JP6387009B2 - 癌細胞トラップ - Google Patents
癌細胞トラップ Download PDFInfo
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- JP6387009B2 JP6387009B2 JP2015538095A JP2015538095A JP6387009B2 JP 6387009 B2 JP6387009 B2 JP 6387009B2 JP 2015538095 A JP2015538095 A JP 2015538095A JP 2015538095 A JP2015538095 A JP 2015538095A JP 6387009 B2 JP6387009 B2 JP 6387009B2
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- cancer
- cancer cell
- cell trap
- cells
- trap
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Description
本出願は、2012年10月20日に出願した米国仮出願第61/716,526号(この内容は、参照によりその全体が本明細書に組み込まれる)の利益を主張する。
本発明は、米国立衛生研究所により授与された認可番号RO1、EB007271−01の下、米国政府の支援を受けて行われた。米国政府は本発明において一定の権利を有する。
一実施形態において、本発明は、癌転移を治療、予防および/または診断するための癌細胞トラップを提供し、その際、癌細胞トラップが対象の中に置かれた時に、転移性癌細胞がある期間にわたって癌細胞トラップに遊走および蓄積できる。
いくつかの実施形態において、癌細胞トラップは足場構造として作製される。いくつかの実施形態において、癌細胞トラップは組織の足場である。いくつかの実施形態において、癌細胞トラップは1以上の細胞外マトリックス成分を含む。いくつかの実施形態において、癌細胞トラップはマイクロバブル足場である。いくつかの実施形態において、癌細胞トラップは合成ポリマーから作られる。いくつかの実施形態において、癌細胞トラップはポリマーおよびタンパク質から作られる。いくつかの実施形態において、足場構造は、1以上のタンパク質、ポリマー、およびそれらの組み合わせから調製される。いくつかの実施形態において、タンパク質は、細胞外マトリックスタンパク質、例えば、コラーゲンI、コラーゲンIII、エラスチンおよびフィブロネクチンである。いくつかの実施形態において、足場は分解性である。いくつかの実施形態において、足場は、生分解性ポリマーおよび1以上のポリペプチドを含む。いくつかの実施形態において、足場は組織から作製でき、その際、細胞外マトリックス成分を含む足場構造を残して細胞が除去される。
いくつかの実施形態において、癌細胞トラップは、微粒子および/またはナノ粒子を用いて作製されてもよい。いくつかの実施形態において、粒子は様々な生物活性分子を放出できる。
いくつかの実施形態において、癌細胞トラップはヒドロゲルを含む。いくつかの実施形態において、ヒドロゲルは制御放出特性を有する。例えば、いくつかの実施形態において、癌細胞トラップはインサイツ固化ヒドロゲルであり得る。いくつかの実施形態において、癌細胞トラップはヒドロゲル基材を用いて作製できる。
いくつかの実施形態において、本発明は、有効量の本発明の癌細胞トラップをそれを必要とする対象に投与することを含む癌転移を治療または予防する方法であって、転移性癌細胞が癌細胞トラップに遊走および蓄積し、それにより対象における転移を治療または予防する方法を提供する。
いくつかの実施形態において、本発明の癌細胞トラップは、対象における癌転移の存在および/または程度を評価するための診断ツールとして使用できる。診断ツールとして使用する場合、癌細胞トラップは癌細胞を動員するために対象に導入される。いくつかの実施形態において、本発明は、癌細胞トラップを対象に投与することを含む癌転移を検出するための方法であって、前記対象中で癌細胞がトラップへ遊走してかつ癌細胞が回収および評価される方法である。
いくつかの実施形態において、本発明の癌細胞トラップは医薬組成物として対象に投与され、それは塩、緩衝剤、防腐剤、または他の薬学的賦形剤を含んでもよい。
実施例1.癌転移を研究するための2ステップインビボモデル
本研究は、炎症媒介性癌転移を支配するプロセスを調査するために、再現可能な動物モデルの開発を目的とした。
癌細胞培養
本研究で使用したB16F10黒色腫細胞、ルイス肺癌(LLC)細胞、ラット前立腺癌細胞株(UHU−31)、ヒト前立腺腺癌(PC−3)、およびヒト乳癌細胞株(MDA−MB−231)は、アメリカン・タイプ・カルチャー・コレクション(ATCC)(米国バージニア州マナッサス)から購入した。B16F10黒色腫細胞は、C57BL/6Jマウスから単離した皮膚黒色腫細胞株である。C57BL/6Jマウスから単離されたLLC細胞は、癌転移のモデルとして広く使用されている。JHU−31細胞はラットに由来し、肺およびリンパ節への高い転移率(>75%)を示す。PC3細胞は、骨転移性前立腺腺癌を有する62歳の男性白人由来である。MDA−MB−231細胞は乳腺癌転移胸水に由来する。全ての細胞を、37℃、5%CO2加湿環境で10%熱不活性化ウシ胎児血清を補充したDMEM中で維持した。インビボ追跡のために、癌細胞のいくつかを、公知の方法(ユーザーマニュアルからの方法を含む)を用いてKodak社製X−Sight 761ナノスフェア(Carestream Health社、米国コネチカット州ニューヘブン)で標識した。Nair A,Shen J,Lotfi P,Ko CY,Zhang CC,Tang L.Biomaterial implants mediate autologous stem cell recruitment in mice.Acta Biomater 2011;およびThevenot PT,Nair AM,Shen J,Lotfi P,Ko CY,Tang L.The effect of incorporation of SDF−1 alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response.Biomaterials 2010;31:3997−4008。
様々な程度の異物反応を促すために、ポリ−L−乳酸(PLA)、水酸化アルミニウム(アルヒドロゲル85)、ガラス(Glasperlen(登録商標)を含む異なる材料で作られたミクロスフェアを本研究で使用した。PLAミクロスフェアを、改変された沈殿法に従って合成した。Weng H,Zhou J,Tang L,Hu Z.Tissue responses to thermally−responsive hydrogel nanoparticles.J Biomater Sci Polym Ed 2004;15:1167−1180;Carvalho MA,Zecchin KG,Seguin F,Bastos DC,Agostini M,Rangel AL,et al.Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell Growth and lymph node metastasis in a mouse melanoma model.Int J Cancer 2008;123:2557−2565;Gerber SA,Rybalko VY,Bigelow CE,Lugade AA,Foster TH,Frelinger JG,et al.Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth.Am J Pathol 2006;169:1739−1752;Hippo Y,Yashiro M,Ishii M,Taniguchi H,Tsutsumi S,Hirakawa K,et al.Differential gene expression profiles of scirrhous gastric cancer cells with high metastatic potential to peritoneum or lymph nodes.Cancer Res 2001;61:889−895;Nair A,Shen J,Lotfi P,Ko CY,Zhang CC,Tang L.Biomaterial implants mediate autologous stem cell recruitment in mice.Acta Biomater 2011;Thevenot PT,Nair AM,Shen J,Lotfi P,Ko CY,Tang L.The effect of incorporation of SDF−1 alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response.Biomaterials 2010;31:3997−4008;およびFessi H,Puisieux F,Devissaguet JP,Ammoury N,Benita S.Nanocapsules formation by interfacial polymer deposition following Solvent displacement.Int J Pharm 1989;55:R1−R4を参照されたい。
ケモカインSDF−1α:(Prospec−Tany TechnoGene(株)、レホヴォト、イスラエル)およびEPO(Cell Sciences社、米国マサチューセッツ州カントン)を放出するPLGA足場を、以前に公開された方法を用いて作製した。Nair A,Thevenot P,Dey J,Shen J,Sun MW,Yang J,et al.Novel polymeric scaffolds using protein Microbubbles as porogen and growth factor carriers.Tissue Eng Part C Methods 2010;16:23−32。
動物実験を、Jackson Laboratory社(米国メイン州バーハーバー)からのC57BL/6マウス(6〜10週齢)を用いて行った。このマウス癌転移モデルは、2つの連続するステップから成る。最初に、生体材料のミクロスフェア(75mg/食塩水0.5ml/マウス)を皮下の局所的な炎症を誘発するためにマウスの背部皮下空間に埋め込んだ。第2に、異なる期間(6時間〜14日)ミクロスフェアを埋め込んだ後に、癌細胞(5×106細胞/0.2ml/マウス)を腹腔内に移植した。腫瘍細胞移植から24時間後に動物を屠殺した。次いで、重要な臓器、リンパ節、ミクロスフェアインプラントおよび周囲組織を回収し、−80℃でOCT包埋培地(Polysciences社、米国ペンシルベニア州ウォリントン)中で凍結した。末梢血もさらなる分析のために収集した。8μmの厚さの切片をLeica社製クリオスタット(CM1850)を用いてスライスし、組織学的および免疫組織化学的分析のために、ポリ−L−リジンをコーティングしたスライド上に置いた。異物反応の程度を低減するために、投与前に、PLAミクロスフェアの一部を、抗炎症剤デキサメタゾン(薬物0.1mg/ミクロスフェア懸濁液0.5ml)に浸漬した。癌細胞遊走の全身イメージングでは、並行試験を行いC57BL/B6マウスにおけるX−Sight 761ナノスフィア標識B16F10細胞の遊走を監視した。その後、動物を、Kodak社製インビボイメージングシステムFXプロ(Carestream Health社、米国コネチカット州ニューヘブン)を用いて画像化した。
動物内での細胞移動を追跡するために、B16F10細胞を緑色蛍光タンパク質を有するAd5ウイルス(pEGFP−N1、Clontech Laboratories社、米国カリフォルニア州マウンテンビュー)で24時間、50のMOIにて形質導入し、その後、腹腔に注入した。実験前に、B16F10へのGFP Ad5の感染力を、蛍光顕微鏡によって可視化したGFP発現によって評価した。生体内分布の分析では、前述したように、培地(0.2ml)に懸濁したGFP−B16F10(1.0×107)をC57BL/6マウスの腹膜に注入した。動物を屠殺した後、組織切片を蛍光顕微鏡下で分析した。癌転移の程度を示すために、異なる組織における癌細胞密度を定量した。いくつかの研究では、生体内分布の分析は、FITC標識癌細胞およびエクスビボでの臓器イメージング法を用いて行うこともできる。研究終了時に、全ての臓器を動物から単離し、様々な臓器における癌細胞の分布を、Kodak社製インビボイメージングシステムを用いて決定した。
癌転移におけるCXCR4/SDF−1αおよびCCR7/CCL21経路の役割を決定するために、AMD3100およびCCL21中和抗体を用いて、それぞれ、CXCR4/SDF−1αおよびCCR7/CCL21経路を遮断した。具体的には、腫瘍注入の1時間前および腫瘍注入の12時間後に、ミクロスフェアを埋め込んだ動物に、AMD3100(250μg/0.1ml/マウス、Sigma−Aldrich社、米国ミズーリ州セントルイス)またはCCL21(1mg/0.1ml/マウス:R&D Systems社、米国ミネソタ州ミネアポリス)の中和抗体のいずれかを腹腔内注射した。
CD11b+炎症細胞およびHMB45+黒色腫細胞について免疫組織学的分析を行い、それぞれ、インプラント媒介性炎症反応および黒色腫細胞遊走の程度を評価した。簡単に説明すると、組織切片を一次抗黒色腫抗体(HMB45、1:50希釈、Abeam社、米国マサチューセッツ州ケンブリッジ)または抗マウスCD11b抗体(1:20希釈、Serotec社、米国ノースカロライナ州ローリー)と共に、37℃で1時間インキュベートした。その後、PBSで3回洗浄した後、スライドをHRP結合二次抗体またはFITC結合二次抗体(1:500希釈、Jackson ImmunoResearch Laboratories、米国ペンシルベニア州ウェストグローブ)のいずれかと共に、37℃で1時間インキュベートした。FITC結合抗体とインキュベートした組織切片は、そのまま画像解析にかけた。HRP結合抗体でインキュベートした切片は、DAB液体基質システムで15分間発色させた。以前に記載されたように、全組織切片の画像を、Retiga−EXi CCDカメラ(Qlmaging、サリー、BC、カナダ)を備えるLeica社製蛍光顕微鏡(Leica Microsystems GmbH社、ウェッツラー、ドイツ)を用いて撮影した。Nair A,Shen J,Lotfi P,Ko CY,Zhang CC,Tang L.Biomaterial implants mediate autologous stem cell recruitment in mice.Acta Biomater 2011;Thevenot PT,Nair AM,Shen J,Lotfi P,Ko CY,Tang L.The effect of incorporation of SDF−1 alpha into PLGA Scaffolds on stem cell recruitment and the inflammatory response.Biomaterials 2010;31:3997−4008;およびNair A,Thevenot P,Dey J,Shen J,Sun MW,Yang J,et al.Novel polymeric scaffolds using protein microbubbles as porogen and growth factor carriers.Tissue Eng Part C Methods 2010;6:23−32。
異なるグループ間の統計的比較を、スチューデントt検定または一方向ANOVAを用いて行った。p<0.05の場合に、差異が統計的に有意であるとみなした。
生体材料媒介炎症反応には、様々な免疫細胞および炎症性サイトカイン/ケモカインの参加を伴う一連のプロセスが関与する。1日たった皮下インプラントは、炎症細胞(CD11b+)および腹腔内移植したB16F10黒色腫細胞(HMB45+)の浸潤を引きつけることが判明した(図1A)。遠隔炎症部位への黒色腫細胞の移行は、炎症性シグナルが黒色腫細胞の化学誘引物質として働き得ることを示唆している。これを試験するために、様々な程度の炎症反応の黒色腫細胞遊走に対する影響を分析した。様々な炎症強度の局所的な環境を作るために、ポリ−L−乳酸(PLA)ミクロスフェアを異なる期間(6時間、12時間、24時間、2日、7日および14日間)皮下空間に埋め込んだ(図1B)。予想されるように、ほとんどの炎症細胞(CD11b+)の動員は、ミクロスフェア埋め込み後12時間以内に生じ、24時間より後には大して増加しなかった(図1C)。癌細胞遊走における炎症プロセスの段階および強度の重要性を決定するために、B16F10黒色腫細胞を、異なる期間、皮下ミクロスフェアインプラントを有するマウスの腹膜に移植した。炎症開始後の様々な時点で、皮下のミクロスフェア埋め込み部位に移行した黒色腫細胞の数を分析した(図1DおよびE)。興味深いことに、動員された黒色腫細胞の数は、異なる期間のインプラントを有するマウスで大きく異なっていることが判明した(図1DおよびE)。黒色腫細胞の蓄積は、12時間〜最大7日のミクロスフェア埋め込みによって誘発された急性炎症反応に応答しているように思われる。しかし、6時間未満かつ2週間超埋め込まれたミクロスフェアでは、ほんのわずかの黒色腫細胞しかミクロスフェア埋め込み部位へ動員されなかった(図1D)。炎症反応媒介性癌転移の特異性は、Kodak社製近赤外X−Sight761ナノスフェアで標識したB16F10黒色腫細胞を用いて、光学撮像方法により証明することもできた。インビボ画像は、移植された黒色腫細胞がミクロスフェアインプラントを有する背側皮膚部位にのみ動員されたことを示す(図1F)。
黒色腫細胞移行の誘発における炎症反応の重要性を確認するために、抗炎症剤デキサメタゾンの存在下または非存在下で、同様の皮下へのPLAミクロスフェア埋め込みを行った。予想されたように、デキサメタゾンで処置したミクロスフェアは、生理食塩水とインキュベートしたミクロスフェア対照よりも、実質的により少なくしか炎症細胞(CD11b+)動員を促進しなかった(図2A、写真のパネル:CD11b+対HMB45+、デキサメタゾン処置対対照)。偶然にも、黒色腫細胞(HMB45+)の動員もデキサメタゾンの局所放出によって減少した(図2A)。炎症細胞および黒色腫細胞の減少に対する局所放出デキサメタゾンの影響は、統計的に有意である(図2B)。これらの結果は、炎症反応が腹腔から皮下ミクロスフェア埋め込み部位への癌細胞遊走の開始に不可欠であるという考えを強力に支持する。
異なる材料が様々な程度の炎症反応を誘発することはよく知られている。生体材料媒介性炎症反応の程度が癌細胞の移行の程度に影響を与えるならば、異なる組織適合性を有する材料は、差次的に黒色腫細胞動員に影響を与える可能性がある。この仮説を試験するために、PLA、水酸化アルミニウム、およびガラスからなるミクロスフェアを、同じ動物モデルを用いて試験した。予想したように、免疫組織化学的分析が示すように、これらの埋め込まれたミクロスフェアは異なる程度の炎症反応および黒色腫細胞移行を引き起こした(図3A)。PLAミクロスフェアは、水酸化アルミニウムおよびガラスからなるミクロスフェアよりも多くの炎症細胞(CD11b+)および黒色腫細胞(HMB45+)の動員を促すことが判明した(図3B)。両方の細胞型の数を比較することによって、発明者らの結果は、炎症反応の程度と黒色腫細胞動員との間に優れた相関がある(R2=0.9197)ことを示した(図3C)。これらの結果は、炎症反応が黒色腫細胞の遊走および、おそらく転移挙動に影響を与えるという発明者らの仮説を強く支持する。
発明者らの組織学的結果は、局所炎症反応が腹腔から皮下埋め込み部位に黒色腫細胞移行を誘引するという考えを支持するが、炎症組織/ミクロスフェア埋め込み部位が遊走している黒色腫細胞にとっての唯一の標的であるか否かは明らかではない。主要な臓器(肺、肝臓、腎臓、脾臓、およびリンパ節を含む)におけるGFP発現B16F10黒色腫細胞の全体的な分布を、組織学的分析を用いて評価した。皮下埋め込み部位に加えて、リンパ節および脾臓に多数の癌細胞が見られた。しかし、比較的低い密度の癌細胞が、皮膚、肺、肝臓、および腎臓に見られた(図4)。脾臓における黒色腫細胞の蓄積は、血液フィルター活性に関連付けられ得る。リンパ節における大量の癌細胞の蓄積は、腹膜から血液への黒色腫細胞遊走がリンパ系を介した通過を伴うことを示唆している。
ミクロスフェア埋め込み部位への癌細胞動員に関する上記の観察にもかかわらず、この動物モデルが、以前の他の癌転移モデルに似た細胞反応および生理学的反応を示すか否かはまだ明らかではなかった。このモデルの妥当性を試験するために、異物反応媒介性癌遊走を支配する分子プロセスを最初に同定した。CXCR4/CXCL12およびCCR7/CCL21の両方の経路が黒色腫癌転移において重要な役割を果たすことが示されているので、異物反応媒介性癌遊走における両経路の潜在的な役割を評価した。
以前の結果は、インプラント関連性の炎症産物が循環癌細胞を活発に動員することを支持する。次の問題は、癌細胞の動員が癌細胞遊走特異的ケモカインによって増強されるのか否かである。この答えを見つけるために、発明者がSDF−1αおよびEPOに興味を持ったのは、これらのケモカインの両方が癌細胞遊走を増強することが示されており、かつ転移性癌細胞で上方制御されているからである。Gomperts BN,Strieter RM.Chemokine−directed metastasis.Contrib Microbiol 2006;13:170−190;およびLugade,A.A.,et al,J Immunol,2005.174(12):p.7516−23。
白血病
AML細胞株を用いて、白血病を治療するための癌細胞トラップの有効性を試験した。AML細胞株の注射によってマウスに白血病を誘導した。循環する白血病細胞が40%に達成するまで異なる期間埋め込んだ後、EPO放出足場または対照足場(EPO無し)のいずれかを動物に埋め込んだ。その後、両群の動物の血液中の白血病細胞数を監視した。白血病細胞数が時間とともに増加することが判明した。一方、図14に示すように、白血病細胞数の増加は実質的に減速した。
近赤外標識B16F10黒色腫細胞を移植したマウスを用いて、癌転移の低減における癌細胞トラップの効果を検討した。具体的には、PEGヒドロゲルを癌細胞トラップの担体として使用した。PEGヒドロゲルを、RANTES(100ng/ml)、IL8(10ng/ml)または(対照として)生理食塩水と混合した。C57マウスに黒色腫細胞(107/マウス)を静脈内移植し、その後癌細胞トラップゲル1mlを皮下に注入した。図15に示すように、24時間の埋め込み後、対照よりも実質的に多くの黒色腫細胞が、RANTESまたはIL−8のいずれかを放出する癌細胞トラップへと動員されたことが判明した。さらに、対照との比較で、末梢血中の黒色腫細胞数は、RANTESまたはIL−8放出ヒドロゲルを有するマウスにおいて、それぞれ76%または82%減少した。
近赤外標識PC3前立腺癌細胞(107/動物)を腹腔内に移植したマウスを用いて、前立腺癌転移の低減における様々な癌細胞トラップの有効性を決定した。そのために、VEGF(50ng/インプラント)またはEPO(1,000 ID/インプラント)のいずれかを放出できる組織足場を作製した。これらの癌細胞トラップを担癌マウスの腹膜に移植した。Kodak社製インビボ撮像システムを用いて癌細胞動員の程度を監視した。図16に示すように、24時間の埋め込み後、対照よりも実質的に多くの前立腺癌細胞がVEGFまたはEPOのいずれかを放出する癌細胞トラップへと動員された。さらに、腹膜洗浄液における前立腺癌数も測定した。対照と比較して、VEGF放出またはEPO放出足場を有するマウスにおける腹膜液中の前立腺癌数は、それぞれ86%または91%低減したことが判明した。
物理吸着は、増殖因子を放出する足場を作製するために多くの研究で使用されてきたが、このような方法では1〜2日間の増殖因子の放出しか可能でない。放出期間を改善するために、増殖因子をコーティングした足場を作製するための化学結合プロセスが開発されてきた。残念ながら、このような化学反応は、足場材料特性および組み込まれたタンパク質の生物活性を変える場合が多く、また追加の複雑な化学反応を必要とする。このような欠点を克服するために、アルブミンマイクロバブル(MB)をポロゲン(図10A)および増殖因子担体として使用する新規な2ステップ多孔質足場作製手順を作り出した。Nair,A.,et al.,Novel polymeric scaffolds using protein microbubbles as porogen and growth factor carriers.Tissue Eng Part C Methods,2010.16(1):p.23−32。
多孔質足場の主な欠点は、外科的処置またはトロカールが埋め込みに必要とされることである。この状況を改善するために、研究を行ってタンパク質放出特性を有する水ベースの温度感受性ヒドロゲルを合成した。この努力の結果により、ポリエチレングリコール−ポリアクリル酸相互貫入ネットワーク(PEG−PAA−IPN)ヒドロゲルを生成した。沈殿重合法を用いてポリエチレンナノ粒子を最初に合成した。Tong Cai,M.M.,and Zhibing Hu,Monodisperse Thermoresponsive Microgels of Poly(ethylene glycol)Analogue−Based Biopolymers.Langmuir,2007.23(17):p.8663−8666を参照されたい。その後、PEGナノ粒子を、二次ポリアクリル酸(PAA)ネットワークを形成するためのシードとして使用した。PEG−PAA−IPNは、室温で様々なケモカインおよび薬物と容易に混合できる。皮下注入後、温度が上昇するにつれて、PEG−PAAナノ粒子は体内で膨潤して固体で多孔性のインプラントを形成した(図11A)。0%、3%、対5%のナノ粒子を含むヒドロゲルからのNIR標識ウシ血清アルブミン(BSA)の放出も監視した。予想されたように、PEG−PAA−IPNは、NIR−BSAの放出を実質的に延長した(図11B)。BSA放出の期間は、ポリマーの重量百分率に依存する(図11C)。同様の制御放出特性が、インスリンおよびEPOなどの他のタンパク質を用いても見出された。発明者らの結果は、PEG−PAA−IPNヒドロゲルが制御された方法で様々なタンパク質放出を容易に行うことができるという考えを支持する。
ケモカイン/増殖因子装填PLGA足場を、発明者らのタンパク質マイクロバブル作製法を用いて作製した。簡単に説明すると、様々なケモカインを有する2〜20%w/vのタンパク質溶液を、窒素ガスで重層し、10秒間、20kHzでプローブソニケータ(Ultrasonix社、ワシントン州ボセル)を用いて超音波処理した。タンパク質溶液は、単一タンパク質または異なる比率のタンパク質混合物で構成できる。潜在的なタンパク質候補には、アルブミン、コラーゲン、ゼラチン、免疫グロブリン、細胞外マトリックスタンパク質、フィブロネクチンなどが含まれる。タンパク質マイクロバブル溶液を1:1の比でPLGA(1,4−ジオキサン中3〜15%w/v)に添加し、穏やかに攪拌できる。その後、それらを液体窒素中で急冷し、0.01〜0.1ミリバールの真空で、フリーゾーン(Freezone)12凍結乾燥機(Labconco社、米国ミズーリ州カンザスシティ)で72時間凍結乾燥した。
近赤外標識PC3前立腺細胞を移植したマウスを用いて、癌転移の低減におけるヒドロゲル癌細胞トラップの効果を検討した。具体的には、PEGヒドロゲルを以下のように作製した。カルボキシル末端PEG誘導体ポリマーを、フリーラジカル重合を用いて合成した。簡単に説明すると、4,4’−アゾビス(4−シアノ吉草酸)および様々な重量比(10:1〜20:1)の2−(2−メトキシエトキシ)エチルメタクリレート(MEO2MA)およびオリゴ(エチレングリコール)モノメチルエーテルメタクリレート(分子量:475;OEOMA475)をエタノールに溶解して20重量%のモノマー溶液を形成した。溶液を10分間窒素ガスでパージし、6時間60℃でインキュベートした。その後、溶媒を真空下で蒸発させて除去し、粗ポリマーをDI水に再溶解し、DI水に対して透析で精製した後、凍結乾燥した。カルボキシル末端PEG誘導体ポリマーの低臨界溶液温度(LCST)を、UV−可視分光計を用いて測定した。OEOMA475に対するMEO2MAのモル比を変化させることにより、32℃のLCSTを有するカルボキシル末端PEG誘導体ポリマーが得られ、このポリマーを用いて下記のように熱ゲル化生物活性ヒドロゲル足場を作製した。PEGヒドロゲルへのケモカイン/サイトカインの組み込みは、物理吸着によって達成された。PEGヒドロゲルを、血管内皮増殖因子(VEGF)(100ng/ml)、エリスロポエチン(EPO)(100国際単位/ml)、間質由来因子−1α(SDF−1α)または(対照として)生理食塩水と混合した。その後、ヒドロゲル試料を20ゲージの針を介して、C57マウスの(皮膚の下の)皮下腔に注入した。その後、マウスに、PC3前立腺癌細胞を静脈内移植した(5×106/マウス)。24時間の移植後、多数のPC3細胞が、蛍光強度の増加によって反映されるように、ヒドロゲルインプラント部位に蓄積することが判明した。発明者らの結果は、VEGF、EPOまたはSDF−1αの局所放出が、インプラント部位(癌細胞トラップ)へのPC3前立腺癌細胞の動員を増加させたことを示している。図17を参照されたい。
異なるサイズのヒアルロン酸(HA)粒子(直径2、10、20および40μm)を、発明者らが公開した手順(米国特許第7,601,704号;Zou L,Nair A,Weng H, Tsai YT,Hu Z,Tang L.Intraocular pressure changes:an important determinant of the biocompatibility of intravitreous implants.PLoS One.2011;6(12):e28720.PMCID:3237488)に従って作製した。以下に説明するように、粒子を生成した。アセトンを、100:80(アセトン:HA溶液)の重量比で0.5重量%のHA溶液に加え、混合物を2時間攪拌した。アジピン酸ジヒドラジド(ADH)およびEDAC(EDACに対するADHのモル比1:1)を、0.05:100(ADH:HA)の重量比で混合物に添加して架橋された混合物を形成した。その後、この混合物を約24時間20℃で攪拌した後、約160:100(アセトン:HA溶液)の重量比で追加のアセトンを添加して最終混合物を形成した。最終混合物を20時間撹拌し、蒸留水に対して透析してHA粒子を形成した。2.5〜3.8の範囲のアセトン/水の重量比を維持しながら、HAの濃度を変えることにより、異なるサイズのHA粒子を作製できる。その後、HAに対するADHの重量比を変えることにより(0.01/100〜0.20/100)、様々な架橋密度を有する一連のHA粒子を調製した。
癌細胞トラップは、転移性癌細胞の動員を誘発するように設計されたインプラントである。このようなデバイスは、癌診断および癌治療の両方に使用できる。
癌細胞トラップからの様々な癌幹細胞ケモカイン/増殖因子の放出速度を決定するために実験を行った。各生体分子の最適な放出速度を以下に列挙する。
癌細胞トラップは、皮下空間および腹腔内の空洞に埋め込むことができる。動物実験を、ジャクソン・ラボラトリー(米国メイン州バーハーバー)からのC57BL/6マウス(6〜10週齢)を用いて行った。このマウス癌転移モデルは、2つの連続したステップで構成されている。最初に、ルイス肺癌(LLC)癌細胞(5×105細胞/0.2ml/マウス)を静脈内注射により動物に移植した。第2に、EPO装填ナノ粒子癌細胞トラップ(600国際単位/1ml)を皮下空間または腹腔内空間に注入した。4週間の癌細胞トラップの埋め込み後、肺における転移癌病巣数を定量した。皮下空間(皮膚の下)および腹腔内空間(腹腔内)の両方への癌細胞トラップの埋め込みは、いずれも肺におけるLLC癌細胞病巣形成の低下に有効であることが見出された。図21を参照されたい。
循環癌細胞の低減または排除におけるヒドロゲル癌細胞トラップの有効性を試験した。動物実験を、ジャクソン・ラボラトリー(米国メイン州バーハーバー)からのC57BL/6マウス(6〜10週齢)を用いて行った。近赤外色素標識したB16F10黒色腫癌細胞またはLLC癌細胞(5×106細胞/0.2ml/マウス)を静脈内注射により動物に移植した。様々なケモカイン/増殖因子(EPO、600国際単位/1ml;SDF−1α 10μg/1ml、RANTES/CCL5 600ng/ml、またはHGF/SF 900ng/ml)を装填したPEGヒドロゲルを、動物の背中の皮下空間に注入した。24時間の癌細胞移植後、血液を各動物から採取し、その後、白血球の総数のうちの癌細胞の割合を、フローサイトメトリー法を用いて定量した。様々な癌細胞トラップが循環中の癌細胞数を低減できることが判明した。図22および図23を参照されたい。
癌細胞トラップの埋め込みが癌細胞の広がり−転移を低減できるか否かを調べるために、さらなる研究を行った。答えを見つけるために、近赤外色素標識LLC癌細胞(5〜106細胞/0.2ml/マウス)を静脈内注射によってC57マウスに移植した。EPO装填PEGヒドロゲル(600国際単位/1ml;ヒドロゲルとして標識)およびEPO装填PLA足場(600国際単位/1ml、足場として標識)をそれぞれ、動物の背中の皮下空間に注入または埋め込んだ。24時間の癌細胞移植後、全ての臓器を動物から単離し、様々な臓器におけるLLC細胞の分布を、Kodak社製インビトロイメージングシステムを用いて決定した。実際、ヒドロゲル癌細胞トラップおよび足場癌細胞トラップの埋め込みは、LLC転移の主な臓器である肝臓、脾臓および肺において動員される癌細胞数を実質的に低減することが判明した。図24を参照されたい。
温度感受性ヒドロゲルナノ粒子の作製は、最近の出版物(Cai T,Hu P,Sun M,Zhou J,Tsai Y−T,Baker DW,Tang L.Novel thermogelling dispersions of polymer nanoparticles for controlled protein release.Nanomedicine 8(8):1301−8,2012)に記載されている。ナノ粒子に、ドキソルビシン(300μg/ml)およびパクリタキセル(30mg/ml)の存在下または非存在下でEPO(600国際単位/1ml)を装填した。そのために、EPO(600国際単位)、ドキソルビシン(300μg)またはパクリタキセル(30mg)を、室温でヒドロゲルナノ粒子50μgと混合した。埋め込み後に、ドキソルビシンおよびパクリタキセルのインビボ放出速度の平均値を、それぞれ10μg/日および1mg/日で測定した。
1Gyでの照射後C57BL/6マウスに0.8×105の競合細胞と共に0.5×105のAE9細胞を移植することにより、AE9 AML(急性骨髄芽球性白血病)モデルを樹立した。その後、末梢血AML細胞がフローサイトメトリーにより10%超検出されるまで、これらの動物をケージで飼育した。マウスを無作為にペアにして、EPO−PLGA足場またはブランクPLGA足場を埋め込んだ。足場の埋め込み後の細胞数および寿命を監視した。図27A〜Cおよび図28A〜Cを参照されたい。
Claims (12)
- 対象の癌転移を治療または予防する方法に用いられる癌細胞トラップであって、前記癌細胞トラップが、
i) 微粒子、
ii) ナノ粒子、
iii)足場構造、または
iV) ヒドロゲル、
を含み、
循環癌細胞が前記癌細胞トラップに動員され、前記循環癌細胞が、白血病細胞、黒色腫細胞、前立腺癌細胞および肺癌細胞からなる群から選択され、前記癌細胞トラップが、当該癌細胞トラップから放出されるエリスロポエチン(EPO)を含み、前記EPOは、前記癌細胞トラップ中の前記循環癌細胞の動員及び蓄積を可能にし、
前記癌細胞トラップは、化学療法剤をさらに含み、および/または、前記方法は、前記癌細胞トラップを放射線に暴露することをさらに含み、それによって前記対象の癌転移を治療または予防する、癌細胞トラップ。 - 前記癌細胞トラップがヒドロゲルを含む、請求項1に記載の癌細胞トラップ。
- 前記癌細胞トラップが足場構造を含む、請求項1に記載の癌細胞トラップ。
- 前記足場が分解性ポリマーおよびポリペプチドを含む、請求項3に記載の癌細胞トラップ。
- 前記癌細胞トラップが微粒子および/またはナノ粒子を含む、請求項1に記載の癌細胞トラップ。
- 前記ヒドロゲルが、1以上のポリマー材料、多糖類、ポリエチレングリコール−ポリアクリル酸貫入ネットワーク(PEG−PAA−IPN)ヒドロゲル、ポリエチレングリコール、細胞外マトリックスタンパク質、フィブリノーゲン、ヒドロゲル微粒子およびそれらの組み合わせからなる群から選択される材料を含む、請求項2に記載の癌細胞トラップ。
- 前記足場が、PLGA、アルブミン、コラーゲン、ゼラチン、免疫グロブリン、細胞外マトリックスタンパク質、フィブロネクチンおよびそれらの組み合わせを含む、請求項3に記載の癌細胞トラップ。
- 前記癌細胞トラップが前記対象に埋め込まれている、請求項1〜7のいずれか1項に記載の癌細胞トラップ。
- 前記癌細胞トラップが前記対象に注入されている、請求項1〜7のいずれか1項に記載の癌細胞トラップ。
- 前記対象がヒトである、請求項1〜9のいずれか1項に記載の癌細胞トラップ。
- 前記癌細胞トラップが化学療法剤をさらに含む、請求項1〜10のいずれか1項に記載の癌細胞トラップ。
- 癌転移を検出するためのエクスビボの方法であって、前記方法は、転移性癌細胞の存在について請求項1〜11のいずれか1項に記載の癌細胞トラップをアッセイすることを含み、前記癌細胞トラップは、対象に投与されており、前記転移性癌細胞が前記癌細胞トラップに遊走および蓄積されており、それによって前記対象における癌転移を検出する、方法。
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