるように、免疫療法による外部からの追加免疫を必要とする。本明細書において記述される能動免疫療法システムは、患者の身体の自身の免疫細胞を用いて抗原特異的な抗腫瘍効果を促進する目的で、患者の免疫系を刺激するように設計された。さらに、クリオゲル-ワクチンにより、腫瘍の再発から防御する持続性の抗腫瘍反応が得られる。樹状細胞(DC)は、免疫系の調節に重要に関係する抗原提示細胞である。ワクチンは、樹状細胞の動員、活性化、およびそのリンパ節への分散のインサイチューでの操作を媒介する。シトシン-グアノシンオリゴヌクレオチド(CpG-ODN)を、ワクチンに対する応答をさらに刺激するためのアジュバントとして用いた。
ポリカチオン/プラスミドDNA複合体に基づく非ウイルス遺伝子送達システムは、ウイルスシステムに固有の免疫原性および毒性問題を回避するその有望性のために、ウイルス遺伝子ベクターに対する代替物として認識されつつある。注射後の周辺組織への遺伝子導入を達成するために、注射可能なクリオゲルに封入された濃縮プラスミドDNAに基づく制御放出システムを用いることが実現可能であるか否かを決定するために試験を行った。クリオゲルに基づく遺伝子送達システムの独自の特色は、ポリマーシステムの生物分解性であり、これはポリマー、架橋密度、質量分率、および凍結ゲル化プロセスの際にもたらされる多孔率に応じて、種々の速度でのDNAの持続的放出を提供することができる。7:1(PEI:DNA)の比率で調製された、有効な遺伝子担体であることが知られている非分解性のカチオンポリマーであるポリエチレンイミン(PEI)と複合体を形成した封入されたDNA、および裸のPEI/DNA複合体を、レポーター遺伝子としてルシフェラーゼを用いてナイーブマウスの背下部の皮下に注射した(図9)。注射後1日目に、封入されたPEI/DNAは、強い生物発光を示し、裸のPEI/DNAによって産生されるよりも約2桁高い約10光子/秒で最も高いトランスジーンの発現を提供した。10日後、裸のPEI/DNAの発現レベルは、1日目とほぼ同じであったが、クリオゲルから制御可能な様式で放出されたことから1桁増加した。29日目までに、封入されたPEI/DNAは依然として、これまでの時点で観察されたレベルと類似の約107光子/秒のトランスジーンの発現レベルを提供した。このレベルは、裸のPEI/DNAによって提供されるレベルよりも有意に高かった。
本発明を、その詳細な説明と共に記述してきたが、前述の説明は本発明を説明することを意図しており、添付の特許請求の範囲によって定義される本発明の範囲を限定することは意図しない。他の局面、利点、および改変は添付の特許請求の範囲の範囲内である。
Claims (28)
- 相互接続したマクロ開口孔を含む、注射可能な、細胞接着クリオゲル組成物であって、
該クリオゲル組成物は、体積で少なくとも75%の孔を含み、
該クリオゲル組成物は、針を通した圧縮による変形後における形状記憶能を有することを特徴とし、
該クリオゲル組成物は、アルギネートポリマーを含み、ここで該アルギネートポリマーは共有結合により架橋されており、
該クリオゲル組成物は、少なくとも50%のポリマー架橋の架橋密度、または、50~98%のポリマー架橋の架橋密度を有する、
組成物。 - アルギネートがアクリル化またはメタクリル化されている、請求項1記載の組成物。
- クリオゲルが、約1%(w/v)の濃度のメタクリル化アルギネートマクロモノマーを含む、請求項2記載の組成物。
- クリオゲルが、
(a) 水和状態で、体積で少なくとも90%の水を含む;または
(b) 圧縮状態で、体積で25%未満の水を含む、
請求項1記載の組成物。 - クリオゲルのサイズが100μm3~100 mm3である、請求項1記載の組成物。
- マクロ孔が、20μm~300μmの直径を有する、請求項1記載の組成物。
- 組成物が、対象に注射されると、クリオゲル組成物中に細胞を動員する、請求項1記載の組成物。
- クリオゲル組成物が生物分解性である、請求項7記載の組成物。
- さらに磁性粒子を含む、請求項1記載の組成物。
- 磁性粒子がFe3O4ナノ粒子またはFe3O4マイクロ粒子を含む、請求項9記載の組成物。
- さらにメカノフォア分子を含む、請求項1記載の組成物。
- メカノフォア分子がポリジアセチレンリポソームを含む、請求項11記載の組成物。
- 1つまたは複数の相互接続したマクロ開口孔中に生体分子を含む、請求項1記載の組成物。
- 生体分子が、小分子、核酸、またはタンパク質を含む、請求項13記載の組成物。
- タンパク質がサイトカインである、請求項14記載の組成物。
- サイトカインがGM-CSFを含む、請求項15記載の組成物。
- 核酸がCpG核酸オリゴヌクレオチド(CpG-ODN)を含む、請求項14記載の組成物。
- 生体分子が病原体関連分子パターン(PAMP)を含む、請求項13記載の組成物。
- 組成物がGM-CSF、および病原体関連分子パターン(PAMP)を含む、請求項13記載の組成物。
- さらにミクロスフェアを含む、請求項1記載の組成物。
- ミクロスフェアが、クリオゲル組成物内に物理的に捕捉されている、請求項20記載の組成物。
- ミクロスフェアがPLGAを含む、請求項20記載の組成物。
- ミクロスフェアがGM-CSFを含む、請求項20記載の組成物。
- ミクロスフェアが薬物を含む、請求項20記載の組成物。
- (i) 針;
(ii) 請求項1~24のいずれか一項記載の組成物を含む、リザーバー;および
(iii) プランジャー
を含む、シリンジ。 - 16ゲージ、18ゲージ、20ゲージ、22ゲージ、24ゲージ、26ゲージ、28ゲージ、30ゲージ、32ゲージ、または34ゲージの針を含む、請求項25記載のシリンジ。
- 18~30ゲージの針を含む、請求項25記載のシリンジ。
- 組成物のサイズが1 mm3~50 mm3である、請求項25記載のシリンジ。
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AU2019201669A1 (en) | 2019-04-04 |
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