JP2008533203A - 官能基化された磁性ナノ粒子およびその使用法 - Google Patents
官能基化された磁性ナノ粒子およびその使用法 Download PDFInfo
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Abstract
Description
本発明は、磁性ナノ粒子の分野、および、組織の画像化、例えば核磁気共鳴画像法における、その使用の分野に属する。なお本出願は、2005年3月21日に出願され、その全体が参照により本明細書に組み入れられている、米国仮特許出願第60/664,046号の恩典を主張するものである。
ナノ粒子は、そのサイズが典型的には直径1ナノメートル程度から数百ナノメートル程度の範囲にわたる、非常に小さな粒子である。その小さなサイズによって、染料及び顔料;美観的または機能的なコーティング;生物学的発見、医学的画像化、および治療のための道具;磁気記録媒体;量子ドット;ならびにさらに均質でナノサイズの半導体などの様々な製品の製造のために、ナノ粒子を活用することができる。
米国特許第6,548,264号(特許文献1)、同第6,767,635号(特許文献2); Berry and Curtis (2003) J Phys. D: Applied Physics 36:R198-R206(非特許文献1); Pankhurst et al. (2003) J Phys. D: Applied Physics 36:R167-R181(非特許文献2); Dousset et al. (1999) Am. J. Neuroradiol. 20:223-227(非特許文献3); Dunning et al. (2004) J Neurosci. 24:9799-9810(非特許文献4); Dousset et al. (1999) Magnetic Resonance in Medicine 41:329-333(非特許文献5); Moghimi et al. (2001) Pharmacol. Rev. 53:283-318(非特許文献6)。
本発明は、官能基を含む、官能基化された磁性ナノ粒子を提供し、該官能基化された磁性ナノ粒子は、脳組織、骨、及び血管組織を含む組織に対する示差的結合を示す。本発明はさらに、本官能基化された磁性ナノ粒子を含む薬学的組成物を含有する組成物を提供する。本発明はさらに、本官能基化された磁性ナノ粒子の使用を含む、診断法及び調査法を提供する。本発明はさらに、核磁気共鳴画像法(MRI)可視薬物送達系、および、その合成法を提供する。MRI可視薬物送達系は、MRIを用いた薬物の分布の決定及び組織特異的薬物送達における用途を有する。
本明細書で使用される「ナノ粒子」という用語は、直径約1〜1000nmの粒子を指す。同様に、「ナノ粒子」という用語は、平均直径が約1〜1000nmの複数の粒子を指す。
本発明は、それに接合した官能部分を有する、官能基化された磁性ナノ粒子を提供し、該官能基化された磁性ナノ粒子は、特定の種類の組織、例えば脳組織、骨、または血管組織に対する示差的結合を示す。本発明はさらに、本官能基化された磁性ナノ粒子を含む組成物を提供する。本発明はさらに、本官能基化された磁性ナノ粒子の使用を含む、診断法、予後判定法、治療法、及び調査法を提供する。本発明はさらに、核磁気共鳴画像法(MRI)可視薬物送達系、および、その合成法を提供する。MRI可視薬物送達系は、MRIを用いた薬物の分布の決定及び組織特異的薬物送達における用途を有する。
本発明は、それに接合した官能部分を有する、官能基化された磁性ナノ粒子(MNP)を提供し、該官能基化された磁性ナノ粒子は、特定の種類の組織、例えば脳、骨、または血管組織に対する示差的結合を示す。本官能基化された磁性ナノ粒子は、様々な診断、予後判定、治療、および調査の用途に関して有用である。
本ナノ粒子は、一般に、約1 nm〜約1000 nm、例えば、約1 nm〜約10 nm、約10 nm〜約50 nm、約50 nm〜約100 nm、約100 nm〜約250 nm、約250 nm〜約500 nm、約500 nm〜約750 nm、または約750 nm〜約1000 nmの範囲の平均サイズを有する。一部の態様において、平均直径は、約10 nm〜約1000 nm、例えば、約10 nm〜約20 nm、約20 nm〜約40 nm、約40 nm〜約60 nm、約60 nm〜約80 nm、約80 nm〜約100 nm、約100 nm〜約200 nm、約200 nm〜約400 nm、約400 nm〜約600 nm、約600 nm〜約800 nm、または約800 nm〜約1000 nmの範囲であると考えられる。
一部の態様において、組織への送達のために、例えば、罹患脳組織、罹患血管組織、または罹患骨組織などの特定の組織への標的化された送達のために、本官能基化された磁性ナノ粒子は1つまたは複数の治療剤をさらに含む。治療剤の性質は、治療される状態または病理に部分的に依存しうる。例えば、疾患がてんかんである場合、適切な治療剤には抗てんかん性の(anti-eizure)薬剤が含まれるが、これに限定されない。疾患が脳腫瘍である場合、適切な治療剤には抗新生物薬が含まれるが、これに限定されない。疾患が、血管組織または骨組織の炎症状態である場合、適切な治療剤には抗炎症剤が含まれるが、これに限定されない。
アセチルコリンおよび合成コリンエステル、天然のコリン作動性アルカロイドおよびその合成コンジナー、抗コリンエステラーゼ薬、神経節興奮薬、アトロピン、スコポラミン、および関連する抗ムスカリン薬、エピネフリン、ノルエピネフリン、およびドーパミンなどのカテコールアミンおよび交感神経作動薬、アドレナリン作動性アゴニスト、アドレナリン作動性受容体アンタゴニスト、GABA、グリシン、グルタメート、アセチルコリン、ドーパミン、5-ヒドロキシトリプタミン、およびヒスタミンなどの伝達物質、神経刺激ペプチド;オピオイド鎮痛剤およびアンタゴニストなどの鎮痛剤および麻酔剤;ベンゾジアゼピン、バルビツレート、抗ヒスタミン剤、フェノチアジン、およびブチルフェノン(butylphenone)などの麻酔前投薬および麻酔投薬;オピオイド;制吐剤;アトロピン、スコポラミン、またはグリコピロレートなどの抗コリン作動薬;コカイン;クロラール誘導体;エトクロルビノール;グルテチミド;メチプリロン;メプロバメート;パラアルデヒド;ジルスフィラム;モルヒネ、フェンタニル、およびナロキソン;中枢作用性鎮咳剤;フェノチアジン、チオキサンテン、およびその他の複素環化合物(例えばハルペリオドール(halperiodol))などの精神病薬;デシミプラミンおよびイミプラミンなどの三環系抗うつ剤;異型抗うつ剤(atypical antidepressant)(例えばフルオキセチンおよびトラゾドン)、イソカルボキサジドなどのモノアミンオキシダーゼ阻害剤;リチウム塩;クロルジアゼポキシドおよびジアゼパムなどの抗不安薬;ヒダントイン、抗痙攣バルビツレート、イミノスチルビン(iminostilbine)(カルバマゼピンなど)、スクシンイミド、バルプロ酸、オキサゾリジンジオン、およびベンゾジアゼピンを含む抗てんかん剤;L-DOPA/CARBIDOPA、D2、およびD3アゴニストおよびアンタゴニスト、アポモルフィン、アマンタジン、エルゴリン、セレジリン(selegeline)、ロピニロール(ropinorole)、メシル酸ブロモクリプチン、および抗コリン作動薬などのパーキンソン病治療薬;バクロフェン、ジアゼパム、およびダントロレンなどの鎮痙剤;興奮性アミノ酸アンタゴニスト、神経栄養因子および脳由来神経栄養因子、毛様神経栄養因子、または神経成長因子などの神経保護剤;ニューロトロフィン(NT)3(NT3);NT4およびNT5;ガングリオシド;神経修復剤;オピオイドアンタゴニストおよび抗うつ剤を含む、依存症および薬物濫用の治療のための薬物;ヒスタミン、ブラジキニン、カリジン、それぞれの各アゴニストおよびアンタゴニストなどのオータコイドおよび抗炎症剤;寄生虫感染症および微生物病に対する化学療法剤;アルキル化剤(例えばニトロソ尿素)および代謝拮抗剤を含む抗癌剤;ナイトロジェンマスタード、エチレンアミン、およびメチルメラミン(methylmelamine);アルキルスルホネート;葉酸類似体;ピリミジン類似体、プリン類似体、ビンカアルカロイド;ならびに抗生物質。
広範な官能基(部分)を、磁性ナノ粒子に接着することができる。磁性ナノ粒子への接着に適した官能基は、予め選択された特定の脳組織、血管組織、または骨組織に、直接的または間接的に、示差的にまたは選択的に結合する。上述したとおり、一部の態様において、官能基は治療剤である。
1) グルコースまたは、フルデオキシグルコースなどのグルコース誘導体、ここでグルコースは、正常な非てんかん組織と比べて、示差的にてんかん組織に取り込まれる;
2) N-メチル-D-アスパルテート(NMDA)、ここでNMDAは、細胞表面のNMDA受容体の増加または減少に応じて、てんかん組織細胞の受容体に示差的に結合する;
3) α-メチルトリプトファン、ここで、α-メチルトリプトファンは、結節性硬化症を有する小児の難知性てんかんにおいて、てんかん誘発性結節(epileptogenic tuber)に選択的に取り込まれる;
4) 腫瘍壊死因子(TNF)およびIL-1、IL-6、IL-10などのインターロイキンなどのサイトカイン、ここで、てんかん組織上のIL-1受容体、IL-6受容体、またはIL-10受容体の発現の増大により、てんかん組織によるIL-1接合磁性ナノ粒子またはIL-6接合磁性ナノ粒子の大量の取り込みがもたらされる;
5) γ-アミノ酪酸(GABA)、ここで、GABAA(GABAA-α1-6、GABAA-β1-3、GABAA-γ2、GABAA-δ、およびGABAA-ε)受容体のレベルにおいて、受容体の神経変性誘発性損失は、歯状回および海馬体のその他部分における受容体サブユニットの著しく改変された発現に付随して起こり、このことは、GABAA受容体の生理学的および薬理学的な改変を示す;
6) アルフェンタニル、ブプレノルフィン、カルフェンタニル(carfentanil)、コデイン、ジヒドロコデイン、ジプレノルフィン、エトルフィン、フェンタニル、ヘロイン、ヒドロコドン、ヒドロモルホン、LAAM、レボルファノール、メペリジン、メタドン、モルヒネ、ナロキソン、ナルトレキソン、β-ヒドロキシ-3-メチルフェンタニル、オキシコドン、オキシモルホン、プロポキシフェン、レミフェンタニル(remifentanil)、スフェンタニル、チリジン、トラマドールなどの、アヘン剤またはオピオイド;
7) セロトニン、例えば5-ヒドロキシトリプタミン-1A(5HT1A)、およびその他のセロトニン受容体アゴニスト;
8) 3-メチルホスフィニコプロピオン酸(3-methylphosphinicopropionic;MPPA);
9) フルマゼニル、ロラゼパム、ジアゼパム、アルプラゾラム、ブロチゾラム、クロルジアゼポキシド、クロバザム、クロナゼパム、クロラゼペート、デモキセパム(demoxepam)、エスタゾラム、フルラゼパム、ハラゼパム、ミダゾラム、ニトラゼパム、ノルダゼパム、オキサゼパム、プラゼパム、クアゼパム、テマゼパム、およびトリアゾラムなどの、ベンゾジアゼピン;
10) グルタメート;ならびに
11) アセチルコリンおよびその他のアセチルコリン受容体アゴニスト。
本発明はさらに、本官能基化された磁性ナノ粒子を含む薬学的組成物を含有する組成物を提供する。本官能基化された磁性ナノ粒子を含む組成物は、1つまたは複数の、塩、緩衝液、pH調節剤、非イオン性界面活性剤、プロテアーゼ阻害剤、ヌクレアーゼ阻害剤などを含有する。
本発明はさらに、血液脳関門(BBB)を横断する、本官能基化された磁性ナノ粒子を作製する方法を提供する。本方法は概して、直接的にまたはリンカーを介して、官能基を磁性ナノ粒子に接着する段階を含む。一部の態様において、磁性ナノ粒子は、共有結合的にまたは非共有結合的に、官能基またはリンカーが接着した層でコーティングされる。官能基化されたMNPは、いくつかの方法のいずれかでBBBを横断して移行するために調製される。
一部の態様において、官能基化されたMNPまたは官能基化されていないMNPは、微生物、例えば細菌またはウイルスに取り込まれる。官能基化されたまたは官能基化されていないMNPを含む微生物は、インビボにおけるそのような微生物の位置および/または動きの可視化(画像化)に有用である。
本発明は、核磁気共鳴画像法(MRI)可視薬物送達系、および、その合成法を提供する。本MRI可視薬物送達系は、上述の官能基化されたMNPを含み、ここで、該官能基化されたMNPは少なくとも1つの薬物(例えば治療剤)を含む。本MRI可視薬物送達系は、体内の薬物分布を決定するための一部の態様において有用である。本MRI可視薬物送達系は、組織特異的薬物送達に関するその他の態様において有用である。例えば、本官能基化されたMNPが組織特異的結合部分および治療剤の両方を含む場合、官能基化されたMNPは組織特異的薬物送達系である。一部の態様において、本薬物送達系は、BBBの横断のために適合化されており、例えば、薬物送達系は、BBBの横断を提供する1つまたは複数の要素を含む。
本発明はさらに、調査用途、診断用途、および治療用途を含む、本官能基化された磁性ナノ粒子の有用性が見出される様々な用途を提供する。
本発明は、特定の脳組織を同定または検出するための診断法を提供する。本方法は、概して、本官能基化された磁性ナノ粒子を個体に投与する段階;および、該官能基化された磁性ナノ粒子が結合した脳の領域を画像化する段階を含む。典型的には、本官能基化された磁性ナノ粒子を含む液状薬学的組成物を個体に注射し(例えば静注)、画像化技術によって、該官能基化された磁性ナノ粒子を検出する。多くの態様において、画像化は、核磁気共鳴画像法により行われる。したがって本発明の方法は、生きた対象における特定の脳組織の画像化を可能にする。本発明の方法は、脳内の罹患組織の検出を可能にし、かつ、医療従事者に、疾病の治療を受けている患者の経過をモニタリングする方法も提供する。
本発明は、本官能基化された磁性ナノ粒子を用いる調査用途を提供する。本官能基化された磁性ナノ粒子を対象に注射し、該官能基化された磁性ナノ粒子を画像化により検出する。調査用途には、所与の被験薬剤が特定の疾病に与える効果の分析が含まれる。調査用途には、様々な外部および内部の刺激が正常なおよび罹患した脳組織に与える効果の試験がさらに含まれる。調査用途には、(外部または内部の)様々な損傷要因(compromising cause)が正常なおよび罹患した血管組織または骨組織に与える効果の試験がさらに含まれる。
調査用途には、所与の被験薬剤が特定の疾病に与える効果を分析するためのスクリーニング法が含まれる。したがって、一部の態様において、本発明は、以下の段階を含む、神経疾患に対する候補治療剤を同定するための方法を提供する:神経疾患の実験用(非ヒト)動物モデル(例えば、多発性硬化症、アルツハイマー病、脳腫瘍、てんかんなどの実験用動物モデル)に、被験薬剤を投与する段階;および、存在する場合、被験薬剤が該神経疾患に関連する神経学的特徴に与える効果を決定する段階。被験薬剤の効果の決定は、以下の段階によって行われる:本官能基化された磁性ナノ粒子を含む組成物を非ヒト動物モデルに投与する段階であって、該官能基化された磁性ナノ粒子が、神経疾患に冒されたまたはそれに関連する罹患脳組織への示差的結合を示す段階;および、該動物の脳において該官能基化された磁性ナノ粒子を検出する段階。典型的には、検出は核磁気共鳴画像法により行われる。
本発明は、疾病、疾患、または状態を治療する方法を提供し、該方法は概して、本官能基化されたMNPの有効量を、その必要がある個人に投与する段階を含む。それらの態様の一部において、本官能基化されたMNPは、治療剤(「薬物」)、および、組織特異的な(例えば罹患組織特異的な)標的化を提供する官能部分を含む。
以下の実施例は、本発明の作製法および使用法についての完全な開示および説明を当業者に提供するために述べられており、またこれは、本発明者らが本発明者らの発明とみなす範囲を制限することも、下記の実験が実施された全てまたは唯一の実験であると示すことも、意図してはいない。使用される数値(例えば、量、温度など)に関する精度を保証するように努力がなされているが、いくらかの実験誤差および偏差が考慮されるべきであろう。特に示さない限り、割合とは重量あたりの割合、分子量とは重量平均分子量、温度とは摂氏度、圧力とは大気圧またはほぼ大気圧である。標準的な略語、例えば、bp(塩基対)、kb(キロベース)、pl(ピコリットル)、sまたはsec(秒)、min(分)、hまたはhr(時間)、aa(アミノ酸)、kb(キロベース)、bp(塩基対)、nt(ヌクレオチド)、i.m.(筋肉内)、i.p.(腹腔内)、s.c(皮下)などが使用されうる。
ナノ粒子調製
ヒト血清アルブミン(HSA)200 mgを、磁性ナノ粒子(MNP;例えば磁鉄鉱粒子)を含む水2.0 mlに溶解させる。0.01 Mおよび0.1 MのNaOH溶液の滴加により、絶えず撹拌しながら溶液のpHを8.4まで上昇させる。絶えず撹拌しながら、エタノール8.0 mlの滴加により10% HSA溶液の脱溶媒和(desolvatation)を行う。エタノールの添加後、8%グルタルアルデヒド溶液235μlを加える。24時間後、得られたナノ粒子を3倍遠心分離(threefold centrifugation)(16.100 g、8 min)によって精製し、水中に再分散させる。再分散は、超音波処理槽中で行う。本方法を用いて合成されるHSA-MNPは、調製物のpHおよび、非接合型MNPまたは接合型MNPの添加に応じて、約60 nm〜約990 mnの平均直径を有する。AMT-MNPナノ粒子の平均直径は約20 nmであり、サイズの範囲は約10 nm〜約40 nmである。
ナノ粒子に結合するNeutrAvidin(商標)
スルフヒドリル反応性粒子系を得るために、精製ナノ粒子を、架橋剤NHS-PEG3400-Mal(Nektar, Huntsville, USA;ここで、「NHS」とは、N-ヒドロキシスクシンイミドであり、「Mal」とはマレイミドであり、「PEG3400」とは、平均分子量3400ダルトンのポリ(エチレングリコール)である)を用いて活性化させる。体積500μlの架橋溶液(PBS緩衝液(pH 8.0)中の60 mg/ml NHS-PEG3400-Mal)を、2.0 mlのナノ粒子(NP)分散(PBS緩衝液(pH 8.0)中の20 mg/ml)に加える。混合物を、振とうしながら室温で1時間インキュベートする。その後、上述のように、活性化されたナノ粒子を遠心分離および再分散によって精製する。
apoEビオチン化
NeutrAvidin(商標)修飾ナノ粒子へのapoEの接着を可能にするために、PFP-ビオチン(Pierce, Rockford, USA)を用いた標準的タンパク質修飾プロトコールにしたがって、apoEをビオチン化する。PFP-ビオチンとは、ビオチンのペンタフルオロフェニルエステルである。apoEを、濃度167μg/mlでPBS(pH7.0)に溶解させる。ビオチン化タンパク質を、デキストラン脱塩カラムによって、低分子量化合物から分離させる。ビオチン化プロセスの効率は、後述のウエスタンブロッティングにより決定する。
薬物を負荷されたNeutrAvidin(商標)修飾ナノ粒子を水中に再分散させ、粒子濃度20 mg/mlにする。続いて、167μgのビオチン化apoE(ビオチン-apoE)を添加し、10 mg/ml NPおよび80μg/ml apoEの最終濃度を得る。12時間のインキュベーション後、後述の免疫ブロット法により、未結合apoEについてNP上清を解析する。
約20 mgの精製NeutrAvidin(商標)修飾HSA-MNPを、6.6 mgの薬物と共に、エタノール/水溶液中でインキュベートする。2時間のインキュベーション期間後、遠心分離および再分散によって、未結合の薬物を除去する。
上述のスルフヒドリル反応性粒子系を達成するため、架橋剤NHS-PEG3400-Malを用いて、HSAナノ粒子を得る。続いて、ヘテロ二官能性架橋によって、apoEを活性化HSAナノ粒子に接合させる。異なるapoE誘導体(apoE3、apoE2 Argl42Cys、apoE Sendai)のアリコート(500μg)を、TEA緩衝液(pH8.0)1.0 mlに溶解させ、2-イミノチオラン(トラウト試薬)を50倍過剰モル濃度で添加する。室温で12時間インキュベートした後、サイズ排除クロマトグラフィー(D-SaltTMカラム)によって、チオレート化タンパク質を精製する。接合のため、チオレート化された精製apoE 500μgを、スルフヒドリル反応性HSAナノ粒子25 mgに加える。混合物を、振とうしながら室温で12時間インキュベートする。未反応のチオレート化apoEを、遠心分離、および、エタノール/水中(2.6%エタノールv/v)の粒子の再分散により除去する。
上述のように、apoEを含まないがポリソルベート80でコーティングされたナノ粒子(NP)を、NeutrAvidin(商標)修飾ナノ粒子への薬物の吸着によって調製する。次に、薬物を負荷されたナノ粒子を、ポリソルベート80(1% m/v)溶液と共に30分間インキュベートし、使用する。
α-メチルトリプトファン(AMT)、神経伝達物質などの組織特異的リガンドは、遊離したアミノ基またはカルボキシル基とHSA中で共役するか、または、ポリカーボンリンカー(例えばPEG)を介して、もしくはチオール結合やその他の接着部分を通じて、共役する。
安定剤(デキストラン70,000またはPluronic F68)0.1 gを、絶えず撹拌しながら10 mlの0.001 M HClに加えた。2種類の溶液を調製した:1) 10 mlの0.001 M HCl中にDextran 70,000(Sigma-Aldrich)0.1 gを含む溶液;および;2) 10 mlの0.001 M HCl中でPluronic F68(Sigma, Inc.)0.1 gを含む第二の溶液。以下の4種類の調製物を調製した:1) 官能基化されていないMNPをPluronic F68溶液に加えた;2) 官能基化されていないMNPをDextran溶液に加えた;3) 官能基化されたMNP(AMT-MNP)をPluronic F68溶液に加えた;および4) 官能基化されたMNP(AMT-MNP)をDextran溶液に加えた。500 rpmで撹拌しながら、100μgのシアノアクリレートモノマー(Sicomet, Sichel-Werke, GmbH)を、各調製物の流体の水面のすぐ下にゆっくりと添加した。
α-メチルトリプトファン(AMT)により官能基化され、デキストランでコーティングされた磁赤鉄鉱(γ-Fe2O3)MNPを、以下の様に調製した。
図3A〜図3Bは、上述の様に調製されたHSAマトリクス内でのAMT-MNPの透過型電子顕微鏡(TEM)画像を示す。図3AはHSA-MNP粒子を示すが、ここで、HSA(矢頭)およびAMT-MNP(矢印)が示されている。図3Bは、HSAマトリクス内のAMT-MNP粒子を示す。図3Cは、MNPの別の分布を示す;図3Dは、図3C内で黒い四角に仕切られた領域の拡大図を示し、これは、MNPのコア内での磁性粒子(TEM高密度領域、矢頭)の存在を示す。図4Aおよび図4Bは、上述の様に調製したPBCA-MNPのTEM顕微鏡写真を示す。図4Aは、PBCA粒子(矢頭)および、PBCA粒子の表面に吸着されたAMT-MNP(矢印)を示す。図4Bは、図4A内で黒い四角に区切られた領域の拡大図を示す。図4Bに示された拡大図は、PBCA粒子の表面へのAMT-MNP(矢印)の吸着を示す。
官能基化されていないMNPおよびAMT接合MNPを、てんかんのカイニン酸(KA)モデルに投与した。データにより、AMT-MNPがてんかん組織に対する親和性を示すことが実証された。
Claims (35)
- 以下を含む、薬学的組成物:
a) 脳内の組織に対して示差的親和性を有する官能基を含む、官能基化された磁性ナノ粒子(MNP)であって、哺乳動物対象の血流に導入された場合、該対象の血液脳関門を横断することができかつ脳組織に特異的に結合することができる、官能基化された磁性ナノ粒子;および
b) 薬学的に許容される担体。 - 組織が罹患組織である、請求項1記載の組成物。
- 罹患組織が、脳腫瘍、てんかん病変、アルツハイマー病に関連するプラーク、多発性硬化症に冒された組織、ハンチントン病に冒された組織、パーキンソン病に冒された組織、および、筋萎縮性側索硬化症に冒された組織から選択される、請求項2記載の組成物。
- 組織が、外部または内部の刺激に曝露された組織である、請求項1記載の組成物。
- 官能基が、脳組織中に存在するエピトープに特異的に結合する抗体である、請求項1記載の組成物。
- 官能基が、脳組織中に存在する細胞の表面または内部に存在する受容体に特異的に結合するリガンドである、請求項1記載の組成物。
- 官能基化されたMNPが治療剤をさらに含む、請求項1記載の組成物。
- 官能基化されたMNPがアルブミンマトリクス内でカプセル化される、請求項1記載の組成物。
- 官能基化されたMNPがアポリポタンパク質を含む、請求項1記載の組成物。
- 官能基化されたMNPがポリ(ブチルシアノアクリレート)(PBCA)を含む、請求項1記載の組成物。
- 官能基化されたMNPがPBCA粒子の表面に接着する、請求項10記載の組成物。
- 官能基化されたMNPが界面活性剤を含む、請求項1記載の組成物。
- 界面活性剤が、モノオレイン酸ポリオキシエチレンソルビタン、モノパルミチン酸ポリオキシエチレンソルビタン、モノステアリン酸ポリオキシエチレンソルビタン、およびモノラウリン酸ポリオキシエチレンソルビタンから選択される、請求項12記載の組成物。
- 界面活性剤が、ポリエチレンオキシドとポリプロピレンオキシドのブロックコポリマーである、請求項12記載の組成物。
- 官能基化されたMNPがポロキサミンを含む、請求項12記載の組成物。
- 以下を含む、薬学的組成物:
a) 再狭窄のリスクを有する炎症を起こした血管組織に対して示差的親和性を有する官能基を含む、官能基化された磁性ナノ粒子であって、哺乳動物対象の血流に注射された場合、炎症を起こした血管組織に特異的に結合することができる、官能基化された磁性ナノ粒子;および
b) 薬学的に許容される担体。 - 以下を含む、薬学的組成物:
a) 罹患骨組織に対して示差的親和性を有する官能基を含む、官能基化された磁性ナノ粒子であって、哺乳動物対象の血流に注射された場合、罹患骨組織に特異的に結合することができる、官能基化された磁性ナノ粒子;および
b) 薬学的に許容される担体。 - 糖尿病、損傷、または、骨組織における炎症反応を引き起こすその他の損傷性の(compromising)要素の結果として、骨組織が炎症を起こす、請求項17記載の組成物。
- 以下を含む、薬学的組成物:
a) 脳内のてんかん組織に対して示差的親和性を有する官能基で誘導体化された磁性ナノ粒子であって、哺乳動物対象の血流に注射された場合、該対象の血液脳関門を横断することができかつ脳内のてんかん組織に特異的に結合することができる、磁性ナノ粒子;および
b) 薬学的に許容される担体。 - 官能基がグルコースである、請求項19記載の薬学的組成物。
- 官能基がN-メチル-D-アスパルテートである、請求項19記載の薬学的組成物。
- 官能基がα-メチルトリプトファンである、請求項19記載の薬学的組成物。
- 官能基がサイトカインである、請求項19記載の薬学的組成物。
- 官能基がγ-アミノ酪酸である、請求項19記載の薬学的組成物。
- 官能基がアヘン剤またはオピオイド化合物である、請求項19記載の薬学的組成物。
- 以下の段階を含む、脳疾患の診断法:
a) 官能基化された磁性ナノ粒子を含む組成物を哺乳動物対象に投与する段階であって、該官能基化された磁性ナノ粒子が、脳疾患に冒された脳内の組織に対して示差的親和性を有する官能基を含み、かつ、哺乳動物対象の血流に注射された場合、該対象の血液脳関門を横断することができる、段階;および
b) 官能基化された磁性ナノ粒子の存在を脳内で検出する段階。 - 脳疾患が、脳腫瘍、てんかん、アルツハイマー病、多発性硬化症、ハンチントン病、パーキンソン病、筋萎縮性側索硬化症、薬物依存、および精神疾患から選択される、請求項26記載の方法。
- 組成物が静脈注射によって投与される、請求項26記載の方法。
- 検出段階が、核磁気共鳴画像法によって行われる、請求項26記載の方法。
- 以下の段階を含む、再狭窄のリスクを有する血管組織を検出する方法:
a) 官能基化された磁性ナノ粒子を含む組成物を哺乳動物対象に投与する段階であって、該官能基化された磁性ナノ粒子が、炎症を起こした血管組織に対して示差的親和性を有する官能基を含み、かつ、哺乳動物対象の血流に注射された場合、炎症を起こした血管組織に特異的に結合することができる、段階;および
b) 官能基化された磁性ナノ粒子の存在を血管組織内で検出する段階。 - 以下の段階を含む、哺乳動物対象における罹患骨組織を検出する方法:
a) 官能基化された磁性ナノ粒子を含む組成物を哺乳動物対象に投与する段階であって、該官能基化された磁性ナノ粒子が、罹患骨組織に対して示差的親和性を有する官能基を含み、かつ、哺乳動物対象の血流に注射された場合、罹患骨組織に特異的に結合することができる、段階;および
b) 官能基化された磁性ナノ粒子の存在を骨組織内で検出する段階。 - 以下の段階を含む、脳疾患を治療する薬剤の同定法:
被験薬剤を、脳疾患の非ヒト動物モデルに投与する段階;および
存在する場合、被験薬剤が脳疾患の神経学的特徴に与える効果を決定する段階であって、該決定段階が、i) 神経疾患に冒されたまたはそれに関連する罹患脳組織への示差的結合を示す官能基化された磁性ナノ粒子を含む組成物を、非ヒト動物モデルに投与すること;および、ii) 官能基化された磁性ナノ粒子を動物の脳内で検出することにより行われる、段階。 - 検出が、核磁気共鳴画像法によって行われる、請求項32記載の方法。
- 請求項1記載の組成物の有効量をその必要がある個体に投与する段階を含む、個体における疾患を治療する方法。
- 官能基化されたMNPが、疾患を治療する治療剤をさらに含む、請求項34記載の方法。
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JP2017048218A (ja) * | 2011-04-21 | 2017-03-09 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | 機能性磁性ナノ粒子、ならびにアミロイド沈着物および神経原繊維濃縮体の画像処理における使用 |
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JP2013040109A (ja) * | 2011-08-11 | 2013-02-28 | Nippon Dental Univ | 医療用薬剤および新規薬剤探索方法 |
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CA2923748A1 (en) | 2006-09-28 |
KR101306641B1 (ko) | 2013-09-12 |
EP1865839A2 (en) | 2007-12-19 |
AU2006227115B2 (en) | 2012-04-19 |
JP5174654B2 (ja) | 2013-04-03 |
CA2600719A1 (en) | 2006-09-28 |
AU2006227115A1 (en) | 2006-09-28 |
EP1865839A4 (en) | 2011-06-29 |
WO2006102377A2 (en) | 2006-09-28 |
WO2006102377A3 (en) | 2006-11-09 |
CN101155549A (zh) | 2008-04-02 |
CA2600719C (en) | 2016-06-07 |
CN101155549B (zh) | 2011-11-16 |
US20080206146A1 (en) | 2008-08-28 |
KR20070121788A (ko) | 2007-12-27 |
CA2923748C (en) | 2017-06-20 |
CN102343098A (zh) | 2012-02-08 |
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